GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer.

PubMed

Pharoah, Paul D P; Tsai, Ya-Yu; Ramus, Susan J; Phelan, Catherine M; Goode, Ellen L; Lawrenson, Kate; Buckley, Melissa; Fridley, Brooke L; Tyrer, Jonathan P; Shen, Howard; Weber, Rachel; Karevan, Rod; Larson, Melissa C; Song, Honglin; Tessier, Daniel C; Bacot, François; Vincent, Daniel; Cunningham, Julie M; Dennis, Joe; Dicks, Ed; Aben, Katja K; Anton-Culver, Hoda; Antonenkova, Natalia; Armasu, Sebastian M; Baglietto, Laura; Bandera, Elisa V; Beckmann, Matthias W; Birrer, Michael J; Bloom, Greg; Bogdanova, Natalia; Brenton, James D; Brinton, Louise A; Brooks-Wilson, Angela; Brown, Robert; Butzow, Ralf; Campbell, Ian; Carney, Michael E; Carvalho, Renato S; Chang-Claude, Jenny; Chen, Y Anne; Chen, Zhihua; Chow, Wong-Ho; Cicek, Mine S; Coetzee, Gerhard; Cook, Linda S; Cramer, Daniel W; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Despierre, Evelyn; Doherty, Jennifer A; Dörk, Thilo; du Bois, Andreas; Dürst, Matthias; Eccles, Diana; Edwards, Robert; Ekici, Arif B; Fasching, Peter A; Fenstermacher, David; Flanagan, James; Gao, Yu-Tang; Garcia-Closas, Montserrat; Gentry-Maharaj, Aleksandra; Giles, Graham; Gjyshi, Anxhela; Gore, Martin; Gronwald, Jacek; Guo, Qi; Halle, Mari K; Harter, Philipp; Hein, Alexander; Heitz, Florian; Hillemanns, Peter; Hoatlin, Maureen; Høgdall, Estrid; Høgdall, Claus K; Hosono, Satoyo; Jakubowska, Anna; Jensen, Allan; Kalli, Kimberly R; Karlan, Beth Y; Kelemen, Linda E; Kiemeney, Lambertus A; Kjaer, Susanne Krüger; Konecny, Gottfried E; Krakstad, Camilla; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D; Lee, Nathan; Lee, Janet; Leminen, Arto; Lim, Boon Kiong; Lissowska, Jolanta; Lubiński, Jan; Lundvall, Lene; Lurie, Galina; Massuger, Leon F A G; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R; Menon, Usha; Modugno, Francesmary; Moysich, Kirsten B; Nakanishi, Toru; Narod, Steven A; Ness, Roberta B; Nevanlinna, Heli; Nickels, Stefan; Noushmehr, Houtan; Odunsi, Kunle; Olson, Sara; Orlow, Irene; Paul, James; Pejovic, Tanja; Pelttari, Liisa M; Permuth-Wey, Jenny; Pike, Malcolm C; Poole, Elizabeth M; Qu, Xiaotao; Risch, Harvey A; Rodriguez-Rodriguez, Lorna; Rossing, Mary Anne; Rudolph, Anja; Runnebaum, Ingo; Rzepecka, Iwona K; Salvesen, Helga B; Schwaab, Ira; Severi, Gianluca; Shen, Hui; Shridhar, Vijayalakshmi; Shu, Xiao-Ou; Sieh, Weiva; Southey, Melissa C; Spellman, Paul; Tajima, Kazuo; Teo, Soo-Hwang; Terry, Kathryn L; Thompson, Pamela J; Timorek, Agnieszka; Tworoger, Shelley S; van Altena, Anne M; van den Berg, David; Vergote, Ignace; Vierkant, Robert A; Vitonis, Allison F; Wang-Gohrke, Shan; Wentzensen, Nicolas; Whittemore, Alice S; Wik, Elisabeth; Winterhoff, Boris; Woo, Yin Ling; Wu, Anna H; Yang, Hannah P; Zheng, Wei; Ziogas, Argyrios; Zulkifli, Famida; Goodman, Marc T; Hall, Per; Easton, Douglas F; Pearce, Celeste L; Berchuck, Andrew; Chenevix-Trench, Georgia; Iversen, Edwin; Monteiro, Alvaro N A; Gayther, Simon A; Schildkraut, Joellen M; Sellers, Thomas A

2013-04-01

Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 × 10(-9)) and 10p12 (rs1243180, P = 1.8 × 10(-8)) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 × 10(-10)). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer.

Variant Discovery and Fine Mapping of Genetic Loci Associated with Blood Pressure Traits in Hispanics and African Americans.

PubMed

Franceschini, Nora; Carty, Cara L; Lu, Yingchang; Tao, Ran; Sung, Yun Ju; Manichaikul, Ani; Haessler, Jeff; Fornage, Myriam; Schwander, Karen; Zubair, Niha; Bien, Stephanie; Hindorff, Lucia A; Guo, Xiuqing; Bielinski, Suzette J; Ehret, Georg; Kaufman, Joel D; Rich, Stephen S; Carlson, Christopher S; Bottinger, Erwin P; North, Kari E; Rao, D C; Chakravarti, Aravinda; Barrett, Paula Q; Loos, Ruth J F; Buyske, Steven; Kooperberg, Charles

2016-01-01

Despite the substantial burden of hypertension in US minority populations, few genetic studies of blood pressure have been conducted in Hispanics and African Americans, and it is unclear whether many of the established loci identified in European-descent populations contribute to blood pressure variation in non-European descent populations. Using the Metabochip array, we sought to characterize the genetic architecture of previously identified blood pressure loci, and identify novel cardiometabolic variants related to systolic and diastolic blood pressure in a multi-ethnic US population including Hispanics (n = 19,706) and African Americans (n = 18,744). Several known blood pressure loci replicated in African Americans and Hispanics. Fourteen variants in three loci (KCNK3, FGF5, ATXN2-SH2B3) were significantly associated with blood pressure in Hispanics. The most significant diastolic blood pressure variant identified in our analysis, rs2586886/KCNK3 (P = 5.2 x 10-9), also replicated in independent Hispanic and European-descent samples. African American and trans-ethnic meta-analysis data identified novel variants in the FGF5, ULK4 and HOXA-EVX1 loci, which have not been previously associated with blood pressure traits. Our identification and independent replication of variants in KCNK3, a gene implicated in primary hyperaldosteronism, as well as a variant in HOTTIP (HOXA-EVX1) suggest that further work to clarify the roles of these genes may be warranted. Overall, our findings suggest that loci identified in European descent populations also contribute to blood pressure variation in diverse populations including Hispanics and African Americans-populations that are understudied for hypertension genetic risk factors.

Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer.

PubMed

Couch, Fergus J; Kuchenbaecker, Karoline B; Michailidou, Kyriaki; Mendoza-Fandino, Gustavo A; Nord, Silje; Lilyquist, Janna; Olswold, Curtis; Hallberg, Emily; Agata, Simona; Ahsan, Habibul; Aittomäki, Kristiina; Ambrosone, Christine; Andrulis, Irene L; Anton-Culver, Hoda; Arndt, Volker; Arun, Banu K; Arver, Brita; Barile, Monica; Barkardottir, Rosa B; Barrowdale, Daniel; Beckmann, Lars; Beckmann, Matthias W; Benitez, Javier; Blank, Stephanie V; Blomqvist, Carl; Bogdanova, Natalia V; Bojesen, Stig E; Bolla, Manjeet K; Bonanni, Bernardo; Brauch, Hiltrud; Brenner, Hermann; Burwinkel, Barbara; Buys, Saundra S; Caldes, Trinidad; Caligo, Maria A; Canzian, Federico; Carpenter, Jane; Chang-Claude, Jenny; Chanock, Stephen J; Chung, Wendy K; Claes, Kathleen B M; Cox, Angela; Cross, Simon S; Cunningham, Julie M; Czene, Kamila; Daly, Mary B; Damiola, Francesca; Darabi, Hatef; de la Hoya, Miguel; Devilee, Peter; Diez, Orland; Ding, Yuan C; Dolcetti, Riccardo; Domchek, Susan M; Dorfling, Cecilia M; Dos-Santos-Silva, Isabel; Dumont, Martine; Dunning, Alison M; Eccles, Diana M; Ehrencrona, Hans; Ekici, Arif B; Eliassen, Heather; Ellis, Steve; Fasching, Peter A; Figueroa, Jonine; Flesch-Janys, Dieter; Försti, Asta; Fostira, Florentia; Foulkes, William D; Friebel, Tara; Friedman, Eitan; Frost, Debra; Gabrielson, Marike; Gammon, Marilie D; Ganz, Patricia A; Gapstur, Susan M; Garber, Judy; Gaudet, Mia M; Gayther, Simon A; Gerdes, Anne-Marie; Ghoussaini, Maya; Giles, Graham G; Glendon, Gord; Godwin, Andrew K; Goldberg, Mark S; Goldgar, David E; González-Neira, Anna; Greene, Mark H; Gronwald, Jacek; Guénel, Pascal; Gunter, Marc; Haeberle, Lothar; Haiman, Christopher A; Hamann, Ute; Hansen, Thomas V O; Hart, Steven; Healey, Sue; Heikkinen, Tuomas; Henderson, Brian E; Herzog, Josef; Hogervorst, Frans B L; Hollestelle, Antoinette; Hooning, Maartje J; Hoover, Robert N; Hopper, John L; Humphreys, Keith; Hunter, David J; Huzarski, Tomasz; Imyanitov, Evgeny N; Isaacs, Claudine; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Jensen, Uffe Birk; John, Esther M; Jones, Michael; Kabisch, Maria; Kar, Siddhartha; Karlan, Beth Y; Khan, Sofia; Khaw, Kay-Tee; Kibriya, Muhammad G; Knight, Julia A; Ko, Yon-Dschun; Konstantopoulou, Irene; Kosma, Veli-Matti; Kristensen, Vessela; Kwong, Ava; Laitman, Yael; Lambrechts, Diether; Lazaro, Conxi; Lee, Eunjung; Le Marchand, Loic; Lester, Jenny; Lindblom, Annika; Lindor, Noralane; Lindstrom, Sara; Liu, Jianjun; Long, Jirong; Lubinski, Jan; Mai, Phuong L; Makalic, Enes; Malone, Kathleen E; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Marme, Frederik; Martens, John W M; McGuffog, Lesley; Meindl, Alfons; Miller, Austin; Milne, Roger L; Miron, Penelope; Montagna, Marco; Mazoyer, Sylvie; Mulligan, Anna M; Muranen, Taru A; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Nordestgaard, Børge G; Nussbaum, Robert L; Offit, Kenneth; Olah, Edith; Olopade, Olufunmilayo I; Olson, Janet E; Osorio, Ana; Park, Sue K; Peeters, Petra H; Peissel, Bernard; Peterlongo, Paolo; Peto, Julian; Phelan, Catherine M; Pilarski, Robert; Poppe, Bruce; Pylkäs, Katri; Radice, Paolo; Rahman, Nazneen; Rantala, Johanna; Rappaport, Christine; Rennert, Gad; Richardson, Andrea; Robson, Mark; Romieu, Isabelle; Rudolph, Anja; Rutgers, Emiel J; Sanchez, Maria-Jose; Santella, Regina M; Sawyer, Elinor J; Schmidt, Daniel F; Schmidt, Marjanka K; Schmutzler, Rita K; Schumacher, Fredrick; Scott, Rodney; Senter, Leigha; Sharma, Priyanka; Simard, Jacques; Singer, Christian F; Sinilnikova, Olga M; Soucy, Penny; Southey, Melissa; Steinemann, Doris; Stenmark-Askmalm, Marie; Stoppa-Lyonnet, Dominique; Swerdlow, Anthony; Szabo, Csilla I; Tamimi, Rulla; Tapper, William; Teixeira, Manuel R; Teo, Soo-Hwang; Terry, Mary B; Thomassen, Mads; Thompson, Deborah; Tihomirova, Laima; Toland, Amanda E; Tollenaar, Robert A E M; Tomlinson, Ian; Truong, Thérèse; Tsimiklis, Helen; Teulé, Alex; Tumino, Rosario; Tung, Nadine; Turnbull, Clare; Ursin, Giski; van Deurzen, Carolien H M; van Rensburg, Elizabeth J; Varon-Mateeva, Raymonda; Wang, Zhaoming; Wang-Gohrke, Shan; Weiderpass, Elisabete; Weitzel, Jeffrey N; Whittemore, Alice; Wildiers, Hans; Winqvist, Robert; Yang, Xiaohong R; Yannoukakos, Drakoulis; Yao, Song; Zamora, M Pilar; Zheng, Wei; Hall, Per; Kraft, Peter; Vachon, Celine; Slager, Susan; Chenevix-Trench, Georgia; Pharoah, Paul D P; Monteiro, Alvaro A N; García-Closas, Montserrat; Easton, Douglas F; Antoniou, Antonis C

2016-04-27

Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.

Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

PubMed Central

Couch, Fergus J.; Kuchenbaecker, Karoline B.; Michailidou, Kyriaki; Mendoza-Fandino, Gustavo A.; Nord, Silje; Lilyquist, Janna; Olswold, Curtis; Hallberg, Emily; Agata, Simona; Ahsan, Habibul; Aittomäki, Kristiina; Ambrosone, Christine; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Arun, Banu K.; Arver, Brita; Barile, Monica; Barkardottir, Rosa B.; Barrowdale, Daniel; Beckmann, Lars; Beckmann, Matthias W.; Benitez, Javier; Blank, Stephanie V.; Blomqvist, Carl; Bogdanova, Natalia V.; Bojesen, Stig E.; Bolla, Manjeet K.; Bonanni, Bernardo; Brauch, Hiltrud; Brenner, Hermann; Burwinkel, Barbara; Buys, Saundra S.; Caldes, Trinidad; Caligo, Maria A.; Canzian, Federico; Carpenter, Jane; Chang-Claude, Jenny; Chanock, Stephen J.; Chung, Wendy K.; Claes, Kathleen B. M.; Cox, Angela; Cross, Simon S.; Cunningham, Julie M.; Czene, Kamila; Daly, Mary B.; Damiola, Francesca; Darabi, Hatef; de la Hoya, Miguel; Devilee, Peter; Diez, Orland; Ding, Yuan C.; Dolcetti, Riccardo; Domchek, Susan M.; Dorfling, Cecilia M.; dos-Santos-Silva, Isabel; Dumont, Martine; Dunning, Alison M.; Eccles, Diana M.; Ehrencrona, Hans; Ekici, Arif B.; Eliassen, Heather; Ellis, Steve; Fasching, Peter A.; Figueroa, Jonine; Flesch-Janys, Dieter; Försti, Asta; Fostira, Florentia; Foulkes, William D.; Friebel, Tara; Friedman, Eitan; Frost, Debra; Gabrielson, Marike; Gammon, Marilie D.; Ganz, Patricia A.; Gapstur, Susan M.; Garber, Judy; Gaudet, Mia M.; Gayther, Simon A.; Gerdes, Anne-Marie; Ghoussaini, Maya; Giles, Graham G.; Glendon, Gord; Godwin, Andrew K.; Goldberg, Mark S.; Goldgar, David E.; González-Neira, Anna; Greene, Mark H.; Gronwald, Jacek; Guénel, Pascal; Gunter, Marc; Haeberle, Lothar; Haiman, Christopher A.; Hamann, Ute; Hansen, Thomas V. O.; Hart, Steven; Healey, Sue; Heikkinen, Tuomas; Henderson, Brian E.; Herzog, Josef; Hogervorst, Frans B. L.; Hollestelle, Antoinette; Hooning, Maartje J.; Hoover, Robert N.; Hopper, John L.; Humphreys, Keith; Hunter, David J.; Huzarski, Tomasz; Imyanitov, Evgeny N.; Isaacs, Claudine; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Jensen, Uffe Birk; John, Esther M.; Jones, Michael; Kabisch, Maria; Kar, Siddhartha; Karlan, Beth Y.; Khan, Sofia; Khaw, Kay-Tee; Kibriya, Muhammad G.; Knight, Julia A.; Ko, Yon-Dschun; Konstantopoulou, Irene; Kosma, Veli-Matti; Kristensen, Vessela; Kwong, Ava; Laitman, Yael; Lambrechts, Diether; Lazaro, Conxi; Lee, Eunjung; Le Marchand, Loic; Lester, Jenny; Lindblom, Annika; Lindor, Noralane; Lindstrom, Sara; Liu, Jianjun; Long, Jirong; Lubinski, Jan; Mai, Phuong L.; Makalic, Enes; Malone, Kathleen E.; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Marme, Frederik; Martens, John W. M.; McGuffog, Lesley; Meindl, Alfons; Miller, Austin; Milne, Roger L.; Miron, Penelope; Montagna, Marco; Mazoyer, Sylvie; Mulligan, Anna M.; Muranen, Taru A.; Nathanson, Katherine L.; Neuhausen, Susan L.; Nevanlinna, Heli; Nordestgaard, Børge G.; Nussbaum, Robert L.; Offit, Kenneth; Olah, Edith; Olopade, Olufunmilayo I.; Olson, Janet E.; Osorio, Ana; Park, Sue K.; Peeters, Petra H.; Peissel, Bernard; Peterlongo, Paolo; Peto, Julian; Phelan, Catherine M.; Pilarski, Robert; Poppe, Bruce; Pylkäs, Katri; Radice, Paolo; Rahman, Nazneen; Rantala, Johanna; Rappaport, Christine; Rennert, Gad; Richardson, Andrea; Robson, Mark; Romieu, Isabelle; Rudolph, Anja; Rutgers, Emiel J.; Sanchez, Maria-Jose; Santella, Regina M.; Sawyer, Elinor J.; Schmidt, Daniel F.; Schmidt, Marjanka K.; Schmutzler, Rita K.; Schumacher, Fredrick; Scott, Rodney; Senter, Leigha; Sharma, Priyanka; Simard, Jacques; Singer, Christian F.; Sinilnikova, Olga M.; Soucy, Penny; Southey, Melissa; Steinemann, Doris; Stenmark-Askmalm, Marie; Stoppa-Lyonnet, Dominique; Swerdlow, Anthony; Szabo, Csilla I.; Tamimi, Rulla; Tapper, William; Teixeira, Manuel R.; Teo, Soo-Hwang; Terry, Mary B.; Thomassen, Mads; Thompson, Deborah; Tihomirova, Laima; Toland, Amanda E.; Tollenaar, Robert A. E. M.; Tomlinson, Ian; Truong, Thérèse; Tsimiklis, Helen; Teulé, Alex; Tumino, Rosario; Tung, Nadine; Turnbull, Clare; Ursin, Giski; van Deurzen, Carolien H. M.; van Rensburg, Elizabeth J.; Varon-Mateeva, Raymonda; Wang, Zhaoming; Wang-Gohrke, Shan; Weiderpass, Elisabete; Weitzel, Jeffrey N.; Whittemore, Alice; Wildiers, Hans; Winqvist, Robert; Yang, Xiaohong R.; Yannoukakos, Drakoulis; Yao, Song; Zamora, M Pilar; Zheng, Wei; Hall, Per; Kraft, Peter; Vachon, Celine; Slager, Susan; Chenevix-Trench, Georgia; Pharoah, Paul D. P.; Monteiro, Alvaro A. N.; García-Closas, Montserrat; Easton, Douglas F.; Antoniou, Antonis C.

2016-01-01

Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10−8) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction. PMID:27117709

A high-resolution genetic map of yellow monkeyflower identifies chemical defense QTLs and recombination rate variation.

PubMed

Holeski, Liza M; Monnahan, Patrick; Koseva, Boryana; McCool, Nick; Lindroth, Richard L; Kelly, John K

2014-03-13

Genotyping-by-sequencing methods have vastly improved the resolution and accuracy of genetic linkage maps by increasing both the number of marker loci as well as the number of individuals genotyped at these loci. Using restriction-associated DNA sequencing, we construct a dense linkage map for a panel of recombinant inbred lines derived from a cross between divergent ecotypes of Mimulus guttatus. We used this map to estimate recombination rate across the genome and to identify quantitative trait loci for the production of several secondary compounds (PPGs) of the phenylpropanoid pathway implicated in defense against herbivores. Levels of different PPGs are correlated across recombinant inbred lines suggesting joint regulation of the phenylpropanoid pathway. However, the three quantitative trait loci identified in this study each act on a distinct PPG. Finally, we map three putative genomic inversions differentiating the two parental populations, including a previously characterized inversion that contributes to life-history differences between the annual/perennial ecotypes. Copyright © 2014 Holeski et al.

Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis

PubMed Central

Voight, Benjamin F; Scott, Laura J; Steinthorsdottir, Valgerdur; Morris, Andrew P; Dina, Christian; Welch, Ryan P; Zeggini, Eleftheria; Huth, Cornelia; Aulchenko, Yurii S; Thorleifsson, Gudmar; McCulloch, Laura J; Ferreira, Teresa; Grallert, Harald; Amin, Najaf; Wu, Guanming; Willer, Cristen J; Raychaudhuri, Soumya; McCarroll, Steve A; Langenberg, Claudia; Hofmann, Oliver M; Dupuis, Josée; Qi, Lu; Segrè, Ayellet V; van Hoek, Mandy; Navarro, Pau; Ardlie, Kristin; Balkau, Beverley; Benediktsson, Rafn; Bennett, Amanda J; Blagieva, Roza; Boerwinkle, Eric; Bonnycastle, Lori L; Boström, Kristina Bengtsson; Bravenboer, Bert; Bumpstead, Suzannah; Burtt, Noisël P; Charpentier, Guillaume; Chines, Peter S; Cornelis, Marilyn; Couper, David J; Crawford, Gabe; Doney, Alex S F; Elliott, Katherine S; Elliott, Amanda L; Erdos, Michael R; Fox, Caroline S; Franklin, Christopher S; Ganser, Martha; Gieger, Christian; Grarup, Niels; Green, Todd; Griffin, Simon; Groves, Christopher J; Guiducci, Candace; Hadjadj, Samy; Hassanali, Neelam; Herder, Christian; Isomaa, Bo; Jackson, Anne U; Johnson, Paul R V; Jørgensen, Torben; Kao, Wen H L; Klopp, Norman; Kong, Augustine; Kraft, Peter; Kuusisto, Johanna; Lauritzen, Torsten; Li, Man; Lieverse, Aloysius; Lindgren, Cecilia M; Lyssenko, Valeriya; Marre, Michel; Meitinger, Thomas; Midthjell, Kristian; Morken, Mario A; Narisu, Narisu; Nilsson, Peter; Owen, Katharine R; Payne, Felicity; Perry, John R B; Petersen, Ann-Kristin; Platou, Carl; Proença, Christine; Prokopenko, Inga; Rathmann, Wolfgang; Rayner, N William; Robertson, Neil R; Rocheleau, Ghislain; Roden, Michael; Sampson, Michael J; Saxena, Richa; Shields, Beverley M; Shrader, Peter; Sigurdsson, Gunnar; Sparsø, Thomas; Strassburger, Klaus; Stringham, Heather M; Sun, Qi; Swift, Amy J; Thorand, Barbara; Tichet, Jean; Tuomi, Tiinamaija; van Dam, Rob M; van Haeften, Timon W; van Herpt, Thijs; van Vliet-Ostaptchouk, Jana V; Walters, G Bragi; Weedon, Michael N; Wijmenga, Cisca; Witteman, Jacqueline; Bergman, Richard N; Cauchi, Stephane; Collins, Francis S; Gloyn, Anna L; Gyllensten, Ulf; Hansen, Torben; Hide, Winston A; Hitman, Graham A; Hofman, Albert; Hunter, David J; Hveem, Kristian; Laakso, Markku; Mohlke, Karen L; Morris, Andrew D; Palmer, Colin N A; Pramstaller, Peter P; Rudan, Igor; Sijbrands, Eric; Stein, Lincoln D; Tuomilehto, Jaakko; Uitterlinden, Andre; Walker, Mark; Wareham, Nicholas J; Watanabe, Richard M; Abecasis, Gonçalo R; Boehm, Bernhard O; Campbell, Harry; Daly, Mark J; Hattersley, Andrew T; Hu, Frank B; Meigs, James B; Pankow, James S; Pedersen, Oluf; Wichmann, H-Erich; Barroso, Inês; Florez, Jose C; Frayling, Timothy M; Groop, Leif; Sladek, Rob; Thorsteinsdottir, Unnur; Wilson, James F; Illig, Thomas; Froguel, Philippe; van Duijn, Cornelia M; Stefansson, Kari; Altshuler, David; Boehnke, Michael; McCarthy, Mark I

2011-01-01

By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combinedP < 5 × 10−8. These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits. PMID:20581827

Genome-wide association analysis identifies 13 new risk loci for schizophrenia.

PubMed

Ripke, Stephan; O'Dushlaine, Colm; Chambert, Kimberly; Moran, Jennifer L; Kähler, Anna K; Akterin, Susanne; Bergen, Sarah E; Collins, Ann L; Crowley, James J; Fromer, Menachem; Kim, Yunjung; Lee, Sang Hong; Magnusson, Patrik K E; Sanchez, Nick; Stahl, Eli A; Williams, Stephanie; Wray, Naomi R; Xia, Kai; Bettella, Francesco; Borglum, Anders D; Bulik-Sullivan, Brendan K; Cormican, Paul; Craddock, Nick; de Leeuw, Christiaan; Durmishi, Naser; Gill, Michael; Golimbet, Vera; Hamshere, Marian L; Holmans, Peter; Hougaard, David M; Kendler, Kenneth S; Lin, Kuang; Morris, Derek W; Mors, Ole; Mortensen, Preben B; Neale, Benjamin M; O'Neill, Francis A; Owen, Michael J; Milovancevic, Milica Pejovic; Posthuma, Danielle; Powell, John; Richards, Alexander L; Riley, Brien P; Ruderfer, Douglas; Rujescu, Dan; Sigurdsson, Engilbert; Silagadze, Teimuraz; Smit, August B; Stefansson, Hreinn; Steinberg, Stacy; Suvisaari, Jaana; Tosato, Sarah; Verhage, Matthijs; Walters, James T; Levinson, Douglas F; Gejman, Pablo V; Kendler, Kenneth S; Laurent, Claudine; Mowry, Bryan J; O'Donovan, Michael C; Owen, Michael J; Pulver, Ann E; Riley, Brien P; Schwab, Sibylle G; Wildenauer, Dieter B; Dudbridge, Frank; Holmans, Peter; Shi, Jianxin; Albus, Margot; Alexander, Madeline; Campion, Dominique; Cohen, David; Dikeos, Dimitris; Duan, Jubao; Eichhammer, Peter; Godard, Stephanie; Hansen, Mark; Lerer, F Bernard; Liang, Kung-Yee; Maier, Wolfgang; Mallet, Jacques; Nertney, Deborah A; Nestadt, Gerald; Norton, Nadine; O'Neill, Francis A; Papadimitriou, George N; Ribble, Robert; Sanders, Alan R; Silverman, Jeremy M; Walsh, Dermot; Williams, Nigel M; Wormley, Brandon; Arranz, Maria J; Bakker, Steven; Bender, Stephan; Bramon, Elvira; Collier, David; Crespo-Facorro, Benedicto; Hall, Jeremy; Iyegbe, Conrad; Jablensky, Assen; Kahn, Rene S; Kalaydjieva, Luba; Lawrie, Stephen; Lewis, Cathryn M; Lin, Kuang; Linszen, Don H; Mata, Ignacio; McIntosh, Andrew; Murray, Robin M; Ophoff, Roel A; Powell, John; Rujescu, Dan; Van Os, Jim; Walshe, Muriel; Weisbrod, Matthias; Wiersma, Durk; Donnelly, Peter; Barroso, Ines; Blackwell, Jenefer M; Bramon, Elvira; Brown, Matthew A; Casas, Juan P; Corvin, Aiden P; Deloukas, Panos; Duncanson, Audrey; Jankowski, Janusz; Markus, Hugh S; Mathew, Christopher G; Palmer, Colin N A; Plomin, Robert; Rautanen, Anna; Sawcer, Stephen J; Trembath, Richard C; Viswanathan, Ananth C; Wood, Nicholas W; Spencer, Chris C A; Band, Gavin; Bellenguez, Céline; Freeman, Colin; Hellenthal, Garrett; Giannoulatou, Eleni; Pirinen, Matti; Pearson, Richard D; Strange, Amy; Su, Zhan; Vukcevic, Damjan; Donnelly, Peter; Langford, Cordelia; Hunt, Sarah E; Edkins, Sarah; Gwilliam, Rhian; Blackburn, Hannah; Bumpstead, Suzannah J; Dronov, Serge; Gillman, Matthew; Gray, Emma; Hammond, Naomi; Jayakumar, Alagurevathi; McCann, Owen T; Liddle, Jennifer; Potter, Simon C; Ravindrarajah, Radhi; Ricketts, Michelle; Tashakkori-Ghanbaria, Avazeh; Waller, Matthew J; Weston, Paul; Widaa, Sara; Whittaker, Pamela; Barroso, Ines; Deloukas, Panos; Mathew, Christopher G; Blackwell, Jenefer M; Brown, Matthew A; Corvin, Aiden P; McCarthy, Mark I; Spencer, Chris C A; Bramon, Elvira; Corvin, Aiden P; O'Donovan, Michael C; Stefansson, Kari; Scolnick, Edward; Purcell, Shaun; McCarroll, Steven A; Sklar, Pamela; Hultman, Christina M; Sullivan, Patrick F

2013-10-01

Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.

Evidence of Bos javanicus x Bos indicus hybridization and major QTLs for birth weight in Indonesian Peranakan Ongole cattle.

PubMed

Hartati, Hartati; Utsunomiya, Yuri Tani; Sonstegard, Tad Stewart; Garcia, José Fernando; Jakaria, Jakaria; Muladno, Muladno

2015-07-04

Peranakan Ongole (PO) is a major Indonesian Bos indicus breed that derives from animals imported from India in the late 19(th) century. Early imports were followed by hybridization with the Bos javanicus subspecies of cattle. Here, we used genomic data to partition the ancestry components of PO cattle and map loci implicated in birth weight. We found that B. javanicus contributes about 6-7% to the average breed composition of PO cattle. Only two nearly fixed B. javanicus haplotypes were identified, suggesting that most of the B. javanicus variants are segregating under drift or by the action of balancing selection. The zebu component of the PO genome was estimated to derive from at least two distinct ancestral pools. Additionally, well-known loci underlying body size in other beef cattle breeds, such as the PLAG1 region on chromosome 14, were found to also affect birth weight in PO cattle. This study is the first attempt to characterize PO at the genome level, and contributes evidence of successful, stabilized B. indicus x B. javanicus hybridization. Additionally, previously described loci implicated in body size in worldwide beef cattle breeds also affect birth weight in PO cattle.

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects.

PubMed

Marshall, Christian R; Howrigan, Daniel P; Merico, Daniele; Thiruvahindrapuram, Bhooma; Wu, Wenting; Greer, Douglas S; Antaki, Danny; Shetty, Aniket; Holmans, Peter A; Pinto, Dalila; Gujral, Madhusudan; Brandler, William M; Malhotra, Dheeraj; Wang, Zhouzhi; Fajarado, Karin V Fuentes; Maile, Michelle S; Ripke, Stephan; Agartz, Ingrid; Albus, Margot; Alexander, Madeline; Amin, Farooq; Atkins, Joshua; Bacanu, Silviu A; Belliveau, Richard A; Bergen, Sarah E; Bertalan, Marcelo; Bevilacqua, Elizabeth; Bigdeli, Tim B; Black, Donald W; Bruggeman, Richard; Buccola, Nancy G; Buckner, Randy L; Bulik-Sullivan, Brendan; Byerley, William; Cahn, Wiepke; Cai, Guiqing; Cairns, Murray J; Campion, Dominique; Cantor, Rita M; Carr, Vaughan J; Carrera, Noa; Catts, Stanley V; Chambert, Kimberley D; Cheng, Wei; Cloninger, C Robert; Cohen, David; Cormican, Paul; Craddock, Nick; Crespo-Facorro, Benedicto; Crowley, James J; Curtis, David; Davidson, Michael; Davis, Kenneth L; Degenhardt, Franziska; Del Favero, Jurgen; DeLisi, Lynn E; Dikeos, Dimitris; Dinan, Timothy; Djurovic, Srdjan; Donohoe, Gary; Drapeau, Elodie; Duan, Jubao; Dudbridge, Frank; Eichhammer, Peter; Eriksson, Johan; Escott-Price, Valentina; Essioux, Laurent; Fanous, Ayman H; Farh, Kai-How; Farrell, Martilias S; Frank, Josef; Franke, Lude; Freedman, Robert; Freimer, Nelson B; Friedman, Joseph I; Forstner, Andreas J; Fromer, Menachem; Genovese, Giulio; Georgieva, Lyudmila; Gershon, Elliot S; Giegling, Ina; Giusti-Rodríguez, Paola; Godard, Stephanie; Goldstein, Jacqueline I; Gratten, Jacob; de Haan, Lieuwe; Hamshere, Marian L; Hansen, Mark; Hansen, Thomas; Haroutunian, Vahram; Hartmann, Annette M; Henskens, Frans A; Herms, Stefan; Hirschhorn, Joel N; Hoffmann, Per; Hofman, Andrea; Huang, Hailiang; Ikeda, Masashi; Joa, Inge; Kähler, Anna K; Kahn, René S; Kalaydjieva, Luba; Karjalainen, Juha; Kavanagh, David; Keller, Matthew C; Kelly, Brian J; Kennedy, James L; Kim, Yunjung; Knowles, James A; Konte, Bettina; Laurent, Claudine; Lee, Phil; Lee, S Hong; Legge, Sophie E; Lerer, Bernard; Levy, Deborah L; Liang, Kung-Yee; Lieberman, Jeffrey; Lönnqvist, Jouko; Loughland, Carmel M; Magnusson, Patrik K E; Maher, Brion S; Maier, Wolfgang; Mallet, Jacques; Mattheisen, Manuel; Mattingsdal, Morten; McCarley, Robert W; McDonald, Colm; McIntosh, Andrew M; Meier, Sandra; Meijer, Carin J; Melle, Ingrid; Mesholam-Gately, Raquelle I; Metspalu, Andres; Michie, Patricia T; Milani, Lili; Milanova, Vihra; Mokrab, Younes; Morris, Derek W; Müller-Myhsok, Bertram; Murphy, Kieran C; Murray, Robin M; Myin-Germeys, Inez; Nenadic, Igor; Nertney, Deborah A; Nestadt, Gerald; Nicodemus, Kristin K; Nisenbaum, Laura; Nordin, Annelie; O'Callaghan, Eadbhard; O'Dushlaine, Colm; Oh, Sang-Yun; Olincy, Ann; Olsen, Line; O'Neill, F Anthony; Van Os, Jim; Pantelis, Christos; Papadimitriou, George N; Parkhomenko, Elena; Pato, Michele T; Paunio, Tiina; Perkins, Diana O; Pers, Tune H; Pietiläinen, Olli; Pimm, Jonathan; Pocklington, Andrew J; Powell, John; Price, Alkes; Pulver, Ann E; Purcell, Shaun M; Quested, Digby; Rasmussen, Henrik B; Reichenberg, Abraham; Reimers, Mark A; Richards, Alexander L; Roffman, Joshua L; Roussos, Panos; Ruderfer, Douglas M; Salomaa, Veikko; Sanders, Alan R; Savitz, Adam; Schall, Ulrich; Schulze, Thomas G; Schwab, Sibylle G; Scolnick, Edward M; Scott, Rodney J; Seidman, Larry J; Shi, Jianxin; Silverman, Jeremy M; Smoller, Jordan W; Söderman, Erik; Spencer, Chris C A; Stahl, Eli A; Strengman, Eric; Strohmaier, Jana; Stroup, T Scott; Suvisaari, Jaana; Svrakic, Dragan M; Szatkiewicz, Jin P; Thirumalai, Srinivas; Tooney, Paul A; Veijola, Juha; Visscher, Peter M; Waddington, John; Walsh, Dermot; Webb, Bradley T; Weiser, Mark; Wildenauer, Dieter B; Williams, Nigel M; Williams, Stephanie; Witt, Stephanie H; Wolen, Aaron R; Wormley, Brandon K; Wray, Naomi R; Wu, Jing Qin; Zai, Clement C; Adolfsson, Rolf; Andreassen, Ole A; Blackwood, Douglas H R; Bramon, Elvira; Buxbaum, Joseph D; Cichon, Sven; Collier, David A; Corvin, Aiden; Daly, Mark J; Darvasi, Ariel; Domenici, Enrico; Esko, Tõnu; Gejman, Pablo V; Gill, Michael; Gurling, Hugh; Hultman, Christina M; Iwata, Nakao; Jablensky, Assen V; Jönsson, Erik G; Kendler, Kenneth S; Kirov, George; Knight, Jo; Levinson, Douglas F; Li, Qingqin S; McCarroll, Steven A; McQuillin, Andrew; Moran, Jennifer L; Mowry, Bryan J; Nöthen, Markus M; Ophoff, Roel A; Owen, Michael J; Palotie, Aarno; Pato, Carlos N; Petryshen, Tracey L; Posthuma, Danielle; Rietschel, Marcella; Riley, Brien P; Rujescu, Dan; Sklar, Pamela; St Clair, David; Walters, James T R; Werge, Thomas; Sullivan, Patrick F; O'Donovan, Michael C; Scherer, Stephen W; Neale, Benjamin M; Sebat, Jonathan

2017-01-01

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10 -15 ), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10 -6 ). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10 -11 ) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10 -5 ). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.

Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies

PubMed Central

2014-01-01

Summary Background The epilepsies are a clinically heterogeneous group of neurological disorders. Despite strong evidence for heritability, genome-wide association studies have had little success in identification of risk loci associated with epilepsy, probably because of relatively small sample sizes and insufficient power. We aimed to identify risk loci through meta-analyses of genome-wide association studies for all epilepsy and the two largest clinical subtypes (genetic generalised epilepsy and focal epilepsy). Methods We combined genome-wide association data from 12 cohorts of individuals with epilepsy and controls from population-based datasets. Controls were ethnically matched with cases. We phenotyped individuals with epilepsy into categories of genetic generalised epilepsy, focal epilepsy, or unclassified epilepsy. After standardised filtering for quality control and imputation to account for different genotyping platforms across sites, investigators at each site conducted a linear mixed-model association analysis for each dataset. Combining summary statistics, we conducted fixed-effects meta-analyses of all epilepsy, focal epilepsy, and genetic generalised epilepsy. We set the genome-wide significance threshold at p<1·66 × 10−8. Findings We included 8696 cases and 26 157 controls in our analysis. Meta-analysis of the all-epilepsy cohort identified loci at 2q24.3 (p=8·71 × 10−10), implicating SCN1A, and at 4p15.1 (p=5·44 × 10−9), harbouring PCDH7, which encodes a protocadherin molecule not previously implicated in epilepsy. For the cohort of genetic generalised epilepsy, we noted a single signal at 2p16.1 (p=9·99 × 10−9), implicating VRK2 or FANCL. No single nucleotide polymorphism achieved genome-wide significance for focal epilepsy. Interpretation This meta-analysis describes a new locus not previously implicated in epilepsy and provides further evidence about the genetic architecture of these disorders, with the ultimate aim of assisting in disease classification and prognosis. The data suggest that specific loci can act pleiotropically raising risk for epilepsy broadly, or can have effects limited to a specific epilepsy subtype. Future genetic analyses might benefit from both lumping (ie, grouping of epilepsy types together) or splitting (ie, analysis of specific clinical subtypes). Funding International League Against Epilepsy and multiple governmental and philanthropic agencies. PMID:25087078

Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure underpinning obesity

PubMed Central

Turcot, Valérie; Lu, Yingchang; Highland, Heather M; Schurmann, Claudia; Justice, Anne E; Fine, Rebecca S; Bradfield, Jonathan P; Esko, Tõnu; Giri, Ayush; Graff, Mariaelisa; Guo, Xiuqing; Hendricks, Audrey E; Karaderi, Tugce; Lempradl, Adelheid; Locke, Adam E; Mahajan, Anubha; Marouli, Eirini; Sivapalaratnam, Suthesh; Young, Kristin L; Alfred, Tamuno; Feitosa, Mary F; Masca, Nicholas GD; Manning, Alisa K; Medina-Gomez, Carolina; Mudgal, Poorva; Ng, Maggie CY; Reiner, Alex P; Vedantam, Sailaja; Willems, Sara M; Winkler, Thomas W; Abecasis, Goncalo; Aben, Katja K; Alam, Dewan S; Alharthi, Sameer E; Allison, Matthew; Amouyel, Philippe; Asselbergs, Folkert W; Auer, Paul L; Balkau, Beverley; Bang, Lia E; Barroso, Inês; Bastarache, Lisa; Benn, Marianne; Bergmann, Sven; Bielak, Lawrence F; Blüher, Matthias; Boehnke, Michael; Boeing, Heiner; Boerwinkle, Eric; Böger, Carsten A; Bork-Jensen, Jette; Bots, Michiel L; Bottinger, Erwin P; Bowden, Donald W; Brandslund, Ivan; Breen, Gerome; Brilliant, Murray H; Broer, Linda; Brumat, Marco; Burt, Amber A; Butterworth, Adam S; Campbell, Peter T; Cappellani, Stefania; Carey, David J; Catamo, Eulalia; Caulfield, Mark J; Chambers, John C; Chasman, Daniel I; Chen, Yii-Der Ida; Chowdhury, Rajiv; Christensen, Cramer; Chu, Audrey Y; Cocca, Massimiliano; Collins, Francis S; Cook, James P; Corley, Janie; Galbany, Jordi Corominas; Cox, Amanda J; Crosslin, David S; Cuellar-Partida, Gabriel; D'Eustacchio, Angela; Danesh, John; Davies, Gail; de Bakker, Paul IW; de Groot, Mark CH; de Mutsert, Renée; Deary, Ian J; Dedoussis, George; Demerath, Ellen W; den Heijer, Martin; den Hollander, Anneke I; den Ruijter, Hester M; Dennis, Joe G; Denny, Josh C; Di Angelantonio, Emanuele; Drenos, Fotios; Du, Mengmeng; Dubé, Marie-Pierre; Dunning, Alison M; Easton, Douglas F; Edwards, Todd L; Ellinghaus, David; Ellinor, Patrick T; Elliott, Paul; Evangelou, Evangelos; Farmaki, Aliki-Eleni; Farooqi, I. Sadaf; Faul, Jessica D; Fauser, Sascha; Feng, Shuang; Ferrannini, Ele; Ferrieres, Jean; Florez, Jose C; Ford, Ian; Fornage, Myriam; Franco, Oscar H; Franke, Andre; Franks, Paul W; Friedrich, Nele; Frikke-Schmidt, Ruth; Galesloot, Tessel E.; Gan, Wei; Gandin, Ilaria; Gasparini, Paolo; Gibson, Jane; Giedraitis, Vilmantas; Gjesing, Anette P; Gordon-Larsen, Penny; Gorski, Mathias; Grabe, Hans-Jörgen; Grant, Struan FA; Grarup, Niels; Griffiths, Helen L; Grove, Megan L; Gudnason, Vilmundur; Gustafsson, Stefan; Haessler, Jeff; Hakonarson, Hakon; Hammerschlag, Anke R; Hansen, Torben; Harris, Kathleen Mullan; Harris, Tamara B; Hattersley, Andrew T; Have, Christian T; Hayward, Caroline; He, Liang; Heard-Costa, Nancy L; Heath, Andrew C; Heid, Iris M; Helgeland, Øyvind; Hernesniemi, Jussi; Hewitt, Alex W; Holmen, Oddgeir L; Hovingh, G Kees; Howson, Joanna MM; Hu, Yao; Huang, Paul L; Huffman, Jennifer E; Ikram, M Arfan; Ingelsson, Erik; Jackson, Anne U; Jansson, Jan-Håkan; Jarvik, Gail P; Jensen, Gorm B; Jia, Yucheng; Johansson, Stefan; Jørgensen, Marit E; Jørgensen, Torben; Jukema, J Wouter; Kahali, Bratati; Kahn, René S; Kähönen, Mika; Kamstrup, Pia R; Kanoni, Stavroula; Kaprio, Jaakko; Karaleftheri, Maria; Kardia, Sharon LR; Karpe, Fredrik; Kathiresan, Sekar; Kee, Frank; Kiemeney, Lambertus A; Kim, Eric; Kitajima, Hidetoshi; Komulainen, Pirjo; Kooner, Jaspal S; Kooperberg, Charles; Korhonen, Tellervo; Kovacs, Peter; Kuivaniemi, Helena; Kutalik, Zoltán; Kuulasmaa, Kari; Kuusisto, Johanna; Laakso, Markku; Lakka, Timo A; Lamparter, David; Lange, Ethan M; Lange, Leslie A; Langenberg, Claudia; Larson, Eric B; Lee, Nanette R; Lehtimäki, Terho; Lewis, Cora E; Li, Huaixing; Li, Jin; Li-Gao, Ruifang; Lin, Honghuang; Lin, Keng-Hung; Lin, Li-An; Lin, Xu; Lind, Lars; Lindström, Jaana; Linneberg, Allan; Liu, Ching-Ti; Liu, Dajiang J; Liu, Yongmei; Lo, Ken Sin; Lophatananon, Artitaya; Lotery, Andrew J; Loukola, Anu; Luan, Jian'an; Lubitz, Steven A; Lyytikäinen, Leo-Pekka; Männistö, Satu; Marenne, Gaëlle; Mazul, Angela L; McCarthy, Mark I; McKean-Cowdin, Roberta; Medland, Sarah E; Meidtner, Karina; Milani, Lili; Mistry, Vanisha; Mitchell, Paul; Mohlke, Karen L; Moilanen, Leena; Moitry, Marie; Montgomery, Grant W; Mook-Kanamori, Dennis O; Moore, Carmel; Mori, Trevor A; Morris, Andrew D; Morris, Andrew P; Müller-Nurasyid, Martina; Munroe, Patricia B; Nalls, Mike A; Narisu, Narisu; Nelson, Christopher P; Neville, Matt; Nielsen, Sune F; Nikus, Kjell; Njølstad, Pål R; Nordestgaard, Børge G; Nyholt, Dale R; O'Connel, Jeffrey R; O’Donoghue, Michelle L.; Olde Loohuis, Loes M; Ophoff, Roel A; Owen, Katharine R; Packard, Chris J; Padmanabhan, Sandosh; Palmer, Colin NA; Palmer, Nicholette D; Pasterkamp, Gerard; Patel, Aniruddh P; Pattie, Alison; Pedersen, Oluf; Peissig, Peggy L; Peloso, Gina M; Pennell, Craig E; Perola, Markus; Perry, James A; Perry, John RB; Pers, Tune H; Person, Thomas N; Peters, Annette; Petersen, Eva RB; Peyser, Patricia A; Pirie, Ailith; Polasek, Ozren; Polderman, Tinca J; Puolijoki, Hannu; Raitakari, Olli T; Rasheed, Asif; Rauramaa, Rainer; Reilly, Dermot F; Renström, Frida; Rheinberger, Myriam; Ridker, Paul M; Rioux, John D; Rivas, Manuel A; Roberts, David J; Robertson, Neil R; Robino, Antonietta; Rolandsson, Olov; Rudan, Igor; Ruth, Katherine S; Saleheen, Danish; Salomaa, Veikko; Samani, Nilesh J; Sapkota, Yadav; Sattar, Naveed; Schoen, Robert E; Schreiner, Pamela J; Schulze, Matthias B; Scott, Robert A; Segura-Lepe, Marcelo P; Shah, Svati H; Sheu, Wayne H-H; Sim, Xueling; Slater, Andrew J; Small, Kerrin S; Smith, Albert Vernon; Southam, Lorraine; Spector, Timothy D; Speliotes, Elizabeth K; Starr, John M; Stefansson, Kari; Steinthorsdottir, Valgerdur; Stirrups, Kathleen E; Strauch, Konstantin; Stringham, Heather M; Stumvoll, Michael; Sun, Liang; Surendran, Praveen; Swift, Amy J; Tada, Hayato; Tansey, Katherine E; Tardif, Jean-Claude; Taylor, Kent D; Teumer, Alexander; Thompson, Deborah J; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Thuesen, Betina H; Tönjes, Anke; Tromp, Gerard; Trompet, Stella; Tsafantakis, Emmanouil; Tuomilehto, Jaakko; Tybjaerg-Hansen, Anne; Tyrer, Jonathan P; Uher, Rudolf; Uitterlinden, André G; Uusitupa, Matti; van der Laan, Sander W; van Duijn, Cornelia M; van Leeuwen, Nienke; van Setten, Jessica; Vanhala, Mauno; Varbo, Anette; Varga, Tibor V; Varma, Rohit; Velez Edwards, Digna R; Vermeulen, Sita H; Veronesi, Giovanni; Vestergaard, Henrik; Vitart, Veronique; Vogt, Thomas F; Völker, Uwe; Vuckovic, Dragana; Wagenknecht, Lynne E; Walker, Mark; Wallentin, Lars; Wang, Feijie; Wang, Carol A; Wang, Shuai; Wang, Yiqin; Ware, Erin B; Wareham, Nicholas J; Warren, Helen R; Waterworth, Dawn M; Wessel, Jennifer; White, Harvey D; Willer, Cristen J; Wilson, James G; Witte, Daniel R; Wood, Andrew R; Wu, Ying; Yaghootkar, Hanieh; Yao, Jie; Yao, Pang; Yerges-Armstrong, Laura M; Young, Robin; Zeggini, Eleftheria; Zhan, Xiaowei; Zhang, Weihua; Zhao, Jing Hua; Zhao, Wei; Zhao, Wei; Zhou, Wei; Zondervan, Krina T; Rotter, Jerome I; Pospisilik, John A; Rivadeneira, Fernando; Borecki, Ingrid B; Deloukas, Panos; Frayling, Timothy M; Lettre, Guillaume; North, Kari E; Lindgren, Cecilia M; Hirschhorn, Joel N; Loos, Ruth JF

2018-01-01

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, non-coding variants from which pinpointing causal genes remains challenging. Here, we combined data from 718,734 individuals to discover rare and low-frequency (MAF<5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which eight in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2, ZNF169) newly implicated in human obesity, two (MC4R, KSR2) previously observed in extreme obesity, and two variants in GIPR. Effect sizes of rare variants are ~10 times larger than of common variants, with the largest effect observed in carriers of an MC4R stop-codon (p.Tyr35Ter, MAF=0.01%), weighing ~7kg more than non-carriers. Pathway analyses confirmed enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically-supported therapeutic targets to treat obesity. PMID:29273807

Genome-Wide Association Study Identifies Four Loci Associated with Eruption of Permanent Teeth

PubMed Central

Zhang, Hao; Shaffer, John R.; Hansen, Thomas; Esserlind, Ann-Louise; Boyd, Heather A.; Nohr, Ellen A.; Timpson, Nicholas J.; Fatemifar, Ghazaleh; Paternoster, Lavinia; Evans, David M.; Weyant, Robert J.; Levy, Steven M.; Lathrop, Mark; Smith, George Davey; Murray, Jeffrey C.; Olesen, Jes; Werge, Thomas; Marazita, Mary L.; Sørensen, Thorkild I. A.; Melbye, Mads

2011-01-01

The sequence and timing of permanent tooth eruption is thought to be highly heritable and can have important implications for the risk of malocclusion, crowding, and periodontal disease. We conducted a genome-wide association study of number of permanent teeth erupted between age 6 and 14 years, analyzed as age-adjusted standard deviation score averaged over multiple time points, based on childhood records for 5,104 women from the Danish National Birth Cohort. Four loci showed association at P<5×10−8 and were replicated in four independent study groups from the United States and Denmark with a total of 3,762 individuals; all combined P-values were below 10−11. Two loci agreed with previous findings in primary tooth eruption and were also known to influence height and breast cancer, respectively. The two other loci pointed to genomic regions without any previous significant genome-wide association study results. The intronic SNP rs7924176 in ADK could be linked to gene expression in monocytes. The combined effect of the four genetic variants was most pronounced between age 10 and 12 years, where children with 6 to 8 delayed tooth eruption alleles had on average 3.5 (95% confidence interval: 2.9–4.1) fewer permanent teeth than children with 0 or 1 of these alleles. PMID:21931568

Identification of 15 genetic loci associated with risk of major depression in individuals of European descent

PubMed Central

Hyde, Craig L.; Nagle, Mike W.; Tian, Chao; Chen, Xing; Paciga, Sara A.; Wendland, Jens R.; Tung, Joyce; Hinds, David A.; Perlis, Roy H.; Winslow, Ashley R.

2016-01-01

Despite strong evidence supporting the heritability of Major Depressive Disorder, previous genome-wide studies were unable to identify risk loci among individuals of European descent. We used self-reported data from 75,607 individuals reporting clinical diagnosis of depression and 231,747 reporting no history of depression through 23andMe, and meta-analyzed these results with published MDD GWAS results. We identified five independent variants from four regions associated with self-report of clinical diagnosis or treatment for depression. Loci with pval<1.0×10−5 in the meta-analysis were further analyzed in a replication dataset (45,773 cases and 106,354 controls) from 23andMe. A total of 17 independent SNPs from 15 regions reached genome-wide significance after joint-analysis over all three datasets. Some of these loci were also implicated in GWAS of related psychiatric traits. These studies provide evidence for large-scale consumer genomic data as a powerful and efficient complement to traditional means of ascertainment for neuropsychiatric disease genomics. PMID:27479909

Genetic Analysis of the Pathogenic Molecular Sub-phenotype Interferon Alpha Identifies Multiple Novel Loci Involved in Systemic Lupus Erythematosus

PubMed Central

Kariuki, Silvia N.; Ghodke-Puranik, Yogita; Dorschner, Jessica M.; Chrabot, Beverly S.; Kelly, Jennifer A.; Tsao, Betty P.; Kimberly, Robert P.; Alarcón-Riquelme, Marta E.; Jacob, Chaim O.; Criswell, Lindsey A.; Sivils, Kathy L.; Langefeld, Carl D.; Harley, John B.; Skol, Andrew D.; Niewold, Timothy B.

2014-01-01

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disorder characterized by inflammation of multiple organ systems and dysregulated interferon responses. SLE is both genetically and phenotypically heterogeneous, greatly reducing the power of case-control studies in SLE. Elevated circulating interferon alpha (IFN-α) is a stable, heritable trait in SLE, which has been implicated in primary disease pathogenesis. 40–50% of patients have high IFN-α, and high levels correspond with clinical differences. To study genetic heterogeneity in SLE, we performed a case-case study comparing patients with high vs. low IFN-α in over 1550 SLE cases, including GWAS and replication cohorts. In meta-analysis, the top associations in European ancestry were PRKG1 rs7897633 (PMeta=2.75 × 10−8) and PNP rs1049564 (PMeta=1.24 × 10−7). We also found evidence for cross-ancestral background associations with the ANKRD44 and PLEKHF2 loci. These loci have not been previously identified in case-control SLE genetic studies. Bioinformatic analyses implicated these loci functionally in dendritic cells and natural killer cells, both of which are involved in IFN-α production in SLE. As case-control studies of heterogeneous diseases reach a limit of feasibility with respect to subject number and detectable effect size, the study of informative pathogenic subphenotypes becomes an attractive strategy for genetic discovery in complex disease. PMID:25338677

Multi-Ethnic Genome-Wide Association Study of Cerebral White Matter Hyperintensities on MRI

PubMed Central

Verhaaren, Benjamin F.J.; Debette, Stéphanie; Bis, Joshua C.; Smith, Jennifer A.; Ikram, M. Kamran; Adams, Hieab H.; Beecham, Ashley H.; Rajan, Kumar B.; Lopez, Lorna M.; Barral, Sandra; van Buchem, Mark A.; van der Grond, Jeroen; Smith, Albert V.; Hegenscheid, Katrin; Aggarwal, Neelum T.; de Andrade, Mariza; Atkinson, Elizabeth J.; Beekman, Marian; Beiser, Alexa S.; Blanton, Susan H.; Boerwinkle, Eric; Brickman, Adam M.; Bryan, R. Nick; Chauhan, Ganesh; Chen, Christopher P.L.H.; Chouraki, Vincent; de Craen, Anton J.M.; Crivello, Fabrice; Deary, Ian J.; Deelen, Joris; De Jager, Philip L.; Dufouil, Carole; Elkind, Mitchell S.V.; Evans, Denis A.; Freudenberger, Paul; Gottesman, Rebecca F.; Guðnason, Vilmundur; Habes, Mohamad; Heckbert, Susan R.; Heiss, Gerardo; Hilal, Saima; Hofer, Edith; Hofman, Albert; Ibrahim-Verbaas, Carla A.; Knopman, David S.; Lewis, Cora E.; Liao, Jiemin; Liewald, David C.M.; Luciano, Michelle; van der Lugt, Aad; Martinez, Oliver O.; Mayeux, Richard; Mazoyer, Bernard; Nalls, Mike; Nauck, Matthias; Niessen, Wiro J.; Oostra, Ben A.; Psaty, Bruce M.; Rice, Kenneth M.; Rotter, Jerome I.; von Sarnowski, Bettina; Schmidt, Helena; Schreiner, Pamela J.; Schuur, Maaike; Sidney, Stephen S.; Sigurdsson, Sigurdur; Slagboom, P. Eline; Stott, David J.M.; van Swieten, John C.; Teumer, Alexander; Töglhofer, Anna Maria; Traylor, Matthew; Trompet, Stella; Turner, Stephen T.; Tzourio, Christophe; Uh, Hae-Won; Uitterlinden, André G.; Vernooij, Meike W.; Wang, Jing J.; Wong, Tien Y.; Wardlaw, Joanna M.; Windham, B. Gwen; Wittfeld, Katharina; Wolf, Christiane; Wright, Clinton B.; Yang, Qiong; Zhao, Wei; Zijdenbos, Alex; Jukema, J. Wouter; Sacco, Ralph L.; Kardia, Sharon L.R.; Amouyel, Philippe; Mosley, Thomas H.; Longstreth, W. T.; DeCarli, Charles C.; van Duijn, Cornelia M.; Schmidt, Reinhold; Launer, Lenore J.; Grabe, Hans J.; Seshadri, Sudha S.; Ikram, M. Arfan; Fornage, Myriam

2015-01-01

Background The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multi-ethnic genome-wide association studies. Methods and Results We included 21,079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (N=17,936), African (N=1,943), Hispanic (N=795), and Asian (N=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each SNP and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (p=2.7×10−19) and identified novel loci on chr10q24 (p=1.6×10−9) and chr2p21 (p=4.4×10−8). In the multi-ethnic meta-analysis, we identified two additional loci, on chr1q22 (p=2.0×10−8) and chr2p16 (p=1.5×10−8). The novel loci contained genes that have been implicated in Alzheimer’s disease (chr2p21, chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24, chr2p16). Conclusions We identified four novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of white matter hyperintensities in addition to previously-proposed ischemic mechanisms. PMID:25663218

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

PubMed Central

Marshall, Christian R.; Howrigan, Daniel P.; Merico, Daniele; Thiruvahindrapuram, Bhooma; Wu, Wenting; Greer, Douglas S.; Antaki, Danny; Shetty, Aniket; Holmans, Peter A.; Pinto, Dalila; Gujral, Madhusudan; Brandler, William M.; Malhotra, Dheeraj; Wang, Zhouzhi; Fajarado, Karin V. Fuentes; Maile, Michelle S.; Ripke, Stephan; Agartz, Ingrid; Albus, Margot; Alexander, Madeline; Amin, Farooq; Atkins, Joshua; Bacanu, Silviu A.; Belliveau, Richard A.; Bergen, Sarah E.; Bertalan, Marcelo; Bevilacqua, Elizabeth; Bigdeli, Tim B.; Black, Donald W.; Bruggeman, Richard; Buccola, Nancy G.; Buckner, Randy L.; Bulik-Sullivan, Brendan; Byerley, William; Cahn, Wiepke; Cai, Guiqing; Cairns, Murray J.; Campion, Dominique; Cantor, Rita M.; Carr, Vaughan J.; Carrera, Noa; Catts, Stanley V.; Chambert, Kimberley D.; Cheng, Wei; Cloninger, C. Robert; Cohen, David; Cormican, Paul; Craddock, Nick; Crespo-Facorro, Benedicto; Crowley, James J.; Curtis, David; Davidson, Michael; Davis, Kenneth L; Degenhardt, Franziska; Del Favero, Jurgen; DeLisi, Lynn E.; Dikeos, Dimitris; Dinan, Timothy; Djurovic, Srdjan; Donohoe, Gary; Drapeau, Elodie; Duan, Jubao; Dudbridge, Frank; Eichhammer, Peter; Eriksson, Johan; Escott-Price, Valentina; Essioux, Laurent; Fanous, Ayman H.; Farh, Kai-How; Farrell, Martilias S.; Frank, Josef; Franke, Lude; Freedman, Robert; Freimer, Nelson B.; Friedman, Joseph I.; Forstner, Andreas J.; Fromer, Menachem; Genovese, Giulio; Georgieva, Lyudmila; Gershon, Elliot S.; Giegling, Ina; Giusti-Rodríguez, Paola; Godard, Stephanie; Goldstein, Jacqueline I.; Gratten, Jacob; de Haan, Lieuwe; Hamshere, Marian L.; Hansen, Mark; Hansen, Thomas; Haroutunian, Vahram; Hartmann, Annette M.; Henskens, Frans A.; Herms, Stefan; Hirschhorn, Joel N.; Hoffmann, Per; Hofman, Andrea; Huang, Hailiang; Ikeda, Masashi; Joa, Inge; Kähler, Anna K; Kahn, René S; Kalaydjieva, Luba; Karjalainen, Juha; Kavanagh, David; Keller, Matthew C.; Kelly, Brian J.; Kennedy, James L.; Kim, Yunjung; Knowles, James A.; Konte, Bettina; Laurent, Claudine; Lee, Phil; Lee, S. Hong; Legge, Sophie E.; Lerer, Bernard; Levy, Deborah L.; Liang, Kung-Yee; Lieberman, Jeffrey; Lönnqvist, Jouko; Loughland, Carmel M.; Magnusson, Patrik K.E.; Maher, Brion S.; Maier, Wolfgang; Mallet, Jacques; Mattheisen, Manuel; Mattingsdal, Morten; McCarley, Robert W; McDonald, Colm; McIntosh, Andrew M.; Meier, Sandra; Meijer, Carin J.; Melle, Ingrid; Mesholam-Gately, Raquelle I.; Metspalu, Andres; Michie, Patricia T.; Milani, Lili; Milanova, Vihra; Mokrab, Younes; Morris, Derek W.; Müller-Myhsok, Bertram; Murphy, Kieran C.; Murray, Robin M.; Myin-Germeys, Inez; Nenadic, Igor; Nertney, Deborah A.; Nestadt, Gerald; Nicodemus, Kristin K.; Nisenbaum, Laura; Nordin, Annelie; O’Callaghan, Eadbhard; O’Dushlaine, Colm; Oh, Sang-Yun; Olincy, Ann; Olsen, Line; O’Neill, F. Anthony; Van Os, Jim; Pantelis, Christos; Papadimitriou, George N.; Parkhomenko, Elena; Pato, Michele T.; Paunio, Tiina; Perkins, Diana O.; Pers, Tune H.; Pietiläinen, Olli; Pimm, Jonathan; Pocklington, Andrew J.; Powell, John; Price, Alkes; Pulver, Ann E.; Purcell, Shaun M.; Quested, Digby; Rasmussen, Henrik B.; Reichenberg, Abraham; Reimers, Mark A.; Richards, Alexander L.; Roffman, Joshua L.; Roussos, Panos; Ruderfer, Douglas M.; Salomaa, Veikko; Sanders, Alan R.; Savitz, Adam; Schall, Ulrich; Schulze, Thomas G.; Schwab, Sibylle G.; Scolnick, Edward M.; Scott, Rodney J.; Seidman, Larry J.; Shi, Jianxin; Silverman, Jeremy M.; Smoller, Jordan W.; Söderman, Erik; Spencer, Chris C.A.; Stahl, Eli A.; Strengman, Eric; Strohmaier, Jana; Stroup, T. Scott; Suvisaari, Jaana; Svrakic, Dragan M.; Szatkiewicz, Jin P.; Thirumalai, Srinivas; Tooney, Paul A.; Veijola, Juha; Visscher, Peter M.; Waddington, John; Walsh, Dermot; Webb, Bradley T.; Weiser, Mark; Wildenauer, Dieter B.; Williams, Nigel M.; Williams, Stephanie; Witt, Stephanie H.; Wolen, Aaron R.; Wormley, Brandon K.; Wray, Naomi R; Wu, Jing Qin; Zai, Clement C.; Adolfsson, Rolf; Andreassen, Ole A.; Blackwood, Douglas H.R.; Bramon, Elvira; Buxbaum, Joseph D.; Cichon, Sven; Collier, David A; Corvin, Aiden; Daly, Mark J.; Darvasi, Ariel; Domenici, Enrico; Esko, Tõnu; Gejman, Pablo V.; Gill, Michael; Gurling, Hugh; Hultman, Christina M.; Iwata, Nakao; Jablensky, Assen V.; Jönsson, Erik G; Kendler, Kenneth S; Kirov, George; Knight, Jo; Levinson, Douglas F.; Li, Qingqin S; McCarroll, Steven A; McQuillin, Andrew; Moran, Jennifer L.; Mowry, Bryan J.; Nöthen, Markus M.; Ophoff, Roel A.; Owen, Michael J.; Palotie, Aarno; Pato, Carlos N.; Petryshen, Tracey L.; Posthuma, Danielle; Rietschel, Marcella; Riley, Brien P.; Rujescu, Dan; Sklar, Pamela; St. Clair, David; Walters, James T.R.; Werge, Thomas; Sullivan, Patrick F.; O’Donovan, Michael C; Scherer, Stephen W.; Neale, Benjamin M.; Sebat, Jonathan

2017-01-01

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (OR=1.11, P=5.7×10−15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7 ×10−6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 ×10−11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3 ×10−5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by non-allelic homologous recombination. PMID:27869829

Biological, clinical and population relevance of 95 loci for blood lipids.

PubMed

Teslovich, Tanya M; Musunuru, Kiran; Smith, Albert V; Edmondson, Andrew C; Stylianou, Ioannis M; Koseki, Masahiro; Pirruccello, James P; Ripatti, Samuli; Chasman, Daniel I; Willer, Cristen J; Johansen, Christopher T; Fouchier, Sigrid W; Isaacs, Aaron; Peloso, Gina M; Barbalic, Maja; Ricketts, Sally L; Bis, Joshua C; Aulchenko, Yurii S; Thorleifsson, Gudmar; Feitosa, Mary F; Chambers, John; Orho-Melander, Marju; Melander, Olle; Johnson, Toby; Li, Xiaohui; Guo, Xiuqing; Li, Mingyao; Shin Cho, Yoon; Jin Go, Min; Jin Kim, Young; Lee, Jong-Young; Park, Taesung; Kim, Kyunga; Sim, Xueling; Twee-Hee Ong, Rick; Croteau-Chonka, Damien C; Lange, Leslie A; Smith, Joshua D; Song, Kijoung; Hua Zhao, Jing; Yuan, Xin; Luan, Jian'an; Lamina, Claudia; Ziegler, Andreas; Zhang, Weihua; Zee, Robert Y L; Wright, Alan F; Witteman, Jacqueline C M; Wilson, James F; Willemsen, Gonneke; Wichmann, H-Erich; Whitfield, John B; Waterworth, Dawn M; Wareham, Nicholas J; Waeber, Gérard; Vollenweider, Peter; Voight, Benjamin F; Vitart, Veronique; Uitterlinden, Andre G; Uda, Manuela; Tuomilehto, Jaakko; Thompson, John R; Tanaka, Toshiko; Surakka, Ida; Stringham, Heather M; Spector, Tim D; Soranzo, Nicole; Smit, Johannes H; Sinisalo, Juha; Silander, Kaisa; Sijbrands, Eric J G; Scuteri, Angelo; Scott, James; Schlessinger, David; Sanna, Serena; Salomaa, Veikko; Saharinen, Juha; Sabatti, Chiara; Ruokonen, Aimo; Rudan, Igor; Rose, Lynda M; Roberts, Robert; Rieder, Mark; Psaty, Bruce M; Pramstaller, Peter P; Pichler, Irene; Perola, Markus; Penninx, Brenda W J H; Pedersen, Nancy L; Pattaro, Cristian; Parker, Alex N; Pare, Guillaume; Oostra, Ben A; O'Donnell, Christopher J; Nieminen, Markku S; Nickerson, Deborah A; Montgomery, Grant W; Meitinger, Thomas; McPherson, Ruth; McCarthy, Mark I; McArdle, Wendy; Masson, David; Martin, Nicholas G; Marroni, Fabio; Mangino, Massimo; Magnusson, Patrik K E; Lucas, Gavin; Luben, Robert; Loos, Ruth J F; Lokki, Marja-Liisa; Lettre, Guillaume; Langenberg, Claudia; Launer, Lenore J; Lakatta, Edward G; Laaksonen, Reijo; Kyvik, Kirsten O; Kronenberg, Florian; König, Inke R; Khaw, Kay-Tee; Kaprio, Jaakko; Kaplan, Lee M; Johansson, Asa; Jarvelin, Marjo-Riitta; Janssens, A Cecile J W; Ingelsson, Erik; Igl, Wilmar; Kees Hovingh, G; Hottenga, Jouke-Jan; Hofman, Albert; Hicks, Andrew A; Hengstenberg, Christian; Heid, Iris M; Hayward, Caroline; Havulinna, Aki S; Hastie, Nicholas D; Harris, Tamara B; Haritunians, Talin; Hall, Alistair S; Gyllensten, Ulf; Guiducci, Candace; Groop, Leif C; Gonzalez, Elena; Gieger, Christian; Freimer, Nelson B; Ferrucci, Luigi; Erdmann, Jeanette; Elliott, Paul; Ejebe, Kenechi G; Döring, Angela; Dominiczak, Anna F; Demissie, Serkalem; Deloukas, Panagiotis; de Geus, Eco J C; de Faire, Ulf; Crawford, Gabriel; Collins, Francis S; Chen, Yii-der I; Caulfield, Mark J; Campbell, Harry; Burtt, Noel P; Bonnycastle, Lori L; Boomsma, Dorret I; Boekholdt, S Matthijs; Bergman, Richard N; Barroso, Inês; Bandinelli, Stefania; Ballantyne, Christie M; Assimes, Themistocles L; Quertermous, Thomas; Altshuler, David; Seielstad, Mark; Wong, Tien Y; Tai, E-Shyong; Feranil, Alan B; Kuzawa, Christopher W; Adair, Linda S; Taylor, Herman A; Borecki, Ingrid B; Gabriel, Stacey B; Wilson, James G; Holm, Hilma; Thorsteinsdottir, Unnur; Gudnason, Vilmundur; Krauss, Ronald M; Mohlke, Karen L; Ordovas, Jose M; Munroe, Patricia B; Kooner, Jaspal S; Tall, Alan R; Hegele, Robert A; Kastelein, John J P; Schadt, Eric E; Rotter, Jerome I; Boerwinkle, Eric; Strachan, David P; Mooser, Vincent; Stefansson, Kari; Reilly, Muredach P; Samani, Nilesh J; Schunkert, Heribert; Cupples, L Adrienne; Sandhu, Manjinder S; Ridker, Paul M; Rader, Daniel J; van Duijn, Cornelia M; Peltonen, Leena; Abecasis, Gonçalo R; Boehnke, Michael; Kathiresan, Sekar

2010-08-05

Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

Transferability of genome-wide associated loci for asthma in African Americans.

PubMed

Faruque, Mezbah U; Chen, Guanjie; Doumatey, Ayo P; Zhou, Jie; Huang, Hanxia; Shriner, Daniel; Adeyemo, Adebowale A; Rotimi, Charles N; Dunston, Georgia M

2017-01-02

Transferability of significantly associated loci or GWAS "hits" adds credibility to genotype-disease associations and provides evidence for generalizability across different ancestral populations. We sought evidence of association of known asthma-associated single nucleotide polymorphisms (SNPs) in an African American population. Subjects comprised 661 participants (261 asthma cases and 400 controls) from the Howard University Family Study. Forty-eight SNPs previously reported to be associated with asthma by GWAS were selected for testing. We adopted a combined strategy by first adopting an "exact" approach where we looked-up only the reported index SNP. For those index SNPs missing form our dataset, we used a "local" approach that examined all the regional SNPs in LD with the index SNP. Out of the 48 SNPs, our cohort had genotype data available for 27, which were examined for exact replication. Of these, two SNPs were found positively associated with asthma. These included: rs10508372 (OR = 1.567 [95%CI, 1.133-2.167], P = 0.0066) and rs2378383 (OR = 2.147 [95%CI, 1.149-4.013], P = 0.0166), located on chromosomal bands 10p14 and 9q21.31, respectively. Local replication of the remaining 21 loci showed association at two chromosomal loci (9p24.1-rs2381413 and 6p21.32-rs3132947; Bonferroni-corrected P values: 0.0033 and 0.0197, respectively). Of note, multiple SNPs in LD with rs2381413 located upstream of IL33 were significantly associated with asthma. This study has successfully transferred four reported asthma-associated loci in an independent African American population. Identification of several asthma-associated SNPs in the upstream of the IL33, a gene previously implicated in allergic inflammation of asthmatic airway, supports the generalizability of this finding.

Novel Loci Associated with PR Interval in a Genome-Wide Association Study of Ten African American Cohorts

PubMed Central

Butler, Anne M.; Yin, Xiaoyan; Evans, Daniel S.; Nalls, Michael A.; Smith, Erin N.; Tanaka, Toshiko; Li, Guo; Buxbaum, Sarah G.; Whitsel, Eric A.; Alonso, Alvaro; Arking, Dan E.; Benjamin, Emelia J.; Berenson, Gerald S.; Bis, Josh C.; Chen, Wei; Deo, Rajat; Ellinor, Patrick T.; Heckbert, Susan R.; Heiss, Gerardo; Hsueh, Wen-Chi; Keating, Brendan J.; Kerr, Kathleen F.; Li, Yun; Limacher, Marian C.; Liu, Yongmei; Lubitz, Steven A.; Marciante, Kristin D.; Mehra, Reena; Meng, Yan A.; Newman, Anne B.; Newton-Cheh, Christopher; North, Kari E.; Palmer, Cameron D.; Psaty, Bruce M.; Quibrera, P. Miguel; Redline, Susan; Reiner, Alex P.; Rotter, Jerome I.; Schnabel, Renate B.; Schork, Nicholas J.; Singleton, Andrew B.; Smith, J. Gustav; Soliman, Elsayed Z.; Srinivasan, Sathanur R.; Zhang, Zhu-ming; Zonderman, Alan B.; Ferrucci, Luigi; Murray, Sarah S.; Evans, Michele K.; Sotoodehnia, Nona; Magnani, Jared W.; Avery, Christy L.

2013-01-01

Background The PR interval (PR) as measured by the resting, standard 12-lead electrocardiogram (ECG) reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at nine loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans. Methods and Results We present results from the largest genome-wide association study to date of PR in 13,415 adults of African descent from ten cohorts. We tested for association between PR (ms) and approximately 2.8 million genotyped and imputed single nucleotide polymorphisms. Imputation was performed using HapMap 2 YRI and CEU panels. Study-specific results, adjusted for global ancestry and clinical correlates of PR, were meta-analyzed using the inverse variance method. Variation in genome-wide test statistic distributions was noted within studies (lambda range: 0.9–1.1), although not after genomic control correction was applied to the overall meta-analysis (lambda: 1.008). In addition to generalizing previously reported associations with MEIS1, SCN5A, ARHGAP24, CAV1, and TBX5 to African American populations at the genome-wide significance level (P<5.0×10−8), we also identified a novel locus: ITGA9, located in a region previously implicated in SCN5A expression. The 3p21 region harboring SCN5A also contained two additional independent secondary signals influencing PR (P<5.0×10−8). Conclusions This study demonstrates the ability to map novel loci in African Americans as well as the generalizability of loci associated with PR across populations of African, European and Asian descent. PMID:23139255

Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism

PubMed Central

Sapkota, Yadav; Steinthorsdottir, Valgerdur; Morris, Andrew P.; Fassbender, Amelie; Rahmioglu, Nilufer; De Vivo, Immaculata; Buring, Julie E.; Zhang, Futao; Edwards, Todd L.; Jones, Sarah; O, Dorien; Peterse, Daniëlle; Rexrode, Kathryn M.; Ridker, Paul M.; Schork, Andrew J.; MacGregor, Stuart; Martin, Nicholas G.; Becker, Christian M.; Adachi, Sosuke; Yoshihara, Kosuke; Enomoto, Takayuki; Takahashi, Atsushi; Kamatani, Yoichiro; Matsuda, Koichi; Kubo, Michiaki; Thorleifsson, Gudmar; Geirsson, Reynir T.; Thorsteinsdottir, Unnur; Wallace, Leanne M.; Werge, Thomas M.; Thompson, Wesley K.; Yang, Jian; Velez Edwards, Digna R.; Nyegaard, Mette; Low, Siew-Kee; Zondervan, Krina T.; Missmer, Stacey A.; D'Hooghe, Thomas; Montgomery, Grant W.; Chasman, Daniel I.; Stefansson, Kari; Tung, Joyce Y.; Nyholt, Dale R.

2017-01-01

Endometriosis is a heritable hormone-dependent gynecological disorder, associated with severe pelvic pain and reduced fertility; however, its molecular mechanisms remain largely unknown. Here we perform a meta-analysis of 11 genome-wide association case-control data sets, totalling 17,045 endometriosis cases and 191,596 controls. In addition to replicating previously reported loci, we identify five novel loci significantly associated with endometriosis risk (P<5 × 10−8), implicating genes involved in sex steroid hormone pathways (FN1, CCDC170, ESR1, SYNE1 and FSHB). Conditional analysis identified five secondary association signals, including two at the ESR1 locus, resulting in 19 independent single nucleotide polymorphisms (SNPs) robustly associated with endometriosis, which together explain up to 5.19% of variance in endometriosis. These results highlight novel variants in or near specific genes with important roles in sex steroid hormone signalling and function, and offer unique opportunities for more targeted functional research efforts. PMID:28537267

Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease

PubMed Central

Zhao, Wei; Rasheed, Asif; Tikkanen, Emmi; Lee, Jung-Jin; Butterworth, Adam S; Howson, Joanna MM; Assimes, Themistocles L; Chowdhury, Rajiv; Orho-Melander, Marju; Damrauer, Scott; Small, Aeron; Asma, Senay; Imamura, Minako; Yamauch, Toshimasa; Chambers, John C; Chen, Peng; Sapkota, Bishwa R; Shah, Nabi; Jabeen, Sehrish; Surendran, Praveen; Lu, Yingchang; Zhang, Weihua; Imran, Atif; Abbas, Shahid; Majeed, Faisal; Trindade, Kevin; Qamar, Nadeem; Mallick, Nadeem Hayyat; Yaqoob, Zia; Saghir, Tahir; Rizvi, Syed Nadeem Hasan; Memon, Anis; Rasheed, Syed Zahed; Memon, Fazal-ur-Rehman; Mehmood, Khalid; Ahmed, Naveeduddin; Qureshi, Irshad Hussain; Tanveer-us-Salam; Iqbal, Wasim; Malik, Uzma; Mehra, Narinder; Kuo, Jane Z; Sheu, Wayne H-H; Guo, Xiuqing; Hsiung, Chao A; Juang, Jyh-Ming J; Taylor, Kent D; Hung, Yi-Jen; Lee, Wen-Jane; Quertermous, Thomas; Lee, I-Te; Hsu, Chih-Cheng; Bottinger, Erwin P.; Ralhan, Sarju; Teo, Yik Ying; Wang, Tzung-Dau; Alam, Dewan S; Di Angelantonio, Emanuele; Epstein, Steve; Nielsen, Sune F; Nordestgaard, Børge G; Tybjaerg-Hansen, Anne; Young, Robin; Benn, Marianne; Frikke-Schmidt, Ruth; Kamstrup, Pia R; Biobank, Michigan; Jukema, J Wouter; Sattar, Naveed; Smit, Roelof; Chung, Ren-Hua; Liang, Kae-Woei; Anand, Sonia; Sanghera, Dharambir K; Ripatti, Samuli; Loos, Ruth J.F.; Kooner, Jaspal S; Tai, E Shyong; Rotter, Jerome I; Chen, Yii-Der Ida; Frossard, Philippe; Maeda, Shiro; Kadowaki, Takashi; Reilly, Muredach; Pare, Guillaume; Melander, Olle; Salomaa, Veikko; Rader, Daniel J; Danesh, John; Voight, Benjamin F; Saleheen, Danish

2018-01-01

To evaluate the shared genetic etiology of type-2 diabetes (T2D) and coronary heart disease (CHD), we conducted a multi-ethnic study of genetic variation genome-wide for both diseases in up to 265,678 subjects for T2D and 260,365 subjects for CHD. We identify 16 previously unreported loci for T2D and one for CHD, including a novel T2D association at a missense variant in HLA-DRB5 (OR=1.29). We show that genetically mediated increase in T2D risk also confers higher CHD risk. Joint analysis of T2D loci demonstrated that 24% are associated with CHD, highlighting eight variants - two of which are coding - where T2D and CHD associations appear to co-localize, and a novel joint T2D/CHD association which also replicated for T2D. Variants associated with both outcomes implicate several novel pathways including cellular proliferation and cardiovascular development. PMID:28869590

Genome sequencing reveals loci under artificial selection that underlie disease phenotypes in the laboratory rat.

PubMed

Atanur, Santosh S; Diaz, Ana Garcia; Maratou, Klio; Sarkis, Allison; Rotival, Maxime; Game, Laurence; Tschannen, Michael R; Kaisaki, Pamela J; Otto, Georg W; Ma, Man Chun John; Keane, Thomas M; Hummel, Oliver; Saar, Kathrin; Chen, Wei; Guryev, Victor; Gopalakrishnan, Kathirvel; Garrett, Michael R; Joe, Bina; Citterio, Lorena; Bianchi, Giuseppe; McBride, Martin; Dominiczak, Anna; Adams, David J; Serikawa, Tadao; Flicek, Paul; Cuppen, Edwin; Hubner, Norbert; Petretto, Enrico; Gauguier, Dominique; Kwitek, Anne; Jacob, Howard; Aitman, Timothy J

2013-08-01

Large numbers of inbred laboratory rat strains have been developed for a range of complex disease phenotypes. To gain insights into the evolutionary pressures underlying selection for these phenotypes, we sequenced the genomes of 27 rat strains, including 11 models of hypertension, diabetes, and insulin resistance, along with their respective control strains. Altogether, we identified more than 13 million single-nucleotide variants, indels, and structural variants across these rat strains. Analysis of strain-specific selective sweeps and gene clusters implicated genes and pathways involved in cation transport, angiotensin production, and regulators of oxidative stress in the development of cardiovascular disease phenotypes in rats. Many of the rat loci that we identified overlap with previously mapped loci for related traits in humans, indicating the presence of shared pathways underlying these phenotypes in rats and humans. These data represent a step change in resources available for evolutionary analysis of complex traits in disease models. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Genome Sequencing Reveals Loci under Artificial Selection that Underlie Disease Phenotypes in the Laboratory Rat

PubMed Central

Atanur, Santosh S.; Diaz, Ana Garcia; Maratou, Klio; Sarkis, Allison; Rotival, Maxime; Game, Laurence; Tschannen, Michael R.; Kaisaki, Pamela J.; Otto, Georg W.; Ma, Man Chun John; Keane, Thomas M.; Hummel, Oliver; Saar, Kathrin; Chen, Wei; Guryev, Victor; Gopalakrishnan, Kathirvel; Garrett, Michael R.; Joe, Bina; Citterio, Lorena; Bianchi, Giuseppe; McBride, Martin; Dominiczak, Anna; Adams, David J.; Serikawa, Tadao; Flicek, Paul; Cuppen, Edwin; Hubner, Norbert; Petretto, Enrico; Gauguier, Dominique; Kwitek, Anne; Jacob, Howard; Aitman, Timothy J.

2013-01-01

Summary Large numbers of inbred laboratory rat strains have been developed for a range of complex disease phenotypes. To gain insights into the evolutionary pressures underlying selection for these phenotypes, we sequenced the genomes of 27 rat strains, including 11 models of hypertension, diabetes, and insulin resistance, along with their respective control strains. Altogether, we identified more than 13 million single-nucleotide variants, indels, and structural variants across these rat strains. Analysis of strain-specific selective sweeps and gene clusters implicated genes and pathways involved in cation transport, angiotensin production, and regulators of oxidative stress in the development of cardiovascular disease phenotypes in rats. Many of the rat loci that we identified overlap with previously mapped loci for related traits in humans, indicating the presence of shared pathways underlying these phenotypes in rats and humans. These data represent a step change in resources available for evolutionary analysis of complex traits in disease models. PaperClip PMID:23890820

The genetics of muscle atrophy and growth: the impact and implications of polymorphisms in animals and humans.

PubMed

Gordon, Erynn S; Gordish Dressman, Heather A; Hoffman, Eric P

2005-10-01

Much of the vast diversity we see in animals and people is governed by genetic loci that have quantitative effects of phenotype (quantitative trait loci; QTLs). Here we review the current knowledge of the genetics of atrophy and hypertrophy in both animal husbandry (meat quantity and quality), and humans (muscle size and performance). The selective breeding of animals for meat has apparently led to a few genetic loci with strong effects, with different loci in different animals. In humans, muscle quantitative trait loci (QTLs) appear to be more complex, with few "major" loci identified to date, although this is likely to change in the near future. We describe how the same phenotypic traits we see as positive, greater lean muscle mass in cattle or a better exercise results in humans, can also have negative "side effects" given specific environmental challenges. We also discuss the strength and limitations of single nucleotide polymorphisms (SNP) association studies; what the reader should look for and expect in a published study. Lastly we discuss the ethical and societal implications of this genetic information. As more and more research into the genetic loci that dictate phenotypic traits become available, the ethical implications of testing for these loci become increasingly important. As a society, most accept testing for genetic diseases or susceptibility, but do we as easily accept testing to determine one's athletic potential to be an Olympic endurance runner, or quarterback on the high school football team.

Investigation of Crohn’s Disease Risk Loci in Ulcerative Colitis Further Defines Their Molecular Relationship

PubMed Central

ANDERSON, CARL A.; MASSEY, DUNECAN C. O.; BARRETT, JEFFREY C.; PRESCOTT, NATALIE J.; TREMELLING, MARK; FISHER, SHEILA A.; GWILLIAM, RHIAN; JACOB, JEMIMA; NIMMO, ELAINE R.; DRUMMOND, HAZEL; LEES, CHARLIE W.; ONNIE, CLIVE M.; HANSON, CATHERINE; BLASZCZYK, KATARZYNA; RAVINDRARAJAH, RADHI; HUNT, SARAH; VARMA, DHIRAJ; HAMMOND, NAOMI; LEWIS, GREGORY; ATTLESEY, HEATHER; WATKINS, NICK; OUWEHAND, WILLEM; STRACHAN, DAVID; MCARDLE, WENDY; LEWIS, CATHRYN M.; LOBO, ALAN; SANDERSON, JEREMY; JEWELL, DEREK P.; DELOUKAS, PANOS; MANSFIELD, JOHN C.; MATHEW, CHRISTOPHER G.; SATSANGI, JACK; PARKES, MILES

2009-01-01

Background & Aims Identifying shared and disease-specific susceptibility loci for Crohn’s disease (CD) and ulcerative colitis (UC) would help define the biologic relationship between the inflammatory bowel diseases. More than 30 CD susceptibility loci have been identified. These represent important candidate susceptibility loci for UC. Loci discovered by the index genome scans in CD have previously been tested for association with UC, but those identified in the recent meta-analysis await such investigation. Furthermore, the recently identified UC locus at ECM1 requires formal testing for association with CD. Methods We analyzed 45 single nucleotide polymorphisms, tagging 29 of the loci recently associated with CD in 2527 UC cases and 4070 population controls. We also genotyped the UC-associated ECM1 variant rs11205387 in 1560 CD patients and 3028 controls. Results Nine regions showed association with UC at a threshold corrected for the 29 loci tested (P < .0017). The strongest association (P = 4.13 × 10-8; odds ratio = 1.27) was identified with a 170-kilobase region on chromosome 1q32 that contains 3 genes. We also found association with JAK2 and replicated a recently reported association with STAT3, further implicating the role of this signaling pathway in inflammatory bowel disease. Additional novel UC susceptibility genes were LYRM4 and CDKAL1. Twenty of the loci were not associated with UC, and several appear to be specific to CD. ECM1 variation was not associated with CD. Conclusions Collectively, these data help define the genetic relationship between CD and UC and characterize common, as well as disease-specific mechanisms of pathogenesis. PMID:19068216

The Role of Copy Number Variation in Susceptibility to Amyotrophic Lateral Sclerosis: Genome-Wide Association Study and Comparison with Published Loci

PubMed Central

Wain, Louise V.; Pedroso, Inti; Landers, John E.; Breen, Gerome; Shaw, Christopher E.; Leigh, P. Nigel; Brown, Robert H.

2009-01-01

Background The genetic contribution to sporadic amyotrophic lateral sclerosis (ALS) has not been fully elucidated. There are increasing efforts to characterise the role of copy number variants (CNVs) in human diseases; two previous studies concluded that CNVs may influence risk of sporadic ALS, with multiple rare CNVs more important than common CNVs. A little-explored issue surrounding genome-wide CNV association studies is that of post-calling filtering and merging of raw CNV calls. We undertook simulations to define filter thresholds and considered optimal ways of merging overlapping CNV calls for association testing, taking into consideration possibly overlapping or nested, but distinct, CNVs and boundary estimation uncertainty. Methodology and Principal Findings In this study we screened Illumina 300K SNP genotyping data from 730 ALS cases and 789 controls for copy number variation. Following quality control filters using thresholds defined by simulation, a total of 11321 CNV calls were made across 575 cases and 621 controls. Using region-based and gene-based association analyses, we identified several loci showing nominally significant association. However, the choice of criteria for combining calls for association testing has an impact on the ranking of the results by their significance. Several loci which were previously reported as being associated with ALS were identified here. However, of another 15 genes previously reported as exhibiting ALS-specific copy number variation, only four exhibited copy number variation in this study. Potentially interesting novel loci, including EEF1D, a translation elongation factor involved in the delivery of aminoacyl tRNAs to the ribosome (a process which has previously been implicated in genetic studies of spinal muscular atrophy) were identified but must be treated with caution due to concerns surrounding genomic location and platform suitability. Conclusions and Significance Interpretation of CNV association findings must take into account the effects of filtering and combining CNV calls when based on early genome-wide genotyping platforms and modest study sizes. PMID:19997636

Identification of four novel variants that influence central corneal thickness in multi-ethnic Asian populations.

PubMed

Cornes, Belinda K; Khor, Chiea Chuen; Nongpiur, Monisha E; Xu, Liang; Tay, Wan-Ting; Zheng, Yingfeng; Lavanya, Raghavan; Li, Yang; Wu, Renyi; Sim, Xueling; Wang, Ya-Xing; Chen, Peng; Teo, Yik Ying; Chia, Kee-Seng; Seielstad, Mark; Liu, Jianjun; Hibberd, Martin L; Cheng, Ching-Yu; Saw, Seang-Mei; Tai, E-Shyong; Jonas, Jost B; Vithana, Eranga N; Wong, Tien Y; Aung, Tin

2012-01-15

Central corneal thickness (CCT) is a highly heritable trait. Genes that significantly influence CCT can be candidate genes for common disorders in which CCT has been implicated, such as primary open-angle glaucoma (POAG) and keratoconus. Because the genetic factors controlling CCT in different Asian populations are unclear, we have built on previous work conducted on Singaporean Indians and Malays and extended our hypothesis to individuals of Chinese descent. We have followed up on all suggestive signals of association with CCT (P < 10(-4)) from the previously reported meta-analysis comprising Indians and Malays in a sample of Chinese individuals (n= 2681). In the combined sample (n= 7711), strong evidence of association was observed at four novel loci: IBTK on chromosome 6q14.1; CHSY1 on chromosome 15q26.3; and intergenic regions on chromosomes 7q11.2 and 9p23 (8.01 × 10(-11) < λ(GC) corrected P(meta) < 8.72 × 10(-8)). These four new loci explain an additional 4.3% of the total CCT variance across the sample cohorts over and above that of previously identified loci. We also extend on a previous finding at a fifth locus (AKAP13) where a new single-nucleotide polymorphism (rs1821481, P(meta) = 9.99 × 10(-9)) was found to be significantly more informative compared with the previously reported rs6496932 (P(meta) = 3.64 × 10(-5)). Performing association analysis in Asians may lead to the discovery of ethnic-specific genes that control CCT, offering further mechanistic insights into the regulation of CCT. In addition, it may also provide several candidate genes for interrogation for POAG, keratoconus and possible racial/ethnic variations. © The Author 2011. Published by Oxford University Press. All rights reserved.

Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval.

PubMed

Lin, Honghuang; van Setten, Jessica; Smith, Albert V; Bihlmeyer, Nathan A; Warren, Helen R; Brody, Jennifer A; Radmanesh, Farid; Hall, Leanne; Grarup, Niels; Müller-Nurasyid, Martina; Boutin, Thibaud; Verweij, Niek; Lin, Henry J; Li-Gao, Ruifang; van den Berg, Marten E; Marten, Jonathan; Weiss, Stefan; Prins, Bram P; Haessler, Jeffrey; Lyytikäinen, Leo-Pekka; Mei, Hao; Harris, Tamara B; Launer, Lenore J; Li, Man; Alonso, Alvaro; Soliman, Elsayed Z; Connell, John M; Huang, Paul L; Weng, Lu-Chen; Jameson, Heather S; Hucker, William; Hanley, Alan; Tucker, Nathan R; Chen, Yii-Der Ida; Bis, Joshua C; Rice, Kenneth M; Sitlani, Colleen M; Kors, Jan A; Xie, Zhijun; Wen, Chengping; Magnani, Jared W; Nelson, Christopher P; Kanters, Jørgen K; Sinner, Moritz F; Strauch, Konstantin; Peters, Annette; Waldenberger, Melanie; Meitinger, Thomas; Bork-Jensen, Jette; Pedersen, Oluf; Linneberg, Allan; Rudan, Igor; de Boer, Rudolf A; van der Meer, Peter; Yao, Jie; Guo, Xiuqing; Taylor, Kent D; Sotoodehnia, Nona; Rotter, Jerome I; Mook-Kanamori, Dennis O; Trompet, Stella; Rivadeneira, Fernando; Uitterlinden, André; Eijgelsheim, Mark; Padmanabhan, Sandosh; Smith, Blair H; Völzke, Henry; Felix, Stephan B; Homuth, Georg; Völker, Uwe; Mangino, Massimo; Spector, Timothy D; Bots, Michiel L; Perez, Marco; Kähönen, Mika; Raitakari, Olli T; Gudnason, Vilmundur; Arking, Dan E; Munroe, Patricia B; Psaty, Bruce M; van Duijn, Cornelia M; Benjamin, Emelia J; Rosand, Jonathan; Samani, Nilesh J; Hansen, Torben; Kääb, Stefan; Polasek, Ozren; van der Harst, Pim; Heckbert, Susan R; Jukema, J Wouter; Stricker, Bruno H; Hayward, Caroline; Dörr, Marcus; Jamshidi, Yalda; Asselbergs, Folkert W; Kooperberg, Charles; Lehtimäki, Terho; Wilson, James G; Ellinor, Patrick T; Lubitz, Steven A; Isaacs, Aaron

2018-05-01

Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability. We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval. We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction ( P <1.2×10 -6 ), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at MYH6 ( P =5.9×10 -11 ) and SCN5A ( P =1.1×10 -7 ) were associated with PR interval. SCN5A locus also was implicated in the common variant analysis, whereas MYH6 was a novel locus. We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health. © 2018 American Heart Association, Inc.

Biological, Clinical, and Population Relevance of 95 Loci for Blood Lipids

PubMed Central

Teslovich, Tanya M.; Musunuru, Kiran; Smith, Albert V.; Edmondson, Andrew C.; Stylianou, Ioannis M.; Koseki, Masahiro; Pirruccello, James P.; Ripatti, Samuli; Chasman, Daniel I.; Willer, Cristen J.; Johansen, Christopher T.; Fouchier, Sigrid W.; Isaacs, Aaron; Peloso, Gina M.; Barbalic, Maja; Ricketts, Sally L.; Bis, Joshua C.; Aulchenko, Yurii S.; Thorleifsson, Gudmar; Feitosa, Mary F.; Chambers, John; Orho-Melander, Marju; Melander, Olle; Johnson, Toby; Li, Xiaohui; Guo, Xiuqing; Li, Mingyao; Cho, Yoon Shin; Go, Min Jin; Kim, Young Jin; Lee, Jong-Young; Park, Taesung; Kim, Kyunga; Sim, Xueling; Ong, Rick Twee-Hee; Croteau-Chonka, Damien C.; Lange, Leslie A.; Smith, Joshua D.; Song, Kijoung; Zhao, Jing Hua; Yuan, Xin; Luan, Jian'an; Lamina, Claudia; Ziegler, Andreas; Zhang, Weihua; Zee, Robert Y.L.; Wright, Alan F.; Witteman, Jacqueline C.M.; Wilson, James F.; Willemsen, Gonneke; Wichmann, H-Erich; Whitfield, John B.; Waterworth, Dawn M.; Wareham, Nicholas J.; Waeber, Gérard; Vollenweider, Peter; Voight, Benjamin F.; Vitart, Veronique; Uitterlinden, Andre G.; Uda, Manuela; Tuomilehto, Jaakko; Thompson, John R.; Tanaka, Toshiko; Surakka, Ida; Stringham, Heather M.; Spector, Tim D.; Soranzo, Nicole; Smit, Johannes H.; Sinisalo, Juha; Silander, Kaisa; Sijbrands, Eric J.G.; Scuteri, Angelo; Scott, James; Schlessinger, David; Sanna, Serena; Salomaa, Veikko; Saharinen, Juha; Sabatti, Chiara; Ruokonen, Aimo; Rudan, Igor; Rose, Lynda M.; Roberts, Robert; Rieder, Mark; Psaty, Bruce M.; Pramstaller, Peter P.; Pichler, Irene; Perola, Markus; Penninx, Brenda W.J.H.; Pedersen, Nancy L.; Pattaro, Cristian; Parker, Alex N.; Pare, Guillaume; Oostra, Ben A.; O'Donnell, Christopher J.; Nieminen, Markku S.; Nickerson, Deborah A.; Montgomery, Grant W.; Meitinger, Thomas; McPherson, Ruth; McCarthy, Mark I.; McArdle, Wendy; Masson, David; Martin, Nicholas G.; Marroni, Fabio; Mangino, Massimo; Magnusson, Patrik K.E.; Lucas, Gavin; Luben, Robert; Loos, Ruth J. F.; Lokki, Maisa; Lettre, Guillaume; Langenberg, Claudia; Launer, Lenore J.; Lakatta, Edward G.; Laaksonen, Reijo; Kyvik, Kirsten O.; Kronenberg, Florian; König, Inke R.; Khaw, Kay-Tee; Kaprio, Jaakko; Kaplan, Lee M.; Johansson, Åsa; Jarvelin, Marjo-Riitta; Janssens, A. Cecile J.W.; Ingelsson, Erik; Igl, Wilmar; Hovingh, G. Kees; Hottenga, Jouke-Jan; Hofman, Albert; Hicks, Andrew A.; Hengstenberg, Christian; Heid, Iris M.; Hayward, Caroline; Havulinna, Aki S.; Hastie, Nicholas D.; Harris, Tamara B.; Haritunians, Talin; Hall, Alistair S.; Gyllensten, Ulf; Guiducci, Candace; Groop, Leif C.; Gonzalez, Elena; Gieger, Christian; Freimer, Nelson B.; Ferrucci, Luigi; Erdmann, Jeanette; Elliott, Paul; Ejebe, Kenechi G.; Döring, Angela; Dominiczak, Anna F.; Demissie, Serkalem; Deloukas, Panagiotis; de Geus, Eco J.C.; de Faire, Ulf; Crawford, Gabriel; Collins, Francis S.; Chen, Yii-der I.; Caulfield, Mark J.; Campbell, Harry; Burtt, Noel P.; Bonnycastle, Lori L.; Boomsma, Dorret I.; Boekholdt, S. Matthijs; Bergman, Richard N.; Barroso, Inês; Bandinelli, Stefania; Ballantyne, Christie M.; Assimes, Themistocles L.; Quertermous, Thomas; Altshuler, David; Seielstad, Mark; Wong, Tien Y.; Tai, E-Shyong; Feranil, Alan B.; Kuzawa, Christopher W.; Adair, Linda S.; Taylor, Herman A.; Borecki, Ingrid B.; Gabriel, Stacey B.; Wilson, James G.; Stefansson, Kari; Thorsteinsdottir, Unnur; Gudnason, Vilmundur; Krauss, Ronald M.; Mohlke, Karen L.; Ordovas, Jose M.; Munroe, Patricia B.; Kooner, Jaspal S.; Tall, Alan R.; Hegele, Robert A.; Kastelein, John J.P.; Schadt, Eric E.; Rotter, Jerome I.; Boerwinkle, Eric; Strachan, David P.; Mooser, Vincent; Holm, Hilma; Reilly, Muredach P.; Samani, Nilesh J; Schunkert, Heribert; Cupples, L. Adrienne; Sandhu, Manjinder S.; Ridker, Paul M; Rader, Daniel J.; van Duijn, Cornelia M.; Peltonen, Leena; Abecasis, Gonçalo R.; Boehnke, Michael; Kathiresan, Sekar

2010-01-01

Serum concentrations of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with serum lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 × 10-8), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (e.g., CYP7A1, NPC1L1, and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and impact lipid traits in three non-European populations (East Asians, South Asians, and African Americans). Our results identify several novel loci associated with serum lipids that are also associated with CAD. Finally, we validated three of the novel genes—GALNT2, PPP1R3B, and TTC39B—with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD. PMID:20686565

Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

PubMed

Turcot, Valérie; Lu, Yingchang; Highland, Heather M; Schurmann, Claudia; Justice, Anne E; Fine, Rebecca S; Bradfield, Jonathan P; Esko, Tõnu; Giri, Ayush; Graff, Mariaelisa; Guo, Xiuqing; Hendricks, Audrey E; Karaderi, Tugce; Lempradl, Adelheid; Locke, Adam E; Mahajan, Anubha; Marouli, Eirini; Sivapalaratnam, Suthesh; Young, Kristin L; Alfred, Tamuno; Feitosa, Mary F; Masca, Nicholas G D; Manning, Alisa K; Medina-Gomez, Carolina; Mudgal, Poorva; Ng, Maggie C Y; Reiner, Alex P; Vedantam, Sailaja; Willems, Sara M; Winkler, Thomas W; Abecasis, Gonçalo; Aben, Katja K; Alam, Dewan S; Alharthi, Sameer E; Allison, Matthew; Amouyel, Philippe; Asselbergs, Folkert W; Auer, Paul L; Balkau, Beverley; Bang, Lia E; Barroso, Inês; Bastarache, Lisa; Benn, Marianne; Bergmann, Sven; Bielak, Lawrence F; Blüher, Matthias; Boehnke, Michael; Boeing, Heiner; Boerwinkle, Eric; Böger, Carsten A; Bork-Jensen, Jette; Bots, Michiel L; Bottinger, Erwin P; Bowden, Donald W; Brandslund, Ivan; Breen, Gerome; Brilliant, Murray H; Broer, Linda; Brumat, Marco; Burt, Amber A; Butterworth, Adam S; Campbell, Peter T; Cappellani, Stefania; Carey, David J; Catamo, Eulalia; Caulfield, Mark J; Chambers, John C; Chasman, Daniel I; Chen, Yii-Der I; Chowdhury, Rajiv; Christensen, Cramer; Chu, Audrey Y; Cocca, Massimiliano; Collins, Francis S; Cook, James P; Corley, Janie; Corominas Galbany, Jordi; Cox, Amanda J; Crosslin, David S; Cuellar-Partida, Gabriel; D'Eustacchio, Angela; Danesh, John; Davies, Gail; Bakker, Paul I W; Groot, Mark C H; Mutsert, Renée; Deary, Ian J; Dedoussis, George; Demerath, Ellen W; Heijer, Martin; Hollander, Anneke I; Ruijter, Hester M; Dennis, Joe G; Denny, Josh C; Di Angelantonio, Emanuele; Drenos, Fotios; Du, Mengmeng; Dubé, Marie-Pierre; Dunning, Alison M; Easton, Douglas F; Edwards, Todd L; Ellinghaus, David; Ellinor, Patrick T; Elliott, Paul; Evangelou, Evangelos; Farmaki, Aliki-Eleni; Farooqi, I Sadaf; Faul, Jessica D; Fauser, Sascha; Feng, Shuang; Ferrannini, Ele; Ferrieres, Jean; Florez, Jose C; Ford, Ian; Fornage, Myriam; Franco, Oscar H; Franke, Andre; Franks, Paul W; Friedrich, Nele; Frikke-Schmidt, Ruth; Galesloot, Tessel E; Gan, Wei; Gandin, Ilaria; Gasparini, Paolo; Gibson, Jane; Giedraitis, Vilmantas; Gjesing, Anette P; Gordon-Larsen, Penny; Gorski, Mathias; Grabe, Hans-Jörgen; Grant, Struan F A; Grarup, Niels; Griffiths, Helen L; Grove, Megan L; Gudnason, Vilmundur; Gustafsson, Stefan; Haessler, Jeff; Hakonarson, Hakon; Hammerschlag, Anke R; Hansen, Torben; Harris, Kathleen Mullan; Harris, Tamara B; Hattersley, Andrew T; Have, Christian T; Hayward, Caroline; He, Liang; Heard-Costa, Nancy L; Heath, Andrew C; Heid, Iris M; Helgeland, Øyvind; Hernesniemi, Jussi; Hewitt, Alex W; Holmen, Oddgeir L; Hovingh, G Kees; Howson, Joanna M M; Hu, Yao; Huang, Paul L; Huffman, Jennifer E; Ikram, M Arfan; Ingelsson, Erik; Jackson, Anne U; Jansson, Jan-Håkan; Jarvik, Gail P; Jensen, Gorm B; Jia, Yucheng; Johansson, Stefan; Jørgensen, Marit E; Jørgensen, Torben; Jukema, J Wouter; Kahali, Bratati; Kahn, René S; Kähönen, Mika; Kamstrup, Pia R; Kanoni, Stavroula; Kaprio, Jaakko; Karaleftheri, Maria; Kardia, Sharon L R; Karpe, Fredrik; Kathiresan, Sekar; Kee, Frank; Kiemeney, Lambertus A; Kim, Eric; Kitajima, Hidetoshi; Komulainen, Pirjo; Kooner, Jaspal S; Kooperberg, Charles; Korhonen, Tellervo; Kovacs, Peter; Kuivaniemi, Helena; Kutalik, Zoltán; Kuulasmaa, Kari; Kuusisto, Johanna; Laakso, Markku; Lakka, Timo A; Lamparter, David; Lange, Ethan M; Lange, Leslie A; Langenberg, Claudia; Larson, Eric B; Lee, Nanette R; Lehtimäki, Terho; Lewis, Cora E; Li, Huaixing; Li, Jin; Li-Gao, Ruifang; Lin, Honghuang; Lin, Keng-Hung; Lin, Li-An; Lin, Xu; Lind, Lars; Lindström, Jaana; Linneberg, Allan; Liu, Ching-Ti; Liu, Dajiang J; Liu, Yongmei; Lo, Ken S; Lophatananon, Artitaya; Lotery, Andrew J; Loukola, Anu; Luan, Jian'an; Lubitz, Steven A; Lyytikäinen, Leo-Pekka; Männistö, Satu; Marenne, Gaëlle; Mazul, Angela L; McCarthy, Mark I; McKean-Cowdin, Roberta; Medland, Sarah E; Meidtner, Karina; Milani, Lili; Mistry, Vanisha; Mitchell, Paul; Mohlke, Karen L; Moilanen, Leena; Moitry, Marie; Montgomery, Grant W; Mook-Kanamori, Dennis O; Moore, Carmel; Mori, Trevor A; Morris, Andrew D; Morris, Andrew P; Müller-Nurasyid, Martina; Munroe, Patricia B; Nalls, Mike A; Narisu, Narisu; Nelson, Christopher P; Neville, Matt; Nielsen, Sune F; Nikus, Kjell; Njølstad, Pål R; Nordestgaard, Børge G; Nyholt, Dale R; O'Connel, Jeffrey R; O'Donoghue, Michelle L; Olde Loohuis, Loes M; Ophoff, Roel A; Owen, Katharine R; Packard, Chris J; Padmanabhan, Sandosh; Palmer, Colin N A; Palmer, Nicholette D; Pasterkamp, Gerard; Patel, Aniruddh P; Pattie, Alison; Pedersen, Oluf; Peissig, Peggy L; Peloso, Gina M; Pennell, Craig E; Perola, Markus; Perry, James A; Perry, John R B; Pers, Tune H; Person, Thomas N; Peters, Annette; Petersen, Eva R B; Peyser, Patricia A; Pirie, Ailith; Polasek, Ozren; Polderman, Tinca J; Puolijoki, Hannu; Raitakari, Olli T; Rasheed, Asif; Rauramaa, Rainer; Reilly, Dermot F; Renström, Frida; Rheinberger, Myriam; Ridker, Paul M; Rioux, John D; Rivas, Manuel A; Roberts, David J; Robertson, Neil R; Robino, Antonietta; Rolandsson, Olov; Rudan, Igor; Ruth, Katherine S; Saleheen, Danish; Salomaa, Veikko; Samani, Nilesh J; Sapkota, Yadav; Sattar, Naveed; Schoen, Robert E; Schreiner, Pamela J; Schulze, Matthias B; Scott, Robert A; Segura-Lepe, Marcelo P; Shah, Svati H; Sheu, Wayne H-H; Sim, Xueling; Slater, Andrew J; Small, Kerrin S; Smith, Albert V; Southam, Lorraine; Spector, Timothy D; Speliotes, Elizabeth K; Starr, John M; Stefansson, Kari; Steinthorsdottir, Valgerdur; Stirrups, Kathleen E; Strauch, Konstantin; Stringham, Heather M; Stumvoll, Michael; Sun, Liang; Surendran, Praveen; Swift, Amy J; Tada, Hayato; Tansey, Katherine E; Tardif, Jean-Claude; Taylor, Kent D; Teumer, Alexander; Thompson, Deborah J; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Thuesen, Betina H; Tönjes, Anke; Tromp, Gerard; Trompet, Stella; Tsafantakis, Emmanouil; Tuomilehto, Jaakko; Tybjaerg-Hansen, Anne; Tyrer, Jonathan P; Uher, Rudolf; Uitterlinden, André G; Uusitupa, Matti; Laan, Sander W; Duijn, Cornelia M; Leeuwen, Nienke; van Setten, Jessica; Vanhala, Mauno; Varbo, Anette; Varga, Tibor V; Varma, Rohit; Velez Edwards, Digna R; Vermeulen, Sita H; Veronesi, Giovanni; Vestergaard, Henrik; Vitart, Veronique; Vogt, Thomas F; Völker, Uwe; Vuckovic, Dragana; Wagenknecht, Lynne E; Walker, Mark; Wallentin, Lars; Wang, Feijie; Wang, Carol A; Wang, Shuai; Wang, Yiqin; Ware, Erin B; Wareham, Nicholas J; Warren, Helen R; Waterworth, Dawn M; Wessel, Jennifer; White, Harvey D; Willer, Cristen J; Wilson, James G; Witte, Daniel R; Wood, Andrew R; Wu, Ying; Yaghootkar, Hanieh; Yao, Jie; Yao, Pang; Yerges-Armstrong, Laura M; Young, Robin; Zeggini, Eleftheria; Zhan, Xiaowei; Zhang, Weihua; Zhao, Jing Hua; Zhao, Wei; Zhao, Wei; Zhou, Wei; Zondervan, Krina T; Rotter, Jerome I; Pospisilik, John A; Rivadeneira, Fernando; Borecki, Ingrid B; Deloukas, Panos; Frayling, Timothy M; Lettre, Guillaume; North, Kari E; Lindgren, Cecilia M; Hirschhorn, Joel N; Loos, Ruth J F

2018-01-01

Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

Meta-Analysis of Genome-Wide Association Studies in Celiac Disease and Rheumatoid Arthritis Identifies Fourteen Non-HLA Shared Loci

PubMed Central

Zhernakova, Alexandra; Stahl, Eli A.; Trynka, Gosia; Raychaudhuri, Soumya; Festen, Eleanora A.; Franke, Lude; Westra, Harm-Jan; Fehrmann, Rudolf S. N.; Kurreeman, Fina A. S.; Thomson, Brian; Gupta, Namrata; Romanos, Jihane; McManus, Ross; Ryan, Anthony W.; Turner, Graham; Brouwer, Elisabeth; Posthumus, Marcel D.; Remmers, Elaine F.; Tucci, Francesca; Toes, Rene; Grandone, Elvira; Mazzilli, Maria Cristina; Rybak, Anna; Cukrowska, Bozena; Coenen, Marieke J. H.; Radstake, Timothy R. D. J.; van Riel, Piet L. C. M.; Li, Yonghong; de Bakker, Paul I. W.; Gregersen, Peter K.; Worthington, Jane; Siminovitch, Katherine A.; Klareskog, Lars; Huizinga, Tom W. J.

2011-01-01

Epidemiology and candidate gene studies indicate a shared genetic basis for celiac disease (CD) and rheumatoid arthritis (RA), but the extent of this sharing has not been systematically explored. Previous studies demonstrate that 6 of the established non-HLA CD and RA risk loci (out of 26 loci for each disease) are shared between both diseases. We hypothesized that there are additional shared risk alleles and that combining genome-wide association study (GWAS) data from each disease would increase power to identify these shared risk alleles. We performed a meta-analysis of two published GWAS on CD (4,533 cases and 10,750 controls) and RA (5,539 cases and 17,231 controls). After genotyping the top associated SNPs in 2,169 CD cases and 2,255 controls, and 2,845 RA cases and 4,944 controls, 8 additional SNPs demonstrated P<5×10−8 in a combined analysis of all 50,266 samples, including four SNPs that have not been previously confirmed in either disease: rs10892279 near the DDX6 gene (Pcombined = 1.2×10−12), rs864537 near CD247 (Pcombined = 2.2×10−11), rs2298428 near UBE2L3 (Pcombined = 2.5×10−10), and rs11203203 near UBASH3A (Pcombined = 1.1×10−8). We also confirmed that 4 gene loci previously established in either CD or RA are associated with the other autoimmune disease at combined P<5×10−8 (SH2B3, 8q24, STAT4, and TRAF1-C5). From the 14 shared gene loci, 7 SNPs showed a genome-wide significant effect on expression of one or more transcripts in the linkage disequilibrium (LD) block around the SNP. These associations implicate antigen presentation and T-cell activation as a shared mechanism of disease pathogenesis and underscore the utility of cross-disease meta-analysis for identification of genetic risk factors with pleiotropic effects between two clinically distinct diseases. PMID:21383967

Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthritis identifies fourteen non-HLA shared loci.

PubMed

Zhernakova, Alexandra; Stahl, Eli A; Trynka, Gosia; Raychaudhuri, Soumya; Festen, Eleanora A; Franke, Lude; Westra, Harm-Jan; Fehrmann, Rudolf S N; Kurreeman, Fina A S; Thomson, Brian; Gupta, Namrata; Romanos, Jihane; McManus, Ross; Ryan, Anthony W; Turner, Graham; Brouwer, Elisabeth; Posthumus, Marcel D; Remmers, Elaine F; Tucci, Francesca; Toes, Rene; Grandone, Elvira; Mazzilli, Maria Cristina; Rybak, Anna; Cukrowska, Bozena; Coenen, Marieke J H; Radstake, Timothy R D J; van Riel, Piet L C M; Li, Yonghong; de Bakker, Paul I W; Gregersen, Peter K; Worthington, Jane; Siminovitch, Katherine A; Klareskog, Lars; Huizinga, Tom W J; Wijmenga, Cisca; Plenge, Robert M

2011-02-01

Epidemiology and candidate gene studies indicate a shared genetic basis for celiac disease (CD) and rheumatoid arthritis (RA), but the extent of this sharing has not been systematically explored. Previous studies demonstrate that 6 of the established non-HLA CD and RA risk loci (out of 26 loci for each disease) are shared between both diseases. We hypothesized that there are additional shared risk alleles and that combining genome-wide association study (GWAS) data from each disease would increase power to identify these shared risk alleles. We performed a meta-analysis of two published GWAS on CD (4,533 cases and 10,750 controls) and RA (5,539 cases and 17,231 controls). After genotyping the top associated SNPs in 2,169 CD cases and 2,255 controls, and 2,845 RA cases and 4,944 controls, 8 additional SNPs demonstrated P<5 × 10(-8) in a combined analysis of all 50,266 samples, including four SNPs that have not been previously confirmed in either disease: rs10892279 near the DDX6 gene (P(combined) =  1.2 × 10(-12)), rs864537 near CD247 (P(combined) =  2.2 × 10(-11)), rs2298428 near UBE2L3 (P(combined) =  2.5 × 10(-10)), and rs11203203 near UBASH3A (P(combined) =  1.1 × 10(-8)). We also confirmed that 4 gene loci previously established in either CD or RA are associated with the other autoimmune disease at combined P<5 × 10(-8) (SH2B3, 8q24, STAT4, and TRAF1-C5). From the 14 shared gene loci, 7 SNPs showed a genome-wide significant effect on expression of one or more transcripts in the linkage disequilibrium (LD) block around the SNP. These associations implicate antigen presentation and T-cell activation as a shared mechanism of disease pathogenesis and underscore the utility of cross-disease meta-analysis for identification of genetic risk factors with pleiotropic effects between two clinically distinct diseases.

Genetic Overlap Between Schizophrenia and Volumes of Hippocampus, Putamen, and Intracranial Volume Indicates Shared Molecular Genetic Mechanisms.

PubMed

Smeland, Olav B; Wang, Yunpeng; Frei, Oleksandr; Li, Wen; Hibar, Derrek P; Franke, Barbara; Bettella, Francesco; Witoelar, Aree; Djurovic, Srdjan; Chen, Chi-Hua; Thompson, Paul M; Dale, Anders M; Andreassen, Ole A

2018-06-06

Schizophrenia (SCZ) is associated with differences in subcortical brain volumes and intracranial volume (ICV). However, little is known about the underlying etiology of these brain alterations. Here, we explored whether brain structure volumes and SCZ share genetic risk factors. Using conditional false discovery rate (FDR) analysis, we integrated genome-wide association study (GWAS) data on SCZ (n = 82315) and GWAS data on 7 subcortical brain volumes and ICV (n = 11840). By conditioning the FDR on overlapping associations, this statistical approach increases power to discover genetic loci. To assess the credibility of our approach, we studied the identified loci in larger GWAS samples on ICV (n = 26577) and hippocampal volume (n = 26814). We observed polygenic overlap between SCZ and volumes of hippocampus, putamen, and ICV. Based on conjunctional FDR < 0.05, we identified 2 loci shared between SCZ and ICV implicating genes FOXO3 (rs10457180) and ITIH4 (rs4687658), 2 loci shared between SCZ and hippocampal volume implicating SLC4A10 (rs4664442) and SPATS2L (rs1653290), and 2 loci shared between SCZ and volume of putamen implicating DCC (rs4632195) and DLG2 (rs11233632). The loci shared between SCZ and hippocampal volume or ICV had not reached significance in the primary GWAS on brain phenotypes. Proving our point of increased power, 2 loci did reach genome-wide significance with ICV (rs10457180) and hippocampal volume (rs4664442) in the larger GWAS. Three of the 6 identified loci are novel for SCZ. Altogether, the findings provide new insights into the relationship between SCZ and brain structure volumes, suggesting that their genetic architectures are not independent.

Genomic copy number variations in three Southeast Asian populations.

PubMed

Ku, Chee-Seng; Pawitan, Yudi; Sim, Xueling; Ong, Rick T H; Seielstad, Mark; Lee, Edmund J D; Teo, Yik-Ying; Chia, Kee-Seng; Salim, Agus

2010-07-01

Research on the role of copy number variations (CNVs) in the genetic risk of diseases in Asian populations has been hampered by a relative lack of reference CNV maps for Asian populations outside the East Asians. In this article, we report the population characteristics of CNVs in Chinese, Malay, and Asian Indian populations in Singapore. Using the Illumina Human 1M Beadchip array, we identify 1,174 CNV loci in these populations that corroborated with findings when the same samples were typed on the Affymetrix 6.0 platform. We identify 441 novel loci not previously reported in the Database of Genomic Variations (DGV). We observe a considerable number of loci that span all three populations and were previously unreported, as well as population-specific loci that are quite common in the respective populations. From this we observe the distribution of CNVs in the Asian Indian population to be considerably different from the Chinese and Malay populations. About half of the deletion loci and three-quarters of duplication loci overlap UCSC genes. Tens of loci show population differentiation and overlap with genes previously known to be associated with genetic risk of diseases. One of these loci is the CYP2A6 deletion, previously linked to reduced susceptibility to lung cancer. (c) 2010 Wiley-Liss, Inc.

Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens

PubMed Central

Kiryluk, Krzysztof; Li, Yifu; Scolari, Francesco; Sanna-Cherchi, Simone; Choi, Murim; Verbitsky, Miguel; Fasel, David; Lata, Sneh; Prakash, Sindhuri; Shapiro, Samantha; Fischman, Clara; Snyder, Holly J.; Appel, Gerald; Izzi, Claudia; Viola, Battista Fabio; Dallera, Nadia; Vecchio, Lucia Del; Barlassina, Cristina; Salvi, Erika; Bertinetto, Francesca Eleonora; Amoroso, Antonio; Savoldi, Silvana; Rocchietti, Marcella; Amore, Alessandro; Peruzzi, Licia; Coppo, Rosanna; Salvadori, Maurizio; Ravani, Pietro; Magistroni, Riccardo; Ghiggeri, Gian Marco; Caridi, Gianluca; Bodria, Monica; Lugani, Francesca; Allegri, Landino; Delsante, Marco; Maiorana, Mariarosa; Magnano, Andrea; Frasca, Giovanni; Boer, Emanuela; Boscutti, Giuliano; Ponticelli, Claudio; Mignani, Renzo; Marcantoni, Carmelita; Di Landro, Domenico; Santoro, Domenico; Pani, Antonello; Polci, Rosaria; Feriozzi, Sandro; Chicca, Silvana; Galliani, Marco; Gigante, Maddalena; Gesualdo, Loreto; Zamboli, Pasquale; Maixnerová, Dita; Tesar, Vladimir; Eitner, Frank; Rauen, Thomas; Floege, Jürgen; Kovacs, Tibor; Nagy, Judit; Mucha, Krzysztof; Pączek, Leszek; Zaniew, Marcin; Mizerska-Wasiak, Małgorzata; Roszkowska-Blaim, Maria; Pawlaczyk, Krzysztof; Gale, Daniel; Barratt, Jonathan; Thibaudin, Lise; Berthoux, Francois; Canaud, Guillaume; Boland, Anne; Metzger, Marie; Panzer, Ulf; Suzuki, Hitoshi; Goto, Shin; Narita, Ichiei; Caliskan, Yasar; Xie, Jingyuan; Hou, Ping; Chen, Nan; Zhang, Hong; Wyatt, Robert J.; Novak, Jan; Julian, Bruce A.; Feehally, John; Stengel, Benedicte; Cusi, Daniele; Lifton, Richard P.; Gharavi, Ali G.

2014-01-01

We performed a genome-wide association study (GWAS) of IgA nephropathy (IgAN), the most common form of glomerulonephritis, with discovery and follow-up in 20,612 individuals of European and East Asian ancestry. We identified six novel genome-wide significant associations, four in ITGAM-ITGAX, VAV3 and CARD9 and two new independent signals at HLA-DQB1 and DEFA. We replicated the nine previously reported signals, including known SNPs in the HLA-DQB1 and DEFA loci. The cumulative burden of risk alleles is strongly associated with age at disease onset. Most loci are either directly associated with risk of inflammatory bowel disease (IBD) or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The geo-spatial distribution of risk alleles is highly suggestive of multi-locus adaptation and the genetic risk correlates strongly with variation in local pathogens, particularly helminth diversity, suggesting a possible role for host-intestinal pathogen interactions in shaping the genetic landscape of IgAN. PMID:25305756

A Pilot Genome-Wide Association Study in Postmenopausal Mexican-Mestizo Women Implicates the RMND1/CCDC170 Locus Is Associated with Bone Mineral Density

PubMed Central

Villalobos-Comparán, Marisela; Estrada, Karol; Parra-Torres, Alma Y.; González-Mercado, Anahí; Patiño, Nelly; Castillejos-López, Manuel; Quiterio, Manuel; Fernandez-López, Juan Carlos; Ibarra, Bertha; Romero-Hidalgo, Sandra; Salmerón, Jorge

2017-01-01

To identify genetic variants influencing bone mineral density (BMD) in the Mexican-Mestizo population, we performed a GWAS for femoral neck (FN) and lumbar spine (LS) in Mexican-Mestizo postmenopausal women. In the discovery sample, 300,000 SNPs were genotyped in a cohort of 411 postmenopausal women and seven SNPs were analyzed in the replication cohort (n = 420). The combined results of a meta-analysis from the discovery and replication samples identified two loci, RMND1 (rs6904364, P = 2.77 × 10−4) and CCDC170 (rs17081341, P = 1.62 × 10−5), associated with FN BMD. We also compared our results with those of the Genetic Factors for Osteoporosis (GEFOS) Consortium meta-analysis. The comparison revealed two loci previously reported in the GEFOS meta-analysis: SOX6 (rs7128738) and PKDCC (rs11887431) associated with FN and LS BMD, respectively, in our study population. Interestingly, rs17081341 rare in Caucasians (minor allele frequency < 0.03) was found in high frequency in our population, which suggests that this association could be specific to non-Caucasian populations. In conclusion, the first pilot Mexican GWA study of BMD confirmed previously identified loci and also demonstrated the importance of studying variability in diverse populations and/or specific populations. PMID:28840121

Statistical aspects of evolution under natural selection, with implications for the advantage of sexual reproduction.

PubMed

Crouch, Daniel J M

2017-10-27

The prevalence of sexual reproduction remains mysterious, as it poses clear evolutionary drawbacks compared to reproducing asexually. Several possible explanations exist, with one of the most likely being that finite population size causes linkage disequilibria to randomly generate and impede the progress of natural selection, and that these are eroded by recombination via sexual reproduction. Previous investigations have either analysed this phenomenon in detail for small numbers of loci, or performed population simulations for many loci. Here we present a quantitative genetic model for fitness, based on the Price Equation, in order to examine the theoretical consequences of randomly generated linkage disequilibria when there are many loci. In addition, most previous work has been concerned with the long-term consequences of deleterious linkage disequilibria for population fitness. The expected change in mean fitness between consecutive generations, a measure of short-term evolutionary success, is shown under random environmental influences to be related to the autocovariance in mean fitness between the generations, capturing the effects of stochastic forces such as genetic drift. Interaction between genetic drift and natural selection, due to randomly generated linkage disequilibria, is demonstrated to be one possible source of mean fitness autocovariance. This suggests a possible role for sexual reproduction in reducing the negative effects of genetic drift, thereby improving the short-term efficacy of natural selection. Copyright © 2017 Elsevier Ltd. All rights reserved.

Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma.

PubMed

Law, Matthew H; Bishop, D Timothy; Lee, Jeffrey E; Brossard, Myriam; Martin, Nicholas G; Moses, Eric K; Song, Fengju; Barrett, Jennifer H; Kumar, Rajiv; Easton, Douglas F; Pharoah, Paul D P; Swerdlow, Anthony J; Kypreou, Katerina P; Taylor, John C; Harland, Mark; Randerson-Moor, Juliette; Akslen, Lars A; Andresen, Per A; Avril, Marie-Françoise; Azizi, Esther; Scarrà, Giovanna Bianchi; Brown, Kevin M; Dębniak, Tadeusz; Duffy, David L; Elder, David E; Fang, Shenying; Friedman, Eitan; Galan, Pilar; Ghiorzo, Paola; Gillanders, Elizabeth M; Goldstein, Alisa M; Gruis, Nelleke A; Hansson, Johan; Helsing, Per; Hočevar, Marko; Höiom, Veronica; Ingvar, Christian; Kanetsky, Peter A; Chen, Wei V; Landi, Maria Teresa; Lang, Julie; Lathrop, G Mark; Lubiński, Jan; Mackie, Rona M; Mann, Graham J; Molven, Anders; Montgomery, Grant W; Novaković, Srdjan; Olsson, Håkan; Puig, Susana; Puig-Butille, Joan Anton; Qureshi, Abrar A; Radford-Smith, Graham L; van der Stoep, Nienke; van Doorn, Remco; Whiteman, David C; Craig, Jamie E; Schadendorf, Dirk; Simms, Lisa A; Burdon, Kathryn P; Nyholt, Dale R; Pooley, Karen A; Orr, Nick; Stratigos, Alexander J; Cust, Anne E; Ward, Sarah V; Hayward, Nicholas K; Han, Jiali; Schulze, Hans-Joachim; Dunning, Alison M; Bishop, Julia A Newton; Demenais, Florence; Amos, Christopher I; MacGregor, Stuart; Iles, Mark M

2015-09-01

Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5 × 10(-8)), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology.

Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma

PubMed Central

Law, Matthew H.; Bishop, D. Timothy; Martin, Nicholas G.; Moses, Eric K.; Song, Fengju; Barrett, Jennifer H.; Kumar, Rajiv; Easton, Douglas F.; Pharoah, Paul D. P.; Swerdlow, Anthony J.; Kypreou, Katerina P.; Taylor, John C.; Harland, Mark; Randerson-Moor, Juliette; Akslen, Lars A.; Andresen, Per A.; Avril, Marie-Françoise; Azizi, Esther; Scarrà, Giovanna Bianchi; Brown, Kevin M.; Dębniak, Tadeusz; Duffy, David L.; Elder, David E.; Fang, Shenying; Friedman, Eitan; Galan, Pilar; Ghiorzo, Paola; Gillanders, Elizabeth M.; Goldstein, Alisa M.; Gruis, Nelleke A.; Hansson, Johan; Helsing, Per; Hočevar, Marko; Höiom, Veronica; Ingvar, Christian; Kanetsky, Peter A.; Chen, Wei V.; Landi, Maria Teresa; Lang, Julie; Lathrop, G. Mark; Lubiński, Jan; Mackie, Rona M.; Mann, Graham J.; Molven, Anders; Montgomery, Grant W.; Novaković, Srdjan; Olsson, Håkan; Puig, Susana; Puig-Butille, Joan Anton; Qureshi, Abrar A.; Radford-Smith, Graham L.; van der Stoep, Nienke; van Doorn, Remco; Whiteman, David C.; Craig, Jamie E.; Schadendorf, Dirk; Simms, Lisa A.; Burdon, Kathryn P.; Nyholt, Dale R.; Pooley, Karen A.; Orr, Nick; Stratigos, Alexander J.; Cust, Anne E.; Ward, Sarah V.; Hayward, Nicholas K.; Han, Jiali; Schulze, Hans-Joachim; Dunning, Alison M.; Bishop, Julia A. Newton; MacGregor, Stuart; Iles, Mark M.

2015-01-01

Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5×10–8), as did two previously-reported but un-replicated loci and all thirteen established loci. Novel SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes including one involved in telomere biology. PMID:26237428

Genetic Mapping of Fixed Phenotypes: Disease Frequency as a Breed Characteristic

PubMed Central

Jones, Paul; Martin, Alan; Ostrander, Elaine A.; Lark, Karl G.

2009-01-01

Traits that have been stringently selected to conform to specific criteria in a closed population are phenotypic stereotypes. In dogs, Canis familiaris, such stereotypes have been produced by breeding for conformation, performance (behaviors), etc. We measured phenotypes on a representative sample to establish breed stereotypes. DNA samples from 147 dog breeds were used to characterize single nucleotide polymorphism allele frequencies for association mapping of breed stereotypes. We identified significant size loci (quantitative trait loci [QTLs]), implicating candidate genes appropriate to regulation of size (e.g., IGF1, IGF2BP2 SMAD2, etc.). Analysis of other morphological stereotypes, also under extreme selection, identified many additional significant loci. Behavioral loci for herding, pointing, and boldness implicated candidate genes appropriate to behavior (e.g., MC2R, DRD1, and PCDH9). Significant loci for longevity, a breed characteristic inversely correlated with breed size, were identified. The power of this approach to identify loci regulating the incidence of specific polygenic diseases is demonstrated by the association of a specific IGF1 haplotype with hip dysplasia, patella luxation, and pacreatitis. PMID:19321632

Genetic mapping of fixed phenotypes: disease frequency as a breed characteristic.

PubMed

Chase, Kevin; Jones, Paul; Martin, Alan; Ostrander, Elaine A; Lark, Karl G

2009-01-01

Traits that have been stringently selected to conform to specific criteria in a closed population are phenotypic stereotypes. In dogs, Canis familiaris, such stereotypes have been produced by breeding for conformation, performance (behaviors), etc. We measured phenotypes on a representative sample to establish breed stereotypes. DNA samples from 147 dog breeds were used to characterize single nucleotide polymorphism allele frequencies for association mapping of breed stereotypes. We identified significant size loci (quantitative trait loci [QTLs]), implicating candidate genes appropriate to regulation of size (e.g., IGF1, IGF2BP2 SMAD2, etc.). Analysis of other morphological stereotypes, also under extreme selection, identified many additional significant loci. Behavioral loci for herding, pointing, and boldness implicated candidate genes appropriate to behavior (e.g., MC2R, DRD1, and PCDH9). Significant loci for longevity, a breed characteristic inversely correlated with breed size, were identified. The power of this approach to identify loci regulating the incidence of specific polygenic diseases is demonstrated by the association of a specific IGF1 haplotype with hip dysplasia, patella luxation, and pancreatitis.

Microcephaly genes evolved adaptively throughout the evolution of eutherian mammals

PubMed Central

2014-01-01

Background Genes associated with the neurodevelopmental disorder microcephaly display a strong signature of adaptive evolution in primates. Comparative data suggest a link between selection on some of these loci and the evolution of primate brain size. Whether or not either positive selection or this phenotypic association are unique to primates is unclear, but recent studies in cetaceans suggest at least two microcephaly genes evolved adaptively in other large brained mammalian clades. Results Here we analyse the evolution of seven microcephaly loci, including three recently identified loci, across 33 eutherian mammals. We find extensive evidence for positive selection having acted on the majority of these loci not just in primates but also across non-primate mammals. Furthermore, the patterns of selection in major mammalian clades are not significantly different. Using phylogenetically corrected comparative analyses, we find that the evolution of two microcephaly loci, ASPM and CDK5RAP2, are correlated with neonatal brain size in Glires and Euungulata, the two most densely sampled non-primate clades. Conclusions Together with previous results, this suggests that ASPM and CDK5RAP2 may have had a consistent role in the evolution of brain size in mammals. Nevertheless, several limitations of currently available data and gene-phenotype tests are discussed, including sparse sampling across large evolutionary distances, averaging gene-wide rates of evolution, potential phenotypic variation and evolutionary reversals. We discuss the implications of our results for studies of the genetic basis of brain evolution, and explicit tests of gene-phenotype hypotheses. PMID:24898820

Meta-analysis of genome-wide association studies identifies genetic risk factors for stroke in African-Americans

PubMed Central

Carty, Cara L.; Keene, Keith L.; Cheng, Yu-Ching; Meschia, James F.; Chen, Wei-Min; Nalls, Mike; Bis, Joshua C.; Kittner, Steven J.; Rich, Stephen S.; Tajuddin, Salman; Zonderman, Alan B.; Evans, Michele K.; Langefeld, Carl D.; Gottesman, Rebecca; Mosley, Thomas H.; Shahar, Eyal; Woo, Daniel; Yaffe, Kristine; Liu, YongMei; Sale, Michèle M.; Dichgans, Martin; Malik, Rainer; Longstreth, WT; Mitchell, Braxton D.; Psaty, Bruce M.; Kooperberg, Charles; Reiner, Alexander; Worrall, Bradford B.; Fornage, Myriam

2015-01-01

Background and Purpose The majority of genome-wide association studies (GWAS) of stroke have focused on European-ancestry populations; however, none has been conducted in African-Americans despite the disproportionately high burden of stroke in this population. The Consortium of Minority Population genome-wide Association Studies of Stroke (COMPASS) was established to identify stroke susceptibility loci in minority populations. Methods Using METAL, we conducted meta-analyses of GWAS in 14,746 African-Americans (1,365 ischemic and 1,592 total stroke cases) from COMPASS, and tested SNPs with P<10−6 for validation in METASTROKE, a consortium of ischemic stroke genetic studies in European-ancestry populations. We also evaluated stroke loci previously identified in European-ancestry populations. Results The 15q21.3 locus linked with lipid levels and hypertension was associated with total stroke (rs4471613, P=3.9×10−8) in African-Americans. Nominal associations (P<10−6) for total or ischemic stroke were observed for 18 variants in or near genes implicated in cell cycle/ mRNA pre-splicing (PTPRG, CDC5L), platelet function (HPS4), blood-brain barrier permeability (CLDN17), immune response (ELTD1, WDFY4, IL1F10-IL1RN), and histone modification (HDAC9). Two of these loci achieved nominal significance in METASTROKE: 5q35.2 (P=0.03), and 1p31.1 (P=0.018). Four of 7 previously reported ischemic stroke loci (PITX2, HDAC9, CDKN2A/CDKN2B and ZFHX3) were nominally associated (P<0.05) with stroke in COMPASS. Conclusions We identified a novel SNP associated with total stroke in African-Americans and found that ischemic stroke loci identified in European-ancestry populations may also be relevant for African-Americans. Our findings support investigation of diverse populations to identify and characterize genetic risk factors, and the importance of shared genetic risk across populations. PMID:26089329

Transferability of genome-wide associated loci for asthma in African Americans

PubMed Central

Faruque, Mezbah U.; Chen, Guanjie; Doumatey, Ayo P.; Zhou, Jie; Huang, Hanxia; Shriner, Daniel; Adeyemo, Adebowale A.; Rotimi, Charles N.; Dunston, Georgia M.

2017-01-01

Objective Transferability of significantly associated loci or GWAS “hits” adds credibility to genotype-disease associations and provides evidence for generalizability across different ancestral populations. We sought evidence of association of known asthma-associated single nucleotide polymorphisms (SNPs) in an African American population. Methods Subjects comprised 661 participants (261 asthma cases and 400 controls) from the Howard University Family Study. Forty-eight SNPs previously reported to be associated with asthma by GWAS were selected for testing. We adopted a combined strategy by first adopting an “exact” approach where we looked-up only the reported index SNP. For those index SNPs missing form our dataset, we used a “local” approach that examined all the regional SNPs in LD with the index SNP. Results Out of the 48 SNPs, our cohort had genotype data available for 27, which were examined for exact replication. Of these, two SNPs were found positively associated with asthma. These included: rs10508372 (OR = 1.567 [95%CI, 1.133–2.167], P = 0.0066) and rs2378383 (OR = 2.147 [95%CI, 1.149–4.013], P = 0.0166), located on chromosomal bands 10p14 and 9q21.31, respectively. Local replication of the remaining 21 loci showed association at two chromosomal loci (9p24.1-rs2381413 and 6p21.32-rs3132947; Bonferroni-corrected P values: 0.0033 and 0.0197, respectively). Of note, multiple SNPs in LD with rs2381413 located upstream of IL33 were significantly associated with asthma. Conclusions This study has successfully transferred four reported asthma-associated loci in an independent African American population. Identification of several asthma-associated SNPs in the upstream of the IL33, a gene previously implicated in allergic inflammation of asthmatic airway, supports the generalizability of this finding. PMID:27177148

Genome-wide methylation analysis in Silver-Russell syndrome patients

PubMed Central

Böhm, S; Frost, JM; Puszyk, W; Abu-Amero, S; Stanier, P; Schulz, R; Moore, GE; Oakey, RJ

2015-01-01

Silver-Russell Syndrome (SRS) is a clinically heterogeneous disorder characterised by severe in utero growth restriction and poor postnatal growth, body asymmetry, irregular craniofacial features and several additional minor malformations. The aetiology of SRS is complex and current evidence strongly implicates imprinted genes. Approximately half of all patients exhibit DNA hypomethylation at the H19/IGF2 imprinted domain, and around 10% have maternal uniparental disomy of chromosome 7. We measured DNA methylation in 18 SRS patients at >485,000 CpG sites using DNA methylation microarrays. Using a novel bioinformatics methodology specifically designed to identify subsets of patients with a shared epimutation, we analysed methylation changes genome-wide as well as at known imprinted regions to identify SRS-associated epimutations. Our analysis identifies epimutations at the previously characterised domains of H19/IGF2 and at imprinted regions on chromosome 7, providing proof of principle that our methodology can detect DNA methylation changes at imprinted loci. In addition we discovered two novel epimutations associated with SRS and located at imprinted loci previously linked to relevant mouse and human phenotypes. We identify RB1 as an additional imprinted locus associated with SRS, with a region near the RB1 DMR hypermethylated in 13/18 (~70 %) patients. We also report 6/18 (~33 %) patients were hypermethylated at a CpG island near the ANKRD11 gene. We do not observe consistent cooccurrence of epimutations at multiple imprinted loci in single SRS individuals. SRS is clinically heterogeneous and the absence of multiple imprinted loci epimutations reflects the heterogeneity at the molecular level. Further stratification of SRS patients by molecular phenotypes might aid the identification of disease causes. PMID:25563730

Genome-wide association meta-analysis of 78,308 individuals identifies new loci and genes influencing human intelligence.

PubMed

Sniekers, Suzanne; Stringer, Sven; Watanabe, Kyoko; Jansen, Philip R; Coleman, Jonathan R I; Krapohl, Eva; Taskesen, Erdogan; Hammerschlag, Anke R; Okbay, Aysu; Zabaneh, Delilah; Amin, Najaf; Breen, Gerome; Cesarini, David; Chabris, Christopher F; Iacono, William G; Ikram, M Arfan; Johannesson, Magnus; Koellinger, Philipp; Lee, James J; Magnusson, Patrik K E; McGue, Matt; Miller, Mike B; Ollier, William E R; Payton, Antony; Pendleton, Neil; Plomin, Robert; Rietveld, Cornelius A; Tiemeier, Henning; van Duijn, Cornelia M; Posthuma, Danielle

2017-07-01

Intelligence is associated with important economic and health-related life outcomes. Despite intelligence having substantial heritability (0.54) and a confirmed polygenic nature, initial genetic studies were mostly underpowered. Here we report a meta-analysis for intelligence of 78,308 individuals. We identify 336 associated SNPs (METAL P < 5 × 10 -8 ) in 18 genomic loci, of which 15 are new. Around half of the SNPs are located inside a gene, implicating 22 genes, of which 11 are new findings. Gene-based analyses identified an additional 30 genes (MAGMA P < 2.73 × 10 -6 ), of which all but one had not been implicated previously. We show that the identified genes are predominantly expressed in brain tissue, and pathway analysis indicates the involvement of genes regulating cell development (MAGMA competitive P = 3.5 × 10 -6 ). Despite the well-known difference in twin-based heritability for intelligence in childhood (0.45) and adulthood (0.80), we show substantial genetic correlation (r g = 0.89, LD score regression P = 5.4 × 10 -29 ). These findings provide new insight into the genetic architecture of intelligence.

Allozyme variation of Port-Orford-Cedar (Chamaecyparis lawsoniana): implications for genetic conservation

Treesearch

Constance I. Millar; Kimberly A. Marshall

1991-01-01

Variation at 32 allozyme loci in nine disjunct populations of Part-Orford-cedar (POC) from the California floristic region was measured to estimate the amount and pattern of genetic variability in natural stands. Variation in electrophoretically detectable loci was moderately high, with mean number of alleles per locus = 1.9, 64.9% polymorphic loci, and observed...

High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry.

PubMed

Sun, Celi; Molineros, Julio E; Looger, Loren L; Zhou, Xu-Jie; Kim, Kwangwoo; Okada, Yukinori; Ma, Jianyang; Qi, Yuan-Yuan; Kim-Howard, Xana; Motghare, Prasenjeet; Bhattarai, Krishna; Adler, Adam; Bang, So-Young; Lee, Hye-Soon; Kim, Tae-Hwan; Kang, Young Mo; Suh, Chang-Hee; Chung, Won Tae; Park, Yong-Beom; Choe, Jung-Yoon; Shim, Seung Cheol; Kochi, Yuta; Suzuki, Akari; Kubo, Michiaki; Sumida, Takayuki; Yamamoto, Kazuhiko; Lee, Shin-Seok; Kim, Young Jin; Han, Bok-Ghee; Dozmorov, Mikhail; Kaufman, Kenneth M; Wren, Jonathan D; Harley, John B; Shen, Nan; Chua, Kek Heng; Zhang, Hong; Bae, Sang-Cheol; Nath, Swapan K

2016-03-01

Systemic lupus erythematosus (SLE) has a strong but incompletely understood genetic architecture. We conducted an association study with replication in 4,478 SLE cases and 12,656 controls from six East Asian cohorts to identify new SLE susceptibility loci and better localize known loci. We identified ten new loci and confirmed 20 known loci with genome-wide significance. Among the new loci, the most significant locus was GTF2IRD1-GTF2I at 7q11.23 (rs73366469, Pmeta = 3.75 × 10(-117), odds ratio (OR) = 2.38), followed by DEF6, IL12B, TCF7, TERT, CD226, PCNXL3, RASGRP1, SYNGR1 and SIGLEC6. We identified the most likely functional variants at each locus by analyzing epigenetic marks and gene expression data. Ten candidate variants are known to alter gene expression in cis or in trans. Enrichment analysis highlights the importance of these loci in B cell and T cell biology. The new loci, together with previously known loci, increase the explained heritability of SLE to 24%. The new loci share functional and ontological characteristics with previously reported loci and are possible drug targets for SLE therapeutics.

A genome-wide scan for signatures of directional selection in domesticated pigs.

PubMed

Moon, Sunjin; Kim, Tae-Hun; Lee, Kyung-Tai; Kwak, Woori; Lee, Taeheon; Lee, Si-Woo; Kim, Myung-Jick; Cho, Kyuho; Kim, Namshin; Chung, Won-Hyong; Sung, Samsun; Park, Taesung; Cho, Seoae; Groenen, Martien Am; Nielsen, Rasmus; Kim, Yuseob; Kim, Heebal

2015-02-25

Animal domestication involved drastic phenotypic changes driven by strong artificial selection and also resulted in new populations of breeds, established by humans. This study aims to identify genes that show evidence of recent artificial selection during pig domestication. Whole-genome resequencing of 30 individual pigs from domesticated breeds, Landrace and Yorkshire, and 10 Asian wild boars at ~16-fold coverage was performed resulting in over 4.3 million SNPs for 19,990 genes. We constructed a comprehensive genome map of directional selection by detecting selective sweeps using an F ST-based approach that detects directional selection in lineages leading to the domesticated breeds and using a haplotype-based test that detects ongoing selective sweeps within the breeds. We show that candidate genes under selection are significantly enriched for loci implicated in quantitative traits important to pig reproduction and production. The candidate gene with the strongest signals of directional selection belongs to group III of the metabolomics glutamate receptors, known to affect brain functions associated with eating behavior, suggesting that loci under strong selection include loci involved in behaviorial traits in domesticated pigs including tameness. We show that a significant proportion of selection signatures coincide with loci that were previously inferred to affect phenotypic variation in pigs. We further identify functional enrichment related to behavior, such as signal transduction and neuronal activities, for those targets of selection during domestication in pigs.

Identification, Replication, and Fine-Mapping of Loci Associated with Adult Height in Individuals of African Ancestry

PubMed Central

Ge, Bing; Tayo, Bamidele; Mathias, Rasika A.; Ding, Jingzhong; Nalls, Michael A.; Adeyemo, Adebowale; Adoue, Véronique; Ambrosone, Christine B.; Atwood, Larry; Bandera, Elisa V.; Becker, Lewis C.; Berndt, Sonja I.; Bernstein, Leslie; Blot, William J.; Boerwinkle, Eric; Britton, Angela; Casey, Graham; Chanock, Stephen J.; Demerath, Ellen; Deming, Sandra L.; Diver, W. Ryan; Fox, Caroline; Harris, Tamara B.; Hernandez, Dena G.; Hu, Jennifer J.; Ingles, Sue A.; John, Esther M.; Johnson, Craig; Keating, Brendan; Kittles, Rick A.; Kolonel, Laurence N.; Kritchevsky, Stephen B.; Le Marchand, Loic; Lohman, Kurt; Liu, Jiankang; Millikan, Robert C.; Murphy, Adam; Musani, Solomon; Neslund-Dudas, Christine; North, Kari E.; Nyante, Sarah; Ogunniyi, Adesola; Ostrander, Elaine A.; Papanicolaou, George; Patel, Sanjay; Pettaway, Curtis A.; Press, Michael F.; Redline, Susan; Rodriguez-Gil, Jorge L.; Rotimi, Charles; Rybicki, Benjamin A.; Salako, Babatunde; Schreiner, Pamela J.; Signorello, Lisa B.; Singleton, Andrew B.; Stanford, Janet L.; Stram, Alex H.; Stram, Daniel O.; Strom, Sara S.; Suktitipat, Bhoom; Thun, Michael J.; Witte, John S.; Yanek, Lisa R.; Ziegler, Regina G.; Zheng, Wei; Zhu, Xiaofeng; Zmuda, Joseph M.; Zonderman, Alan B.; Evans, Michele K.; Liu, Yongmei; Becker, Diane M.; Cooper, Richard S.; Pastinen, Tomi; Henderson, Brian E.; Hirschhorn, Joel N.; Lettre, Guillaume; Haiman, Christopher A.

2011-01-01

Adult height is a classic polygenic trait of high heritability (h 2 ∼0.8). More than 180 single nucleotide polymorphisms (SNPs), identified mostly in populations of European descent, are associated with height. These variants convey modest effects and explain ∼10% of the variance in height. Discovery efforts in other populations, while limited, have revealed loci for height not previously implicated in individuals of European ancestry. Here, we performed a meta-analysis of genome-wide association (GWA) results for adult height in 20,427 individuals of African ancestry with replication in up to 16,436 African Americans. We found two novel height loci (Xp22-rs12393627, P = 3.4×10−12 and 2p14-rs4315565, P = 1.2×10−8). As a group, height associations discovered in European-ancestry samples replicate in individuals of African ancestry (P = 1.7×10−4 for overall replication). Fine-mapping of the European height loci in African-ancestry individuals showed an enrichment of SNPs that are associated with expression of nearby genes when compared to the index European height SNPs (P<0.01). Our results highlight the utility of genetic studies in non-European populations to understand the etiology of complex human diseases and traits. PMID:21998595

Alignment of genetic maps and QTLs between inter- and intra-specific sorghum populations.

PubMed

Feltus, F A; Hart, G E; Schertz, K F; Casa, A M; Kresovich, S; Abraham, S; Klein, P E; Brown, P J; Paterson, A H

2006-05-01

To increase the value of associated molecular tools and also to begin to explore the degree to which interspecific and intraspecific genetic variation in Sorghum is attributable to corresponding genetic loci, we have aligned genetic maps derived from two sorghum populations that share one common parent (Sorghum bicolor L. Moench accession BTx623) but differ in morphological and evolutionarily distant alternate parents (S. propinquum or S. bicolor accession IS3620C). A total of 106 well-distributed DNA markers provide for map alignment, revealing only six nominal differences in marker order that are readily explained by sampling variation or mapping of paralogous loci. We also report a total of 61 new QTLs detected from 17 traits in these crosses. Among eight corresponding traits (some new, some previously published) that could be directly compared between the two maps, QTLs for two (tiller height and tiller number) were found to correspond in a non-random manner (P<0.05). For several other traits, correspondence of subsets of QTLs narrowly missed statistical significance. In particular, several QTLs for leaf senescence were near loci previously mapped for 'stay-green' that have been implicated by others in drought tolerance. These data provide strong validation for the value of molecular tools developed in the interspecific cross for utilization in cultivated sorghum, and begin to separate QTLs that distinguish among Sorghum species from those that are informative within the cultigen (S. bicolor).

Conserved DNA motifs in the type II-A CRISPR leader region.

PubMed

Van Orden, Mason J; Klein, Peter; Babu, Kesavan; Najar, Fares Z; Rajan, Rakhi

2017-01-01

The Clustered Regularly Interspaced Short Palindromic Repeats associated (CRISPR-Cas) systems consist of RNA-protein complexes that provide bacteria and archaea with sequence-specific immunity against bacteriophages, plasmids, and other mobile genetic elements. Bacteria and archaea become immune to phage or plasmid infections by inserting short pieces of the intruder DNA (spacer) site-specifically into the leader-repeat junction in a process called adaptation. Previous studies have shown that parts of the leader region, especially the 3' end of the leader, are indispensable for adaptation. However, a comprehensive analysis of leader ends remains absent. Here, we have analyzed the leader, repeat, and Cas proteins from 167 type II-A CRISPR loci. Our results indicate two distinct conserved DNA motifs at the 3' leader end: ATTTGAG (noted previously in the CRISPR1 locus of Streptococcus thermophilus DGCC7710) and a newly defined CTRCGAG, associated with the CRISPR3 locus of S. thermophilus DGCC7710. A third group with a very short CG DNA conservation at the 3' leader end is observed mostly in lactobacilli. Analysis of the repeats and Cas proteins revealed clustering of these CRISPR components that mirrors the leader motif clustering, in agreement with the coevolution of CRISPR-Cas components. Based on our analysis of the type II-A CRISPR loci, we implicate leader end sequences that could confer site-specificity for the adaptation-machinery in the different subsets of type II-A CRISPR loci.

Conserved DNA motifs in the type II-A CRISPR leader region

PubMed Central

Babu, Kesavan; Najar, Fares Z.

2017-01-01

The Clustered Regularly Interspaced Short Palindromic Repeats associated (CRISPR-Cas) systems consist of RNA-protein complexes that provide bacteria and archaea with sequence-specific immunity against bacteriophages, plasmids, and other mobile genetic elements. Bacteria and archaea become immune to phage or plasmid infections by inserting short pieces of the intruder DNA (spacer) site-specifically into the leader-repeat junction in a process called adaptation. Previous studies have shown that parts of the leader region, especially the 3′ end of the leader, are indispensable for adaptation. However, a comprehensive analysis of leader ends remains absent. Here, we have analyzed the leader, repeat, and Cas proteins from 167 type II-A CRISPR loci. Our results indicate two distinct conserved DNA motifs at the 3′ leader end: ATTTGAG (noted previously in the CRISPR1 locus of Streptococcus thermophilus DGCC7710) and a newly defined CTRCGAG, associated with the CRISPR3 locus of S. thermophilus DGCC7710. A third group with a very short CG DNA conservation at the 3′ leader end is observed mostly in lactobacilli. Analysis of the repeats and Cas proteins revealed clustering of these CRISPR components that mirrors the leader motif clustering, in agreement with the coevolution of CRISPR-Cas components. Based on our analysis of the type II-A CRISPR loci, we implicate leader end sequences that could confer site-specificity for the adaptation-machinery in the different subsets of type II-A CRISPR loci. PMID:28392985

Proteins Encoded in Genomic Regions Associated with Immune-Mediated Disease Physically Interact and Suggest Underlying Biology

PubMed Central

Rossin, Elizabeth J.; Lage, Kasper; Raychaudhuri, Soumya; Xavier, Ramnik J.; Tatar, Diana; Benita, Yair

2011-01-01

Genome-wide association studies (GWAS) have defined over 150 genomic regions unequivocally containing variation predisposing to immune-mediated disease. Inferring disease biology from these observations, however, hinges on our ability to discover the molecular processes being perturbed by these risk variants. It has previously been observed that different genes harboring causal mutations for the same Mendelian disease often physically interact. We sought to evaluate the degree to which this is true of genes within strongly associated loci in complex disease. Using sets of loci defined in rheumatoid arthritis (RA) and Crohn's disease (CD) GWAS, we build protein–protein interaction (PPI) networks for genes within associated loci and find abundant physical interactions between protein products of associated genes. We apply multiple permutation approaches to show that these networks are more densely connected than chance expectation. To confirm biological relevance, we show that the components of the networks tend to be expressed in similar tissues relevant to the phenotypes in question, suggesting the network indicates common underlying processes perturbed by risk loci. Furthermore, we show that the RA and CD networks have predictive power by demonstrating that proteins in these networks, not encoded in the confirmed list of disease associated loci, are significantly enriched for association to the phenotypes in question in extended GWAS analysis. Finally, we test our method in 3 non-immune traits to assess its applicability to complex traits in general. We find that genes in loci associated to height and lipid levels assemble into significantly connected networks but did not detect excess connectivity among Type 2 Diabetes (T2D) loci beyond chance. Taken together, our results constitute evidence that, for many of the complex diseases studied here, common genetic associations implicate regions encoding proteins that physically interact in a preferential manner, in line with observations in Mendelian disease. PMID:21249183

Multiple loci on 8q24 associated with prostate cancer susceptibility.

PubMed

Al Olama, Ali Amin; Kote-Jarai, Zsofia; Giles, Graham G; Guy, Michelle; Morrison, Jonathan; Severi, Gianluca; Leongamornlert, Daniel A; Tymrakiewicz, Malgorzata; Jhavar, Sameer; Saunders, Ed; Hopper, John L; Southey, Melissa C; Muir, Kenneth R; English, Dallas R; Dearnaley, David P; Ardern-Jones, Audrey T; Hall, Amanda L; O'Brien, Lynne T; Wilkinson, Rosemary A; Sawyer, Emma; Lophatananon, Artitaya; Horwich, Alan; Huddart, Robert A; Khoo, Vincent S; Parker, Christopher C; Woodhouse, Christopher J; Thompson, Alan; Christmas, Tim; Ogden, Chris; Cooper, Colin; Donovan, Jenny L; Hamdy, Freddie C; Neal, David E; Eeles, Rosalind A; Easton, Douglas F

2009-10-01

Previous studies have identified multiple loci on 8q24 associated with prostate cancer risk. We performed a comprehensive analysis of SNP associations across 8q24 by genotyping tag SNPs in 5,504 prostate cancer cases and 5,834 controls. We confirmed associations at three previously reported loci and identified additional loci in two other linkage disequilibrium blocks (rs1006908: per-allele OR = 0.87, P = 7.9 x 10(-8); rs620861: OR = 0.90, P = 4.8 x 10(-8)). Eight SNPs in five linkage disequilibrium blocks were independently associated with prostate cancer susceptibility.

Meta-analysis of loci associated with age at natural menopause in African-American women

PubMed Central

Chen, Christina T.L.; Liu, Ching-Ti; Chen, Gary K.; Andrews, Jeanette S.; Arnold, Alice M.; Dreyfus, Jill; Franceschini, Nora; Garcia, Melissa E.; Kerr, Kathleen F.; Li, Guo; Lohman, Kurt K.; Musani, Solomon K.; Nalls, Michael A.; Raffel, Leslie J.; Smith, Jennifer; Ambrosone, Christine B.; Bandera, Elisa V.; Bernstein, Leslie; Britton, Angela; Brzyski, Robert G.; Cappola, Anne; Carlson, Christopher S.; Couper, David; Deming, Sandra L.; Goodarzi, Mark O.; Heiss, Gerardo; John, Esther M.; Lu, Xiaoning; Le Marchand, Loic; Marciante, Kristin; Mcknight, Barbara; Millikan, Robert; Nock, Nora L.; Olshan, Andrew F.; Press, Michael F.; Vaiyda, Dhananjay; Woods, Nancy F.; Taylor, Herman A.; Zhao, Wei; Zheng, Wei; Evans, Michele K.; Harris, Tamara B.; Henderson, Brian E.; Kardia, Sharon L.R.; Kooperberg, Charles; Liu, Yongmei; Mosley, Thomas H.; Psaty, Bruce; Wellons, Melissa; Windham, Beverly G.; Zonderman, Alan B.; Cupples, L. Adrienne; Demerath, Ellen W.; Haiman, Christopher; Murabito, Joanne M.; Rajkovic, Aleksandar

2014-01-01

Age at menopause marks the end of a woman's reproductive life and its timing associates with risks for cancer, cardiovascular and bone disorders. GWAS and candidate gene studies conducted in women of European ancestry have identified 27 loci associated with age at menopause. The relevance of these loci to women of African ancestry has not been previously studied. We therefore sought to uncover additional menopause loci and investigate the relevance of European menopause loci by performing a GWAS meta-analysis in 6510 women with African ancestry derived from 11 studies across the USA. We did not identify any additional loci significantly associated with age at menopause in African Americans. We replicated the associations between six loci and age at menopause (P-value < 0.05): AMHR2, RHBLD2, PRIM1, HK3/UMC1, BRSK1/TMEM150B and MCM8. In addition, associations of 14 loci are directionally consistent with previous reports. We provide evidence that genetic variants influencing reproductive traits identified in European populations are also important in women of African ancestry residing in USA. PMID:24493794

High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry

PubMed Central

Sun, Celi; Molineros, Julio E.; Looger, Loren L.; Zhou, Xu-jie; Kim, Kwangwoo; Okada, Yukinori; Ma, Jianyang; Qi, Yuan-yuan; Kim-Howard, Xana; Motghare, Prasenjeet; Bhattarai, Krishna; Adler, Adam; Bang, So-Young; Lee, Hye-Soon; Kim, Tae-Hwan; Kang, Young Mo; Suh, Chang-Hee; Chung, Won Tae; Park, Yong-Beom; Choe, Jung-Yoon; Shim, Seung Cheol; Kochi, Yuta; Suzuki, Akari; Kubo, Michiaki; Sumida, Takayuki; Yamamoto, Kazuhiko; Lee, Shin-Seok; Kim, Young Jin; Han, Bok-Ghee; Dozmorov, Mikhail; Kaufman, Kenneth M.; Wren, Jonathan D.; Harley, John B.; Shen, Nan; Chua, Kek Heng; Zhang, Hong; Bae, Sang-Cheol; Nath, Swapan K.

2016-01-01

Systemic lupus erythematosus (SLE) has a strong but incompletely understood genetic architecture. We conducted an association study with replication in 4,492 SLE cases and 12,675 controls from six East-Asian cohorts, to identify novel and better localize known SLE susceptibility loci. We identified 10 novel loci as well as 20 known loci with genome-wide significance. Among the novel loci, the most significant was GTF2IRD1-GTF2I at 7q11.23 (rs73366469, Pmeta=3.75×10−117, OR=2.38), followed by DEF6, IL12B, TCF7, TERT, CD226, PCNXL3, RASGRP1, SYNGR1 and SIGLEC6. We localized the most likely functional variants for each locus by analyzing epigenetic marks and gene regulation data. Ten putative variants are known to alter cis- or trans-gene expression. Enrichment analysis highlights the importance of these loci in B- and T-cell biology. Together with previously known loci, the explained heritability of SLE increases to 24%. Novel loci share functional and ontological characteristics with previously reported loci, and are possible drug targets for SLE therapeutics. PMID:26808113

Genome-wide Analysis of Genetic Loci Associated with Alzheimer’s Disease

PubMed Central

Seshadri, Sudha; Fitzpatrick, Annette L.; Arfan Ikram, M; DeStefano, Anita L.; Gudnason, Vilmundur; Boada, Merce; Bis, Joshua C.; Smith, Albert V.; Carassquillo, Minerva M.; Charles Lambert, Jean; Harold, Denise; Schrijvers, Elisabeth M. C.; Ramirez-Lorca, Reposo; Debette, Stephanie; Longstreth, W.T.; Janssens, A. Cecile J.W.; Shane Pankratz, V.; Dartigues, Jean François; Hollingworth, Paul; Aspelund, Thor; Hernandez, Isabel; Beiser, Alexa; Kuller, Lewis H.; Koudstaal, Peter J.; Dickson, Dennis W.; Tzourio, Christophe; Abraham, Richard; Antunez, Carmen; Du, Yangchun; Rotter, Jerome I.; Aulchenko, Yurii S.; Harris, Tamara B.; Petersen, Ronald C.; Berr, Claudine; Owen, Michael J.; Lopez-Arrieta, Jesus; Varadarajan, Badri N.; Becker, James T.; Rivadeneira, Fernando; Nalls, Michael A.; Graff-Radford, Neill R.; Campion, Dominique; Auerbach, Sanford; Rice, Kenneth; Hofman, Albert; Jonsson, Palmi V.; Schmidt, Helena; Lathrop, Mark; Mosley, Thomas H.; Au, Rhoda; Psaty, Bruce M.; Uitterlinden, Andre G.; Farrer, Lindsay A.; Lumley, Thomas; Ruiz, Agustin; Williams, Julie; Amouyel, Philippe; Younkin, Steve G.; Wolf, Philip A.; Launer, Lenore J.; Lopez, Oscar L.; van Duijn, Cornelia M.; Breteler, Monique M. B.

2010-01-01

Context Genome wide association studies (GWAS) have recently identified CLU, PICALM and CR1 as novel genes for late-onset Alzheimer’s disease (AD). Objective In a three-stage analysis of new and previously published GWAS on over 35000 persons (8371 AD cases), we sought to identify and strengthen additional loci associated with AD and confirm these in an independent sample. We also examined the contribution of recently identified genes to AD risk prediction. Design, Setting, and Participants We identified strong genetic associations (p<10−3) in a Stage 1 sample of 3006 AD cases and 14642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (1367 AD cases (973 incident)) with previously reported results from the Translational Genomics Research Institute (TGEN) and Mayo AD GWAS. We identified 2708 single nucleotide polymorphisms (SNPs) with p-values<10−3, and in Stage 2 pooled results for these SNPs with the European AD Initiative (2032 cases, 5328 controls) to identify ten loci with p-values<10−5. In Stage 3, we combined data for these ten loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases, 6995 controls) to identify four SNPs with a p-value<1.7×10−8. These four SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls). Main outcome measure Alzheimer’s Disease. Results We showed genome-wide significance for two new loci: rs744373 near BIN1 (OR:1.13; 95%CI:1.06–1.21 per copy of the minor allele; p=1.6×10−11) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (OR:1.18; 95%CI1.07–1.29; p=6.5×10−9). Associations of CLU, PICALM, BIN1 and EXOC3L2 with AD were confirmed in the Spanish sample (p<0.05). However, CLU and PICALM did not improve incident AD prediction beyond age, sex, and APOE (improvement in area under receiver-operating-characteristic curve <0.003). Conclusions Two novel genetic loci for AD are reported that for the first time reach genome-wide statistical significance; these findings were replicated in an independent population. Two recently reported associations were also confirmed, but these loci did not improve AD risk prediction, although they implicate biological pathways that may be useful targets for potential interventions. PMID:20460622

Genetics of Paget's disease of bone

PubMed Central

Albagha, Omar ME

2015-01-01

Paget's disease of bone (PDB) is a common metabolic bone disease characterised by focal areas of increased bone turnover, which primarily affects people over the age of 55 years. Genetic factors have a fundamental role in the pathogenesis of PDB and are probably the main predisposing factor for the disease. The genetic contribution to PDB susceptibility ranges from rare pathogenic mutations in the single gene SQSTM1 to more common, small effect variants in at least seven genetic loci that predispose to the disease. These loci have additive effects on disease susceptibility and interact with SQSTM1 mutations to affect disease severity, making them a potentially useful tool in predicting disease risk and complication and in managing treatments. Many of these loci harbour genes that have important function in osteoclast differentiation such as CSF1, DCSTAMP and TNFRSF11A. Other susceptibility loci have highlighted new molecular pathways that have not been previously implicated in regulation of bone metabolism such as OPTN, which was recently found to negatively regulate osteoclast differentiation. PDB-susceptibility variants exert their effect either by affecting the protein coding sequence such as variants found in SQSTM1 and RIN3 or by influencing gene expression such as those found in OPTN and DCSTAMP. Epidemiological studies indicate that environmental triggers also have a key role in PDB and interact with genetic factors to influence manifestation and severity of the disease; however, further studies are needed to identify these triggers. PMID:26587225

Six Novel Loci Associated with Circulating VEGF Levels Identified by a Meta-analysis of Genome-Wide Association Studies

PubMed Central

Song, Ci; Nutile, Teresa; Vernon Smith, Albert; Concas, Maria Pina; Traglia, Michela; Barbieri, Caterina; Ndiaye, Ndeye Coumba; Stathopoulou, Maria G.; Lagou, Vasiliki; Maestrale, Giovanni Battista; Sala, Cinzia; Debette, Stephanie; Kovacs, Peter; Lind, Lars; Lamont, John; Fitzgerald, Peter; Tönjes, Anke; Gudnason, Vilmundur; Toniolo, Daniela; Pirastu, Mario; Bellenguez, Celine; Vasan, Ramachandran S.; Ingelsson, Erik; Leutenegger, Anne-Louise; Johnson, Andrew D.; DeStefano, Anita L.; Visvikis-Siest, Sophie; Seshadri, Sudha; Ciullo, Marina

2016-01-01

Vascular endothelial growth factor (VEGF) is an angiogenic and neurotrophic factor, secreted by endothelial cells, known to impact various physiological and disease processes from cancer to cardiovascular disease and to be pharmacologically modifiable. We sought to identify novel loci associated with circulating VEGF levels through a genome-wide association meta-analysis combining data from European-ancestry individuals and using a dense variant map from 1000 genomes imputation panel. Six discovery cohorts including 13,312 samples were analyzed, followed by in-silico and de-novo replication studies including an additional 2,800 individuals. A total of 10 genome-wide significant variants were identified at 7 loci. Four were novel loci (5q14.3, 10q21.3, 16q24.2 and 18q22.3) and the leading variants at these loci were rs114694170 (MEF2C, P = 6.79x10-13), rs74506613 (JMJD1C, P = 1.17x10-19), rs4782371 (ZFPM1, P = 1.59x10-9) and rs2639990 (ZADH2, P = 1.72x10-8), respectively. We also identified two new independent variants (rs34528081, VEGFA, P = 1.52x10-18; rs7043199, VLDLR-AS1, P = 5.12x10-14) at the 3 previously identified loci and strengthened the evidence for the four previously identified SNPs (rs6921438, LOC100132354, P = 7.39x10-1467; rs1740073, C6orf223, P = 2.34x10-17; rs6993770, ZFPM2, P = 2.44x10-60; rs2375981, KCNV2, P = 1.48x10-100). These variants collectively explained up to 52% of the VEGF phenotypic variance. We explored biological links between genes in the associated loci using Ingenuity Pathway Analysis that emphasized their roles in embryonic development and function. Gene set enrichment analysis identified the ERK5 pathway as enriched in genes containing VEGF associated variants. eQTL analysis showed, in three of the identified regions, variants acting as both cis and trans eQTLs for multiple genes. Most of these genes, as well as some of those in the associated loci, were involved in platelet biogenesis and functionality, suggesting the importance of this process in regulation of VEGF levels. This work also provided new insights into the involvement of genes implicated in various angiogenesis related pathologies in determining circulating VEGF levels. The understanding of the molecular mechanisms by which the identified genes affect circulating VEGF levels could be important in the development of novel VEGF-related therapies for such diseases. PMID:26910538

Identification of two novel mammographic density loci at 6Q25.1.

PubMed

Brand, Judith S; Li, Jingmei; Humphreys, Keith; Karlsson, Robert; Eriksson, Mikael; Ivansson, Emma; Hall, Per; Czene, Kamila

2015-06-03

Mammographic density (MD) is a strong heritable and intermediate phenotype for breast cancer, but much of its genetic variation remains unexplained. We performed a large-scale genetic association study including 8,419 women of European ancestry to identify MD loci. Participants of three Swedish studies were genotyped on a custom Illumina iSelect genotyping array and percent and absolute mammographic density were ascertained using semiautomated and fully automated methods from film and digital mammograms. Linear regression analysis was used to test for SNP-MD associations, adjusting for age, body mass index, menopausal status and six principal components. Meta-analyses were performed by combining P values taking sample size, study-specific inflation factor and direction of effect into account. Genome-wide significant associations were observed for two previously identified loci: ZNF365 (rs10995194, P = 2.3 × 10(-8) for percent MD and P = 8.7 × 10(-9) for absolute MD) and AREG (rs10034692, P = 6.7 × 10(-9) for absolute MD). In addition, we found evidence of association for two variants at 6q25.1, both of which are known breast cancer susceptibility loci: rs9485370 in the TAB2 gene (P = 4.8 × 10(-9) for percent MD and P = 2.5 × 10(-8) for absolute MD) and rs60705924 in the CCDC170/ESR1 region (P = 2.2 × 10(-8) for absolute MD). Both regions have been implicated in estrogen receptor signaling with TAB2 being a potential regulator of tamoxifen response. We identified two novel MD loci at 6q25.1. These findings underscore the importance of 6q25.1 as a susceptibility region and provide more insight into the mechanisms through which MD influences breast cancer risk.

Genetic susceptibility for Alzheimer disease neuritic plaque pathology.

PubMed

Shulman, Joshua M; Chen, Kewei; Keenan, Brendan T; Chibnik, Lori B; Fleisher, Adam; Thiyyagura, Pradeep; Roontiva, Auttawut; McCabe, Cristin; Patsopoulos, Nikolaos A; Corneveaux, Jason J; Yu, Lei; Huentelman, Matthew J; Evans, Denis A; Schneider, Julie A; Reiman, Eric M; De Jager, Philip L; Bennett, David A

2013-09-01

While numerous genetic susceptibility loci have been identified for clinical Alzheimer disease (AD), it is important to establish whether these variants are risk factors for the underlying disease pathology, including neuritic plaques. To investigate whether AD susceptibility loci from genome-wide association studies affect neuritic plaque pathology and to additionally identify novel risk loci for this trait. Candidate analysis of single-nucleotide polymorphisms and genome-wide association study in a joint clinicopathologic cohort, including 725 deceased subjects from the Religious Orders Study and the Rush Memory and Aging Project (2 prospective, community-based studies), followed by targeted validation in an independent neuroimaging cohort, including 114 subjects from multiple clinical and research centers. A quantitative measure of neuritic plaque pathologic burden, based on assessments of silver-stained tissue averaged from multiple brain regions. Validation based on β-amyloid load by immunocytochemistry, and replication with fibrillar β-amyloid positron emission tomographic imaging with Pittsburgh Compound B or florbetapir. Besides the previously reported APOE and CR1 loci, we found that the ABCA7 (rs3764650; P = .02) and CD2AP (rs9349407; P = .03) AD susceptibility loci are associated with neuritic plaque burden. In addition, among the top results of our genome-wide association study, we discovered a novel variant near the amyloid precursor protein gene (APP, rs2829887) that is associated with neuritic plaques (P = 3.3 × 10-6). This polymorphism was associated with postmortem β-amyloid load as well as fibrillar β-amyloid in 2 independent cohorts of adults with normal cognition. These findings enhance understanding of AD risk factors by relating validated susceptibility alleles to increased neuritic plaque pathology and implicate common genetic variation at the APP locus in the earliest, presymptomatic stages of AD.

Fine-mapping diabetes-related traits, including insulin resistance, in heterogeneous stock rats

PubMed Central

Holl, Katie L.; Oreper, Daniel; Xie, Yuying; Tsaih, Shirng-Wern; Valdar, William

2012-01-01

Type 2 diabetes (T2D) is a disease of relative insulin deficiency resulting from both insulin resistance and beta cell failure. We have previously used heterogeneous stock (HS) rats to fine-map a locus for glucose tolerance. We show here that glucose intolerance in the founder strains of the HS colony is mediated by different mechanisms: insulin resistance in WKY and an insulin secretion defect in ACI, and we demonstrate a high degree of variability for measures of insulin resistance and insulin secretion in HS rats. As such, our goal was to use HS rats to fine-map several diabetes-related traits within a region on rat chromosome 1. We measured blood glucose and plasma insulin levels after a glucose tolerance test in 782 male HS rats. Using 97 SSLP markers, we genotyped a 68 Mb region on rat chromosome 1 previously implicated in glucose and insulin regulation. We used linkage disequilibrium mapping by mixed model regression with inferred descent to identify a region from 198.85 to 205.9 that contains one or more quantitative trait loci (QTL) for fasting insulin and a measure of insulin resistance, the quantitative insulin sensitivity check index. This region also encompasses loci identified for fasting glucose and Insulin_AUC (area under the curve). A separate <3 Mb QTL was identified for body weight. Using a novel penalized regression method we then estimated effects of alternative haplotype pairings under each locus. These studies highlight the utility of HS rats for fine-mapping genetic loci involved in the underlying causes of T2D. PMID:22947656

Hundreds of variants clustered in genomic loci and biological pathways affect human height

PubMed Central

Lango Allen, Hana; Estrada, Karol; Lettre, Guillaume; Berndt, Sonja I.; Weedon, Michael N.; Rivadeneira, Fernando; Willer, Cristen J.; Jackson, Anne U.; Vedantam, Sailaja; Raychaudhuri, Soumya; Ferreira, Teresa; Wood, Andrew R.; Weyant, Robert J.; Segrè, Ayellet V.; Speliotes, Elizabeth K.; Wheeler, Eleanor; Soranzo, Nicole; Park, Ju-Hyun; Yang, Jian; Gudbjartsson, Daniel; Heard-Costa, Nancy L.; Randall, Joshua C.; Qi, Lu; Smith, Albert Vernon; Mägi, Reedik; Pastinen, Tomi; Liang, Liming; Heid, Iris M.; Luan, Jian'an; Thorleifsson, Gudmar; Winkler, Thomas W.; Goddard, Michael E.; Lo, Ken Sin; Palmer, Cameron; Workalemahu, Tsegaselassie; Aulchenko, Yurii S.; Johansson, Åsa; Zillikens, M.Carola; Feitosa, Mary F.; Esko, Tõnu; Johnson, Toby; Ketkar, Shamika; Kraft, Peter; Mangino, Massimo; Prokopenko, Inga; Absher, Devin; Albrecht, Eva; Ernst, Florian; Glazer, Nicole L.; Hayward, Caroline; Hottenga, Jouke-Jan; Jacobs, Kevin B.; Knowles, Joshua W.; Kutalik, Zoltán; Monda, Keri L.; Polasek, Ozren; Preuss, Michael; Rayner, Nigel W.; Robertson, Neil R.; Steinthorsdottir, Valgerdur; Tyrer, Jonathan P.; Voight, Benjamin F.; Wiklund, Fredrik; Xu, Jianfeng; Zhao, Jing Hua; Nyholt, Dale R.; Pellikka, Niina; Perola, Markus; Perry, John R.B.; Surakka, Ida; Tammesoo, Mari-Liis; Altmaier, Elizabeth L.; Amin, Najaf; Aspelund, Thor; Bhangale, Tushar; Boucher, Gabrielle; Chasman, Daniel I.; Chen, Constance; Coin, Lachlan; Cooper, Matthew N.; Dixon, Anna L.; Gibson, Quince; Grundberg, Elin; Hao, Ke; Junttila, M. Juhani; Kaplan, Lee M.; Kettunen, Johannes; König, Inke R.; Kwan, Tony; Lawrence, Robert W.; Levinson, Douglas F.; Lorentzon, Mattias; McKnight, Barbara; Morris, Andrew P.; Müller, Martina; Ngwa, Julius Suh; Purcell, Shaun; Rafelt, Suzanne; Salem, Rany M.; Salvi, Erika; Sanna, Serena; Shi, Jianxin; Sovio, Ulla; Thompson, John R.; Turchin, Michael C.; Vandenput, Liesbeth; Verlaan, Dominique J.; Vitart, Veronique; White, Charles C.; Ziegler, Andreas; Almgren, Peter; Balmforth, Anthony J.; Campbell, Harry; Citterio, Lorena; De Grandi, Alessandro; Dominiczak, Anna; Duan, Jubao; Elliott, Paul; Elosua, Roberto; Eriksson, Johan G.; Freimer, Nelson B.; Geus, Eco J.C.; Glorioso, Nicola; Haiqing, Shen; Hartikainen, Anna-Liisa; Havulinna, Aki S.; Hicks, Andrew A.; Hui, Jennie; Igl, Wilmar; Illig, Thomas; Jula, Antti; Kajantie, Eero; Kilpeläinen, Tuomas O.; Koiranen, Markku; Kolcic, Ivana; Koskinen, Seppo; Kovacs, Peter; Laitinen, Jaana; Liu, Jianjun; Lokki, Marja-Liisa; Marusic, Ana; Maschio, Andrea; Meitinger, Thomas; Mulas, Antonella; Paré, Guillaume; Parker, Alex N.; Peden, John F.; Petersmann, Astrid; Pichler, Irene; Pietiläinen, Kirsi H.; Pouta, Anneli; Ridderstråle, Martin; Rotter, Jerome I.; Sambrook, Jennifer G.; Sanders, Alan R.; Schmidt, Carsten Oliver; Sinisalo, Juha; Smit, Jan H.; Stringham, Heather M.; Walters, G.Bragi; Widen, Elisabeth; Wild, Sarah H.; Willemsen, Gonneke; Zagato, Laura; Zgaga, Lina; Zitting, Paavo; Alavere, Helene; Farrall, Martin; McArdle, Wendy L.; Nelis, Mari; Peters, Marjolein J.; Ripatti, Samuli; van Meurs, Joyce B.J.; Aben, Katja K.; Ardlie, Kristin G; Beckmann, Jacques S.; Beilby, John P.; Bergman, Richard N.; Bergmann, Sven; Collins, Francis S.; Cusi, Daniele; den Heijer, Martin; Eiriksdottir, Gudny; Gejman, Pablo V.; Hall, Alistair S.; Hamsten, Anders; Huikuri, Heikki V.; Iribarren, Carlos; Kähönen, Mika; Kaprio, Jaakko; Kathiresan, Sekar; Kiemeney, Lambertus; Kocher, Thomas; Launer, Lenore J.; Lehtimäki, Terho; Melander, Olle; Mosley, Tom H.; Musk, Arthur W.; Nieminen, Markku S.; O'Donnell, Christopher J.; Ohlsson, Claes; Oostra, Ben; Palmer, Lyle J.; Raitakari, Olli; Ridker, Paul M.; Rioux, John D.; Rissanen, Aila; Rivolta, Carlo; Schunkert, Heribert; Shuldiner, Alan R.; Siscovick, David S.; Stumvoll, Michael; Tönjes, Anke; Tuomilehto, Jaakko; van Ommen, Gert-Jan; Viikari, Jorma; Heath, Andrew C.; Martin, Nicholas G.; Montgomery, Grant W.; Province, Michael A.; Kayser, Manfred; Arnold, Alice M.; Atwood, Larry D.; Boerwinkle, Eric; Chanock, Stephen J.; Deloukas, Panos; Gieger, Christian; Grönberg, Henrik; Hall, Per; Hattersley, Andrew T.; Hengstenberg, Christian; Hoffman, Wolfgang; Lathrop, G.Mark; Salomaa, Veikko; Schreiber, Stefan; Uda, Manuela; Waterworth, Dawn; Wright, Alan F.; Assimes, Themistocles L.; Barroso, Inês; Hofman, Albert; Mohlke, Karen L.; Boomsma, Dorret I.; Caulfield, Mark J.; Cupples, L.Adrienne; Erdmann, Jeanette; Fox, Caroline S.; Gudnason, Vilmundur; Gyllensten, Ulf; Harris, Tamara B.; Hayes, Richard B.; Jarvelin, Marjo-Riitta; Mooser, Vincent; Munroe, Patricia B.; Ouwehand, Willem H.; Penninx, Brenda W.; Pramstaller, Peter P.; Quertermous, Thomas; Rudan, Igor; Samani, Nilesh J.; Spector, Timothy D.; Völzke, Henry; Watkins, Hugh; Wilson, James F.; Groop, Leif C.; Haritunians, Talin; Hu, Frank B.; Kaplan, Robert C.; Metspalu, Andres; North, Kari E.; Schlessinger, David; Wareham, Nicholas J.; Hunter, David J.; O'Connell, Jeffrey R.; Strachan, David P.; Wichmann, H.-Erich; Borecki, Ingrid B.; van Duijn, Cornelia M.; Schadt, Eric E.; Thorsteinsdottir, Unnur; Peltonen, Leena; Uitterlinden, André; Visscher, Peter M.; Chatterjee, Nilanjan; Loos, Ruth J.F.; Boehnke, Michael; McCarthy, Mark I.; Ingelsson, Erik; Lindgren, Cecilia M.; Abecasis, Gonçalo R.; Stefansson, Kari; Frayling, Timothy M.; Hirschhorn, Joel N

2010-01-01

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence phenotype. Genome-wide association (GWA) studies have identified >600 variants associated with human traits1, but these typically explain small fractions of phenotypic variation, raising questions about the utility of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait2,3. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P=0.016), and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants, and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented amongst variants that alter amino acid structure of proteins and expression levels of nearby genes. Our data explain ∼10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to ∼16% of phenotypic variation (∼20% of heritable variation). Although additional approaches are needed to fully dissect the genetic architecture of polygenic human traits, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways. PMID:20881960

DNA Methylation in Osteoarthritis: Current Status and Therapeutic Implications

PubMed Central

Miranda-Duarte, Antonio

2018-01-01

Background: Primary Osteoarthritis (OA) is a multifactorial disease in which genetic factors are strongly associated with its development; however, recently it has been observed that epigenetic modifications are also involved in the pathogenesis of OA. DNA methylation is related to gene silencing, and several studies have investigated its role in the loci of different pathways or molecules associated to OA. Objective: This review is focused on the current status of DNA methylation studies related to OA pathogenesis. Method: A review of the literature was conducted on searching in PUBMED for original papers on DNA methylation in OA. Conclusion: The DNA methylation research of loci related to OA pathogenesis has shown a correlation between methylation and gene repression; however, there are some exceptions to this rule. Recently, the development of genome-wide methylation and genome-wide hydroxymethylation profiles has demonstrated that several genes previously associated with OA can have changes in their methylation status, favoring the development of the disease, and these have even shown the role of other epigenetic markers. PMID:29682093

Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits.

PubMed

Teumer, Alexander; Qi, Qibin; Nethander, Maria; Aschard, Hugues; Bandinelli, Stefania; Beekman, Marian; Berndt, Sonja I; Bidlingmaier, Martin; Broer, Linda; Cappola, Anne; Ceda, Gian Paolo; Chanock, Stephen; Chen, Ming-Huei; Chen, Tai C; Chen, Yii-Der Ida; Chung, Jonathan; Del Greco Miglianico, Fabiola; Eriksson, Joel; Ferrucci, Luigi; Friedrich, Nele; Gnewuch, Carsten; Goodarzi, Mark O; Grarup, Niels; Guo, Tingwei; Hammer, Elke; Hayes, Richard B; Hicks, Andrew A; Hofman, Albert; Houwing-Duistermaat, Jeanine J; Hu, Frank; Hunter, David J; Husemoen, Lise L; Isaacs, Aaron; Jacobs, Kevin B; Janssen, Joop A M J L; Jansson, John-Olov; Jehmlich, Nico; Johnson, Simon; Juul, Anders; Karlsson, Magnus; Kilpelainen, Tuomas O; Kovacs, Peter; Kraft, Peter; Li, Chao; Linneberg, Allan; Liu, Yongmei; Loos, Ruth J F; Lorentzon, Mattias; Lu, Yingchang; Maggio, Marcello; Magi, Reedik; Meigs, James; Mellström, Dan; Nauck, Matthias; Newman, Anne B; Pollak, Michael N; Pramstaller, Peter P; Prokopenko, Inga; Psaty, Bruce M; Reincke, Martin; Rimm, Eric B; Rotter, Jerome I; Saint Pierre, Aude; Schurmann, Claudia; Seshadri, Sudha; Sjögren, Klara; Slagboom, P Eline; Strickler, Howard D; Stumvoll, Michael; Suh, Yousin; Sun, Qi; Zhang, Cuilin; Svensson, Johan; Tanaka, Toshiko; Tare, Archana; Tönjes, Anke; Uh, Hae-Won; van Duijn, Cornelia M; van Heemst, Diana; Vandenput, Liesbeth; Vasan, Ramachandran S; Völker, Uwe; Willems, Sara M; Ohlsson, Claes; Wallaschofski, Henri; Kaplan, Robert C

2016-10-01

The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype-phenotype associations between men and women, were found only for associations of IGFBP-3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity-associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF-I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF-I- and IGFBP-3-associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF-I and IGFBP-3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity-associated loci. © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Meta-analysis of loci associated with age at natural menopause in African-American women.

PubMed

Chen, Christina T L; Liu, Ching-Ti; Chen, Gary K; Andrews, Jeanette S; Arnold, Alice M; Dreyfus, Jill; Franceschini, Nora; Garcia, Melissa E; Kerr, Kathleen F; Li, Guo; Lohman, Kurt K; Musani, Solomon K; Nalls, Michael A; Raffel, Leslie J; Smith, Jennifer; Ambrosone, Christine B; Bandera, Elisa V; Bernstein, Leslie; Britton, Angela; Brzyski, Robert G; Cappola, Anne; Carlson, Christopher S; Couper, David; Deming, Sandra L; Goodarzi, Mark O; Heiss, Gerardo; John, Esther M; Lu, Xiaoning; Le Marchand, Loic; Marciante, Kristin; Mcknight, Barbara; Millikan, Robert; Nock, Nora L; Olshan, Andrew F; Press, Michael F; Vaiyda, Dhananjay; Woods, Nancy F; Taylor, Herman A; Zhao, Wei; Zheng, Wei; Evans, Michele K; Harris, Tamara B; Henderson, Brian E; Kardia, Sharon L R; Kooperberg, Charles; Liu, Yongmei; Mosley, Thomas H; Psaty, Bruce; Wellons, Melissa; Windham, Beverly G; Zonderman, Alan B; Cupples, L Adrienne; Demerath, Ellen W; Haiman, Christopher; Murabito, Joanne M; Rajkovic, Aleksandar

2014-06-15

Age at menopause marks the end of a woman's reproductive life and its timing associates with risks for cancer, cardiovascular and bone disorders. GWAS and candidate gene studies conducted in women of European ancestry have identified 27 loci associated with age at menopause. The relevance of these loci to women of African ancestry has not been previously studied. We therefore sought to uncover additional menopause loci and investigate the relevance of European menopause loci by performing a GWAS meta-analysis in 6510 women with African ancestry derived from 11 studies across the USA. We did not identify any additional loci significantly associated with age at menopause in African Americans. We replicated the associations between six loci and age at menopause (P-value < 0.05): AMHR2, RHBLD2, PRIM1, HK3/UMC1, BRSK1/TMEM150B and MCM8. In addition, associations of 14 loci are directionally consistent with previous reports. We provide evidence that genetic variants influencing reproductive traits identified in European populations are also important in women of African ancestry residing in USA. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Replication of british rheumatoid arthritis susceptibility Loci in two unrelated chinese population groups.

PubMed

Li, Hua; Hu, Yonghe; Zhang, Tao; Liu, Yang; Wang, Yantang; Yang, Tai; Li, Minhui; Luo, Qiaoli; Cheng, Yu; Zou, Qiang

2013-01-01

Previous genome-wide association study by WTCCC identified many susceptibility loci of common autoimmune diseases in British, including rheumatoid arthritis (RA). Because of the genetic heterogeneity of RA, it is necessary to replicate these susceptibility loci in other populations. Here, three SNPs with strong RA association signal in the British were analyzed in Han Chinese, and two SNPs (rs6457617 and rs11761231) were genotyped in the test cohort firstly. The rs6457617 was significantly associated with RA in the test cohort. The individuals bearing the homozygous genotype CC had 0.39-fold risk than these bearing the wild-type genotype TT (P = 0.004, OR 0.39, [95% CI 0.21-0.74]). And the protective effect of allele C was confirmed in another validation cohort with 1514 samples (P genotye CC/TT = 5.9 ×  10(-10), OR 0.34, [95% CI 0.24-0.48]). The rs6457617 can be used as a tagSNP of HLA-DQA1∗03 which encoded MHC-II α chain. Since MHC restriction is important for primary T-cells in positive selection and negative selection stages, MHC protein polymorphisms may be implicated in shaping the T-cell repertoire, including the emergence of a T-cell clone involved in the inflammatory arthritis.

Lack of replication of higher genetic risk load in men than in women with systemic lupus erythematosus.

PubMed

Alonso-Perez, Elisa; Suarez-Gestal, Marian; Calaza, Manuel; Blanco, Francisco J; Suarez, Ana; Santos, Maria Jose; Papasteriades, Chryssa; Carreira, Patricia; Pullmann, Rudolf; Ordi-Ros, Josep; Marchini, Maurizio; Skopouli, Fotini N; Bijl, Marc; Barrizone, Nadia; Sebastiani, Gian Domenico; Migliaresi, Sergio; Witte, Torsten; Lauwerys, Bernard R; Kovacs, Attila; Ruzickova, Sarka; Gomez-Reino, Juan J; Gonzalez, Antonio

2014-06-19

We aimed to replicate a recent study which showed higher genetic risk load at 15 loci in men than in women with systemic lupus erythematosus (SLE). This difference was very significant, and it was interpreted as indicating that men require more genetic susceptibility than women to develop SLE. Nineteen SLE-associated loci (thirteen of which are shared with the previous study) were analyzed in 1,457 SLE patients and 1,728 healthy controls of European ancestry. Genetic risk load was calculated as sex-specific sum genetic risk scores (GRS(s)). Our results did not replicate those of the previous study at either the level of individual loci or the global level of GRS(s). GRS(s) were larger in women than in men (4.20 ± 1.07 in women vs. 3.27 ± 0.98 in men). This very significant difference (P < 10(-16)) was more dependent on the six new loci not included in the previous study (59% of the difference) than on the thirteen loci that are shared (the remaining 41%). However, the 13 shared loci also showed a higher genetic risk load in women than in men in our study (P = 6.6 × 10(-7)), suggesting that heterogeneity of participants, in addition to different loci, contributed to the opposite results. Our results show the lack of a clear trend toward higher genetic risk in one of the sexes for the analyzed SLE loci. They also highlight several limitations of assessments of genetic risk load, including the possibility of ascertainment bias with loci discovered in studies that have included mainly women.

Lack of replication of higher genetic risk load in men than in women with systemic lupus erythematosus

PubMed Central

2014-01-01

Introduction We aimed to replicate a recent study which showed higher genetic risk load at 15 loci in men than in women with systemic lupus erythematosus (SLE). This difference was very significant, and it was interpreted as indicating that men require more genetic susceptibility than women to develop SLE. Methods Nineteen SLE-associated loci (thirteen of which are shared with the previous study) were analyzed in 1,457 SLE patients and 1,728 healthy controls of European ancestry. Genetic risk load was calculated as sex-specific sum genetic risk scores (GRSs). Results Our results did not replicate those of the previous study at either the level of individual loci or the global level of GRSs. GRSs were larger in women than in men (4.20 ± 1.07 in women vs. 3.27 ± 0.98 in men). This very significant difference (P < 10−16) was more dependent on the six new loci not included in the previous study (59% of the difference) than on the thirteen loci that are shared (the remaining 41%). However, the 13 shared loci also showed a higher genetic risk load in women than in men in our study (P = 6.6 × 10−7), suggesting that heterogeneity of participants, in addition to different loci, contributed to the opposite results. Conclusion Our results show the lack of a clear trend toward higher genetic risk in one of the sexes for the analyzed SLE loci. They also highlight several limitations of assessments of genetic risk load, including the possibility of ascertainment bias with loci discovered in studies that have included mainly women. PMID:24946689

Association Analysis of the Extended MHC Region in Celiac Disease Implicates Multiple Independent Susceptibility Loci

PubMed Central

Ahn, Richard; Ding, Yuan Chun; Murray, Joseph; Fasano, Alessio; Green, Peter H. R.; Neuhausen, Susan L.; Garner, Chad

2012-01-01

Celiac disease is a common autoimmune disease caused by sensitivity to the dietary protein gluten. Forty loci have been implicated in the disease. All disease loci have been characterized as low-penetrance, with the exception of the high-risk genotypes in the HLA-DQA1 and HLA-DQB1 genes, which are necessary but not sufficient to cause the disease. The very strong effects from the known HLA loci and the genetically complex nature of the major histocompatibility complex (MHC) have precluded a thorough investigation of the region. The purpose of this study was to test the hypothesis that additional celiac disease loci exist within the extended MHC (xMHC). A set of 1898 SNPs was analyzed for association across the 7.6 Mb xMHC region in 1668 confirmed celiac disease cases and 517 unaffected controls. Conditional recursive partitioning was used to create an informative indicator of the known HLA-DQA1 and HLA-DQB1 high-risk genotypes that was included in the association analysis to account for their effects. A linkage disequilibrium-based grouping procedure was utilized to estimate the number of independent celiac disease loci present in the xMHC after accounting for the known effects. There was significant statistical evidence for four new independent celiac disease loci within the classic MHC region. This study is the first comprehensive association analysis of the xMHC in celiac disease that specifically accounts for the known HLA disease genotypes and the genetic complexity of the region. PMID:22615847

Genome-wide association analyses identify 18 new loci associated with serum urate concentrations

PubMed Central

Köttgen, Anna; Albrecht, Eva; Teumer, Alexander; Vitart, Veronique; Krumsiek, Jan; Hundertmark, Claudia; Pistis, Giorgio; Ruggiero, Daniela; O’Seaghdha, Conall M; Haller, Toomas; Yang, Qiong; Tanaka, Toshiko; Johnson, Andrew D; Kutalik, Zoltán; Smith, Albert V; Shi, Julia; Struchalin, Maksim; Middelberg, Rita P S; Brown, Morris J; Gaffo, Angelo L; Pirastu, Nicola; Li, Guo; Hayward, Caroline; Zemunik, Tatijana; Huffman, Jennifer; Yengo, Loic; Zhao, Jing Hua; Demirkan, Ayse; Feitosa, Mary F; Liu, Xuan; Malerba, Giovanni; Lopez, Lorna M; van der Harst, Pim; Li, Xinzhong; Kleber, Marcus E; Hicks, Andrew A; Nolte, Ilja M; Johansson, Asa; Murgia, Federico; Wild, Sarah H; Bakker, Stephan J L; Peden, John F; Dehghan, Abbas; Steri, Maristella; Tenesa, Albert; Lagou, Vasiliki; Salo, Perttu; Mangino, Massimo; Rose, Lynda M; Lehtimäki, Terho; Woodward, Owen M; Okada, Yukinori; Tin, Adrienne; Müller, Christian; Oldmeadow, Christopher; Putku, Margus; Czamara, Darina; Kraft, Peter; Frogheri, Laura; Thun, Gian Andri; Grotevendt, Anne; Gislason, Gauti Kjartan; Harris, Tamara B; Launer, Lenore J; McArdle, Patrick; Shuldiner, Alan R; Boerwinkle, Eric; Coresh, Josef; Schmidt, Helena; Schallert, Michael; Martin, Nicholas G; Montgomery, Grant W; Kubo, Michiaki; Nakamura, Yusuke; Tanaka, Toshihiro; Munroe, Patricia B; Samani, Nilesh J; Jacobs, David R; Liu, Kiang; D’Adamo, Pio; Ulivi, Sheila; Rotter, Jerome I; Psaty, Bruce M; Vollenweider, Peter; Waeber, Gerard; Campbell, Susan; Devuyst, Olivier; Navarro, Pau; Kolcic, Ivana; Hastie, Nicholas; Balkau, Beverley; Froguel, Philippe; Esko, Tõnu; Salumets, Andres; Khaw, Kay Tee; Langenberg, Claudia; Wareham, Nicholas J; Isaacs, Aaron; Kraja, Aldi; Zhang, Qunyuan; Wild, Philipp S; Scott, Rodney J; Holliday, Elizabeth G; Org, Elin; Viigimaa, Margus; Bandinelli, Stefania; Metter, Jeffrey E; Lupo, Antonio; Trabetti, Elisabetta; Sorice, Rossella; Döring, Angela; Lattka, Eva; Strauch, Konstantin; Theis, Fabian; Waldenberger, Melanie; Wichmann, H-Erich; Davies, Gail; Gow, Alan J; Bruinenberg, Marcel; Study, LifeLines Cohort; Stolk, Ronald P; Kooner, Jaspal S; Zhang, Weihua; Winkelmann, Bernhard R; Boehm, Bernhard O; Lucae, Susanne; Penninx, Brenda W; Smit, Johannes H; Curhan, Gary; Mudgal, Poorva; Plenge, Robert M; Portas, Laura; Persico, Ivana; Kirin, Mirna; Wilson, James F; Leach, Irene Mateo; van Gilst, Wiek H; Goel, Anuj; Ongen, Halit; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G; Imboden, Medea; von Eckardstein, Arnold; Cucca, Francesco; Nagaraja, Ramaiah; Piras, Maria Grazia; Nauck, Matthias; Schurmann, Claudia; Budde, Kathrin; Ernst, Florian; Farrington, Susan M; Theodoratou, Evropi; Prokopenko, Inga; Stumvoll, Michael; Jula, Antti; Perola, Markus; Salomaa, Veikko; Shin, So-Youn; Spector, Tim D; Sala, Cinzia; Ridker, Paul M; Kähönen, Mika; Viikari, Jorma; Hengstenberg, Christian; Nelson, Christopher P; Consortium, CARDIoGRAM; Consortium, DIAGRAM; Consortium, ICBP; Consortium, MAGIC; Meschia, James F; Nalls, Michael A; Sharma, Pankaj; Singleton, Andrew B; Kamatani, Naoyuki; Zeller, Tanja; Burnier, Michel; Attia, John; Laan, Maris; Klopp, Norman; Hillege, Hans L; Kloiber, Stefan; Choi, Hyon; Pirastu, Mario; Tore, Silvia; Probst-Hensch, Nicole M; Völzke, Henry; Gudnason, Vilmundur; Parsa, Afshin; Schmidt, Reinhold; Whitfield, John B; Fornage, Myriam; Gasparini, Paolo; Siscovick, David S; Polašek, Ozren; Campbell, Harry; Rudan, Igor; Bouatia-Naji, Nabila; Metspalu, Andres; Loos, Ruth J F; van Duijn, Cornelia M; Borecki, Ingrid B; Ferrucci, Luigi; Gambaro, Giovanni; Deary, Ian J; Wolffenbuttel, Bruce H R; Chambers, John C; März, Winfried; Pramstaller, Peter P; Snieder, Harold; Gyllensten, Ulf; Wright, Alan F; Navis, Gerjan; Watkins, Hugh; Witteman, Jacqueline C M; Sanna, Serena; Schipf, Sabine; Dunlop, Malcolm G; Tönjes, Anke; Ripatti, Samuli; Soranzo, Nicole; Toniolo, Daniela; Chasman, Daniel I; Raitakari, Olli; Kao, W H Linda; Ciullo, Marina; Fox, Caroline S; Caulfield, Mark; Bochud, Murielle; Gieger, Christian

2013-01-01

Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout. PMID:23263486

Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis.

PubMed

Hobbs, Brian D; de Jong, Kim; Lamontagne, Maxime; Bossé, Yohan; Shrine, Nick; Artigas, María Soler; Wain, Louise V; Hall, Ian P; Jackson, Victoria E; Wyss, Annah B; London, Stephanie J; North, Kari E; Franceschini, Nora; Strachan, David P; Beaty, Terri H; Hokanson, John E; Crapo, James D; Castaldi, Peter J; Chase, Robert P; Bartz, Traci M; Heckbert, Susan R; Psaty, Bruce M; Gharib, Sina A; Zanen, Pieter; Lammers, Jan W; Oudkerk, Matthijs; Groen, H J; Locantore, Nicholas; Tal-Singer, Ruth; Rennard, Stephen I; Vestbo, Jørgen; Timens, Wim; Paré, Peter D; Latourelle, Jeanne C; Dupuis, Josée; O'Connor, George T; Wilk, Jemma B; Kim, Woo Jin; Lee, Mi Kyeong; Oh, Yeon-Mok; Vonk, Judith M; de Koning, Harry J; Leng, Shuguang; Belinsky, Steven A; Tesfaigzi, Yohannes; Manichaikul, Ani; Wang, Xin-Qun; Rich, Stephen S; Barr, R Graham; Sparrow, David; Litonjua, Augusto A; Bakke, Per; Gulsvik, Amund; Lahousse, Lies; Brusselle, Guy G; Stricker, Bruno H; Uitterlinden, André G; Ampleford, Elizabeth J; Bleecker, Eugene R; Woodruff, Prescott G; Meyers, Deborah A; Qiao, Dandi; Lomas, David A; Yim, Jae-Joon; Kim, Deog Kyeom; Hawrylkiewicz, Iwona; Sliwinski, Pawel; Hardin, Megan; Fingerlin, Tasha E; Schwartz, David A; Postma, Dirkje S; MacNee, William; Tobin, Martin D; Silverman, Edwin K; Boezen, H Marike; Cho, Michael H

2017-03-01

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10 -6 ) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.

An Enhanced Linkage Map of the Sheep Genome Comprising More Than 1000 Loci

PubMed Central

Maddox, Jillian F.; Davies, Kizanne P.; Crawford, Allan M.; Hulme, Dennis J.; Vaiman, Daniel; Cribiu, Edmond P.; Freking, Bradley A.; Beh, Ken J.; Cockett, Noelle E.; Kang, Nina; Riffkin, Christopher D.; Drinkwater, Roger; Moore, Stephen S.; Dodds, Ken G.; Lumsden, Joanne M.; van Stijn, Tracey C.; Phua, Sin H.; Adelson, David L.; Burkin, Heather R.; Broom, Judith E.; Buitkamp, Johannes; Cambridge, Lisa; Cushwa, William T.; Gerard, Emily; Galloway, Susan M.; Harrison, Blair; Hawken, Rachel J.; Hiendleder, Stefan; Henry, Hannah M.; Medrano, Juan F.; Paterson, Korena A.; Schibler, Laurent; Stone, Roger T.; van Hest, Beryl

2001-01-01

A medium-density linkage map of the ovine genome has been developed. Marker data for 550 new loci were generated and merged with the previous sheep linkage map. The new map comprises 1093 markers representing 1062 unique loci (941 anonymous loci, 121 genes) and spans 3500 cM (sex-averaged) for the autosomes and 132 cM (female) on the X chromosome. There is an average spacing of 3.4 cM between autosomal loci and 8.3 cM between highly polymorphic [polymorphic information content (PIC) ≥ 0.7] autosomal loci. The largest gap between markers is 32.5 cM, and the number of gaps of >20 cM between loci, or regions where loci are missing from chromosome ends, has been reduced from 40 in the previous map to 6. Five hundred and seventy-three of the loci can be ordered on a framework map with odds of >1000 : 1. The sheep linkage map contains strong links to both the cattle and goat maps. Five hundred and seventy-two of the loci positioned on the sheep linkage map have also been mapped by linkage analysis in cattle, and 209 of the loci mapped on the sheep linkage map have also been placed on the goat linkage map. Inspection of ruminant linkage maps indicates that the genomic coverage by the current sheep linkage map is comparable to that of the available cattle maps. The sheep map provides a valuable resource to the international sheep, cattle, and goat gene mapping community. PMID:11435411

Insight into the molecular genetics of myopia

PubMed Central

Li, Jiali

2017-01-01

Myopia is the most common cause of visual impairment worldwide. Genetic and environmental factors contribute to the development of myopia. Studies on the molecular genetics of myopia are well established and have implicated the important role of genetic factors. With linkage analysis, association studies, sequencing analysis, and experimental myopia studies, many of the loci and genes associated with myopia have been identified. Thus far, there has been no systemic review of the loci and genes related to non-syndromic and syndromic myopia based on the different approaches. Such a systemic review of the molecular genetics of myopia will provide clues to identify additional plausible genes for myopia and help us to understand the molecular mechanisms underlying myopia. This paper reviews recent genetic studies on myopia, summarizes all possible reported genes and loci related to myopia, and suggests implications for future studies on the molecular genetics of myopia. PMID:29386878

Insight into the molecular genetics of myopia.

PubMed

Li, Jiali; Zhang, Qingjiong

2017-01-01

Myopia is the most common cause of visual impairment worldwide. Genetic and environmental factors contribute to the development of myopia. Studies on the molecular genetics of myopia are well established and have implicated the important role of genetic factors. With linkage analysis, association studies, sequencing analysis, and experimental myopia studies, many of the loci and genes associated with myopia have been identified. Thus far, there has been no systemic review of the loci and genes related to non-syndromic and syndromic myopia based on the different approaches. Such a systemic review of the molecular genetics of myopia will provide clues to identify additional plausible genes for myopia and help us to understand the molecular mechanisms underlying myopia. This paper reviews recent genetic studies on myopia, summarizes all possible reported genes and loci related to myopia, and suggests implications for future studies on the molecular genetics of myopia.

Comprehensive Analysis of Human Endogenous Retrovirus Group HERV-W Locus Transcription in Multiple Sclerosis Brain Lesions by High-Throughput Amplicon Sequencing

PubMed Central

Schmitt, Katja; Richter, Christin; Backes, Christina; Meese, Eckart; Ruprecht, Klemens

2013-01-01

Human endogenous retroviruses (HERVs) of the HERV-W group comprise hundreds of loci in the human genome. Deregulated HERV-W expression and HERV-W locus ERVWE1-encoded Syncytin-1 protein have been implicated in the pathogenesis of multiple sclerosis (MS). However, the actual transcription of HERV-W loci in the MS context has not been comprehensively analyzed. We investigated transcription of HERV-W in MS brain lesions and white matter brain tissue from healthy controls by employing next-generation amplicon sequencing of HERV-W env-specific reverse transcriptase (RT) PCR products, thus revealing transcribed HERV-W loci and the relative transcript levels of those loci. We identified more than 100 HERV-W loci that were transcribed in the human brain, with a limited number of loci being predominantly transcribed. Importantly, relative transcript levels of HERV-W loci were very similar between MS and healthy brain tissue samples, refuting deregulated transcription of HERV-W env in MS brain lesions, including the high-level-transcribed ERVWE1 locus encoding Syncytin-1. Quantitative RT-PCR likewise did not reveal differences in MS regarding HERV-W env general transcript or ERVWE1- and ERVWE2-specific transcript levels. However, we obtained evidence for interindividual differences in HERV-W transcript levels. Reporter gene assays indicated promoter activity of many HERV-W long terminal repeats (LTRs), including structurally incomplete LTRs. Our comprehensive analysis of HERV-W transcription in the human brain thus provides important information on the biology of HERV-W in MS lesions and normal human brain, implications for study design, and mechanisms by which HERV-W may (or may not) be involved in MS. PMID:24109235

The abundance of cis-acting loci leading to differential allele expression in F1 mice and their relationship to loci harboring genes affecting complex traits.

PubMed

Yeo, Seungeun; Hodgkinson, Colin A; Zhou, Zhifeng; Jung, Jeesun; Leung, Ming; Yuan, Qiaoping; Goldman, David

2016-08-11

Genome-wide surveys have detected cis-acting quantitative trait loci altering levels of RNA transcripts (RNA-eQTLs) by associating SNV alleles to transcript levels. However, the sensitivity and specificity of detection of cis- expression quantitative trait loci (eQTLs) by genetic approaches, reliant as it is on measurements of transcript levels in recombinant inbred strains or offspring from arranged crosses, is unknown, as is their relationship to QTL's for complex phenotypes. We used transcriptome-wide differential allele expression (DAE) to detect cis-eQTLs in forebrain and kidney from reciprocal crosses between three mouse inbred strains, 129S1/SvlmJ, DBA/2J, and CAST/EiJ and C57BL/6 J. Two of these crosses were previously characterized for cis-eQTLs and QTLs for various complex phenotypes by genetic analysis of recombinant inbred (RI) strains. 5.4 %, 1.9 % and 1.5 % of genes assayed in forebrain of B6/129SF1, B6/DBAF1, and B6/CASTF1 mice, respectively, showed differential allelic expression, indicative of cis-acting alleles at these genes. Moreover, the majority of DAE QTLs were observed to be tissue-specific with only a small fraction showing cis-effects in both tissues. Comparing DAE QTLs in F1 mice to cis-eQTLs previously mapped in RI strains we observed that many of the cis-eQTLs were not confirmed by DAE. Additionally several novel DAE-QTLs not identified as cis-eQTLs were identified suggesting that there are differences in sensitivity and specificity for QTL detection between the two methodologies. Strain specific DAE QTLs in B6/DBAF1 mice were located in excess at candidate genes for alcohol use disorders, seizures, and angiogenesis previously implicated by genetic linkage in C57BL/6J × DBA/2JF2 mice or BXD RI strains. Via a survey for differential allele expression in F1 mice, a substantial proportion of genes were found to have alleles altering expression in cis-acting fashion. Comparing forebrain and kidney, many or most of these alleles were tissue-specific in action. The identification of strain specific DAE QTLs, can assist in assessment of candidate genes located within the large intervals associated with trait QTLs.

Phylogeny and strain typing of Escherichia coli, inferred from variation at mononucleotide repeat loci.

PubMed

Diamant, Eran; Palti, Yniv; Gur-Arie, Riva; Cohen, Helit; Hallerman, Eric M; Kashi, Yechezkel

2004-04-01

Multilocus sequencing of housekeeping genes has been used previously for bacterial strain typing and for inferring evolutionary relationships among strains of Escherichia coli. In this study, we used shorter intergenic sequences that contained simple sequence repeats (SSRs) of repeating mononucleotide motifs (mononucleotide repeats [MNRs]) to infer the phylogeny of pathogenic and commensal E. coli strains. Seven noncoding loci (four MNRs and three non-SSRs) were sequenced in 27 strains, including enterohemorrhagic (six isolates of O157:H7), enteropathogenic, enterotoxigenic, B, and K-12 strains. The four MNRs were also sequenced in 20 representative strains of the E. coli reference (ECOR) collection. Sequence polymorphism was significantly higher at the MNR loci, including the flanking sequences, indicating a higher mutation rate in the sequences flanking the MNR tracts. The four MNR loci were amplifiable by PCR in the standard ECOR A, B1, and D groups, but only one (yaiN) in the B2 group was amplified, which is consistent with previous studies that suggested that B2 is the most ancient group. High sequence compatibility was found between the four MNR loci, indicating that they are in the same clonal frame. The phylogenetic trees that were constructed from the sequence data were in good agreement with those of previous studies that used multilocus enzyme electrophoresis. The results demonstrate that MNR loci are useful for inferring phylogenetic relationships and provide much higher sequence variation than housekeeping genes. Therefore, the use of MNR loci for multilocus sequence typing should prove efficient for clinical diagnostics, epidemiology, and evolutionary study of bacteria.

Phylogeny and Strain Typing of Escherichia coli, Inferred from Variation at Mononucleotide Repeat Loci

PubMed Central

Diamant, Eran; Palti, Yniv; Gur-Arie, Riva; Cohen, Helit; Hallerman, Eric M.; Kashi, Yechezkel

2004-01-01

Multilocus sequencing of housekeeping genes has been used previously for bacterial strain typing and for inferring evolutionary relationships among strains of Escherichia coli. In this study, we used shorter intergenic sequences that contained simple sequence repeats (SSRs) of repeating mononucleotide motifs (mononucleotide repeats [MNRs]) to infer the phylogeny of pathogenic and commensal E. coli strains. Seven noncoding loci (four MNRs and three non-SSRs) were sequenced in 27 strains, including enterohemorrhagic (six isolates of O157:H7), enteropathogenic, enterotoxigenic, B, and K-12 strains. The four MNRs were also sequenced in 20 representative strains of the E. coli reference (ECOR) collection. Sequence polymorphism was significantly higher at the MNR loci, including the flanking sequences, indicating a higher mutation rate in the sequences flanking the MNR tracts. The four MNR loci were amplifiable by PCR in the standard ECOR A, B1, and D groups, but only one (yaiN) in the B2 group was amplified, which is consistent with previous studies that suggested that B2 is the most ancient group. High sequence compatibility was found between the four MNR loci, indicating that they are in the same clonal frame. The phylogenetic trees that were constructed from the sequence data were in good agreement with those of previous studies that used multilocus enzyme electrophoresis. The results demonstrate that MNR loci are useful for inferring phylogenetic relationships and provide much higher sequence variation than housekeeping genes. Therefore, the use of MNR loci for multilocus sequence typing should prove efficient for clinical diagnostics, epidemiology, and evolutionary study of bacteria. PMID:15066845

GAB2 as an Alzheimer disease susceptibility gene: follow-up of genomewide association results.

PubMed

Schjeide, Brit-Maren M; Hooli, Basavaraj; Parkinson, Michele; Hogan, Meghan F; DiVito, Jason; Mullin, Kristina; Blacker, Deborah; Tanzi, Rudolph E; Bertram, Lars

2009-02-01

Genomewide association (GWA) studies have recently implicated 4 novel Alzheimer disease (AD) susceptibility loci (GAB2, GOLM1, and 2 uncharacterized loci to date on chromosomes 9p and 15q). To our knowledge, these findings have not been independently replicated. To assess these GWA findings in 4 large data sets of families affected by AD. Follow-up of genetic association findings in previous studies. Academic research. More than 4000 DNA samples from almost 1300 families affected with AD. Genetic association analysis testing of 4 GWA signals (rs7101429 [GAB2], rs7019241 [GOLM1], rs10519262 [chromosome 15q], and rs9886784 [chromosome 9p]) using family-based methods. In the combined analyses, only rs7101429 in GAB2 yielded significant evidence of association with the same allele as in the original GWA study (P =.002). The results are in agreement with recent meta-analyses of this and other GAB2 polymorphisms suggesting approximately a 30% decrease in risk for AD among carriers of the minor alleles. None of the other 3 tested loci showed consistent evidence for association with AD across the investigated data sets. GAB2 contains genetic variants that may lead to a modest change in the risk for AD. Despite these promising results, more data from independent samples are needed to better evaluate the potential contribution of GAB2 to AD risk in the general population.

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

PubMed Central

Dupuis, Josée; Langenberg, Claudia; Prokopenko, Inga; Saxena, Richa; Soranzo, Nicole; Jackson, Anne U; Wheeler, Eleanor; Glazer, Nicole L; Bouatia-Naji, Nabila; Gloyn, Anna L; Lindgren, Cecilia M; Mägi, Reedik; Morris, Andrew P; Randall, Joshua; Johnson, Toby; Elliott, Paul; Rybin, Denis; Thorleifsson, Gudmar; Steinthorsdottir, Valgerdur; Henneman, Peter; Grallert, Harald; Dehghan, Abbas; Hottenga, Jouke Jan; Franklin, Christopher S; Navarro, Pau; Song, Kijoung; Goel, Anuj; Perry, John R B; Egan, Josephine M; Lajunen, Taina; Grarup, Niels; Sparsø, Thomas; Doney, Alex; Voight, Benjamin F; Stringham, Heather M; Li, Man; Kanoni, Stavroula; Shrader, Peter; Cavalcanti-Proença, Christine; Kumari, Meena; Qi, Lu; Timpson, Nicholas J; Gieger, Christian; Zabena, Carina; Rocheleau, Ghislain; Ingelsson, Erik; An, Ping; O’Connell, Jeffrey; Luan, Jian'an; Elliott, Amanda; McCarroll, Steven A; Payne, Felicity; Roccasecca, Rosa Maria; Pattou, François; Sethupathy, Praveen; Ardlie, Kristin; Ariyurek, Yavuz; Balkau, Beverley; Barter, Philip; Beilby, John P; Ben-Shlomo, Yoav; Benediktsson, Rafn; Bennett, Amanda J; Bergmann, Sven; Bochud, Murielle; Boerwinkle, Eric; Bonnefond, Amélie; Bonnycastle, Lori L; Borch-Johnsen, Knut; Böttcher, Yvonne; Brunner, Eric; Bumpstead, Suzannah J; Charpentier, Guillaume; Chen, Yii-Der Ida; Chines, Peter; Clarke, Robert; Coin, Lachlan J M; Cooper, Matthew N; Cornelis, Marilyn; Crawford, Gabe; Crisponi, Laura; Day, Ian N M; de Geus, Eco; Delplanque, Jerome; Dina, Christian; Erdos, Michael R; Fedson, Annette C; Fischer-Rosinsky, Antje; Forouhi, Nita G; Fox, Caroline S; Frants, Rune; Franzosi, Maria Grazia; Galan, Pilar; Goodarzi, Mark O; Graessler, Jürgen; Groves, Christopher J; Grundy, Scott; Gwilliam, Rhian; Gyllensten, Ulf; Hadjadj, Samy; Hallmans, Göran; Hammond, Naomi; Han, Xijing; Hartikainen, Anna-Liisa; Hassanali, Neelam; Hayward, Caroline; Heath, Simon C; Hercberg, Serge; Herder, Christian; Hicks, Andrew A; Hillman, David R; Hingorani, Aroon D; Hofman, Albert; Hui, Jennie; Hung, Joe; Isomaa, Bo; Johnson, Paul R V; Jørgensen, Torben; Jula, Antti; Kaakinen, Marika; Kaprio, Jaakko; Kesaniemi, Y Antero; Kivimaki, Mika; Knight, Beatrice; Koskinen, Seppo; Kovacs, Peter; Kyvik, Kirsten Ohm; Lathrop, G Mark; Lawlor, Debbie A; Le Bacquer, Olivier; Lecoeur, Cécile; Li, Yun; Lyssenko, Valeriya; Mahley, Robert; Mangino, Massimo; Manning, Alisa K; Martínez-Larrad, María Teresa; McAteer, Jarred B; McCulloch, Laura J; McPherson, Ruth; Meisinger, Christa; Melzer, David; Meyre, David; Mitchell, Braxton D; Morken, Mario A; Mukherjee, Sutapa; Naitza, Silvia; Narisu, Narisu; Neville, Matthew J; Oostra, Ben A; Orrù, Marco; Pakyz, Ruth; Palmer, Colin N A; Paolisso, Giuseppe; Pattaro, Cristian; Pearson, Daniel; Peden, John F; Pedersen, Nancy L.; Perola, Markus; Pfeiffer, Andreas F H; Pichler, Irene; Polasek, Ozren; Posthuma, Danielle; Potter, Simon C; Pouta, Anneli; Province, Michael A; Psaty, Bruce M; Rathmann, Wolfgang; Rayner, Nigel W; Rice, Kenneth; Ripatti, Samuli; Rivadeneira, Fernando; Roden, Michael; Rolandsson, Olov; Sandbaek, Annelli; Sandhu, Manjinder; Sanna, Serena; Sayer, Avan Aihie; Scheet, Paul; Scott, Laura J; Seedorf, Udo; Sharp, Stephen J; Shields, Beverley; Sigurðsson, Gunnar; Sijbrands, Erik J G; Silveira, Angela; Simpson, Laila; Singleton, Andrew; Smith, Nicholas L; Sovio, Ulla; Swift, Amy; Syddall, Holly; Syvänen, Ann-Christine; Tanaka, Toshiko; Thorand, Barbara; Tichet, Jean; Tönjes, Anke; Tuomi, Tiinamaija; Uitterlinden, André G; van Dijk, Ko Willems; van Hoek, Mandy; Varma, Dhiraj; Visvikis-Siest, Sophie; Vitart, Veronique; Vogelzangs, Nicole; Waeber, Gérard; Wagner, Peter J; Walley, Andrew; Walters, G Bragi; Ward, Kim L; Watkins, Hugh; Weedon, Michael N; Wild, Sarah H; Willemsen, Gonneke; Witteman, Jaqueline C M; Yarnell, John W G; Zeggini, Eleftheria; Zelenika, Diana; Zethelius, Björn; Zhai, Guangju; Zhao, Jing Hua; Zillikens, M Carola; Borecki, Ingrid B; Loos, Ruth J F; Meneton, Pierre; Magnusson, Patrik K E; Nathan, David M; Williams, Gordon H; Hattersley, Andrew T; Silander, Kaisa; Salomaa, Veikko; Smith, George Davey; Bornstein, Stefan R; Schwarz, Peter; Spranger, Joachim; Karpe, Fredrik; Shuldiner, Alan R; Cooper, Cyrus; Dedoussis, George V; Serrano-Ríos, Manuel; Morris, Andrew D; Lind, Lars; Palmer, Lyle J; Hu, Frank B.; Franks, Paul W; Ebrahim, Shah; Marmot, Michael; Kao, W H Linda; Pankow, James S; Sampson, Michael J; Kuusisto, Johanna; Laakso, Markku; Hansen, Torben; Pedersen, Oluf; Pramstaller, Peter Paul; Wichmann, H Erich; Illig, Thomas; Rudan, Igor; Wright, Alan F; Stumvoll, Michael; Campbell, Harry; Wilson, James F; Hamsten, Anders; Bergman, Richard N; Buchanan, Thomas A; Collins, Francis S; Mohlke, Karen L; Tuomilehto, Jaakko; Valle, Timo T; Altshuler, David; Rotter, Jerome I; Siscovick, David S; Penninx, Brenda W J H; Boomsma, Dorret; Deloukas, Panos; Spector, Timothy D; Frayling, Timothy M; Ferrucci, Luigi; Kong, Augustine; Thorsteinsdottir, Unnur; Stefansson, Kari; van Duijn, Cornelia M; Aulchenko, Yurii S; Cao, Antonio; Scuteri, Angelo; Schlessinger, David; Uda, Manuela; Ruokonen, Aimo; Jarvelin, Marjo-Riitta; Waterworth, Dawn M; Vollenweider, Peter; Peltonen, Leena; Mooser, Vincent; Abecasis, Goncalo R; Wareham, Nicholas J; Sladek, Robert; Froguel, Philippe; Watanabe, Richard M; Meigs, James B; Groop, Leif; Boehnke, Michael; McCarthy, Mark I; Florez, Jose C; Barroso, Inês

2010-01-01

Circulating glucose levels are tightly regulated. To identify novel glycemic loci, we performed meta-analyses of 21 genome-wide associations studies informative for fasting glucose (FG), fasting insulin (FI) and indices of β-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 non-diabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with FG/HOMA-B and two associated with FI/HOMA-IR. These include nine new FG loci (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and FAM148B) and one influencing FI/HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB/TMEM195 with type 2 diabetes (T2D). Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify T2D risk loci, as well as loci that elevate FG modestly, but do not cause overt diabetes. PMID:20081858

Diverse types of genetic variation converge on functional gene networks involved in schizophrenia.

PubMed

Gilman, Sarah R; Chang, Jonathan; Xu, Bin; Bawa, Tejdeep S; Gogos, Joseph A; Karayiorgou, Maria; Vitkup, Dennis

2012-12-01

Despite the successful identification of several relevant genomic loci, the underlying molecular mechanisms of schizophrenia remain largely unclear. We developed a computational approach (NETBAG+) that allows an integrated analysis of diverse disease-related genetic data using a unified statistical framework. The application of this approach to schizophrenia-associated genetic variations, obtained using unbiased whole-genome methods, allowed us to identify several cohesive gene networks related to axon guidance, neuronal cell mobility, synaptic function and chromosomal remodeling. The genes forming the networks are highly expressed in the brain, with higher brain expression during prenatal development. The identified networks are functionally related to genes previously implicated in schizophrenia, autism and intellectual disability. A comparative analysis of copy number variants associated with autism and schizophrenia suggests that although the molecular networks implicated in these distinct disorders may be related, the mutations associated with each disease are likely to lead, at least on average, to different functional consequences.

Shared genetic aetiology of puberty timing between sexes and with health-related outcomes

PubMed Central

Day, Felix R.; Bulik-Sullivan, Brendan; Hinds, David A.; Finucane, Hilary K.; Murabito, Joanne M.; Tung, Joyce Y.; Ong, Ken K.; Perry, John R.B.

2015-01-01

Understanding of the genetic regulation of puberty timing has come largely from studies of rare disorders and population-based studies in women. Here, we report the largest genomic analysis for puberty timing in 55,871 men, based on recalled age at voice breaking. Analysis across all genomic variants reveals strong genetic correlation (0.74, P=2.7 × 10−70) between male and female puberty timing. However, some loci show sex-divergent effects, including directionally opposite effects between sexes at the SIM1/MCHR2 locus (Pheterogeneity=1.6 × 10−12). We find five novel loci for puberty timing (P<5 × 10−8), in addition to nine signals in men that were previously reported in women. Newly implicated genes include two retinoic acid-related receptors, RORB and RXRA, and two genes reportedly disrupted in rare disorders of puberty, LEPR and KAL1. Finally, we identify genetic correlations that indicate shared aetiologies in both sexes between puberty timing and body mass index, fasting insulin levels, lipid levels, type 2 diabetes and cardiovascular disease. PMID:26548314

Shared genetic aetiology of puberty timing between sexes and with health-related outcomes.

PubMed

Day, Felix R; Bulik-Sullivan, Brendan; Hinds, David A; Finucane, Hilary K; Murabito, Joanne M; Tung, Joyce Y; Ong, Ken K; Perry, John R B

2015-11-09

Understanding of the genetic regulation of puberty timing has come largely from studies of rare disorders and population-based studies in women. Here, we report the largest genomic analysis for puberty timing in 55,871 men, based on recalled age at voice breaking. Analysis across all genomic variants reveals strong genetic correlation (0.74, P=2.7 × 10(-70)) between male and female puberty timing. However, some loci show sex-divergent effects, including directionally opposite effects between sexes at the SIM1/MCHR2 locus (Pheterogeneity=1.6 × 10(-12)). We find five novel loci for puberty timing (P<5 × 10(-8)), in addition to nine signals in men that were previously reported in women. Newly implicated genes include two retinoic acid-related receptors, RORB and RXRA, and two genes reportedly disrupted in rare disorders of puberty, LEPR and KAL1. Finally, we identify genetic correlations that indicate shared aetiologies in both sexes between puberty timing and body mass index, fasting insulin levels, lipid levels, type 2 diabetes and cardiovascular disease.

Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease.

PubMed

Zhao, Wei; Rasheed, Asif; Tikkanen, Emmi; Lee, Jung-Jin; Butterworth, Adam S; Howson, Joanna M M; Assimes, Themistocles L; Chowdhury, Rajiv; Orho-Melander, Marju; Damrauer, Scott; Small, Aeron; Asma, Senay; Imamura, Minako; Yamauch, Toshimasa; Chambers, John C; Chen, Peng; Sapkota, Bishwa R; Shah, Nabi; Jabeen, Sehrish; Surendran, Praveen; Lu, Yingchang; Zhang, Weihua; Imran, Atif; Abbas, Shahid; Majeed, Faisal; Trindade, Kevin; Qamar, Nadeem; Mallick, Nadeem Hayyat; Yaqoob, Zia; Saghir, Tahir; Rizvi, Syed Nadeem Hasan; Memon, Anis; Rasheed, Syed Zahed; Memon, Fazal-Ur-Rehman; Mehmood, Khalid; Ahmed, Naveeduddin; Qureshi, Irshad Hussain; Tanveer-Us-Salam; Iqbal, Wasim; Malik, Uzma; Mehra, Narinder; Kuo, Jane Z; Sheu, Wayne H-H; Guo, Xiuqing; Hsiung, Chao A; Juang, Jyh-Ming J; Taylor, Kent D; Hung, Yi-Jen; Lee, Wen-Jane; Quertermous, Thomas; Lee, I-Te; Hsu, Chih-Cheng; Bottinger, Erwin P; Ralhan, Sarju; Teo, Yik Ying; Wang, Tzung-Dau; Alam, Dewan S; Di Angelantonio, Emanuele; Epstein, Steve; Nielsen, Sune F; Nordestgaard, Børge G; Tybjaerg-Hansen, Anne; Young, Robin; Benn, Marianne; Frikke-Schmidt, Ruth; Kamstrup, Pia R; Jukema, J Wouter; Sattar, Naveed; Smit, Roelof; Chung, Ren-Hua; Liang, Kae-Woei; Anand, Sonia; Sanghera, Dharambir K; Ripatti, Samuli; Loos, Ruth J F; Kooner, Jaspal S; Tai, E Shyong; Rotter, Jerome I; Chen, Yii-Der Ida; Frossard, Philippe; Maeda, Shiro; Kadowaki, Takashi; Reilly, Muredach; Pare, Guillaume; Melander, Olle; Salomaa, Veikko; Rader, Daniel J; Danesh, John; Voight, Benjamin F; Saleheen, Danish

2017-10-01

To evaluate the shared genetic etiology of type 2 diabetes (T2D) and coronary heart disease (CHD), we conducted a genome-wide, multi-ancestry study of genetic variation for both diseases in up to 265,678 subjects for T2D and 260,365 subjects for CHD. We identify 16 previously unreported loci for T2D and 1 locus for CHD, including a new T2D association at a missense variant in HLA-DRB5 (odds ratio (OR) = 1.29). We show that genetically mediated increase in T2D risk also confers higher CHD risk. Joint T2D-CHD analysis identified eight variants-two of which are coding-where T2D and CHD associations appear to colocalize, including a new joint T2D-CHD association at the CCDC92 locus that also replicated for T2D. The variants associated with both outcomes implicate new pathways as well as targets of existing drugs, including icosapent ethyl and adipocyte fatty-acid-binding protein.

Meta-analysis identifies common variants associated with body mass index in East Asians

PubMed Central

Wen, Wanqing; Cho, Yoon Shin; Zheng, Wei; Dorajoo, Rajkumar; Kato, Norihiro; Qi, Lu; Chen, Chien-Hsiun; Delahanty, Ryan J.; Okada, Yukinori; Tabara, Yasuharu; Gu, Dongfeng; Zhu, Dingliang; Haiman, Christopher A.; Mo, Zengnan; Gao, Yu-Tang; Saw, Seang Mei; Go, Min Jin; Takeuchi, Fumihiko; Chang, Li-Ching; Kokubo, Yoshihiro; Liang, Jun; Hao, Mei; Marchand, Loic Le; Zhang, Yi; Hu, Yanling; Wong, Tien Yin; Long, Jirong; Han, Bok-Ghee; Kubo, Michiaki; Yamamoto, Ken; Su, Mei-Hsin; Miki, Tetsuro; Henderson, Brian E.; Song, Huaidong; Tan, Aihua; He, Jiang; Ng, Daniel P.-K.; Cai, Qiuyin; Tsunoda, Tatsuhiko; Tsai, Fuu-Jen; Iwai, Naoharu; Chen, Gary K.; Shi, Jiajun; Xu, Jianfeng; Sim, Xueling; Xiang, Yong-Bing; Maeda, Shiro; Ong, Rick T.H.; Li, Chun; Nakamura, Yusuke; Aung, Tin; Kamatani, Naoyuki; Liu, Jian Jun; Lu, Wei; Yokota, Mitsuhiro; Seielstad, Mark; Fann, Cathy S.J.; Wu, Jer-Yuarn; Lee, Jong-Young; Hu, Frank B.; Tanaka, Toshihiro; Tai, E. Shyong; Shu, Xiao Ou

2012-01-01

Multiple genetic loci associated with obesity or body mass index (BMI) have been identified through genome-wide association studies conducted predominantly in populations of European ancestry. We conducted a meta-analysis of associations between BMI and approximately 2.4 million SNPs in 27,715 East Asians, followed by in silico and de novo replication in 37,691 and 17,642 additional East Asians, respectively. We identified ten BMI-associated loci at the genome-wide significance level (P<5.0×10−8), including seven previously identified loci (FTO, SEC16B, MC4R, GIPR/QPCTL, ADCY3/RBJ, BDNF, and MAP2K5) and three novel loci in or near the CDKAL1,PCSK1, and GP2 genes. Three additional loci nearly reached the genome-wide significance threshold, including two previously identified loci in the GNPDA2 and TFAP2B genes and a new locus near PAX6, which all had P<5.0×10−7. Findings from this study may shed light on new pathways involved in obesity and demonstrate the value of conducting genetic studies in non-European populations. PMID:22344219

Multiple Genetic Associations with Irish Wolfhound Dilated Cardiomyopathy.

PubMed

Simpson, Siobhan; Dunning, Mark D; Brownlie, Serena; Patel, Janika; Godden, Megan; Cobb, Malcolm; Mongan, Nigel P; Rutland, Catrin S

2016-01-01

Cardiac disease is a leading cause of morbidity and mortality in dogs and humans, with dilated cardiomyopathy being a large contributor to this. The Irish Wolfhound (IWH) is one of the most commonly affected breeds and one of the few breeds with genetic loci associated with the disease. Mutations in more than 50 genes are associated with human dilated cardiomyopathy (DCM), yet very few are also associated with canine DCM. Furthermore, none of the identified canine loci explain many cases of the disease and previous work has indicated that genotypes at multiple loci may act together to influence disease development. In this study, loci previously associated with DCM in IWH were tested for associations in a new cohort both individually and in combination. We have identified loci significantly associated with the disease individually, but no genotypes individually or in pairs conferred a significantly greater risk of developing DCM than the population risk. However combining three loci together did result in the identification of a genotype which conferred a greater risk of disease than the overall population risk. This study suggests multiple rather than individual genetic factors, cooperating to influence DCM risk in IWH.

Multiple Genetic Associations with Irish Wolfhound Dilated Cardiomyopathy

PubMed Central

Dunning, Mark D.; Brownlie, Serena

2016-01-01

Cardiac disease is a leading cause of morbidity and mortality in dogs and humans, with dilated cardiomyopathy being a large contributor to this. The Irish Wolfhound (IWH) is one of the most commonly affected breeds and one of the few breeds with genetic loci associated with the disease. Mutations in more than 50 genes are associated with human dilated cardiomyopathy (DCM), yet very few are also associated with canine DCM. Furthermore, none of the identified canine loci explain many cases of the disease and previous work has indicated that genotypes at multiple loci may act together to influence disease development. In this study, loci previously associated with DCM in IWH were tested for associations in a new cohort both individually and in combination. We have identified loci significantly associated with the disease individually, but no genotypes individually or in pairs conferred a significantly greater risk of developing DCM than the population risk. However combining three loci together did result in the identification of a genotype which conferred a greater risk of disease than the overall population risk. This study suggests multiple rather than individual genetic factors, cooperating to influence DCM risk in IWH. PMID:28070514

Conservation genomics of anadromous Atlantic salmon across its North American range: outlier loci identify the same patterns of population structure as neutral loci.

PubMed

Moore, Jean-Sébastien; Bourret, Vincent; Dionne, Mélanie; Bradbury, Ian; O'Reilly, Patrick; Kent, Matthew; Chaput, Gérald; Bernatchez, Louis

2014-12-01

Anadromous Atlantic salmon (Salmo salar) is a species of major conservation and management concern in North America, where population abundance has been declining over the past 30 years. Effective conservation actions require the delineation of conservation units to appropriately reflect the spatial scale of intraspecific variation and local adaptation. Towards this goal, we used the most comprehensive genetic and genomic database for Atlantic salmon to date, covering the entire North American range of the species. The database included microsatellite data from 9142 individuals from 149 sampling locations and data from a medium-density SNP array providing genotypes for >3000 SNPs for 50 sampling locations. We used neutral and putatively selected loci to integrate adaptive information in the definition of conservation units. Bayesian clustering with the microsatellite data set and with neutral SNPs identified regional groupings largely consistent with previously published regional assessments. The use of outlier SNPs did not result in major differences in the regional groupings, suggesting that neutral markers can reflect the geographic scale of local adaptation despite not being under selection. We also performed assignment tests to compare power obtained from microsatellites, neutral SNPs and outlier SNPs. Using SNP data substantially improved power compared to microsatellites, and an assignment success of 97% to the population of origin and of 100% to the region of origin was achieved when all SNP loci were used. Using outlier SNPs only resulted in minor improvements to assignment success to the population of origin but improved regional assignment. We discuss the implications of these new genetic resources for the conservation and management of Atlantic salmon in North America. © 2014 John Wiley & Sons Ltd.

Diversity of secretion systems associated with virulence characteristics of the classical bordetellae.

PubMed

Park, Jihye; Zhang, Ying; Chen, Chun; Dudley, Edward G; Harvill, Eric T

2015-12-01

Secretion systems are key virulence factors, modulating interactions between pathogens and the host's immune response. Six potential secretion systems (types 1-6; T1SS-T6SS) have been discussed in classical bordetellae, respiratory commensals/pathogens of mammals. The prototypical Bordetella bronchiseptica strain RB50 genome seems to contain all six systems, whilst two human-restricted subspecies, Bordetella parapertussis and Bordetella pertussis, have lost different subsets of these. This implicates secretion systems in the divergent evolutionary histories that have led to their success in different niches. Based on our previous work demonstrating that changes in secretion systems are associated with virulence characteristics, we hypothesized there would be substantial divergence of the loci encoding each amongst sequenced strains. Here, we describe extensive differences in secretion system loci; 10 of the 11 sequenced strains had lost subsets of genes or one entire secretion system locus. These loci contained genes homologous to those present in the respective loci in distantly related organisms, as well as genes unique to bordetellae, suggesting novel and/or auxiliary functions. The high degree of conservation of the T3SS locus, a complex machine with interdependent parts that must be conserved, stands in dramatic contrast to repeated loss of T5aSS 'autotransporters', which function as an autonomous unit. This comparative analysis provided insights into critical aspects of each pathogen's adaptation to its different niche, and the relative contributions of recombination, mutation and horizontal gene transfer. In addition, the relative conservation of various secretion systems is an important consideration in the ongoing search for more highly conserved protective antigens for the next generation of pertussis vaccines.

Genetic variation in GABRB3 is associated with Asperger syndrome and multiple endophenotypes relevant to autism

PubMed Central

2013-01-01

Background Autism spectrum conditions (ASC) are associated with deficits in social interaction and communication, alongside repetitive, restricted, and stereotyped behavior. ASC is highly heritable. The gamma-aminobutyric acid (GABA)-ergic system has been associated consistently with atypicalities in autism, in both genetic association and expression studies. A key component of the GABA-ergic system is encoded by the GABRB3 gene, which has been previously implicated both in ASC and in individual differences in empathy. Methods In this study, 45 genotyped single nucleotide polymorphisms (SNPs) within GABRB3 were tested for association with Asperger syndrome (AS), and related quantitative traits measured through the following tests: the Empathy Quotient (EQ), the Autism Spectrum Quotient (AQ), the Systemizing Quotient-Revised (SQ-R), the Embedded Figures Test (EFT), the Reading the Mind in the Eyes Test (RMET), and the Mental Rotation Test (MRT). Two-loci, three-loci, four-loci haplotype analyses, and one seven-loci haplotype analysis were also performed in the AS case–control sample. Results Three SNPs (rs7180158, rs7165604, rs12593579) were significantly associated with AS, and two SNPs (rs9806546, rs11636966) were significantly associated with EQ. Two SNP-SNP pairs, rs12438141-rs1035751 and rs12438141-rs7179514, showed significant association with variation in the EFT scores. One SNP-SNP pair, rs7174437-rs1863455, was significantly associated with variation in the MRT scores. Additionally, a few haplotypes, including a 19 kb genomic region that formed a linkage disequilibrium (LD) block in our sample and contained several nominally significant SNPs, were found to be significantly associated with AS. Conclusion The current study confirms the role of GABRB3 as an important candidate gene in both ASC and normative variation in related endophenotypes. PMID:24321478

Implications of discoveries from genome-wide association studies in current cardiovascular practice

PubMed Central

Jeemon, Panniyammakal; Pettigrew, Kerry; Sainsbury, Christopher; Prabhakaran, Dorairaj; Padmanabhan, Sandosh

2011-01-01

Genome-wide association studies (GWAS) have identified several genetic variants associated with coronary heart disease (CHD), and variations in plasma lipoproteins and blood pressure (BP). Loci corresponding to CDKN2A/CDKN2B/ANRIL, MTHFD1L, CELSR2, PSRC1 and SORT1 genes have been associated with CHD, and TMEM57, DOCK7, CELSR2, APOB, ABCG5, HMGCR, TRIB1, FADS2/S3, LDLR, NCAN and TOMM40-APOE with total cholesterol. Similarly, CELSR2-PSRC1-SORT1, PCSK9, APOB, HMGCR, NCAN-CILP2-PBX4, LDLR, TOMM40-APOE, and APOC1-APOE are associated with variations in low-density lipoprotein cholesterol levels. Altogether, forty, forty three and twenty loci have been associated with high-density lipoprotein cholesterol, triglycerides and BP phenotypes, respectively. Some of these identified loci are common for all the traits, some do not map to functional genes, and some are located in genes that encode for proteins not previously known to be involved in the biological pathway of the trait. GWAS have been successful at identifying new and unexpected genetic loci common to diseases and traits, thus rapidly providing key novel insights into disease biology. Since genotype information is fixed, with minimum biological variability, it is useful in early life risk prediction. However, these variants explain only a small proportion of the observed variance of these traits. Therefore, the utility of genetic determinants in assessing risk at later stages of life has limited immediate clinical impact. The future application of genetic screening will be in identifying risk groups early in life to direct targeted preventive measures. PMID:21860704

Genome-wide association study of suicide attempts in mood disorder patients.

PubMed

Perlis, Roy H; Huang, Jie; Purcell, Shaun; Fava, Maurizio; Rush, A John; Sullivan, Patrick F; Hamilton, Steven P; McMahon, Francis J; Schulze, Thomas G; Schulze, Thomas; Potash, James B; Zandi, Peter P; Willour, Virginia L; Penninx, Brenda W; Boomsma, Dorret I; Vogelzangs, Nicole; Middeldorp, Christel M; Rietschel, Marcella; Nöthen, Markus; Cichon, Sven; Gurling, Hugh; Bass, Nick; McQuillin, Andrew; Hamshere, Marian; Craddock, Nick; Sklar, Pamela; Smoller, Jordan W

2010-12-01

Family and twin studies suggest that liability for suicide attempts is heritable and distinct from mood disorder susceptibility. The authors therefore examined the association between common genomewide variation and lifetime suicide attempts. The authors analyzed data on lifetime suicide attempts from genomewide association studies of bipolar I and II disorder as well as major depressive disorder. Bipolar disorder subjects were drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder cohort, the Wellcome Trust Case Control Consortium bipolar cohort, and the University College London cohort. Replication was pursued in the NIMH Genetic Association Information Network bipolar disorder project and a German clinical cohort. Depression subjects were drawn from the Sequential Treatment Alternatives to Relieve Depression cohort, with replication in the Netherlands Study of Depression and Anxiety/Netherlands Twin Register depression cohort. Strongest evidence of association for suicide attempt in bipolar disorder was observed in a region without identified genes (rs1466846); five loci also showed suggestive evidence of association. In major depression, strongest evidence of association was observed for a single nucleotide polymorphism in ABI3BP, with six loci also showing suggestive association. Replication cohorts did not provide further support for these loci. However, meta-analysis incorporating approximately 8,700 mood disorder subjects identified four additional regions that met the threshold for suggestive association, including the locus containing the gene coding for protein kinase C-epsilon, previously implicated in models of mood and anxiety. The results suggest that inherited risk for suicide among mood disorder patients is unlikely to be the result of individual common variants of large effect. They nonetheless provide suggestive evidence for multiple loci, which merit further investigation.

Genome-Wide Association Study of Suicide Attempts in Mood Disorder Patients

PubMed Central

Perlis, Roy H.; Huang, Jie; Purcell, Shaun; Fava, Maurizio; Rush, A. John; Sullivan, Patrick F.; Hamilton, Steven P.; McMahon, Francis J.; Schulze, Thomas; Potash, James B.; Zandi, Peter P.; Willour, Virginia L.; Penninx, Brenda W.; Boomsma, Dorret I.; Vogelzangs, Nicole; Middeldorp, Christel M.; Rietschel, Marcella; Nöthen, Markus; Cichon, Sven; Gurling, Hugh; Bass, Nick; McQuillin, Andrew; Hamshere, Marian; Craddock, Nick; Sklar, Pamela; Smoller, Jordan W.

2013-01-01

Objective Family and twin studies suggest that liability for suicide attempts is heritable and distinct from mood disorder susceptibility. The authors therefore examined the association between common genomewide variation and lifetime suicide attempts. Method The authors analyzed data on lifetime suicide attempts from genomewide association studies of bipolar I and II disorder as well as major depressive disorder. Bipolar disorder subjects were drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder cohort, the Wellcome Trust Case Control Consortium bipolar cohort, and the University College London cohort. Replication was pursued in the NIMH Genetic Association Information Network bipolar disorder project and a German clinical cohort. Depression subjects were drawn from the Sequential Treatment Alternatives to Relieve Depression cohort, with replication in the Netherlands Study of Depression and Anxiety/Netherlands Twin Register depression cohort. Results Strongest evidence of association for suicide attempt in bipolar disorder was observed in a region without identified genes (rs1466846); five loci also showed suggestive evidence of association. In major depression, strongest evidence of association was observed for a single nucleotide polymorphism in ABI3BP, with six loci also showing suggestive association. Replication cohorts did not provide further support for these loci. However, meta-analysis incorporating approximately 8,700 mood disorder subjects identified four additional regions that met the threshold for suggestive association, including the locus containing the gene coding for protein kinase C-epsilon, previously implicated in models of mood and anxiety. Conclusions The results suggest that inherited risk for suicide among mood disorder patients is unlikely to be the result of individual common variants of large effect. They nonetheless provide suggestive evidence for multiple loci, which merit further investigation. PMID:21041247

Genetic regulation of bone metabolism in the chicken: similarities and differences to Mammalian systems.

PubMed

Johnsson, Martin; Jonsson, Kenneth B; Andersson, Leif; Jensen, Per; Wright, Dominic

2015-05-01

Birds have a unique bone physiology, due to the demands placed on them through egg production. In particular their medullary bone serves as a source of calcium for eggshell production during lay and undergoes continuous and rapid remodelling. We take advantage of the fact that bone traits have diverged massively during chicken domestication to map the genetic basis of bone metabolism in the chicken. We performed a quantitative trait locus (QTL) and expression QTL (eQTL) mapping study in an advanced intercross based on Red Junglefowl (the wild progenitor of the modern domestic chicken) and White Leghorn chickens. We measured femoral bone traits in 456 chickens by peripheral computerised tomography and femoral gene expression in a subset of 125 females from the cross with microarrays. This resulted in 25 loci for female bone traits, 26 loci for male bone traits and 6318 local eQTL loci. We then overlapped bone and gene expression loci, before checking for an association between gene expression and trait values to identify candidate quantitative trait genes for bone traits. A handful of our candidates have been previously associated with bone traits in mice, but our results also implicate unexpected and largely unknown genes in bone metabolism. In summary, by utilising the unique bone metabolism of an avian species, we have identified a number of candidate genes affecting bone allocation and metabolism. These findings can have ramifications not only for the understanding of bone metabolism genetics in general, but could also be used as a potential model for osteoporosis as well as revealing new aspects of vertebrate bone regulation or features that distinguish avian and mammalian bone.

Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index

PubMed Central

Hinney, Anke; Kesselmeier, Miriam; Jall, Sigrid; Volckmar, Anna-Lena; Föcker, Manuel; Antel, Jochen; Heid, Iris M.; Winkler, Thomas W.; Grant, Struan F. A.; Guo, Yiran; Bergen, Andrew W.; Kaye, Walter; Berrettini, Wade; Hakonarson, Hakon; Herpertz-Dahlmann, Beate; de Zwaan, Martina; Herzog, Wolfgang; Ehrlich, Stefan; Zipfel, Stephan; Egberts, Karin Maria; Adan, Roger; Brandys, Marek; van Elburg, Annemarie; Perica, Vesna Boraska; Franklin, Christopher S.; Tschöp, Matthias H.; Zeggini, Eleftheria; Bulik, Cynthia M.; Collier, David; Scherag, André; Müller, Timo D.; Hebebrand, Johannes

2016-01-01

The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation may also be relevant for AN and vice versa. Our primary analysis comprised a cross-trait analysis of the 1000 single nucleotide polymorphisms (SNPs) with the lowest p-values in a genome-wide association meta-analysis (GWAMA) of AN (GCAN) for evidence of association in the largest published GWAMA for BMI (GIANT). Subsequently we performed sex-stratified analyses for these 1000 SNPs. Functional ex vivo studies on four genes ensued. Lastly, a look-up of GWAMA-derived BMI related loci was performed in the AN GWAMA. We detected significant associations (p-values < 5×10−5, Bonferroni corrected p < 0.05) for 9 SNP alleles at 3 independent loci. Interestingly, all AN susceptibility alleles were consistently associated with increased BMI. None of the genes (chr. 10: CTBP2, chr. 19: CCNE1, chr. 2: CARF and NBEAL1; the latter is a region with high linkage disequilibrium) nearest to these SNPs has previously been associated with AN or obesity. Sex-stratified analyses revealed that the strongest BMI signal originated predominantly from females (chr. 10 rs1561589; poverall: 2.47 × 10−06/pfemales: 3.45 × 10−07/pmales: 0.043). Functional ex vivo studies in mice revealed reduced hypothalamic expression of Ctbp2 and Nbeal1 after fasting. Hypothalamic expression of Ctbp2 was increased in diet induced obese (DIO) mice as compared to age-matched lean controls. We observed no evidence for associations for the look-up of BMI related loci in the AN GWAMA. A cross-trait analysis of AN and BMI loci revealed variants at three chromosomal loci with potential joint impact. The chromosome 10 locus is particularly promising given that the association with obesity was primarily driven by females. In addition, the detected altered hypothalamic expression patterns of Ctbp2 and Nbeal1 as a result of fasting and DIO implicate these genes in weight regulation. PMID:27184124

Evidence for three genetic loci involved in both anorexia nervosa risk and variation of body mass index.

PubMed

Hinney, A; Kesselmeier, M; Jall, S; Volckmar, A-L; Föcker, M; Antel, J; Heid, I M; Winkler, T W; Grant, S F A; Guo, Y; Bergen, A W; Kaye, W; Berrettini, W; Hakonarson, H; Herpertz-Dahlmann, B; de Zwaan, M; Herzog, W; Ehrlich, S; Zipfel, S; Egberts, K M; Adan, R; Brandys, M; van Elburg, A; Boraska Perica, V; Franklin, C S; Tschöp, M H; Zeggini, E; Bulik, C M; Collier, D; Scherag, A; Müller, T D; Hebebrand, J

2017-02-01

The maintenance of normal body weight is disrupted in patients with anorexia nervosa (AN) for prolonged periods of time. Prior to the onset of AN, premorbid body mass index (BMI) spans the entire range from underweight to obese. After recovery, patients have reduced rates of overweight and obesity. As such, loci involved in body weight regulation may also be relevant for AN and vice versa. Our primary analysis comprised a cross-trait analysis of the 1000 single-nucleotide polymorphisms (SNPs) with the lowest P-values in a genome-wide association meta-analysis (GWAMA) of AN (GCAN) for evidence of association in the largest published GWAMA for BMI (GIANT). Subsequently we performed sex-stratified analyses for these 1000 SNPs. Functional ex vivo studies on four genes ensued. Lastly, a look-up of GWAMA-derived BMI-related loci was performed in the AN GWAMA. We detected significant associations (P-values <5 × 10 -5 , Bonferroni-corrected P<0.05) for nine SNP alleles at three independent loci. Interestingly, all AN susceptibility alleles were consistently associated with increased BMI. None of the genes (chr. 10: CTBP2, chr. 19: CCNE1, chr. 2: CARF and NBEAL1; the latter is a region with high linkage disequilibrium) nearest to these SNPs has previously been associated with AN or obesity. Sex-stratified analyses revealed that the strongest BMI signal originated predominantly from females (chr. 10 rs1561589; P overall : 2.47 × 10 -06 /P females : 3.45 × 10 -07 /P males : 0.043). Functional ex vivo studies in mice revealed reduced hypothalamic expression of Ctbp2 and Nbeal1 after fasting. Hypothalamic expression of Ctbp2 was increased in diet-induced obese (DIO) mice as compared with age-matched lean controls. We observed no evidence for associations for the look-up of BMI-related loci in the AN GWAMA. A cross-trait analysis of AN and BMI loci revealed variants at three chromosomal loci with potential joint impact. The chromosome 10 locus is particularly promising given that the association with obesity was primarily driven by females. In addition, the detected altered hypothalamic expression patterns of Ctbp2 and Nbeal1 as a result of fasting and DIO implicate these genes in weight regulation.

Age at menarche and age at natural menopause in East Asian women: a genome-wide association study.

PubMed

Shi, Jiajun; Zhang, Ben; Choi, Ji-Yeob; Gao, Yu-Tang; Li, Huaixing; Lu, Wei; Long, Jirong; Kang, Daehee; Xiang, Yong-Bing; Wen, Wanqing; Park, Sue K; Ye, Xingwang; Noh, Dong-Young; Zheng, Ying; Wang, Yiqin; Chung, Seokang; Lin, Xu; Cai, Qiuyin; Shu, Xiao-Ou

2016-12-01

Age at menarche (AM) and age at natural menopause (ANM) are complex traits with a high heritability. Abnormal timing of menarche or menopause is associated with a reduced span of fertility and risk for several age-related diseases including breast, endometrial and ovarian cancer, cardiovascular disease, and osteoporosis. To identify novel genetic loci for AM or ANM in East Asian women and to replicate previously identified loci primarily in women of European ancestry by genome-wide association studies (GWASs), we conducted a two-stage GWAS. Stage I aimed to discover promising novel AM and ANM loci using GWAS data of 8073 women from Shanghai, China. The Stage II replication study used the data from another Chinese GWAS (n = 1230 for AM and n = 1458 for ANM), a Korean GWAS (n = 4215 for AM and n = 1739 for ANM), and de novo genotyping of 2877 additional Chinese women. Previous GWAS-identified loci for AM and ANM were also evaluated. We identified two suggestive menarcheal age loci tagged by rs79195475 at 10q21.3 (beta = -0.118 years, P = 3.4 × 10 -6 ) and rs1023935 at 4p15.1 (beta = -0.145 years, P = 4.9 × 10 -6 ) and one menopausal age locus tagged by rs3818134 at 22q12.2 (beta = -0.276 years, P = 8.8 × 10 -6 ). These suggestive loci warrant a further validation in independent populations. Although limited by low statistical power, we replicated 19 of the 98 menarche loci and 5 of the 20 menopause loci previously identified in women of European ancestry in East Asian women, suggesting a shared genetic architecture for these two traits across populations.

Proactive control of proactive interference using the method of loci.

PubMed

Bass, Willa S; Oswald, Karl M

2014-01-01

Proactive interferencebuilds up with exposure to multiple lists of similar items with a resulting reduction in recall. This study examined the effectiveness of using a proactive strategy of the method of loci to reduce proactive interference in a list recall paradigm of categorically similar words. While all participants reported using some form of strategy to recall list words, this study demonstrated that young adults were able to proactively use the method of loci after 25 min of instruction to reduce proactive interference as compared with other personal spontaneous strategies. The implications of this study are that top-down proactive strategies such as the method of loci can significantly reduce proactive interference, and that the use of image and sequence or location are especially useful in this regard.

Proactive control of proactive interference using the method of loci

PubMed Central

Bass, Willa S.; Oswald, Karl M.

2014-01-01

Proactive interferencebuilds up with exposure to multiple lists of similar items with a resulting reduction in recall. This study examined the effectiveness of using a proactive strategy of the method of loci to reduce proactive interference in a list recall paradigm of categorically similar words. While all participants reported using some form of strategy to recall list words, this study demonstrated that young adults were able to proactively use the method of loci after 25 min of instruction to reduce proactive interference as compared with other personal spontaneous strategies. The implications of this study are that top-down proactive strategies such as the method of loci can significantly reduce proactive interference, and that the use of image and sequence or location are especially useful in this regard. PMID:25157300

Meta-analysis identifies six new susceptibility loci for atrial fibrillation

PubMed Central

Ellinor, Patrick T; Lunetta, Kathryn L; Albert, Christine M; Glazer, Nicole L; Ritchie, Marylyn D; Smith, Albert V; Arking, Dan E; Müller-Nurasyid, Martina; Krijthe, Bouwe P; Lubitz, Steven A; Bis, Joshua C; Chung, Mina K; Dörr, Marcus; Ozaki, Kouichi; Roberts, Jason D; Smith, J Gustav; Pfeufer, Arne; Sinner, Moritz F; Lohman, Kurt; Ding, Jingzhong; Smith, Nicholas L; Smith, Jonathan D; Rienstra, Michiel; Rice, Kenneth M; Van Wagoner, David R; Magnani, Jared W; Wakili, Reza; Clauss, Sebastian; Rotter, Jerome I; Steinbeck, Gerhard; Launer, Lenore J; Davies, Robert W; Borkovich, Matthew; Harris, Tamara B; Lin, Honghuang; Völker, Uwe; Völzke, Henry; Milan, David J; Hofman, Albert; Boerwinkle, Eric; Chen, Lin Y; Soliman, Elsayed Z; Voight, Benjamin F; Li, Guo; Chakravarti, Aravinda; Kubo, Michiaki; Tedrow, Usha B; Rose, Lynda M; Ridker, Paul M; Conen, David; Tsunoda, Tatsuhiko; Furukawa, Tetsushi; Sotoodehnia, Nona; Xu, Siyan; Kamatani, Naoyuki; Levy, Daniel; Nakamura, Yusuke; Parvez, Babar; Mahida, Saagar; Furie, Karen L; Rosand, Jonathan; Muhammad, Raafia; Psaty, Bruce M; Meitinger, Thomas; Perz, Siegfried; Wichmann, H-Erich; Witteman, Jacqueline C M; Kao, W H Linda; Kathiresan, Sekar; Roden, Dan M; Uitterlinden, Andre G; Rivadeneira, Fernando; McKnight, Barbara; Sjögren, Marketa; Newman, Anne B; Liu, Yongmei; Gollob, Michael H; Melander, Olle; Tanaka, Toshihiro; Ch Stricker, Bruno H; Felix, Stephan B; Alonso, Alvaro; Darbar, Dawood; Barnard, John; Chasman, Daniel I; Heckbert, Susan R; Benjamin, Emelia J; Gudnason, Vilmundur; Kääb, Stefan

2012-01-01

Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death1. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 1 0,030 subjects without atrial fibrillation (P < 5 × 10−8). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules. PMID:22544366

A Two-Stage Meta-Analysis Identifies Several New Loci for Parkinson's Disease

PubMed Central

2011-01-01

A previous genome-wide association (GWA) meta-analysis of 12,386 PD cases and 21,026 controls conducted by the International Parkinson's Disease Genomics Consortium (IPDGC) discovered or confirmed 11 Parkinson's disease (PD) loci. This first analysis of the two-stage IPDGC study focused on the set of loci that passed genome-wide significance in the first stage GWA scan. However, the second stage genotyping array, the ImmunoChip, included a larger set of 1,920 SNPs selected on the basis of the GWA analysis. Here, we analyzed this set of 1,920 SNPs, and we identified five additional PD risk loci (combined p<5×10−10, PARK16/1q32, STX1B/16p11, FGF20/8p22, STBD1/4q21, and GPNMB/7p15). Two of these five loci have been suggested by previous association studies (PARK16/1q32, FGF20/8p22), and this study provides further support for these findings. Using a dataset of post-mortem brain samples assayed for gene expression (n = 399) and methylation (n = 292), we identified methylation and expression changes associated with PD risk variants in PARK16/1q32, GPNMB/7p15, and STX1B/16p11 loci, hence suggesting potential molecular mechanisms and candidate genes at these risk loci. PMID:21738488

Mapping loci influencing blood pressure in the Framingham pedigrees using model-free LOD score analysis of a quantitative trait.

PubMed

Knight, Jo; North, Bernard V; Sham, Pak C; Curtis, David

2003-12-31

This paper presents a method of performing model-free LOD-score based linkage analysis on quantitative traits. It is implemented in the QMFLINK program. The method is used to perform a genome screen on the Framingham Heart Study data. A number of markers that show some support for linkage in our study coincide substantially with those implicated in other linkage studies of hypertension. Although the new method needs further testing on additional real and simulated data sets we can already say that it is straightforward to apply and may offer a useful complementary approach to previously available methods for the linkage analysis of quantitative traits.

Mapping loci influencing blood pressure in the Framingham pedigrees using model-free LOD score analysis of a quantitative trait

PubMed Central

Knight, Jo; North, Bernard V; Sham, Pak C; Curtis, David

2003-01-01

This paper presents a method of performing model-free LOD-score based linkage analysis on quantitative traits. It is implemented in the QMFLINK program. The method is used to perform a genome screen on the Framingham Heart Study data. A number of markers that show some support for linkage in our study coincide substantially with those implicated in other linkage studies of hypertension. Although the new method needs further testing on additional real and simulated data sets we can already say that it is straightforward to apply and may offer a useful complementary approach to previously available methods for the linkage analysis of quantitative traits. PMID:14975142

An update on the genetic architecture of hyperuricemia and gout.

PubMed

Merriman, Tony R

2015-04-10

Genome-wide association studies that scan the genome for common genetic variants associated with phenotype have greatly advanced medical knowledge. Hyperuricemia is no exception, with 28 loci identified. However, genetic control of pathways determining gout in the presence of hyperuricemia is still poorly understood. Two important pathways determining hyperuricemia have been confirmed (renal and gut excretion of uric acid with glycolysis now firmly implicated). Major urate loci are SLC2A9 and ABCG2. Recent studies show that SLC2A9 is involved in renal and gut excretion of uric acid and is implicated in antioxidant defense. Although etiological variants at SLC2A9 are yet to be identified, it is clear that considerable genetic complexity exists at the SLC2A9 locus, with multiple statistically independent genetic variants and local epistatic interactions. The positions of implicated genetic variants within or near chromatin regions involved in transcriptional control suggest that this mechanism (rather than structural changes in SLC2A9) is important in regulating the activity of SLC2A9. ABCG2 is involved primarily in extra-renal uric acid under-excretion with the etiological variant influencing expression. At the other 26 loci, probable causal genes can be identified at three (PDZK1, SLC22A11, and INHBB) with strong candidates at a further 10 loci. Confirmation of the causal gene will require a combination of re-sequencing, trans-ancestral mapping, and correlation of genetic association data with expression data. As expected, the urate loci associate with gout, although inconsistent effect sizes for gout require investigation. Finally, there has been no genome-wide association study using clinically ascertained cases to investigate the causes of gout in the presence of hyperuricemia. In such a study, use of asymptomatic hyperurcemic controls would be expected to increase the ability to detect genetic associations with gout.

High-Density Genotyping of Immune Loci in Koreans and Europeans Identifies Eight New Rheumatoid Arthritis Risk Loci

PubMed Central

Kim, Kwangwoo; Bang, So-Young; Lee, Hye-Soon; Cho, Soo-Kyung; Choi, Chan-Bum; Sung, Yoon-Kyoung; Kim, Tae-Hwan; Jun, Jae-Bum; Yoo, Dae Hyun; Kang, Young Mo; Kim, Seong-Kyu; Suh, Chang-Hee; Shim, Seung-Cheol; Lee, Shin-Seok; Lee, Jisoo; Chung, Won Tae; Choe, Jung-Yoon; Shin, Hyoung Doo; Lee, Jong-Young; Han, Bok-Ghee; Nath, Swapan K.; Eyre, Steve; Bowes, John; Pappas, Dimitrios A.; Kremer, Joel M.; Gonzalez-Gay, Miguel A; Rodriguez-Rodriguez, Luis; Ärlestig, Lisbeth; Okada, Yukinori; Diogo, Dorothée; Liao, Katherine P.; Karlson, Elizabeth W.; Raychaudhuri, Soumya; Rantapää-Dahlqvist, Solbritt; Martin, Javier; Klareskog, Lars; Padyukov, Leonid; Gregersen, Peter K.; Worthington, Jane; Greenberg, Jeffrey D.; Plenge, Robert M.; Bae, Sang-Cheol

2015-01-01

Objective A highly polygenic etiology and high degree of allele-sharing between ancestries have been well-elucidated in genetic studies of rheumatoid arthritis. Recently, the high-density genotyping array Immunochip for immune disease loci identified 14 new rheumatoid arthritis risk loci among individuals of European ancestry. Here, we aimed to identify new rheumatoid arthritis risk loci using Korean-specific Immunochip data. Methods We analyzed Korean rheumatoid arthritis case-control samples using the Immunochip and GWAS array to search for new risk alleles of rheumatoid arthritis with anti-citrullinated peptide antibodies. To increase power, we performed a meta-analysis of Korean data with previously published European Immunochip and GWAS data, for a total sample size of 9,299 Korean and 45,790 European case-control samples. Results We identified 8 new rheumatoid arthritis susceptibility loci (TNFSF4, LBH, EOMES, ETS1–FLI1, COG6, RAD51B, UBASH3A and SYNGR1) that passed a genome-wide significance threshold (p<5×10−8), with evidence for three independent risk alleles at 1q25/TNFSF4. The risk alleles from the 7 new loci except for the TNFSF4 locus (monomorphic in Koreans), together with risk alleles from previously established RA risk loci, exhibited a high correlation of effect sizes between ancestries. Further, we refined the number of SNPs that represent potentially causal variants through a trans-ethnic comparison of densely genotyped SNPs. Conclusion This study demonstrates the advantage of dense-mapping and trans-ancestral analysis for identification of potentially causal SNPs. In addition, our findings support the importance of T cells in the pathogenesis and the fact of frequent overlap of risk loci among diverse autoimmune diseases. PMID:24532676

Cross-disease Meta-analysis of Genome-wide Association Studies for Systemic Sclerosis and Rheumatoid Arthritis Reveals IRF4 as a New Common Susceptibility Locus

PubMed Central

López-Isac, Elena; Martín, Jose-Ezequiel; Assassi, Shervin; Simeón, Carmen P; Carreira, Patricia; Ortego-Centeno, Norberto; Freire, Mayka; Beltrán, Emma; Narváez, Javier; Alegre-Sancho, Juan J; Fernández-Gutiérrez, Benjamín; Balsa, Alejandro; Ortiz, Ana M; González-Gay, Miguel A; Beretta, Lorenzo; Santaniello, Alessandro; Bellocchi, Chiara; Lunardi, Claudio; Moroncini, Gianluca; Gabrielli, Armando; Witte, Torsten; Hunzelmann, Nicolas; Distler, Jörg HW; Riekemasten, Gabriella; van der Helm-van Mil, Annete H; de Vries-Bouwstra, Jeska; Magro-Checa, Cesar; Voskuyl, Alexandre E; Vonk, Madelon C; Molberg, Øyvind; Merriman, Tony; Hesselstrand, Roger; Nordin, Annika; Padyukov, Leonid; Herrick, Ariane; Eyre, Steve; Koeleman, Bobby PC; Denton, Christopher P; Fonseca, Carmen; Radstake, Timothy RDJ; Worthington, Jane; Mayes, Maureen D; Martín, Javier

2017-01-01

Objectives Systemic sclerosis (SSc) and rheumatoid arthritis (RA) are autoimmune diseases that share clinical and immunological characteristics. To date, several shared SSc-RA loci have been identified independently. In this study, we aimed to systematically search for new common SSc-RA loci through an inter-disease meta-GWAS strategy. Methods We performed a meta-analysis combining GWAS datasets of SSc and RA using a strategy that allowed identification of loci with both same-direction and opposing-direction allelic effects. The top single-nucleotide polymorphisms (SNPs) were followed-up in independent SSc and RA case-control cohorts. This allowed us to increase the sample size to a total of 8,830 SSc patients, 16,870 RA patients and 43,393 controls. Results The cross-disease meta-analysis of the GWAS datasets identified several loci with nominal association signals (P-value < 5 × 10-6), which also showed evidence of association in the disease-specific GWAS scan. These loci included several genomic regions not previously reported as shared loci, besides risk factors associated with both diseases in previous studies. The follow-up of the putatively new SSc-RA loci identified IRF4 as a shared risk factor for these two diseases (Pcombined = 3.29 × 10-12). In addition, the analysis of the biological relevance of the known SSc-RA shared loci pointed to the type I interferon and the interleukin 12 signaling pathways as the main common etiopathogenic factors. Conclusions Our study has identified a novel shared locus, IRF4, for SSc and RA and highlighted the usefulness of cross-disease GWAS meta-analysis in the identification of common risk loci. PMID:27111665

Comparing GWAS Results of Complex Traits Using Full Genetic Model and Additive Models for Revealing Genetic Architecture

PubMed Central

Monir, Md. Mamun; Zhu, Jun

2017-01-01

Most of the genome-wide association studies (GWASs) for human complex diseases have ignored dominance, epistasis and ethnic interactions. We conducted comparative GWASs for total cholesterol using full model and additive models, which illustrate the impacts of the ignoring genetic variants on analysis results and demonstrate how genetic effects of multiple loci could differ across different ethnic groups. There were 15 quantitative trait loci with 13 individual loci and 3 pairs of epistasis loci identified by full model, whereas only 14 loci (9 common loci and 5 different loci) identified by multi-loci additive model. Again, 4 full model detected loci were not detected using multi-loci additive model. PLINK-analysis identified two loci and GCTA-analysis detected only one locus with genome-wide significance. Full model identified three previously reported genes as well as several new genes. Bioinformatics analysis showed some new genes are related with cholesterol related chemicals and/or diseases. Analyses of cholesterol data and simulation studies revealed that the full model performs were better than the additive-model performs in terms of detecting power and unbiased estimations of genetic variants of complex traits. PMID:28079101

The impact of low-frequency and rare variants on lipid levels

PubMed Central

Surakka, Ida; Horikoshi, Momoko; Mägi, Reedik; Sarin, Antti-Pekka; Mahajan, Anubha; Lagou, Vasiliki; Marullo, Letizia; Ferreira, Teresa; Miraglio, Benjamin; Timonen, Sanna; Kettunen, Johannes; Pirinen, Matti; Karjalainen, Juha; Thorleifsson, Gudmar; Hägg, Sara; Hottenga, Jouke-Jan; Isaacs, Aaron; Ladenvall, Claes; Beekman, Marian; Esko, Tõnu; Ried, Janina S; Nelson, Christopher P; Willenborg, Christina; Gustafsson, Stefan; Westra, Harm-Jan; Blades, Matthew; de Craen, Anton JM; de Geus, Eco J; Deelen, Joris; Grallert, Harald; Hamsten, Anders; Havulinna, Aki S.; Hengstenberg, Christian; Houwing-Duistermaat, Jeanine J; Hyppönen, Elina; Karssen, Lennart C; Lehtimäki, Terho; Lyssenko, Valeriya; Magnusson, Patrik KE; Mihailov, Evelin; Müller-Nurasyid, Martina; Mpindi, John-Patrick; Pedersen, Nancy L; Penninx, Brenda WJH; Perola, Markus; Pers, Tune H; Peters, Annette; Rung, Johan; Smit, Johannes H; Steinthorsdottir, Valgerdur; Tobin, Martin D; Tsernikova, Natalia; van Leeuwen, Elisabeth M; Viikari, Jorma S; Willems, Sara M; Willemsen, Gonneke; Schunkert, Heribert; Erdmann, Jeanette; Samani, Nilesh J; Kaprio, Jaakko; Lind, Lars; Gieger, Christian; Metspalu, Andres; Slagboom, P Eline; Groop, Leif; van Duijn, Cornelia M; Eriksson, Johan G; Jula, Antti; Salomaa, Veikko; Boomsma, Dorret I; Power, Christine; Raitakari, Olli T; Ingelsson, Erik; Järvelin, Marjo-Riitta; Stefansson, Kari; Franke, Lude; Ikonen, Elina; Kallioniemi, Olli; Pietiäinen, Vilja; Lindgren, Cecilia M; Thorsteinsdottir, Unnur; Palotie, Aarno; McCarthy, Mark I; Morris, Andrew P; Prokopenko, Inga; Ripatti, Samuli

2016-01-01

Using a genome-wide screen of 9.6 million genetic variants achieved through 1000 Genomes imputation in 62,166 samples, we identify association to lipids in 93 loci including 79 previously identified loci with new lead-SNPs, 10 new loci, 15 loci with a low-frequency and 10 loci with missense lead-SNPs, and, 2 loci with an accumulation of rare variants. In six loci, SNPs with established function in lipid genetics (CELSR2, GCKR, LIPC, and APOE), or candidate missense mutations with predicted damaging function (CD300LG and TM6SF2), explained the locus associations. The low-frequency variants increased the proportion of variance explained, particularly for LDL-C and TC. Altogether, our results highlight the impact of low-frequency variants in complex traits and show that imputation offers a cost-effective alternative to re-sequencing. PMID:25961943

Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer's disease.

PubMed

Gjoneska, Elizabeta; Pfenning, Andreas R; Mathys, Hansruedi; Quon, Gerald; Kundaje, Anshul; Tsai, Li-Huei; Kellis, Manolis

2015-02-19

Alzheimer's disease (AD) is a severe age-related neurodegenerative disorder characterized by accumulation of amyloid-β plaques and neurofibrillary tangles, synaptic and neuronal loss, and cognitive decline. Several genes have been implicated in AD, but chromatin state alterations during neurodegeneration remain uncharacterized. Here we profile transcriptional and chromatin state dynamics across early and late pathology in the hippocampus of an inducible mouse model of AD-like neurodegeneration. We find a coordinated downregulation of synaptic plasticity genes and regulatory regions, and upregulation of immune response genes and regulatory regions, which are targeted by factors that belong to the ETS family of transcriptional regulators, including PU.1. Human regions orthologous to increasing-level enhancers show immune-cell-specific enhancer signatures as well as immune cell expression quantitative trait loci, while decreasing-level enhancer orthologues show fetal-brain-specific enhancer activity. Notably, AD-associated genetic variants are specifically enriched in increasing-level enhancer orthologues, implicating immune processes in AD predisposition. Indeed, increasing enhancers overlap known AD loci lacking protein-altering variants, and implicate additional loci that do not reach genome-wide significance. Our results reveal new insights into the mechanisms of neurodegeneration and establish the mouse as a useful model for functional studies of AD regulatory regions.

1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function

PubMed Central

Gorski, Mathias; van der Most, Peter J.; Teumer, Alexander; Chu, Audrey Y.; Li, Man; Mijatovic, Vladan; Nolte, Ilja M.; Cocca, Massimiliano; Taliun, Daniel; Gomez, Felicia; Li, Yong; Tayo, Bamidele; Tin, Adrienne; Feitosa, Mary F.; Aspelund, Thor; Attia, John; Biffar, Reiner; Bochud, Murielle; Boerwinkle, Eric; Borecki, Ingrid; Bottinger, Erwin P.; Chen, Ming-Huei; Chouraki, Vincent; Ciullo, Marina; Coresh, Josef; Cornelis, Marilyn C.; Curhan, Gary C.; d’Adamo, Adamo Pio; Dehghan, Abbas; Dengler, Laura; Ding, Jingzhong; Eiriksdottir, Gudny; Endlich, Karlhans; Enroth, Stefan; Esko, Tõnu; Franco, Oscar H.; Gasparini, Paolo; Gieger, Christian; Girotto, Giorgia; Gottesman, Omri; Gudnason, Vilmundur; Gyllensten, Ulf; Hancock, Stephen J.; Harris, Tamara B.; Helmer, Catherine; Höllerer, Simon; Hofer, Edith; Hofman, Albert; Holliday, Elizabeth G.; Homuth, Georg; Hu, Frank B.; Huth, Cornelia; Hutri-Kähönen, Nina; Hwang, Shih-Jen; Imboden, Medea; Johansson, Åsa; Kähönen, Mika; König, Wolfgang; Kramer, Holly; Krämer, Bernhard K.; Kumar, Ashish; Kutalik, Zoltan; Lambert, Jean-Charles; Launer, Lenore J.; Lehtimäki, Terho; de Borst, Martin; Navis, Gerjan; Swertz, Morris; Liu, Yongmei; Lohman, Kurt; Loos, Ruth J. F.; Lu, Yingchang; Lyytikäinen, Leo-Pekka; McEvoy, Mark A.; Meisinger, Christa; Meitinger, Thomas; Metspalu, Andres; Metzger, Marie; Mihailov, Evelin; Mitchell, Paul; Nauck, Matthias; Oldehinkel, Albertine J.; Olden, Matthias; WJH Penninx, Brenda; Pistis, Giorgio; Pramstaller, Peter P.; Probst-Hensch, Nicole; Raitakari, Olli T.; Rettig, Rainer; Ridker, Paul M.; Rivadeneira, Fernando; Robino, Antonietta; Rosas, Sylvia E.; Ruderfer, Douglas; Ruggiero, Daniela; Saba, Yasaman; Sala, Cinzia; Schmidt, Helena; Schmidt, Reinhold; Scott, Rodney J.; Sedaghat, Sanaz; Smith, Albert V.; Sorice, Rossella; Stengel, Benedicte; Stracke, Sylvia; Strauch, Konstantin; Toniolo, Daniela; Uitterlinden, Andre G.; Ulivi, Sheila; Viikari, Jorma S.; Völker, Uwe; Vollenweider, Peter; Völzke, Henry; Vuckovic, Dragana; Waldenberger, Melanie; Jin Wang, Jie; Yang, Qiong; Chasman, Daniel I.; Tromp, Gerard; Snieder, Harold; Heid, Iris M.; Fox, Caroline S.; Köttgen, Anna; Pattaro, Cristian; Böger, Carsten A.; Fuchsberger, Christian

2017-01-01

HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10−8 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples. PMID:28452372

1000 Genomes-based meta-analysis identifies 10 novel loci for kidney function.

PubMed

Gorski, Mathias; van der Most, Peter J; Teumer, Alexander; Chu, Audrey Y; Li, Man; Mijatovic, Vladan; Nolte, Ilja M; Cocca, Massimiliano; Taliun, Daniel; Gomez, Felicia; Li, Yong; Tayo, Bamidele; Tin, Adrienne; Feitosa, Mary F; Aspelund, Thor; Attia, John; Biffar, Reiner; Bochud, Murielle; Boerwinkle, Eric; Borecki, Ingrid; Bottinger, Erwin P; Chen, Ming-Huei; Chouraki, Vincent; Ciullo, Marina; Coresh, Josef; Cornelis, Marilyn C; Curhan, Gary C; d'Adamo, Adamo Pio; Dehghan, Abbas; Dengler, Laura; Ding, Jingzhong; Eiriksdottir, Gudny; Endlich, Karlhans; Enroth, Stefan; Esko, Tõnu; Franco, Oscar H; Gasparini, Paolo; Gieger, Christian; Girotto, Giorgia; Gottesman, Omri; Gudnason, Vilmundur; Gyllensten, Ulf; Hancock, Stephen J; Harris, Tamara B; Helmer, Catherine; Höllerer, Simon; Hofer, Edith; Hofman, Albert; Holliday, Elizabeth G; Homuth, Georg; Hu, Frank B; Huth, Cornelia; Hutri-Kähönen, Nina; Hwang, Shih-Jen; Imboden, Medea; Johansson, Åsa; Kähönen, Mika; König, Wolfgang; Kramer, Holly; Krämer, Bernhard K; Kumar, Ashish; Kutalik, Zoltan; Lambert, Jean-Charles; Launer, Lenore J; Lehtimäki, Terho; de Borst, Martin; Navis, Gerjan; Swertz, Morris; Liu, Yongmei; Lohman, Kurt; Loos, Ruth J F; Lu, Yingchang; Lyytikäinen, Leo-Pekka; McEvoy, Mark A; Meisinger, Christa; Meitinger, Thomas; Metspalu, Andres; Metzger, Marie; Mihailov, Evelin; Mitchell, Paul; Nauck, Matthias; Oldehinkel, Albertine J; Olden, Matthias; Wjh Penninx, Brenda; Pistis, Giorgio; Pramstaller, Peter P; Probst-Hensch, Nicole; Raitakari, Olli T; Rettig, Rainer; Ridker, Paul M; Rivadeneira, Fernando; Robino, Antonietta; Rosas, Sylvia E; Ruderfer, Douglas; Ruggiero, Daniela; Saba, Yasaman; Sala, Cinzia; Schmidt, Helena; Schmidt, Reinhold; Scott, Rodney J; Sedaghat, Sanaz; Smith, Albert V; Sorice, Rossella; Stengel, Benedicte; Stracke, Sylvia; Strauch, Konstantin; Toniolo, Daniela; Uitterlinden, Andre G; Ulivi, Sheila; Viikari, Jorma S; Völker, Uwe; Vollenweider, Peter; Völzke, Henry; Vuckovic, Dragana; Waldenberger, Melanie; Jin Wang, Jie; Yang, Qiong; Chasman, Daniel I; Tromp, Gerard; Snieder, Harold; Heid, Iris M; Fox, Caroline S; Köttgen, Anna; Pattaro, Cristian; Böger, Carsten A; Fuchsberger, Christian

2017-04-28

HapMap imputed genome-wide association studies (GWAS) have revealed >50 loci at which common variants with minor allele frequency >5% are associated with kidney function. GWAS using more complete reference sets for imputation, such as those from The 1000 Genomes project, promise to identify novel loci that have been missed by previous efforts. To investigate the value of such a more complete variant catalog, we conducted a GWAS meta-analysis of kidney function based on the estimated glomerular filtration rate (eGFR) in 110,517 European ancestry participants using 1000 Genomes imputed data. We identified 10 novel loci with p-value < 5 × 10 -8 previously missed by HapMap-based GWAS. Six of these loci (HOXD8, ARL15, PIK3R1, EYA4, ASTN2, and EPB41L3) are tagged by common SNPs unique to the 1000 Genomes reference panel. Using pathway analysis, we identified 39 significant (FDR < 0.05) genes and 127 significantly (FDR < 0.05) enriched gene sets, which were missed by our previous analyses. Among those, the 10 identified novel genes are part of pathways of kidney development, carbohydrate metabolism, cardiac septum development and glucose metabolism. These results highlight the utility of re-imputing from denser reference panels, until whole-genome sequencing becomes feasible in large samples.

Polymorphic microsatellite loci for two Atlantic oyster species: Crassostrea rhizophorae and C. gasar.

PubMed

Cavaleiro, Nathalia P; Solé-Cava, Antonio M; Lazoski, Cristiano; Cunha, Haydée A

2013-12-01

Using a CA/CAA enriched library screening procedure, we isolated and characterised a total of seventeen polymorphic microsatellite loci for two species of Crassostrea with recognised economic importance. Eleven microsatellite loci were developed for C. rhizophorae, a Western Atlantic species for which no microsatellites were previously known. Another six loci were developed for C. gasar, a species that occurs on both sides of the South Atlantic, adding to the ten loci previously described for the species. The levels of polymorphism were estimated using 24 C. rhizophorae from Southeast Brazil (São Paulo) and 23 C. gasar individuals from North Brazil (Maranhão). The number of alleles per polymorphic locus varied from 3 to 27, and the observed and expected heterozygosities ranged between 0.174 and 0.958 and between 0.237 and 0.972 in C. rhizophorae and C. gasar, respectively. No linkage disequilibrium was found between any locus pair, and four of them exhibited deviations from Hardy-Weinberg expectations. Of the 17 loci developed, 8 cross-amplified in C. gigas and 13 in C. virginica. These markers are useful for evolution and population genetics studies of Crassostrea species and may provide fundamental data for the future cultivation of native oysters in Western Atlantic.

Isolation and characterization of ten novel microsatellite loci in the red-winged tinamou (Rhynchotus rufescens, Tinamiformes, Aves) and cross-amplification in other tinamous.

PubMed

Santos, Dimas O; Moreira, Lucas R; Tonhati, Humberto; Caparroz, Renato

2012-04-01

We describe the isolation and characterization of ten microsatellite loci from the red-winged tinamou (Rhynchotus rufescens) and also evaluated the cross-amplification of these loci and other ten loci previously developed for the great tinamou (Tinamus major) in other tinamous. Genetic variability was assessed using 24 individuals. Six loci were polymorphic with moderate to high number of alleles per locus (2-12 alleles) and showed expected heterozygosity (HE) ranging from 0.267 to 0.860. All loci conformed to the Hardy-Weinberg expectation and linkage disequilibrium was not significant for any pair of loci. This battery of polymorphic loci showed high paternity exclusion probability (0.986) and low genetic identity probability (4.95 × 10(-5)), proving to be helpful for parentage tests and population analyses in the red-winged tinamou. The cross-amplification was moderate where of the 160 locus/taxon combinations, 46 (28.75%) successfully amplified.

GAB2 as an Alzheimer Disease Susceptibility Gene

PubMed Central

Schjeide, Brit-Maren M.; Hooli, Basavaraj; Parkinson, Michele; Hogan, Meghan F.; DiVito, Jason; Mullin, Kristina; Blacker, Deborah; Tanzi, Rudolph E.; Bertram, Lars

2009-01-01

Background Genomewide association (GWA) studies have recently implicated 4 novel Alzheimer disease (AD) susceptibility loci (GAB2, GOLM1, and 2 uncharacterized loci to date on chromosomes 9p and 15q). To our knowledge, these findings have not been independently replicated. Objective To assess these GWA findings in 4 large data sets of families affected by AD. Design Follow-up of genetic association findings in previous studies. Setting Academic research. Participants More than 4000 DNA samples from almost 1300 families affected with AD. Main Outcome Measures Genetic association analysis testing of 4 GWA signals (rs7101429 [GAB2], rs7019241 [GOLM1], rs10519262 [chromosome 15q], and rs9886784 [chromosome 9p]) using family-based methods. Results In the combined analyses, only rs7101429 in GAB2 yielded significant evidence of association with the same allele as in the original GWA study (P = .002). The results are in agreement with recent meta-analyses of this and other GAB2 polymorphisms suggesting approximately a 30% decrease in risk for AD among carriers of the minor alleles. None of the other 3 tested loci showed consistent evidence for association with AD across the investigated data sets. Conclusions GAB2 contains genetic variants that may lead to a modest change in the risk for AD. Despite these promising results, more data from independent samples are needed to better evaluate the potential contribution of GAB2 to AD risk in the general population. PMID:19204163

Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations.

PubMed

Liu, Jimmy Z; van Sommeren, Suzanne; Huang, Hailiang; Ng, Siew C; Alberts, Rudi; Takahashi, Atsushi; Ripke, Stephan; Lee, James C; Jostins, Luke; Shah, Tejas; Abedian, Shifteh; Cheon, Jae Hee; Cho, Judy; Dayani, Naser E; Franke, Lude; Fuyuno, Yuta; Hart, Ailsa; Juyal, Ramesh C; Juyal, Garima; Kim, Won Ho; Morris, Andrew P; Poustchi, Hossein; Newman, William G; Midha, Vandana; Orchard, Timothy R; Vahedi, Homayon; Sood, Ajit; Sung, Joseph Y; Malekzadeh, Reza; Westra, Harm-Jan; Yamazaki, Keiko; Yang, Suk-Kyun; Barrett, Jeffrey C; Alizadeh, Behrooz Z; Parkes, Miles; Bk, Thelma; Daly, Mark J; Kubo, Michiaki; Anderson, Carl A; Weersma, Rinse K

2015-09-01

Ulcerative colitis and Crohn's disease are the two main forms of inflammatory bowel disease (IBD). Here we report the first trans-ancestry association study of IBD, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and Immunochip data from 9,846 individuals of East Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time. For the majority of the IBD risk loci, the direction and magnitude of effect are consistent in European and non-European cohorts. Nevertheless, we observe genetic heterogeneity between divergent populations at several established risk loci driven by differences in allele frequency (NOD2) or effect size (TNFSF15 and ATG16L1) or a combination of these factors (IL23R and IRGM). Our results provide biological insights into the pathogenesis of IBD and demonstrate the usefulness of trans-ancestry association studies for mapping loci associated with complex diseases and understanding genetic architecture across diverse populations.

New genetic loci link adipose and insulin biology to body fat distribution.

PubMed

Shungin, Dmitry; Winkler, Thomas W; Croteau-Chonka, Damien C; Ferreira, Teresa; Locke, Adam E; Mägi, Reedik; Strawbridge, Rona J; Pers, Tune H; Fischer, Krista; Justice, Anne E; Workalemahu, Tsegaselassie; Wu, Joseph M W; Buchkovich, Martin L; Heard-Costa, Nancy L; Roman, Tamara S; Drong, Alexander W; Song, Ci; Gustafsson, Stefan; Day, Felix R; Esko, Tonu; Fall, Tove; Kutalik, Zoltán; Luan, Jian'an; Randall, Joshua C; Scherag, André; Vedantam, Sailaja; Wood, Andrew R; Chen, Jin; Fehrmann, Rudolf; Karjalainen, Juha; Kahali, Bratati; Liu, Ching-Ti; Schmidt, Ellen M; Absher, Devin; Amin, Najaf; Anderson, Denise; Beekman, Marian; Bragg-Gresham, Jennifer L; Buyske, Steven; Demirkan, Ayse; Ehret, Georg B; Feitosa, Mary F; Goel, Anuj; Jackson, Anne U; Johnson, Toby; Kleber, Marcus E; Kristiansson, Kati; Mangino, Massimo; Leach, Irene Mateo; Medina-Gomez, Carolina; Palmer, Cameron D; Pasko, Dorota; Pechlivanis, Sonali; Peters, Marjolein J; Prokopenko, Inga; Stančáková, Alena; Sung, Yun Ju; Tanaka, Toshiko; Teumer, Alexander; Van Vliet-Ostaptchouk, Jana V; Yengo, Loïc; Zhang, Weihua; Albrecht, Eva; Ärnlöv, Johan; Arscott, Gillian M; Bandinelli, Stefania; Barrett, Amy; Bellis, Claire; Bennett, Amanda J; Berne, Christian; Blüher, Matthias; Böhringer, Stefan; Bonnet, Fabrice; Böttcher, Yvonne; Bruinenberg, Marcel; Carba, Delia B; Caspersen, Ida H; Clarke, Robert; Daw, E Warwick; Deelen, Joris; Deelman, Ewa; Delgado, Graciela; Doney, Alex Sf; Eklund, Niina; Erdos, Michael R; Estrada, Karol; Eury, Elodie; Friedrich, Nele; Garcia, Melissa E; Giedraitis, Vilmantas; Gigante, Bruna; Go, Alan S; Golay, Alain; Grallert, Harald; Grammer, Tanja B; Gräßler, Jürgen; Grewal, Jagvir; Groves, Christopher J; Haller, Toomas; Hallmans, Goran; Hartman, Catharina A; Hassinen, Maija; Hayward, Caroline; Heikkilä, Kauko; Herzig, Karl-Heinz; Helmer, Quinta; Hillege, Hans L; Holmen, Oddgeir; Hunt, Steven C; Isaacs, Aaron; Ittermann, Till; James, Alan L; Johansson, Ingegerd; Juliusdottir, Thorhildur; Kalafati, Ioanna-Panagiota; Kinnunen, Leena; Koenig, Wolfgang; Kooner, Ishminder K; Kratzer, Wolfgang; Lamina, Claudia; Leander, Karin; Lee, Nanette R; Lichtner, Peter; Lind, Lars; Lindström, Jaana; Lobbens, Stéphane; Lorentzon, Mattias; Mach, François; Magnusson, Patrik Ke; Mahajan, Anubha; McArdle, Wendy L; Menni, Cristina; Merger, Sigrun; Mihailov, Evelin; Milani, Lili; Mills, Rebecca; Moayyeri, Alireza; Monda, Keri L; Mooijaart, Simon P; Mühleisen, Thomas W; Mulas, Antonella; Müller, Gabriele; Müller-Nurasyid, Martina; Nagaraja, Ramaiah; Nalls, Michael A; Narisu, Narisu; Glorioso, Nicola; Nolte, Ilja M; Olden, Matthias; Rayner, Nigel W; Renstrom, Frida; Ried, Janina S; Robertson, Neil R; Rose, Lynda M; Sanna, Serena; Scharnagl, Hubert; Scholtens, Salome; Sennblad, Bengt; Seufferlein, Thomas; Sitlani, Colleen M; Smith, Albert Vernon; Stirrups, Kathleen; Stringham, Heather M; Sundström, Johan; Swertz, Morris A; Swift, Amy J; Syvänen, Ann-Christine; Tayo, Bamidele O; Thorand, Barbara; Thorleifsson, Gudmar; Tomaschitz, Andreas; Troffa, Chiara; van Oort, Floor Va; Verweij, Niek; Vonk, Judith M; Waite, Lindsay L; Wennauer, Roman; Wilsgaard, Tom; Wojczynski, Mary K; Wong, Andrew; Zhang, Qunyuan; Zhao, Jing Hua; Brennan, Eoin P; Choi, Murim; Eriksson, Per; Folkersen, Lasse; Franco-Cereceda, Anders; Gharavi, Ali G; Hedman, Åsa K; Hivert, Marie-France; Huang, Jinyan; Kanoni, Stavroula; Karpe, Fredrik; Keildson, Sarah; Kiryluk, Krzysztof; Liang, Liming; Lifton, Richard P; Ma, Baoshan; McKnight, Amy J; McPherson, Ruth; Metspalu, Andres; Min, Josine L; Moffatt, Miriam F; Montgomery, Grant W; Murabito, Joanne M; Nicholson, George; Nyholt, Dale R; Olsson, Christian; Perry, John Rb; Reinmaa, Eva; Salem, Rany M; Sandholm, Niina; Schadt, Eric E; Scott, Robert A; Stolk, Lisette; Vallejo, Edgar E; Westra, Harm-Jan; Zondervan, Krina T; Amouyel, Philippe; Arveiler, Dominique; Bakker, Stephan Jl; Beilby, John; Bergman, Richard N; Blangero, John; Brown, Morris J; Burnier, Michel; Campbell, Harry; Chakravarti, Aravinda; Chines, Peter S; Claudi-Boehm, Simone; Collins, Francis S; Crawford, Dana C; Danesh, John; de Faire, Ulf; de Geus, Eco Jc; Dörr, Marcus; Erbel, Raimund; Eriksson, Johan G; Farrall, Martin; Ferrannini, Ele; Ferrières, Jean; Forouhi, Nita G; Forrester, Terrence; Franco, Oscar H; Gansevoort, Ron T; Gieger, Christian; Gudnason, Vilmundur; Haiman, Christopher A; Harris, Tamara B; Hattersley, Andrew T; Heliövaara, Markku; Hicks, Andrew A; Hingorani, Aroon D; Hoffmann, Wolfgang; Hofman, Albert; Homuth, Georg; Humphries, Steve E; Hyppönen, Elina; Illig, Thomas; Jarvelin, Marjo-Riitta; Johansen, Berit; Jousilahti, Pekka; Jula, Antti M; Kaprio, Jaakko; Kee, Frank; Keinanen-Kiukaanniemi, Sirkka M; Kooner, Jaspal S; Kooperberg, Charles; Kovacs, Peter; Kraja, Aldi T; Kumari, Meena; Kuulasmaa, Kari; Kuusisto, Johanna; Lakka, Timo A; Langenberg, Claudia; Le Marchand, Loic; Lehtimäki, Terho; Lyssenko, Valeriya; Männistö, Satu; Marette, André; Matise, Tara C; McKenzie, Colin A; McKnight, Barbara; Musk, Arthur W; Möhlenkamp, Stefan; Morris, Andrew D; Nelis, Mari; Ohlsson, Claes; Oldehinkel, Albertine J; Ong, Ken K; Palmer, Lyle J; Penninx, Brenda W; Peters, Annette; Pramstaller, Peter P; Raitakari, Olli T; Rankinen, Tuomo; Rao, D C; Rice, Treva K; Ridker, Paul M; Ritchie, Marylyn D; Rudan, Igor; Salomaa, Veikko; Samani, Nilesh J; Saramies, Jouko; Sarzynski, Mark A; Schwarz, Peter Eh; Shuldiner, Alan R; Staessen, Jan A; Steinthorsdottir, Valgerdur; Stolk, Ronald P; Strauch, Konstantin; Tönjes, Anke; Tremblay, Angelo; Tremoli, Elena; Vohl, Marie-Claude; Völker, Uwe; Vollenweider, Peter; Wilson, James F; Witteman, Jacqueline C; Adair, Linda S; Bochud, Murielle; Boehm, Bernhard O; Bornstein, Stefan R; Bouchard, Claude; Cauchi, Stéphane; Caulfield, Mark J; Chambers, John C; Chasman, Daniel I; Cooper, Richard S; Dedoussis, George; Ferrucci, Luigi; Froguel, Philippe; Grabe, Hans-Jörgen; Hamsten, Anders; Hui, Jennie; Hveem, Kristian; Jöckel, Karl-Heinz; Kivimaki, Mika; Kuh, Diana; Laakso, Markku; Liu, Yongmei; März, Winfried; Munroe, Patricia B; Njølstad, Inger; Oostra, Ben A; Palmer, Colin Na; Pedersen, Nancy L; Perola, Markus; Pérusse, Louis; Peters, Ulrike; Power, Chris; Quertermous, Thomas; Rauramaa, Rainer; Rivadeneira, Fernando; Saaristo, Timo E; Saleheen, Danish; Sinisalo, Juha; Slagboom, P Eline; Snieder, Harold; Spector, Tim D; Stefansson, Kari; Stumvoll, Michael; Tuomilehto, Jaakko; Uitterlinden, André G; Uusitupa, Matti; van der Harst, Pim; Veronesi, Giovanni; Walker, Mark; Wareham, Nicholas J; Watkins, Hugh; Wichmann, H-Erich; Abecasis, Goncalo R; Assimes, Themistocles L; Berndt, Sonja I; Boehnke, Michael; Borecki, Ingrid B; Deloukas, Panos; Franke, Lude; Frayling, Timothy M; Groop, Leif C; Hunter, David J; Kaplan, Robert C; O'Connell, Jeffrey R; Qi, Lu; Schlessinger, David; Strachan, David P; Thorsteinsdottir, Unnur; van Duijn, Cornelia M; Willer, Cristen J; Visscher, Peter M; Yang, Jian; Hirschhorn, Joel N; Zillikens, M Carola; McCarthy, Mark I; Speliotes, Elizabeth K; North, Kari E; Fox, Caroline S; Barroso, Inês; Franks, Paul W; Ingelsson, Erik; Heid, Iris M; Loos, Ruth Jf; Cupples, L Adrienne; Morris, Andrew P; Lindgren, Cecilia M; Mohlke, Karen L

2015-02-12

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations

PubMed Central

Huang, Hailiang; Ng, Siew C; Alberts, Rudi; Takahashi, Atsushi; Ripke, Stephan; Lee, James C; Jostins, Luke; Shah, Tejas; Abedian, Shifteh; Cheon, Jae Hee; Cho, Judy; Dayani, Naser E; Franke, Lude; Fuyuno, Yuta; Hart, Ailsa; Juyal, Ramesh C; Juyal, Garima; Kim, Won Ho; Morris, Andrew P; Poustchi, Hossein; Newman, William G; Midha, Vandana; Orchard, Timothy R; Vahedi, Homayon; Sood, Ajit; Sung, Joseph Y; Malekzadeh, Reza; Westra, Harm-Jan; Yamazaki, Keiko; Yang, Suk-Kyun; Barrett, Jeffrey C; Alizadeh, Behrooz Z; Parkes, Miles; BK, Thelma; Daly, Mark J; Kubo, Michiaki; Anderson, Carl A; Weersma, Rinse K

2016-01-01

Ulcerative colitis and Crohn’s disease are the two main forms of inflammatory bowel disease (IBD). Here, we report the first trans-ethnic association study of IBD, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and Immunochip data from 9,846 individuals of East-Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time. For the majority of IBD risk loci, the direction and magnitude of effect is consistent in European and non-European cohorts. Nevertheless, we observe genetic heterogeneity between divergent populations at several established risk loci driven by a combination of differences in allele frequencies (NOD2), effect sizes (TNFSF15, ATG16L1) or a combination of both (IL23R, IRGM). Our results provide biological insights into the pathogenesis of IBD, and demonstrate the utility of trans-ethnic association studies for mapping complex disease loci and understanding genetic architecture across diverse populations. PMID:26192919

New genetic loci link adipose and insulin biology to body fat distribution

PubMed Central

Strawbridge, Rona J; Pers, Tune H; Fischer, Krista; Justice, Anne E; Workalemahu, Tsegaselassie; Wu, Joseph M.W.; Buchkovich, Martin L; Heard-Costa, Nancy L; Roman, Tamara S; Drong, Alexander W; Song, Ci; Gustafsson, Stefan; Day, Felix R; Esko, Tonu; Fall, Tove; Kutalik, Zoltán; Luan, Jian’an; Randall, Joshua C; Scherag, André; Vedantam, Sailaja; Wood, Andrew R; Chen, Jin; Fehrmann, Rudolf; Karjalainen, Juha; Kahali, Bratati; Liu, Ching-Ti; Schmidt, Ellen M; Absher, Devin; Amin, Najaf; Anderson, Denise; Beekman, Marian; Bragg-Gresham, Jennifer L; Buyske, Steven; Demirkan, Ayse; Ehret, Georg B; Feitosa, Mary F; Goel, Anuj; Jackson, Anne U; Johnson, Toby; Kleber, Marcus E; Kristiansson, Kati; Mangino, Massimo; Leach, Irene Mateo; Medina-Gomez, Carolina; Palmer, Cameron D; Pasko, Dorota; Pechlivanis, Sonali; Peters, Marjolein J; Prokopenko, Inga; Stančáková, Alena; Sung, Yun Ju; Tanaka, Toshiko; Teumer, Alexander; Van Vliet-Ostaptchouk, Jana V; Yengo, Loïc; Zhang, Weihua; Albrecht, Eva; Ärnlöv, Johan; Arscott, Gillian M; Bandinelli, Stefania; Barrett, Amy; Bellis, Claire; Bennett, Amanda J; Berne, Christian; Blüher, Matthias; Böhringer, Stefan; Bonnet, Fabrice; Böttcher, Yvonne; Bruinenberg, Marcel; Carba, Delia B; Caspersen, Ida H; Clarke, Robert; Daw, E Warwick; Deelen, Joris; Deelman, Ewa; Delgado, Graciela; Doney, Alex SF; Eklund, Niina; Erdos, Michael R; Estrada, Karol; Eury, Elodie; Friedrich, Nele; Garcia, Melissa E; Giedraitis, Vilmantas; Gigante, Bruna; Go, Alan S; Golay, Alain; Grallert, Harald; Grammer, Tanja B; Gräßler, Jürgen; Grewal, Jagvir; Groves, Christopher J; Haller, Toomas; Hallmans, Goran; Hartman, Catharina A; Hassinen, Maija; Hayward, Caroline; Heikkilä, Kauko; Herzig, Karl-Heinz; Helmer, Quinta; Hillege, Hans L; Holmen, Oddgeir; Hunt, Steven C; Isaacs, Aaron; Ittermann, Till; James, Alan L; Johansson, Ingegerd; Juliusdottir, Thorhildur; Kalafati, Ioanna-Panagiota; Kinnunen, Leena; Koenig, Wolfgang; Kooner, Ishminder K; Kratzer, Wolfgang; Lamina, Claudia; Leander, Karin; Lee, Nanette R; Lichtner, Peter; Lind, Lars; Lindström, Jaana; Lobbens, Stéphane; Lorentzon, Mattias; Mach, François; Magnusson, Patrik KE; Mahajan, Anubha; McArdle, Wendy L; Menni, Cristina; Merger, Sigrun; Mihailov, Evelin; Milani, Lili; Mills, Rebecca; Moayyeri, Alireza; Monda, Keri L; Mooijaart, Simon P; Mühleisen, Thomas W; Mulas, Antonella; Müller, Gabriele; Müller-Nurasyid, Martina; Nagaraja, Ramaiah; Nalls, Michael A; Narisu, Narisu; Glorioso, Nicola; Nolte, Ilja M; Olden, Matthias; Rayner, Nigel W; Renstrom, Frida; Ried, Janina S; Robertson, Neil R; Rose, Lynda M; Sanna, Serena; Scharnagl, Hubert; Scholtens, Salome; Sennblad, Bengt; Seufferlein, Thomas; Sitlani, Colleen M; Smith, Albert Vernon; Stirrups, Kathleen; Stringham, Heather M; Sundström, Johan; Swertz, Morris A; Swift, Amy J; Syvänen, Ann-Christine; Tayo, Bamidele O; Thorand, Barbara; Thorleifsson, Gudmar; Tomaschitz, Andreas; Troffa, Chiara; van Oort, Floor VA; Verweij, Niek; Vonk, Judith M; Waite, Lindsay L; Wennauer, Roman; Wilsgaard, Tom; Wojczynski, Mary K; Wong, Andrew; Zhang, Qunyuan; Zhao, Jing Hua; Brennan, Eoin P.; Choi, Murim; Eriksson, Per; Folkersen, Lasse; Franco-Cereceda, Anders; Gharavi, Ali G; Hedman, Åsa K; Hivert, Marie-France; Huang, Jinyan; Kanoni, Stavroula; Karpe, Fredrik; Keildson, Sarah; Kiryluk, Krzysztof; Liang, Liming; Lifton, Richard P; Ma, Baoshan; McKnight, Amy J; McPherson, Ruth; Metspalu, Andres; Min, Josine L; Moffatt, Miriam F; Montgomery, Grant W; Murabito, Joanne M; Nicholson, George; Nyholt, Dale R; Olsson, Christian; Perry, John RB; Reinmaa, Eva; Salem, Rany M; Sandholm, Niina; Schadt, Eric E; Scott, Robert A; Stolk, Lisette; Vallejo, Edgar E.; Westra, Harm-Jan; Zondervan, Krina T; Amouyel, Philippe; Arveiler, Dominique; Bakker, Stephan JL; Beilby, John; Bergman, Richard N; Blangero, John; Brown, Morris J; Burnier, Michel; Campbell, Harry; Chakravarti, Aravinda; Chines, Peter S; Claudi-Boehm, Simone; Collins, Francis S; Crawford, Dana C; Danesh, John; de Faire, Ulf; de Geus, Eco JC; Dörr, Marcus; Erbel, Raimund; Eriksson, Johan G; Farrall, Martin; Ferrannini, Ele; Ferrières, Jean; Forouhi, Nita G; Forrester, Terrence; Franco, Oscar H; Gansevoort, Ron T; Gieger, Christian; Gudnason, Vilmundur; Haiman, Christopher A; Harris, Tamara B; Hattersley, Andrew T; Heliövaara, Markku; Hicks, Andrew A; Hingorani, Aroon D; Hoffmann, Wolfgang; Hofman, Albert; Homuth, Georg; Humphries, Steve E; Hyppönen, Elina; Illig, Thomas; Jarvelin, Marjo-Riitta; Johansen, Berit; Jousilahti, Pekka; Jula, Antti M; Kaprio, Jaakko; Kee, Frank; Keinanen-Kiukaanniemi, Sirkka M; Kooner, Jaspal S; Kooperberg, Charles; Kovacs, Peter; Kraja, Aldi T; Kumari, Meena; Kuulasmaa, Kari; Kuusisto, Johanna; Lakka, Timo A; Langenberg, Claudia; Le Marchand, Loic; Lehtimäki, Terho; Lyssenko, Valeriya; Männistö, Satu; Marette, André; Matise, Tara C; McKenzie, Colin A; McKnight, Barbara; Musk, Arthur W; Möhlenkamp, Stefan; Morris, Andrew D; Nelis, Mari; Ohlsson, Claes; Oldehinkel, Albertine J; Ong, Ken K; Palmer, Lyle J; Penninx, Brenda W; Peters, Annette; Pramstaller, Peter P; Raitakari, Olli T; Rankinen, Tuomo; Rao, DC; Rice, Treva K; Ridker, Paul M; Ritchie, Marylyn D.; Rudan, Igor; Salomaa, Veikko; Samani, Nilesh J; Saramies, Jouko; Sarzynski, Mark A; Schwarz, Peter EH; Shuldiner, Alan R; Staessen, Jan A; Steinthorsdottir, Valgerdur; Stolk, Ronald P; Strauch, Konstantin; Tönjes, Anke; Tremblay, Angelo; Tremoli, Elena; Vohl, Marie-Claude; Völker, Uwe; Vollenweider, Peter; Wilson, James F; Witteman, Jacqueline C; Adair, Linda S; Bochud, Murielle; Boehm, Bernhard O; Bornstein, Stefan R; Bouchard, Claude; Cauchi, Stéphane; Caulfield, Mark J; Chambers, John C; Chasman, Daniel I; Cooper, Richard S; Dedoussis, George; Ferrucci, Luigi; Froguel, Philippe; Grabe, Hans-Jörgen; Hamsten, Anders; Hui, Jennie; Hveem, Kristian; Jöckel, Karl-Heinz; Kivimaki, Mika; Kuh, Diana; Laakso, Markku; Liu, Yongmei; März, Winfried; Munroe, Patricia B; Njølstad, Inger; Oostra, Ben A; Palmer, Colin NA; Pedersen, Nancy L; Perola, Markus; Pérusse, Louis; Peters, Ulrike; Power, Chris; Quertermous, Thomas; Rauramaa, Rainer; Rivadeneira, Fernando; Saaristo, Timo E; Saleheen, Danish; Sinisalo, Juha; Slagboom, P Eline; Snieder, Harold; Spector, Tim D; Stefansson, Kari; Stumvoll, Michael; Tuomilehto, Jaakko; Uitterlinden, André G; Uusitupa, Matti; van der Harst, Pim; Veronesi, Giovanni; Walker, Mark; Wareham, Nicholas J; Watkins, Hugh; Wichmann, H-Erich; Abecasis, Goncalo R; Assimes, Themistocles L; Berndt, Sonja I; Boehnke, Michael; Borecki, Ingrid B; Deloukas, Panos; Franke, Lude; Frayling, Timothy M; Groop, Leif C; Hunter, David J.; Kaplan, Robert C; O’Connell, Jeffrey R; Qi, Lu; Schlessinger, David; Strachan, David P; Thorsteinsdottir, Unnur; van Duijn, Cornelia M; Willer, Cristen J; Visscher, Peter M; Yang, Jian; Hirschhorn, Joel N; Zillikens, M Carola; McCarthy, Mark I; Speliotes, Elizabeth K; North, Kari E; Fox, Caroline S; Barroso, Inês; Franks, Paul W; Ingelsson, Erik; Heid, Iris M; Loos, Ruth JF; Cupples, L Adrienne; Morris, Andrew P; Lindgren, Cecilia M; Mohlke, Karen L

2014-01-01

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, we conducted genome-wide association meta-analyses of waist and hip circumference-related traits in up to 224,459 individuals. We identified 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (WHRadjBMI) and an additional 19 loci newly associated with related waist and hip circumference measures (P<5×10−8). Twenty of the 49 WHRadjBMI loci showed significant sexual dimorphism, 19 of which displayed a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation, and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms. PMID:25673412

Epigenetic Patterns in Blood Associated With Lipid Traits Predict Incident Coronary Heart Disease Events and Are Enriched for Results From Genome-Wide Association Studies.

PubMed

Hedman, Åsa K; Mendelson, Michael M; Marioni, Riccardo E; Gustafsson, Stefan; Joehanes, Roby; Irvin, Marguerite R; Zhi, Degui; Sandling, Johanna K; Yao, Chen; Liu, Chunyu; Liang, Liming; Huan, Tianxiao; McRae, Allan F; Demissie, Serkalem; Shah, Sonia; Starr, John M; Cupples, L Adrienne; Deloukas, Panos; Spector, Timothy D; Sundström, Johan; Krauss, Ronald M; Arnett, Donna K; Deary, Ian J; Lind, Lars; Levy, Daniel; Ingelsson, Erik

2017-01-01

Genome-wide association studies have identified loci influencing circulating lipid concentrations in humans; further information on novel contributing genes, pathways, and biology may be gained through studies of epigenetic modifications. To identify epigenetic changes associated with lipid concentrations, we assayed genome-wide DNA methylation at cytosine-guanine dinucleotides (CpGs) in whole blood from 2306 individuals from 2 population-based cohorts, with replication of findings in 2025 additional individuals. We identified 193 CpGs associated with lipid levels in the discovery stage ( P <1.08E-07) and replicated 33 (at Bonferroni-corrected P <0.05), including 25 novel CpGs not previously associated with lipids. Genes at lipid-associated CpGs were enriched in lipid and amino acid metabolism processes. A differentially methylated locus associated with triglycerides and high-density lipoprotein cholesterol (HDL-C; cg27243685; P =8.1E-26 and 9.3E-19) was associated with cis -expression of a reverse cholesterol transporter ( ABCG1; P =7.2E-28) and incident cardiovascular disease events (hazard ratio per SD increment, 1.38; 95% confidence interval, 1.15-1.66; P =0.0007). We found significant cis -methylation quantitative trait loci at 64% of the 193 CpGs with an enrichment of signals from genome-wide association studies of lipid levels ( P TC =0.004, P HDL-C =0.008 and P triglycerides =0.00003) and coronary heart disease ( P =0.0007). For example, genome-wide significant variants associated with low-density lipoprotein cholesterol and coronary heart disease at APOB were cis -methylation quantitative trait loci for a low-density lipoprotein cholesterol-related differentially methylated locus. We report novel associations of DNA methylation with lipid levels, describe epigenetic mechanisms related to previous genome-wide association studies discoveries, and provide evidence implicating epigenetic regulation of reverse cholesterol transport in blood in relation to occurrence of cardiovascular disease events. © 2017 The Authors.

A trans-ethnic genome-wide association study identifies gender-specific loci influencing pediatric aBMD and BMC at the distal radius.

PubMed

Chesi, Alessandra; Mitchell, Jonathan A; Kalkwarf, Heidi J; Bradfield, Jonathan P; Lappe, Joan M; McCormack, Shana E; Gilsanz, Vicente; Oberfield, Sharon E; Hakonarson, Hakon; Shepherd, John A; Kelly, Andrea; Zemel, Babette S; Grant, Struan F A

2015-09-01

Childhood fractures are common, with the forearm being the most common site. Genome-wide association studies (GWAS) have identified more than 60 loci associated with bone mineral density (BMD) in adults but less is known about genetic influences specific to bone in childhood. To identify novel genetic factors that influence pediatric bone strength at a common site for childhood fractures, we performed a sex-stratified trans-ethnic genome-wide association study of areal BMD (aBMD) and bone mineral content (BMC) Z-scores measured by dual energy X-ray absorptiometry at the one-third distal radius, in a cohort of 1399 children without clinical abnormalities in bone health. We tested signals with P < 5 × 10(-6) for replication in an independent, same-age cohort of 486 Caucasian children. Two loci yielded a genome-wide significant combined P-value: rs7797976 within CPED1 in females [P = 2.4 × 10(-11), β =- 0.30 standard deviations (SD) per T allele; aBMD-Z] and rs7035284 at 9p21.3 in males (P = 1.2 × 10(-8), β = 0.28 SD per G allele; BMC-Z). Signals at the CPED1-WNT16-FAM3C locus have been previously associated with BMD at other skeletal sites in adults and children. Our result at the distal radius underscores the importance of this locus at multiple skeletal sites. The 9p21.3 locus is within a gene desert, with the nearest gene flanking each side being MIR31HG and MTAP, neither of which has been implicated in BMD or BMC previously. These findings suggest that genetic determinants of childhood bone accretion at the radius, a skeletal site that is primarily cortical bone, exist and also differ by sex. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Construction of a reference genetic linkage map for carnation (Dianthus caryophyllus L.)

PubMed Central

2013-01-01

Background Genetic linkage maps are important tools for many genetic applications including mapping of quantitative trait loci (QTLs), identifying DNA markers for fingerprinting, and map-based gene cloning. Carnation (Dianthus caryophyllus L.) is an important ornamental flower worldwide. We previously reported a random amplified polymorphic DNA (RAPD)-based genetic linkage map derived from Dianthus capitatus ssp. andrezejowskianus and a simple sequence repeat (SSR)-based genetic linkage map constructed using data from intraspecific F2 populations; however, the number of markers was insufficient, and so the number of linkage groups (LGs) did not coincide with the number of chromosomes (x = 15). Therefore, we aimed to produce a high-density genetic map to improve its usefulness for breeding purposes and genetic research. Results We improved the SSR-based genetic linkage map using SSR markers derived from a genomic library, expression sequence tags, and RNA-seq data. Linkage analysis revealed that 412 SSR loci (including 234 newly developed SSR loci) could be mapped to 17 linkage groups (LGs) covering 969.6 cM. Comparison of five minor LGs covering less than 50 cM with LGs in our previous RAPD-based genetic map suggested that four LGs could be integrated into two LGs by anchoring common SSR loci. Consequently, the number of LGs corresponded to the number of chromosomes (x = 15). We added 192 new SSRs, eight RAPD, and two sequence-tagged site loci to refine the RAPD-based genetic linkage map, which comprised 15 LGs consisting of 348 loci covering 978.3 cM. The two maps had 125 SSR loci in common, and most of the positions of markers were conserved between them. We identified 635 loci in carnation using the two linkage maps. We also mapped QTLs for two traits (bacterial wilt resistance and anthocyanin pigmentation in the flower) and a phenotypic locus for flower-type by analyzing previously reported genotype and phenotype data. Conclusions The improved genetic linkage maps and SSR markers developed in this study will serve as reference genetic linkage maps for members of the genus Dianthus, including carnation, and will be useful for mapping QTLs associated with various traits, and for improving carnation breeding programs. PMID:24160306

Construction of a reference genetic linkage map for carnation (Dianthus caryophyllus L.).

PubMed

Yagi, Masafumi; Yamamoto, Toshiya; Isobe, Sachiko; Hirakawa, Hideki; Tabata, Satoshi; Tanase, Koji; Yamaguchi, Hiroyasu; Onozaki, Takashi

2013-10-26

Genetic linkage maps are important tools for many genetic applications including mapping of quantitative trait loci (QTLs), identifying DNA markers for fingerprinting, and map-based gene cloning. Carnation (Dianthus caryophyllus L.) is an important ornamental flower worldwide. We previously reported a random amplified polymorphic DNA (RAPD)-based genetic linkage map derived from Dianthus capitatus ssp. andrezejowskianus and a simple sequence repeat (SSR)-based genetic linkage map constructed using data from intraspecific F2 populations; however, the number of markers was insufficient, and so the number of linkage groups (LGs) did not coincide with the number of chromosomes (x = 15). Therefore, we aimed to produce a high-density genetic map to improve its usefulness for breeding purposes and genetic research. We improved the SSR-based genetic linkage map using SSR markers derived from a genomic library, expression sequence tags, and RNA-seq data. Linkage analysis revealed that 412 SSR loci (including 234 newly developed SSR loci) could be mapped to 17 linkage groups (LGs) covering 969.6 cM. Comparison of five minor LGs covering less than 50 cM with LGs in our previous RAPD-based genetic map suggested that four LGs could be integrated into two LGs by anchoring common SSR loci. Consequently, the number of LGs corresponded to the number of chromosomes (x = 15). We added 192 new SSRs, eight RAPD, and two sequence-tagged site loci to refine the RAPD-based genetic linkage map, which comprised 15 LGs consisting of 348 loci covering 978.3 cM. The two maps had 125 SSR loci in common, and most of the positions of markers were conserved between them. We identified 635 loci in carnation using the two linkage maps. We also mapped QTLs for two traits (bacterial wilt resistance and anthocyanin pigmentation in the flower) and a phenotypic locus for flower-type by analyzing previously reported genotype and phenotype data. The improved genetic linkage maps and SSR markers developed in this study will serve as reference genetic linkage maps for members of the genus Dianthus, including carnation, and will be useful for mapping QTLs associated with various traits, and for improving carnation breeding programs.

Meta-Analysis of Genome-Wide Association Studies in African Americans Provides Insights into the Genetic Architecture of Type 2 Diabetes

PubMed Central

Chen, Brian H.; Li, Jiang; Chen, Wei-Min; Guo, Xiuqing; Liu, Jiankang; Bielinski, Suzette J.; Yanek, Lisa R.; Nalls, Michael A.; Comeau, Mary E.; Rasmussen-Torvik, Laura J.; Jensen, Richard A.; Evans, Daniel S.; Sun, Yan V.; An, Ping; Patel, Sanjay R.; Lu, Yingchang; Long, Jirong; Armstrong, Loren L.; Wagenknecht, Lynne; Yang, Lingyao; Snively, Beverly M.; Palmer, Nicholette D.; Mudgal, Poorva; Langefeld, Carl D.; Keene, Keith L.; Freedman, Barry I.; Mychaleckyj, Josyf C.; Nayak, Uma; Raffel, Leslie J.; Goodarzi, Mark O.; Chen, Y-D Ida; Taylor, Herman A.; Correa, Adolfo; Sims, Mario; Couper, David; Pankow, James S.; Boerwinkle, Eric; Adeyemo, Adebowale; Doumatey, Ayo; Chen, Guanjie; Mathias, Rasika A.; Vaidya, Dhananjay; Singleton, Andrew B.; Zonderman, Alan B.; Igo, Robert P.; Sedor, John R.; Kabagambe, Edmond K.; Siscovick, David S.; McKnight, Barbara; Rice, Kenneth; Liu, Yongmei; Hsueh, Wen-Chi; Zhao, Wei; Bielak, Lawrence F.; Kraja, Aldi; Province, Michael A.; Bottinger, Erwin P.; Gottesman, Omri; Cai, Qiuyin; Zheng, Wei; Blot, William J.; Lowe, William L.; Pacheco, Jennifer A.; Crawford, Dana C.; Grundberg, Elin; Rich, Stephen S.; Hayes, M. Geoffrey; Shu, Xiao-Ou; Loos, Ruth J. F.; Borecki, Ingrid B.; Peyser, Patricia A.; Cummings, Steven R.; Psaty, Bruce M.; Fornage, Myriam; Iyengar, Sudha K.; Evans, Michele K.; Becker, Diane M.; Kao, W. H. Linda; Wilson, James G.; Rotter, Jerome I.; Sale, Michèle M.; Liu, Simin; Rotimi, Charles N.; Bowden, Donald W.

2014-01-01

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15×10−94

Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes.

PubMed

Ng, Maggie C Y; Shriner, Daniel; Chen, Brian H; Li, Jiang; Chen, Wei-Min; Guo, Xiuqing; Liu, Jiankang; Bielinski, Suzette J; Yanek, Lisa R; Nalls, Michael A; Comeau, Mary E; Rasmussen-Torvik, Laura J; Jensen, Richard A; Evans, Daniel S; Sun, Yan V; An, Ping; Patel, Sanjay R; Lu, Yingchang; Long, Jirong; Armstrong, Loren L; Wagenknecht, Lynne; Yang, Lingyao; Snively, Beverly M; Palmer, Nicholette D; Mudgal, Poorva; Langefeld, Carl D; Keene, Keith L; Freedman, Barry I; Mychaleckyj, Josyf C; Nayak, Uma; Raffel, Leslie J; Goodarzi, Mark O; Chen, Y-D Ida; Taylor, Herman A; Correa, Adolfo; Sims, Mario; Couper, David; Pankow, James S; Boerwinkle, Eric; Adeyemo, Adebowale; Doumatey, Ayo; Chen, Guanjie; Mathias, Rasika A; Vaidya, Dhananjay; Singleton, Andrew B; Zonderman, Alan B; Igo, Robert P; Sedor, John R; Kabagambe, Edmond K; Siscovick, David S; McKnight, Barbara; Rice, Kenneth; Liu, Yongmei; Hsueh, Wen-Chi; Zhao, Wei; Bielak, Lawrence F; Kraja, Aldi; Province, Michael A; Bottinger, Erwin P; Gottesman, Omri; Cai, Qiuyin; Zheng, Wei; Blot, William J; Lowe, William L; Pacheco, Jennifer A; Crawford, Dana C; Grundberg, Elin; Rich, Stephen S; Hayes, M Geoffrey; Shu, Xiao-Ou; Loos, Ruth J F; Borecki, Ingrid B; Peyser, Patricia A; Cummings, Steven R; Psaty, Bruce M; Fornage, Myriam; Iyengar, Sudha K; Evans, Michele K; Becker, Diane M; Kao, W H Linda; Wilson, James G; Rotter, Jerome I; Sale, Michèle M; Liu, Simin; Rotimi, Charles N; Bowden, Donald W

2014-08-01

Type 2 diabetes (T2D) is more prevalent in African Americans than in Europeans. However, little is known about the genetic risk in African Americans despite the recent identification of more than 70 T2D loci primarily by genome-wide association studies (GWAS) in individuals of European ancestry. In order to investigate the genetic architecture of T2D in African Americans, the MEta-analysis of type 2 DIabetes in African Americans (MEDIA) Consortium examined 17 GWAS on T2D comprising 8,284 cases and 15,543 controls in African Americans in stage 1 analysis. Single nucleotide polymorphisms (SNPs) association analysis was conducted in each study under the additive model after adjustment for age, sex, study site, and principal components. Meta-analysis of approximately 2.6 million genotyped and imputed SNPs in all studies was conducted using an inverse variance-weighted fixed effect model. Replications were performed to follow up 21 loci in up to 6,061 cases and 5,483 controls in African Americans, and 8,130 cases and 38,987 controls of European ancestry. We identified three known loci (TCF7L2, HMGA2 and KCNQ1) and two novel loci (HLA-B and INS-IGF2) at genome-wide significance (4.15 × 10(-94)

Association of human height-related genetic variants with familial short stature in Han Chinese in Taiwan.

PubMed

Lin, Ying-Ju; Liao, Wen-Ling; Wang, Chung-Hsing; Tsai, Li-Ping; Tang, Chih-Hsin; Chen, Chien-Hsiun; Wu, Jer-Yuarn; Liang, Wen-Miin; Hsieh, Ai-Ru; Cheng, Chi-Fung; Chen, Jin-Hua; Chien, Wen-Kuei; Lin, Ting-Hsu; Wu, Chia-Ming; Liao, Chiu-Chu; Huang, Shao-Mei; Tsai, Fuu-Jen

2017-07-25

Human height can be described as a classical and inherited trait model. Genome-wide association studies (GWAS) have revealed susceptible loci and provided insights into the polygenic nature of human height. Familial short stature (FSS) represents a suitable trait for investigating short stature genetics because disease associations with short stature have been ruled out in this case. In addition, FSS is caused only by genetically inherited factors. In this study, we explored the correlations of FSS risk with the genetic loci associated with human height in previous GWAS, alone and cumulatively. We systematically evaluated 34 known human height single nucleotide polymorphisms (SNPs) in relation to FSS in the additive model (p < 0.00005). A cumulative effect was observed: the odds ratios gradually increased with increasing genetic risk score quartiles (p < 0.001; Cochran-Armitage trend test). Six affected genes-ZBTB38, ZNF638, LCORL, CABLES1, CDK10, and TSEN15-are located in the nucleus and have been implicated in embryonic, organismal, and tissue development. In conclusion, our study suggests that 13 human height GWAS-identified SNPs are associated with FSS risk both alone and cumulatively.

Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders

PubMed Central

Pinto, Dalila; Delaby, Elsa; Merico, Daniele; Barbosa, Mafalda; Merikangas, Alison; Klei, Lambertus; Thiruvahindrapuram, Bhooma; Xu, Xiao; Ziman, Robert; Wang, Zhuozhi; Vorstman, Jacob A.S.; Thompson, Ann; Regan, Regina; Pilorge, Marion; Pellecchia, Giovanna; Pagnamenta, Alistair T.; Oliveira, Bárbara; Marshall, Christian R.; Magalhaes, Tiago R.; Lowe, Jennifer K.; Howe, Jennifer L.; Griswold, Anthony J.; Gilbert, John; Duketis, Eftichia; Dombroski, Beth A.; De Jonge, Maretha V.; Cuccaro, Michael; Crawford, Emily L.; Correia, Catarina T.; Conroy, Judith; Conceição, Inês C.; Chiocchetti, Andreas G.; Casey, Jillian P.; Cai, Guiqing; Cabrol, Christelle; Bolshakova, Nadia; Bacchelli, Elena; Anney, Richard; Gallinger, Steven; Cotterchio, Michelle; Casey, Graham; Zwaigenbaum, Lonnie; Wittemeyer, Kerstin; Wing, Kirsty; Wallace, Simon; van Engeland, Herman; Tryfon, Ana; Thomson, Susanne; Soorya, Latha; Rogé, Bernadette; Roberts, Wendy; Poustka, Fritz; Mouga, Susana; Minshew, Nancy; McInnes, L. Alison; McGrew, Susan G.; Lord, Catherine; Leboyer, Marion; Le Couteur, Ann S.; Kolevzon, Alexander; Jiménez González, Patricia; Jacob, Suma; Holt, Richard; Guter, Stephen; Green, Jonathan; Green, Andrew; Gillberg, Christopher; Fernandez, Bridget A.; Duque, Frederico; Delorme, Richard; Dawson, Geraldine; Chaste, Pauline; Café, Cátia; Brennan, Sean; Bourgeron, Thomas; Bolton, Patrick F.; Bölte, Sven; Bernier, Raphael; Baird, Gillian; Bailey, Anthony J.; Anagnostou, Evdokia; Almeida, Joana; Wijsman, Ellen M.; Vieland, Veronica J.; Vicente, Astrid M.; Schellenberg, Gerard D.; Pericak-Vance, Margaret; Paterson, Andrew D.; Parr, Jeremy R.; Oliveira, Guiomar; Nurnberger, John I.; Monaco, Anthony P.; Maestrini, Elena; Klauck, Sabine M.; Hakonarson, Hakon; Haines, Jonathan L.; Geschwind, Daniel H.; Freitag, Christine M.; Folstein, Susan E.; Ennis, Sean; Coon, Hilary; Battaglia, Agatino; Szatmari, Peter; Sutcliffe, James S.; Hallmayer, Joachim; Gill, Michael; Cook, Edwin H.; Buxbaum, Joseph D.; Devlin, Bernie; Gallagher, Louise; Betancur, Catalina; Scherer, Stephen W.

2014-01-01

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10−5) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10−15, ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation. PMID:24768552

Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence.

PubMed

Savage, Jeanne E; Jansen, Philip R; Stringer, Sven; Watanabe, Kyoko; Bryois, Julien; de Leeuw, Christiaan A; Nagel, Mats; Awasthi, Swapnil; Barr, Peter B; Coleman, Jonathan R I; Grasby, Katrina L; Hammerschlag, Anke R; Kaminski, Jakob A; Karlsson, Robert; Krapohl, Eva; Lam, Max; Nygaard, Marianne; Reynolds, Chandra A; Trampush, Joey W; Young, Hannah; Zabaneh, Delilah; Hägg, Sara; Hansell, Narelle K; Karlsson, Ida K; Linnarsson, Sten; Montgomery, Grant W; Muñoz-Manchado, Ana B; Quinlan, Erin B; Schumann, Gunter; Skene, Nathan G; Webb, Bradley T; White, Tonya; Arking, Dan E; Avramopoulos, Dimitrios; Bilder, Robert M; Bitsios, Panos; Burdick, Katherine E; Cannon, Tyrone D; Chiba-Falek, Ornit; Christoforou, Andrea; Cirulli, Elizabeth T; Congdon, Eliza; Corvin, Aiden; Davies, Gail; Deary, Ian J; DeRosse, Pamela; Dickinson, Dwight; Djurovic, Srdjan; Donohoe, Gary; Conley, Emily Drabant; Eriksson, Johan G; Espeseth, Thomas; Freimer, Nelson A; Giakoumaki, Stella; Giegling, Ina; Gill, Michael; Glahn, David C; Hariri, Ahmad R; Hatzimanolis, Alex; Keller, Matthew C; Knowles, Emma; Koltai, Deborah; Konte, Bettina; Lahti, Jari; Le Hellard, Stephanie; Lencz, Todd; Liewald, David C; London, Edythe; Lundervold, Astri J; Malhotra, Anil K; Melle, Ingrid; Morris, Derek; Need, Anna C; Ollier, William; Palotie, Aarno; Payton, Antony; Pendleton, Neil; Poldrack, Russell A; Räikkönen, Katri; Reinvang, Ivar; Roussos, Panos; Rujescu, Dan; Sabb, Fred W; Scult, Matthew A; Smeland, Olav B; Smyrnis, Nikolaos; Starr, John M; Steen, Vidar M; Stefanis, Nikos C; Straub, Richard E; Sundet, Kjetil; Tiemeier, Henning; Voineskos, Aristotle N; Weinberger, Daniel R; Widen, Elisabeth; Yu, Jin; Abecasis, Goncalo; Andreassen, Ole A; Breen, Gerome; Christiansen, Lene; Debrabant, Birgit; Dick, Danielle M; Heinz, Andreas; Hjerling-Leffler, Jens; Ikram, M Arfan; Kendler, Kenneth S; Martin, Nicholas G; Medland, Sarah E; Pedersen, Nancy L; Plomin, Robert; Polderman, Tinca J C; Ripke, Stephan; van der Sluis, Sophie; Sullivan, Patrick F; Vrieze, Scott I; Wright, Margaret J; Posthuma, Danielle

2018-06-25

Intelligence is highly heritable 1 and a major determinant of human health and well-being 2 . Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence 3-7 , but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.

High-resolution mapping of the x-linked hypohidrotic ectodermal dysplasia (EDA) locus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zonana, J.; Jones, M.; Litt, M.

1992-11-01

The X-linked hypohidrotic ectodermal dysplasia (EDA) locus has been previously localized to the subchromosomal region Xq11-q21.1. The authors have extended previous linkage studies and analyzed linkage between the EDA locus and 10 marker loci, including five new loci, in 41 families. Four of the marker loci showed no recombination with the EDA locus, and six other loci were also linked to the EDA locus with recombination fractions of .009-.075. Multipoint analysis gave support to the placement of the PGK1P1 locus proximal to the EDA locus and the DXS453 and PGK1 loci distal to EDA. Further ordering of the loci couldmore » be inferred from a human-rodent somatic cell hybrid derived from an affected female with EDA and an X;9 translocation and from studies of an affected male with EDA and a submicroscopic deletion. Three of the proximal marker loci, which showed no recombination with the EDA locus, when used in combination, were informative in 92% of females. The closely linked flanking polymorphic loci DXS339 and DXS453 had heterozygosites of 72% and 76%, respectively, and when used jointly, they were doubly informative in 52% of females. The human DXS732 locus was defined by a conserved mouse probe pcos169E/4 (DXCrc169 locus) that consegregates with the mouse tabby (Ta) locus, a potential homologue to the EDA locus. The absence of recombination between EDA and the DXSA732 locus lends support to the hypothesis that the DXCrc169 locus in the mouse and the DXS732 locus in humans may contain candidate sequences for the Ta and EDA genes, respectively. 36 refs., 1 fig., 5 tabs.« less

Meiotic drive influences the outcome of sexually antagonistic selection at a linked locus.

PubMed

Patten, M M

2014-11-01

Most meiotic drivers, such as the t-haplotype in Mus and the segregation distorter (SD) in Drosophila, act in a sex-specific manner, gaining a transmission advantage through one sex although suffering only the fitness costs associated with the driver in the other. Their inheritance is thus more likely through one of the two sexes, a property they share with sexually antagonistic alleles. Previous theory has shown that pairs of linked loci segregating for sexually antagonistic alleles are more likely to remain polymorphic and that linkage disequilibrium accrues between them. I probe this similarity between drive and sexual antagonism and examine the evolution of chromosomes experiencing these selection pressures simultaneously. Reminiscent of previous theory, I find that: the opportunity for polymorphism increases for a sexually antagonistic locus that is physically linked to a driving locus; the opportunity for polymorphism at a driving locus also increases when linked to a sexually antagonistic locus; and stable linkage disequilibrium accompanies any polymorphic equilibrium. Additionally, I find that drive at a linked locus favours the fixation of sexually antagonistic alleles that benefit the sex in which drive occurs. Further, I show that under certain conditions reduced recombination between these two loci is selectively favoured. These theoretical results provide clear, testable predictions about the nature of sexually antagonistic variation on driving chromosomes and have implications for the evolution of genomic architecture. © 2014 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2014 European Society For Evolutionary Biology.

Evidence for a major retinitis pigmentosa locus on 19q13.4 (RP11), and association with a unique bimodal expressivity phenotype

DOE Office of Scientific and Technical Information (OSTI.GOV)

Al-Maghtheh, M.; Vithana, E.; Tarttelin, E.

Retinitis pigmentosa (RP) is the name given to a heterogeneous group of retinal degenerations mapping to at least 16 loci. The autosomal dominant form (adRP), accounting for {approximately}25% of cases, can be caused by mutations in two genes, rhodopsin and peripherin/RDS, and by at least six other loci identified by linkage analysis. The RP11 locus for adRP has previously been mapped to chromosome 19q13.4 in a large English family. This linkage has been independently confirmed in a Japanese family, and we now report three additional unrelated linked U.K. families, suggesting that this is a major locus for RP. Linkage analysismore » in the U.K. families refines the RP11 interval to 5 cM between markers D19S180 and AFMc001yb1. All linked families exhibit incomplete penetrance; some obligate gene carriers remain asymptomatic throughout their lives, whereas symptomatic individuals experience night blindness and visual field loss in their teens and are generally registered as blind by their 30s. This {open_quotes}bimodal expressivity{close_quotes} contrasts with the variable-expressivity RP mapping to chromosome 7p (RP9) in another family, which has implications for diagnosis and counseling of RP11 families. These results may also imply that a proportion of sporadic RP, previously assumed to be recessive, might result from mutations at this locus. 27 refs., 3 figs., 1 tab.« less

Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance.

PubMed

Lotta, Luca A; Gulati, Pawan; Day, Felix R; Payne, Felicity; Ongen, Halit; van de Bunt, Martijn; Gaulton, Kyle J; Eicher, John D; Sharp, Stephen J; Luan, Jian'an; De Lucia Rolfe, Emanuella; Stewart, Isobel D; Wheeler, Eleanor; Willems, Sara M; Adams, Claire; Yaghootkar, Hanieh; Forouhi, Nita G; Khaw, Kay-Tee; Johnson, Andrew D; Semple, Robert K; Frayling, Timothy; Perry, John R B; Dermitzakis, Emmanouil; McCarthy, Mark I; Barroso, Inês; Wareham, Nicholas J; Savage, David B; Langenberg, Claudia; O'Rahilly, Stephen; Scott, Robert A

2017-01-01

Insulin resistance is a key mediator of obesity-related cardiometabolic disease, yet the mechanisms underlying this link remain obscure. Using an integrative genomic approach, we identify 53 genomic regions associated with insulin resistance phenotypes (higher fasting insulin levels adjusted for BMI, lower HDL cholesterol levels and higher triglyceride levels) and provide evidence that their link with higher cardiometabolic risk is underpinned by an association with lower adipose mass in peripheral compartments. Using these 53 loci, we show a polygenic contribution to familial partial lipodystrophy type 1, a severe form of insulin resistance, and highlight shared molecular mechanisms in common/mild and rare/severe insulin resistance. Population-level genetic analyses combined with experiments in cellular models implicate CCDC92, DNAH10 and L3MBTL3 as previously unrecognized molecules influencing adipocyte differentiation. Our findings support the notion that limited storage capacity of peripheral adipose tissue is an important etiological component in insulin-resistant cardiometabolic disease and highlight genes and mechanisms underpinning this link.

Global population genetic structure and male-mediated gene flow in the green sea turtle (Chelonia mydas): analysis of microsatellite loci.

PubMed Central

Roberts, Mark A; Schwartz, Tonia S; Karl, Stephen A

2004-01-01

We assessed the degree of population subdivision among global populations of green sea turtles, Chelonia mydas, using four microsatellite loci. Previously, a single-copy nuclear DNA study indicated significant male-mediated gene flow among populations alternately fixed for different mitochondrial DNA haplotypes and that genetic divergence between populations in the Atlantic and Pacific Oceans was more common than subdivisions among populations within ocean basins. Even so, overall levels of variation at single-copy loci were low and inferences were limited. Here, the markedly more variable microsatellite loci confirm the presence of male-mediated gene flow among populations within ocean basins. This analysis generally confirms the genetic divergence between the Atlantic and Pacific. As with the previous study, phylogenetic analyses of genetic distances based on the microsatellite loci indicate a close genetic relationship among eastern Atlantic and Indian Ocean populations. Unlike the single-copy study, however, the results here cannot be attributed to an artifact of general low variability and likely represent recent or ongoing migration between ocean basins. Sequence analyses of regions flanking the microsatellite repeat reveal considerable amounts of cryptic variation and homoplasy and significantly aid in our understanding of population connectivity. Assessment of the allele frequency distributions indicates that at least some of the loci may not be evolving by the stepwise mutation model. PMID:15126404

Parent-of-origin specific allelic associations among 106 genomic loci for age at menarche

PubMed Central

Thompson, Deborah J; Ferreira, Teresa; He, Chunyan; Chasman, Daniel I; Esko, Tõnu; Thorleifsson, Gudmar; Albrecht, Eva; Ang, Wei Q; Corre, Tanguy; Cousminer, Diana L; Feenstra, Bjarke; Franceschini, Nora; Ganna, Andrea; Johnson, Andrew D; Kjellqvist, Sanela; Lunetta, Kathryn L; McMahon, George; Nolte, Ilja M; Paternoster, Lavinia; Porcu, Eleonora; Smith, Albert V; Stolk, Lisette; Teumer, Alexander; Tšernikova, Natalia; Tikkanen, Emmi; Ulivi, Sheila; Wagner, Erin K; Amin, Najaf; Bierut, Laura J; Byrne, Enda M; Hottenga, Jouke-Jan; Koller, Daniel L; Mangino, Massimo; Pers, Tune H; Yerges-Armstrong, Laura M; Zhao, Jing Hua; Andrulis, Irene L; Anton-Culver, Hoda; Atsma, Femke; Bandinelli, Stefania; Beckmann, Matthias W; Benitez, Javier; Blomqvist, Carl; Bojesen, Stig E; Bolla, Manjeet K; Bonanni, Bernardo; Brauch, Hiltrud; Brenner, Hermann; Buring, Julie E; Chang-Claude, Jenny; Chanock, Stephen; Chen, Jinhui; Chenevix-Trench, Georgia; Collée, J. Margriet; Couch, Fergus J; Couper, David; Coveillo, Andrea D; Cox, Angela; Czene, Kamila; D’adamo, Adamo Pio; Smith, George Davey; De Vivo, Immaculata; Demerath, Ellen W; Dennis, Joe; Devilee, Peter; Dieffenbach, Aida K; Dunning, Alison M; Eiriksdottir, Gudny; Eriksson, Johan G; Fasching, Peter A; Ferrucci, Luigi; Flesch-Janys, Dieter; Flyger, Henrik; Foroud, Tatiana; Franke, Lude; Garcia, Melissa E; García-Closas, Montserrat; Geller, Frank; de Geus, Eco EJ; Giles, Graham G; Gudbjartsson, Daniel F; Gudnason, Vilmundur; Guénel, Pascal; Guo, Suiqun; Hall, Per; Hamann, Ute; Haring, Robin; Hartman, Catharina A; Heath, Andrew C; Hofman, Albert; Hooning, Maartje J; Hopper, John L; Hu, Frank B; Hunter, David J; Karasik, David; Kiel, Douglas P; Knight, Julia A; Kosma, Veli-Matti; Kutalik, Zoltan; Lai, Sandra; Lambrechts, Diether; Lindblom, Annika; Mägi, Reedik; Magnusson, Patrik K; Mannermaa, Arto; Martin, Nicholas G; Masson, Gisli; McArdle, Patrick F; McArdle, Wendy L; Melbye, Mads; Michailidou, Kyriaki; Mihailov, Evelin; Milani, Lili; Milne, Roger L; Nevanlinna, Heli; Neven, Patrick; Nohr, Ellen A; Oldehinkel, Albertine J; Oostra, Ben A; Palotie, Aarno; Peacock, Munro; Pedersen, Nancy L; Peterlongo, Paolo; Peto, Julian; Pharoah, Paul DP; Postma, Dirkje S; Pouta, Anneli; Pylkäs, Katri; Radice, Paolo; Ring, Susan; Rivadeneira, Fernando; Robino, Antonietta; Rose, Lynda M; Rudolph, Anja; Salomaa, Veikko; Sanna, Serena; Schlessinger, David; Schmidt, Marjanka K; Southey, Mellissa C; Sovio, Ulla; Stampfer, Meir J; Stöckl, Doris; Storniolo, Anna M; Timpson, Nicholas J; Tyrer, Jonathan; Visser, Jenny A; Vollenweider, Peter; Völzke, Henry; Waeber, Gerard; Waldenberger, Melanie; Wallaschofski, Henri; Wang, Qin; Willemsen, Gonneke; Winqvist, Robert; Wolffenbuttel, Bruce HR; Wright, Margaret J; Boomsma, Dorret I; Econs, Michael J; Khaw, Kay-Tee; Loos, Ruth JF; McCarthy, Mark I; Montgomery, Grant W; Rice, John P; Streeten, Elizabeth A; Thorsteinsdottir, Unnur; van Duijn, Cornelia M; Alizadeh, Behrooz Z; Bergmann, Sven; Boerwinkle, Eric; Boyd, Heather A; Crisponi, Laura; Gasparini, Paolo; Gieger, Christian; Harris, Tamara B; Ingelsson, Erik; Järvelin, Marjo-Riitta; Kraft, Peter; Lawlor, Debbie; Metspalu, Andres; Pennell, Craig E; Ridker, Paul M; Snieder, Harold; Sørensen, Thorkild IA; Spector, Tim D; Strachan, David P; Uitterlinden, André G; Wareham, Nicholas J; Widen, Elisabeth; Zygmunt, Marek; Murray, Anna; Easton, Douglas F

2014-01-01

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality1. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation2,3, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P<5×10−8) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1/WDR25, MKRN3/MAGEL2 and KCNK9) demonstrating parent-of-origin specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signaling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition. PMID:25231870

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

PubMed

Perry, John Rb; Day, Felix; Elks, Cathy E; Sulem, Patrick; Thompson, Deborah J; Ferreira, Teresa; He, Chunyan; Chasman, Daniel I; Esko, Tõnu; Thorleifsson, Gudmar; Albrecht, Eva; Ang, Wei Q; Corre, Tanguy; Cousminer, Diana L; Feenstra, Bjarke; Franceschini, Nora; Ganna, Andrea; Johnson, Andrew D; Kjellqvist, Sanela; Lunetta, Kathryn L; McMahon, George; Nolte, Ilja M; Paternoster, Lavinia; Porcu, Eleonora; Smith, Albert V; Stolk, Lisette; Teumer, Alexander; Tšernikova, Natalia; Tikkanen, Emmi; Ulivi, Sheila; Wagner, Erin K; Amin, Najaf; Bierut, Laura J; Byrne, Enda M; Hottenga, Jouke-Jan; Koller, Daniel L; Mangino, Massimo; Pers, Tune H; Yerges-Armstrong, Laura M; Zhao, Jing Hua; Andrulis, Irene L; Anton-Culver, Hoda; Atsma, Femke; Bandinelli, Stefania; Beckmann, Matthias W; Benitez, Javier; Blomqvist, Carl; Bojesen, Stig E; Bolla, Manjeet K; Bonanni, Bernardo; Brauch, Hiltrud; Brenner, Hermann; Buring, Julie E; Chang-Claude, Jenny; Chanock, Stephen; Chen, Jinhui; Chenevix-Trench, Georgia; Collée, J Margriet; Couch, Fergus J; Couper, David; Coveillo, Andrea D; Cox, Angela; Czene, Kamila; D'adamo, Adamo Pio; Smith, George Davey; De Vivo, Immaculata; Demerath, Ellen W; Dennis, Joe; Devilee, Peter; Dieffenbach, Aida K; Dunning, Alison M; Eiriksdottir, Gudny; Eriksson, Johan G; Fasching, Peter A; Ferrucci, Luigi; Flesch-Janys, Dieter; Flyger, Henrik; Foroud, Tatiana; Franke, Lude; Garcia, Melissa E; García-Closas, Montserrat; Geller, Frank; de Geus, Eco Ej; Giles, Graham G; Gudbjartsson, Daniel F; Gudnason, Vilmundur; Guénel, Pascal; Guo, Suiqun; Hall, Per; Hamann, Ute; Haring, Robin; Hartman, Catharina A; Heath, Andrew C; Hofman, Albert; Hooning, Maartje J; Hopper, John L; Hu, Frank B; Hunter, David J; Karasik, David; Kiel, Douglas P; Knight, Julia A; Kosma, Veli-Matti; Kutalik, Zoltan; Lai, Sandra; Lambrechts, Diether; Lindblom, Annika; Mägi, Reedik; Magnusson, Patrik K; Mannermaa, Arto; Martin, Nicholas G; Masson, Gisli; McArdle, Patrick F; McArdle, Wendy L; Melbye, Mads; Michailidou, Kyriaki; Mihailov, Evelin; Milani, Lili; Milne, Roger L; Nevanlinna, Heli; Neven, Patrick; Nohr, Ellen A; Oldehinkel, Albertine J; Oostra, Ben A; Palotie, Aarno; Peacock, Munro; Pedersen, Nancy L; Peterlongo, Paolo; Peto, Julian; Pharoah, Paul Dp; Postma, Dirkje S; Pouta, Anneli; Pylkäs, Katri; Radice, Paolo; Ring, Susan; Rivadeneira, Fernando; Robino, Antonietta; Rose, Lynda M; Rudolph, Anja; Salomaa, Veikko; Sanna, Serena; Schlessinger, David; Schmidt, Marjanka K; Southey, Mellissa C; Sovio, Ulla; Stampfer, Meir J; Stöckl, Doris; Storniolo, Anna M; Timpson, Nicholas J; Tyrer, Jonathan; Visser, Jenny A; Vollenweider, Peter; Völzke, Henry; Waeber, Gerard; Waldenberger, Melanie; Wallaschofski, Henri; Wang, Qin; Willemsen, Gonneke; Winqvist, Robert; Wolffenbuttel, Bruce Hr; Wright, Margaret J; Boomsma, Dorret I; Econs, Michael J; Khaw, Kay-Tee; Loos, Ruth Jf; McCarthy, Mark I; Montgomery, Grant W; Rice, John P; Streeten, Elizabeth A; Thorsteinsdottir, Unnur; van Duijn, Cornelia M; Alizadeh, Behrooz Z; Bergmann, Sven; Boerwinkle, Eric; Boyd, Heather A; Crisponi, Laura; Gasparini, Paolo; Gieger, Christian; Harris, Tamara B; Ingelsson, Erik; Järvelin, Marjo-Riitta; Kraft, Peter; Lawlor, Debbie; Metspalu, Andres; Pennell, Craig E; Ridker, Paul M; Snieder, Harold; Sørensen, Thorkild Ia; Spector, Tim D; Strachan, David P; Uitterlinden, André G; Wareham, Nicholas J; Widen, Elisabeth; Zygmunt, Marek; Murray, Anna; Easton, Douglas F; Stefansson, Kari; Murabito, Joanne M; Ong, Ken K

2014-10-02

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

Exome chip meta-analysis identifies novel loci and East Asian-specific coding variants that contribute to lipid levels and coronary artery disease.

PubMed

Lu, Xiangfeng; Peloso, Gina M; Liu, Dajiang J; Wu, Ying; Zhang, He; Zhou, Wei; Li, Jun; Tang, Clara Sze-Man; Dorajoo, Rajkumar; Li, Huaixing; Long, Jirong; Guo, Xiuqing; Xu, Ming; Spracklen, Cassandra N; Chen, Yang; Liu, Xuezhen; Zhang, Yan; Khor, Chiea Chuen; Liu, Jianjun; Sun, Liang; Wang, Laiyuan; Gao, Yu-Tang; Hu, Yao; Yu, Kuai; Wang, Yiqin; Cheung, Chloe Yu Yan; Wang, Feijie; Huang, Jianfeng; Fan, Qiao; Cai, Qiuyin; Chen, Shufeng; Shi, Jinxiu; Yang, Xueli; Zhao, Wanting; Sheu, Wayne H-H; Cherny, Stacey Shawn; He, Meian; Feranil, Alan B; Adair, Linda S; Gordon-Larsen, Penny; Du, Shufa; Varma, Rohit; Chen, Yii-Der Ida; Shu, Xiao-Ou; Lam, Karen Siu Ling; Wong, Tien Yin; Ganesh, Santhi K; Mo, Zengnan; Hveem, Kristian; Fritsche, Lars G; Nielsen, Jonas Bille; Tse, Hung-Fat; Huo, Yong; Cheng, Ching-Yu; Chen, Y Eugene; Zheng, Wei; Tai, E Shyong; Gao, Wei; Lin, Xu; Huang, Wei; Abecasis, Goncalo; Kathiresan, Sekar; Mohlke, Karen L; Wu, Tangchun; Sham, Pak Chung; Gu, Dongfeng; Willer, Cristen J

2017-12-01

Most genome-wide association studies have been of European individuals, even though most genetic variation in humans is seen only in non-European samples. To search for novel loci associated with blood lipid levels and clarify the mechanism of action at previously identified lipid loci, we used an exome array to examine protein-coding genetic variants in 47,532 East Asian individuals. We identified 255 variants at 41 loci that reached chip-wide significance, including 3 novel loci and 14 East Asian-specific coding variant associations. After a meta-analysis including >300,000 European samples, we identified an additional nine novel loci. Sixteen genes were identified by protein-altering variants in both East Asians and Europeans, and thus are likely to be functional genes. Our data demonstrate that most of the low-frequency or rare coding variants associated with lipids are population specific, and that examining genomic data across diverse ancestries may facilitate the identification of functional genes at associated loci.

Exome chip meta-analysis identifies novel loci and East Asian-specific coding variants contributing to lipid levels and coronary artery disease

PubMed Central

Lu, Xiangfeng; Peloso, Gina M; Liu, Dajiang J.; Wu, Ying; Zhang, He; Zhou, Wei; Li, Jun; Tang, Clara Sze-man; Dorajoo, Rajkumar; Li, Huaixing; Long, Jirong; Guo, Xiuqing; Xu, Ming; Spracklen, Cassandra N.; Chen, Yang; Liu, Xuezhen; Zhang, Yan; Khor, Chiea Chuen; Liu, Jianjun; Sun, Liang; Wang, Laiyuan; Gao, Yu-Tang; Hu, Yao; Yu, Kuai; Wang, Yiqin; Cheung, Chloe Yu Yan; Wang, Feijie; Huang, Jianfeng; Fan, Qiao; Cai, Qiuyin; Chen, Shufeng; Shi, Jinxiu; Yang, Xueli; Zhao, Wanting; Sheu, Wayne H.-H.; Cherny, Stacey Shawn; He, Meian; Feranil, Alan B.; Adair, Linda S.; Gordon-Larsen, Penny; Du, Shufa; Varma, Rohit; da Chen, Yii-Der I; Shu, XiaoOu; Lam, Karen Siu Ling; Wong, Tien Yin; Ganesh, Santhi K.; Mo, Zengnan; Hveem, Kristian; Fritsche, Lars; Nielsen, Jonas Bille; Tse, Hung-fat; Huo, Yong; Cheng, Ching-Yu; Chen, Y. Eugene; Zheng, Wei; Tai, E Shyong; Gao, Wei; Lin, Xu; Huang, Wei; Abecasis, Goncalo; Consortium, GLGC; Kathiresan, Sekar; Mohlke, Karen L.; Wu, Tangchun; Sham, Pak Chung; Gu, Dongfeng; Willer, Cristen J

2017-01-01

Most genome-wide association studies have been conducted in European individuals, even though most genetic variation in humans is seen only in non-European samples. To search for novel loci associated with blood lipid levels and clarify the mechanism of action at previously identified lipid loci, we examined protein-coding genetic variants in 47,532 East Asian individuals using an exome array. We identified 255 variants at 41 loci reaching chip-wide significance, including 3 novel loci and 14 East Asian-specific coding variant associations. After meta-analysis with > 300,000 European samples, we identified an additional 9 novel loci. The same 16 genes were identified by the protein-altering variants in both East Asians and Europeans, likely pointing to the functional genes. Our data demonstrate that most of the low-frequency or rare coding variants associated with lipids are population-specific, and that examining genomic data across diverse ancestries may facilitate the identification of functional genes at associated loci. PMID:29083407

Discovery and Refinement of Loci Associated with Lipid Levels

PubMed Central

Peloso, Gina M.; Gustafsson, Stefan; Kanoni, Stavroula; Ganna, Andrea; Chen, Jin; Buchkovich, Martin L.; Mora, Samia; Beckmann, Jacques S.; Bragg-Gresham, Jennifer L.; Chang, Hsing-Yi; Demirkan, Ayşe; Den Hertog, Heleen M.; Do, Ron; Donnelly, Louise A.; Ehret, Georg B.; Esko, Tõnu; Feitosa, Mary F.; Ferreira, Teresa; Fischer, Krista; Fontanillas, Pierre; Fraser, Ross M.; Freitag, Daniel F.; Gurdasani, Deepti; Heikkilä, Kauko; Hyppönen, Elina; Isaacs, Aaron; Jackson, Anne U.; Johansson, Åsa; Johnson, Toby; Kaakinen, Marika; Kettunen, Johannes; Kleber, Marcus E.; Li, Xiaohui; Luan, Jian’an; Lyytikäinen, Leo-Pekka; Magnusson, Patrik K.E.; Mangino, Massimo; Mihailov, Evelin; Montasser, May E.; Müller-Nurasyid, Martina; Nolte, Ilja M.; O’Connell, Jeffrey R.; Palmer, Cameron D.; Perola, Markus; Petersen, Ann-Kristin; Sanna, Serena; Saxena, Richa; Service, Susan K.; Shah, Sonia; Shungin, Dmitry; Sidore, Carlo; Song, Ci; Strawbridge, Rona J.; Surakka, Ida; Tanaka, Toshiko; Teslovich, Tanya M.; Thorleifsson, Gudmar; Van den Herik, Evita G.; Voight, Benjamin F.; Volcik, Kelly A.; Waite, Lindsay L.; Wong, Andrew; Wu, Ying; Zhang, Weihua; Absher, Devin; Asiki, Gershim; Barroso, Inês; Been, Latonya F.; Bolton, Jennifer L.; Bonnycastle, Lori L; Brambilla, Paolo; Burnett, Mary S.; Cesana, Giancarlo; Dimitriou, Maria; Doney, Alex S.F.; Döring, Angela; Elliott, Paul; Epstein, Stephen E.; Ingi Eyjolfsson, Gudmundur; Gigante, Bruna; Goodarzi, Mark O.; Grallert, Harald; Gravito, Martha L.; Groves, Christopher J.; Hallmans, Göran; Hartikainen, Anna-Liisa; Hayward, Caroline; Hernandez, Dena; Hicks, Andrew A.; Holm, Hilma; Hung, Yi-Jen; Illig, Thomas; Jones, Michelle R.; Kaleebu, Pontiano; Kastelein, John J.P.; Khaw, Kay-Tee; Kim, Eric; Klopp, Norman; Komulainen, Pirjo; Kumari, Meena; Langenberg, Claudia; Lehtimäki, Terho; Lin, Shih-Yi; Lindström, Jaana; Loos, Ruth J.F.; Mach, François; McArdle, Wendy L; Meisinger, Christa; Mitchell, Braxton D.; Müller, Gabrielle; Nagaraja, Ramaiah; Narisu, Narisu; Nieminen, Tuomo V.M.; Nsubuga, Rebecca N.; Olafsson, Isleifur; Ong, Ken K.; Palotie, Aarno; Papamarkou, Theodore; Pomilla, Cristina; Pouta, Anneli; Rader, Daniel J.; Reilly, Muredach P.; Ridker, Paul M.; Rivadeneira, Fernando; Rudan, Igor; Ruokonen, Aimo; Samani, Nilesh; Scharnagl, Hubert; Seeley, Janet; Silander, Kaisa; Stančáková, Alena; Stirrups, Kathleen; Swift, Amy J.; Tiret, Laurence; Uitterlinden, Andre G.; van Pelt, L. Joost; Vedantam, Sailaja; Wainwright, Nicholas; Wijmenga, Cisca; Wild, Sarah H.; Willemsen, Gonneke; Wilsgaard, Tom; Wilson, James F.; Young, Elizabeth H.; Zhao, Jing Hua; Adair, Linda S.; Arveiler, Dominique; Assimes, Themistocles L.; Bandinelli, Stefania; Bennett, Franklyn; Bochud, Murielle; Boehm, Bernhard O.; Boomsma, Dorret I.; Borecki, Ingrid B.; Bornstein, Stefan R.; Bovet, Pascal; Burnier, Michel; Campbell, Harry; Chakravarti, Aravinda; Chambers, John C.; Chen, Yii-Der Ida; Collins, Francis S.; Cooper, Richard S.; Danesh, John; Dedoussis, George; de Faire, Ulf; Feranil, Alan B.; Ferrières, Jean; Ferrucci, Luigi; Freimer, Nelson B.; Gieger, Christian; Groop, Leif C.; Gudnason, Vilmundur; Gyllensten, Ulf; Hamsten, Anders; Harris, Tamara B.; Hingorani, Aroon; Hirschhorn, Joel N.; Hofman, Albert; Hovingh, G. Kees; Hsiung, Chao Agnes; Humphries, Steve E.; Hunt, Steven C.; Hveem, Kristian; Iribarren, Carlos; Järvelin, Marjo-Riitta; Jula, Antti; Kähönen, Mika; Kaprio, Jaakko; Kesäniemi, Antero; Kivimaki, Mika; Kooner, Jaspal S.; Koudstaal, Peter J.; Krauss, Ronald M.; Kuh, Diana; Kuusisto, Johanna; Kyvik, Kirsten O.; Laakso, Markku; Lakka, Timo A.; Lind, Lars; Lindgren, Cecilia M.; Martin, Nicholas G.; März, Winfried; McCarthy, Mark I.; McKenzie, Colin A.; Meneton, Pierre; Metspalu, Andres; Moilanen, Leena; Morris, Andrew D.; Munroe, Patricia B.; Njølstad, Inger; Pedersen, Nancy L.; Power, Chris; Pramstaller, Peter P.; Price, Jackie F.; Psaty, Bruce M.; Quertermous, Thomas; Rauramaa, Rainer; Saleheen, Danish; Salomaa, Veikko; Sanghera, Dharambir K.; Saramies, Jouko; Schwarz, Peter E.H.; Sheu, Wayne H-H; Shuldiner, Alan R.; Siegbahn, Agneta; Spector, Tim D.; Stefansson, Kari; Strachan, David P.; Tayo, Bamidele O.; Tremoli, Elena; Tuomilehto, Jaakko; Uusitupa, Matti; van Duijn, Cornelia M.; Vollenweider, Peter; Wallentin, Lars; Wareham, Nicholas J.; Whitfield, John B.; Wolffenbuttel, Bruce H.R.; Ordovas, Jose M.; Boerwinkle, Eric; Palmer, Colin N.A.; Thorsteinsdottir, Unnur; Chasman, Daniel I.; Rotter, Jerome I.; Franks, Paul W.; Ripatti, Samuli; Cupples, L. Adrienne; Sandhu, Manjinder S.; Rich, Stephen S.

2013-01-01

Low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and total cholesterol are heritable, modifiable, risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,578 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5×10−8, including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian, and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipids are often associated with cardiovascular and metabolic traits including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio, and body mass index. Our results illustrate the value of genetic data from individuals of diverse ancestries and provide insights into biological mechanisms regulating blood lipids to guide future genetic, biological, and therapeutic research. PMID:24097068

Discovery and refinement of loci associated with lipid levels.

PubMed

Willer, Cristen J; Schmidt, Ellen M; Sengupta, Sebanti; Peloso, Gina M; Gustafsson, Stefan; Kanoni, Stavroula; Ganna, Andrea; Chen, Jin; Buchkovich, Martin L; Mora, Samia; Beckmann, Jacques S; Bragg-Gresham, Jennifer L; Chang, Hsing-Yi; Demirkan, Ayşe; Den Hertog, Heleen M; Do, Ron; Donnelly, Louise A; Ehret, Georg B; Esko, Tõnu; Feitosa, Mary F; Ferreira, Teresa; Fischer, Krista; Fontanillas, Pierre; Fraser, Ross M; Freitag, Daniel F; Gurdasani, Deepti; Heikkilä, Kauko; Hyppönen, Elina; Isaacs, Aaron; Jackson, Anne U; Johansson, Åsa; Johnson, Toby; Kaakinen, Marika; Kettunen, Johannes; Kleber, Marcus E; Li, Xiaohui; Luan, Jian'an; Lyytikäinen, Leo-Pekka; Magnusson, Patrik K E; Mangino, Massimo; Mihailov, Evelin; Montasser, May E; Müller-Nurasyid, Martina; Nolte, Ilja M; O'Connell, Jeffrey R; Palmer, Cameron D; Perola, Markus; Petersen, Ann-Kristin; Sanna, Serena; Saxena, Richa; Service, Susan K; Shah, Sonia; Shungin, Dmitry; Sidore, Carlo; Song, Ci; Strawbridge, Rona J; Surakka, Ida; Tanaka, Toshiko; Teslovich, Tanya M; Thorleifsson, Gudmar; Van den Herik, Evita G; Voight, Benjamin F; Volcik, Kelly A; Waite, Lindsay L; Wong, Andrew; Wu, Ying; Zhang, Weihua; Absher, Devin; Asiki, Gershim; Barroso, Inês; Been, Latonya F; Bolton, Jennifer L; Bonnycastle, Lori L; Brambilla, Paolo; Burnett, Mary S; Cesana, Giancarlo; Dimitriou, Maria; Doney, Alex S F; Döring, Angela; Elliott, Paul; Epstein, Stephen E; Ingi Eyjolfsson, Gudmundur; Gigante, Bruna; Goodarzi, Mark O; Grallert, Harald; Gravito, Martha L; Groves, Christopher J; Hallmans, Göran; Hartikainen, Anna-Liisa; Hayward, Caroline; Hernandez, Dena; Hicks, Andrew A; Holm, Hilma; Hung, Yi-Jen; Illig, Thomas; Jones, Michelle R; Kaleebu, Pontiano; Kastelein, John J P; Khaw, Kay-Tee; Kim, Eric; Klopp, Norman; Komulainen, Pirjo; Kumari, Meena; Langenberg, Claudia; Lehtimäki, Terho; Lin, Shih-Yi; Lindström, Jaana; Loos, Ruth J F; Mach, François; McArdle, Wendy L; Meisinger, Christa; Mitchell, Braxton D; Müller, Gabrielle; Nagaraja, Ramaiah; Narisu, Narisu; Nieminen, Tuomo V M; Nsubuga, Rebecca N; Olafsson, Isleifur; Ong, Ken K; Palotie, Aarno; Papamarkou, Theodore; Pomilla, Cristina; Pouta, Anneli; Rader, Daniel J; Reilly, Muredach P; Ridker, Paul M; Rivadeneira, Fernando; Rudan, Igor; Ruokonen, Aimo; Samani, Nilesh; Scharnagl, Hubert; Seeley, Janet; Silander, Kaisa; Stančáková, Alena; Stirrups, Kathleen; Swift, Amy J; Tiret, Laurence; Uitterlinden, Andre G; van Pelt, L Joost; Vedantam, Sailaja; Wainwright, Nicholas; Wijmenga, Cisca; Wild, Sarah H; Willemsen, Gonneke; Wilsgaard, Tom; Wilson, James F; Young, Elizabeth H; Zhao, Jing Hua; Adair, Linda S; Arveiler, Dominique; Assimes, Themistocles L; Bandinelli, Stefania; Bennett, Franklyn; Bochud, Murielle; Boehm, Bernhard O; Boomsma, Dorret I; Borecki, Ingrid B; Bornstein, Stefan R; Bovet, Pascal; Burnier, Michel; Campbell, Harry; Chakravarti, Aravinda; Chambers, John C; Chen, Yii-Der Ida; Collins, Francis S; Cooper, Richard S; Danesh, John; Dedoussis, George; de Faire, Ulf; Feranil, Alan B; Ferrières, Jean; Ferrucci, Luigi; Freimer, Nelson B; Gieger, Christian; Groop, Leif C; Gudnason, Vilmundur; Gyllensten, Ulf; Hamsten, Anders; Harris, Tamara B; Hingorani, Aroon; Hirschhorn, Joel N; Hofman, Albert; Hovingh, G Kees; Hsiung, Chao Agnes; Humphries, Steve E; Hunt, Steven C; Hveem, Kristian; Iribarren, Carlos; Järvelin, Marjo-Riitta; Jula, Antti; Kähönen, Mika; Kaprio, Jaakko; Kesäniemi, Antero; Kivimaki, Mika; Kooner, Jaspal S; Koudstaal, Peter J; Krauss, Ronald M; Kuh, Diana; Kuusisto, Johanna; Kyvik, Kirsten O; Laakso, Markku; Lakka, Timo A; Lind, Lars; Lindgren, Cecilia M; Martin, Nicholas G; März, Winfried; McCarthy, Mark I; McKenzie, Colin A; Meneton, Pierre; Metspalu, Andres; Moilanen, Leena; Morris, Andrew D; Munroe, Patricia B; Njølstad, Inger; Pedersen, Nancy L; Power, Chris; Pramstaller, Peter P; Price, Jackie F; Psaty, Bruce M; Quertermous, Thomas; Rauramaa, Rainer; Saleheen, Danish; Salomaa, Veikko; Sanghera, Dharambir K; Saramies, Jouko; Schwarz, Peter E H; Sheu, Wayne H-H; Shuldiner, Alan R; Siegbahn, Agneta; Spector, Tim D; Stefansson, Kari; Strachan, David P; Tayo, Bamidele O; Tremoli, Elena; Tuomilehto, Jaakko; Uusitupa, Matti; van Duijn, Cornelia M; Vollenweider, Peter; Wallentin, Lars; Wareham, Nicholas J; Whitfield, John B; Wolffenbuttel, Bruce H R; Ordovas, Jose M; Boerwinkle, Eric; Palmer, Colin N A; Thorsteinsdottir, Unnur; Chasman, Daniel I; Rotter, Jerome I; Franks, Paul W; Ripatti, Samuli; Cupples, L Adrienne; Sandhu, Manjinder S; Rich, Stephen S; Boehnke, Michael; Deloukas, Panos; Kathiresan, Sekar; Mohlke, Karen L; Ingelsson, Erik; Abecasis, Gonçalo R

2013-11-01

Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.

Genetic studies of body mass index yield new insights for obesity biology.

PubMed

Locke, Adam E; Kahali, Bratati; Berndt, Sonja I; Justice, Anne E; Pers, Tune H; Day, Felix R; Powell, Corey; Vedantam, Sailaja; Buchkovich, Martin L; Yang, Jian; Croteau-Chonka, Damien C; Esko, Tonu; Fall, Tove; Ferreira, Teresa; Gustafsson, Stefan; Kutalik, Zoltán; Luan, Jian'an; Mägi, Reedik; Randall, Joshua C; Winkler, Thomas W; Wood, Andrew R; Workalemahu, Tsegaselassie; Faul, Jessica D; Smith, Jennifer A; Zhao, Jing Hua; Zhao, Wei; Chen, Jin; Fehrmann, Rudolf; Hedman, Åsa K; Karjalainen, Juha; Schmidt, Ellen M; Absher, Devin; Amin, Najaf; Anderson, Denise; Beekman, Marian; Bolton, Jennifer L; Bragg-Gresham, Jennifer L; Buyske, Steven; Demirkan, Ayse; Deng, Guohong; Ehret, Georg B; Feenstra, Bjarke; Feitosa, Mary F; Fischer, Krista; Goel, Anuj; Gong, Jian; Jackson, Anne U; Kanoni, Stavroula; Kleber, Marcus E; Kristiansson, Kati; Lim, Unhee; Lotay, Vaneet; Mangino, Massimo; Leach, Irene Mateo; Medina-Gomez, Carolina; Medland, Sarah E; Nalls, Michael A; Palmer, Cameron D; Pasko, Dorota; Pechlivanis, Sonali; Peters, Marjolein J; Prokopenko, Inga; Shungin, Dmitry; Stančáková, Alena; Strawbridge, Rona J; Sung, Yun Ju; Tanaka, Toshiko; Teumer, Alexander; Trompet, Stella; van der Laan, Sander W; van Setten, Jessica; Van Vliet-Ostaptchouk, Jana V; Wang, Zhaoming; Yengo, Loïc; Zhang, Weihua; Isaacs, Aaron; Albrecht, Eva; Ärnlöv, Johan; Arscott, Gillian M; Attwood, Antony P; Bandinelli, Stefania; Barrett, Amy; Bas, Isabelita N; Bellis, Claire; Bennett, Amanda J; Berne, Christian; Blagieva, Roza; Blüher, Matthias; Böhringer, Stefan; Bonnycastle, Lori L; Böttcher, Yvonne; Boyd, Heather A; Bruinenberg, Marcel; Caspersen, Ida H; Chen, Yii-Der Ida; Clarke, Robert; Daw, E Warwick; de Craen, Anton J M; Delgado, Graciela; Dimitriou, Maria; Doney, Alex S F; Eklund, Niina; Estrada, Karol; Eury, Elodie; Folkersen, Lasse; Fraser, Ross M; Garcia, Melissa E; Geller, Frank; Giedraitis, Vilmantas; Gigante, Bruna; Go, Alan S; Golay, Alain; Goodall, Alison H; Gordon, Scott D; Gorski, Mathias; Grabe, Hans-Jörgen; Grallert, Harald; Grammer, Tanja B; Gräßler, Jürgen; Grönberg, Henrik; Groves, Christopher J; Gusto, Gaëlle; Haessler, Jeffrey; Hall, Per; Haller, Toomas; Hallmans, Goran; Hartman, Catharina A; Hassinen, Maija; Hayward, Caroline; Heard-Costa, Nancy L; Helmer, Quinta; Hengstenberg, Christian; Holmen, Oddgeir; Hottenga, Jouke-Jan; James, Alan L; Jeff, Janina M; Johansson, Åsa; Jolley, Jennifer; Juliusdottir, Thorhildur; Kinnunen, Leena; Koenig, Wolfgang; Koskenvuo, Markku; Kratzer, Wolfgang; Laitinen, Jaana; Lamina, Claudia; Leander, Karin; Lee, Nanette R; Lichtner, Peter; Lind, Lars; Lindström, Jaana; Lo, Ken Sin; Lobbens, Stéphane; Lorbeer, Roberto; Lu, Yingchang; Mach, François; Magnusson, Patrik K E; Mahajan, Anubha; McArdle, Wendy L; McLachlan, Stela; Menni, Cristina; Merger, Sigrun; Mihailov, Evelin; Milani, Lili; Moayyeri, Alireza; Monda, Keri L; Morken, Mario A; Mulas, Antonella; Müller, Gabriele; Müller-Nurasyid, Martina; Musk, Arthur W; Nagaraja, Ramaiah; Nöthen, Markus M; Nolte, Ilja M; Pilz, Stefan; Rayner, Nigel W; Renstrom, Frida; Rettig, Rainer; Ried, Janina S; Ripke, Stephan; Robertson, Neil R; Rose, Lynda M; Sanna, Serena; Scharnagl, Hubert; Scholtens, Salome; Schumacher, Fredrick R; Scott, William R; Seufferlein, Thomas; Shi, Jianxin; Smith, Albert Vernon; Smolonska, Joanna; Stanton, Alice V; Steinthorsdottir, Valgerdur; Stirrups, Kathleen; Stringham, Heather M; Sundström, Johan; Swertz, Morris A; Swift, Amy J; Syvänen, Ann-Christine; Tan, Sian-Tsung; Tayo, Bamidele O; Thorand, Barbara; Thorleifsson, Gudmar; Tyrer, Jonathan P; Uh, Hae-Won; Vandenput, Liesbeth; Verhulst, Frank C; Vermeulen, Sita H; Verweij, Niek; Vonk, Judith M; Waite, Lindsay L; Warren, Helen R; Waterworth, Dawn; Weedon, Michael N; Wilkens, Lynne R; Willenborg, Christina; Wilsgaard, Tom; Wojczynski, Mary K; Wong, Andrew; Wright, Alan F; Zhang, Qunyuan; Brennan, Eoin P; Choi, Murim; Dastani, Zari; Drong, Alexander W; Eriksson, Per; Franco-Cereceda, Anders; Gådin, Jesper R; Gharavi, Ali G; Goddard, Michael E; Handsaker, Robert E; Huang, Jinyan; Karpe, Fredrik; Kathiresan, Sekar; Keildson, Sarah; Kiryluk, Krzysztof; Kubo, Michiaki; Lee, Jong-Young; Liang, Liming; Lifton, Richard P; Ma, Baoshan; McCarroll, Steven A; McKnight, Amy J; Min, Josine L; Moffatt, Miriam F; Montgomery, Grant W; Murabito, Joanne M; Nicholson, George; Nyholt, Dale R; Okada, Yukinori; Perry, John R B; Dorajoo, Rajkumar; Reinmaa, Eva; Salem, Rany M; Sandholm, Niina; Scott, Robert A; Stolk, Lisette; Takahashi, Atsushi; Tanaka, Toshihiro; van 't Hooft, Ferdinand M; Vinkhuyzen, Anna A E; Westra, Harm-Jan; Zheng, Wei; Zondervan, Krina T; Heath, Andrew C; Arveiler, Dominique; Bakker, Stephan J L; Beilby, John; Bergman, Richard N; Blangero, John; Bovet, Pascal; Campbell, Harry; Caulfield, Mark J; Cesana, Giancarlo; Chakravarti, Aravinda; Chasman, Daniel I; Chines, Peter S; Collins, Francis S; Crawford, Dana C; Cupples, L Adrienne; Cusi, Daniele; Danesh, John; de Faire, Ulf; den Ruijter, Hester M; Dominiczak, Anna F; Erbel, Raimund; Erdmann, Jeanette; Eriksson, Johan G; Farrall, Martin; Felix, Stephan B; Ferrannini, Ele; Ferrières, Jean; Ford, Ian; Forouhi, Nita G; Forrester, Terrence; Franco, Oscar H; Gansevoort, Ron T; Gejman, Pablo V; Gieger, Christian; Gottesman, Omri; Gudnason, Vilmundur; Gyllensten, Ulf; Hall, Alistair S; Harris, Tamara B; Hattersley, Andrew T; Hicks, Andrew A; Hindorff, Lucia A; Hingorani, Aroon D; Hofman, Albert; Homuth, Georg; Hovingh, G Kees; Humphries, Steve E; Hunt, Steven C; Hyppönen, Elina; Illig, Thomas; Jacobs, Kevin B; Jarvelin, Marjo-Riitta; Jöckel, Karl-Heinz; Johansen, Berit; Jousilahti, Pekka; Jukema, J Wouter; Jula, Antti M; Kaprio, Jaakko; Kastelein, John J P; Keinanen-Kiukaanniemi, Sirkka M; Kiemeney, Lambertus A; Knekt, Paul; Kooner, Jaspal S; Kooperberg, Charles; Kovacs, Peter; Kraja, Aldi T; Kumari, Meena; Kuusisto, Johanna; Lakka, Timo A; Langenberg, Claudia; Marchand, Loic Le; Lehtimäki, Terho; Lyssenko, Valeriya; Männistö, Satu; Marette, André; Matise, Tara C; McKenzie, Colin A; McKnight, Barbara; Moll, Frans L; Morris, Andrew D; Morris, Andrew P; Murray, Jeffrey C; Nelis, Mari; Ohlsson, Claes; Oldehinkel, Albertine J; Ong, Ken K; Madden, Pamela A F; Pasterkamp, Gerard; Peden, John F; Peters, Annette; Postma, Dirkje S; Pramstaller, Peter P; Price, Jackie F; Qi, Lu; Raitakari, Olli T; Rankinen, Tuomo; Rao, D C; Rice, Treva K; Ridker, Paul M; Rioux, John D; Ritchie, Marylyn D; Rudan, Igor; Salomaa, Veikko; Samani, Nilesh J; Saramies, Jouko; Sarzynski, Mark A; Schunkert, Heribert; Schwarz, Peter E H; Sever, Peter; Shuldiner, Alan R; Sinisalo, Juha; Stolk, Ronald P; Strauch, Konstantin; Tönjes, Anke; Trégouët, David-Alexandre; Tremblay, Angelo; Tremoli, Elena; Virtamo, Jarmo; Vohl, Marie-Claude; Völker, Uwe; Waeber, Gérard; Willemsen, Gonneke; Witteman, Jacqueline C; Zillikens, M Carola; Adair, Linda S; Amouyel, Philippe; Asselbergs, Folkert W; Assimes, Themistocles L; Bochud, Murielle; Boehm, Bernhard O; Boerwinkle, Eric; Bornstein, Stefan R; Bottinger, Erwin P; Bouchard, Claude; Cauchi, Stéphane; Chambers, John C; Chanock, Stephen J; Cooper, Richard S; de Bakker, Paul I W; Dedoussis, George; Ferrucci, Luigi; Franks, Paul W; Froguel, Philippe; Groop, Leif C; Haiman, Christopher A; Hamsten, Anders; Hui, Jennie; Hunter, David J; Hveem, Kristian; Kaplan, Robert C; Kivimaki, Mika; Kuh, Diana; Laakso, Markku; Liu, Yongmei; Martin, Nicholas G; März, Winfried; Melbye, Mads; Metspalu, Andres; Moebus, Susanne; Munroe, Patricia B; Njølstad, Inger; Oostra, Ben A; Palmer, Colin N A; Pedersen, Nancy L; Perola, Markus; Pérusse, Louis; Peters, Ulrike; Power, Chris; Quertermous, Thomas; Rauramaa, Rainer; Rivadeneira, Fernando; Saaristo, Timo E; Saleheen, Danish; Sattar, Naveed; Schadt, Eric E; Schlessinger, David; Slagboom, P Eline; Snieder, Harold; Spector, Tim D; Thorsteinsdottir, Unnur; Stumvoll, Michael; Tuomilehto, Jaakko; Uitterlinden, André G; Uusitupa, Matti; van der Harst, Pim; Walker, Mark; Wallaschofski, Henri; Wareham, Nicholas J; Watkins, Hugh; Weir, David R; Wichmann, H-Erich; Wilson, James F; Zanen, Pieter; Borecki, Ingrid B; Deloukas, Panos; Fox, Caroline S; Heid, Iris M; O'Connell, Jeffrey R; Strachan, David P; Stefansson, Kari; van Duijn, Cornelia M; Abecasis, Gonçalo R; Franke, Lude; Frayling, Timothy M; McCarthy, Mark I; Visscher, Peter M; Scherag, André; Willer, Cristen J; Boehnke, Michael; Mohlke, Karen L; Lindgren, Cecilia M; Beckmann, Jacques S; Barroso, Inês; North, Kari E; Ingelsson, Erik; Hirschhorn, Joel N; Loos, Ruth J F; Speliotes, Elizabeth K

2015-02-12

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.

Genetic studies of body mass index yield new insights for obesity biology

PubMed Central

Day, Felix R.; Powell, Corey; Vedantam, Sailaja; Buchkovich, Martin L.; Yang, Jian; Croteau-Chonka, Damien C.; Esko, Tonu; Fall, Tove; Ferreira, Teresa; Gustafsson, Stefan; Kutalik, Zoltán; Luan, Jian’an; Mägi, Reedik; Randall, Joshua C.; Winkler, Thomas W.; Wood, Andrew R.; Workalemahu, Tsegaselassie; Faul, Jessica D.; Smith, Jennifer A.; Zhao, Jing Hua; Zhao, Wei; Chen, Jin; Fehrmann, Rudolf; Hedman, Åsa K.; Karjalainen, Juha; Schmidt, Ellen M.; Absher, Devin; Amin, Najaf; Anderson, Denise; Beekman, Marian; Bolton, Jennifer L.; Bragg-Gresham, Jennifer L.; Buyske, Steven; Demirkan, Ayse; Deng, Guohong; Ehret, Georg B.; Feenstra, Bjarke; Feitosa, Mary F.; Fischer, Krista; Goel, Anuj; Gong, Jian; Jackson, Anne U.; Kanoni, Stavroula; Kleber, Marcus E.; Kristiansson, Kati; Lim, Unhee; Lotay, Vaneet; Mangino, Massimo; Leach, Irene Mateo; Medina-Gomez, Carolina; Medland, Sarah E.; Nalls, Michael A.; Palmer, Cameron D.; Pasko, Dorota; Pechlivanis, Sonali; Peters, Marjolein J.; Prokopenko, Inga; Shungin, Dmitry; Stančáková, Alena; Strawbridge, Rona J.; Sung, Yun Ju; Tanaka, Toshiko; Teumer, Alexander; Trompet, Stella; van der Laan, Sander W.; van Setten, Jessica; Van Vliet-Ostaptchouk, Jana V.; Wang, Zhaoming; Yengo, Loïc; Zhang, Weihua; Isaacs, Aaron; Albrecht, Eva; Ärnlöv, Johan; Arscott, Gillian M.; Attwood, Antony P.; Bandinelli, Stefania; Barrett, Amy; Bas, Isabelita N.; Bellis, Claire; Bennett, Amanda J.; Berne, Christian; Blagieva, Roza; Blüher, Matthias; Böhringer, Stefan; Bonnycastle, Lori L.; Böttcher, Yvonne; Boyd, Heather A.; Bruinenberg, Marcel; Caspersen, Ida H.; Chen, Yii-Der Ida; Clarke, Robert; Daw, E. Warwick; de Craen, Anton J. M.; Delgado, Graciela; Dimitriou, Maria; Doney, Alex S. F.; Eklund, Niina; Estrada, Karol; Eury, Elodie; Folkersen, Lasse; Fraser, Ross M.; Garcia, Melissa E.; Geller, Frank; Giedraitis, Vilmantas; Gigante, Bruna; Go, Alan S.; Golay, Alain; Goodall, Alison H.; Gordon, Scott D.; Gorski, Mathias; Grabe, Hans-Jörgen; Grallert, Harald; Grammer, Tanja B.; Gräßler, Jürgen; Grönberg, Henrik; Groves, Christopher J.; Gusto, Gaëlle; Haessler, Jeffrey; Hall, Per; Haller, Toomas; Hallmans, Goran; Hartman, Catharina A.; Hassinen, Maija; Hayward, Caroline; Heard-Costa, Nancy L.; Helmer, Quinta; Hengstenberg, Christian; Holmen, Oddgeir; Hottenga, Jouke-Jan; James, Alan L.; Jeff, Janina M.; Johansson, Åsa; Jolley, Jennifer; Juliusdottir, Thorhildur; Kinnunen, Leena; Koenig, Wolfgang; Koskenvuo, Markku; Kratzer, Wolfgang; Laitinen, Jaana; Lamina, Claudia; Leander, Karin; Lee, Nanette R.; Lichtner, Peter; Lind, Lars; Lindström, Jaana; Lo, Ken Sin; Lobbens, Stéphane; Lorbeer, Roberto; Lu, Yingchang; Mach, François; Magnusson, Patrik K. E.; Mahajan, Anubha; McArdle, Wendy L.; McLachlan, Stela; Menni, Cristina; Merger, Sigrun; Mihailov, Evelin; Milani, Lili; Moayyeri, Alireza; Monda, Keri L.; Morken, Mario A.; Mulas, Antonella; Müller, Gabriele; Müller-Nurasyid, Martina; Musk, Arthur W.; Nagaraja, Ramaiah; Nöthen, Markus M.; Nolte, Ilja M.; Pilz, Stefan; Rayner, Nigel W.; Renstrom, Frida; Rettig, Rainer; Ried, Janina S.; Ripke, Stephan; Robertson, Neil R.; Rose, Lynda M.; Sanna, Serena; Scharnagl, Hubert; Scholtens, Salome; Schumacher, Fredrick R.; Scott, William R.; Seufferlein, Thomas; Shi, Jianxin; Smith, Albert Vernon; Smolonska, Joanna; Stanton, Alice V.; Steinthorsdottir, Valgerdur; Stirrups, Kathleen; Stringham, Heather M.; Sundström, Johan; Swertz, Morris A.; Swift, Amy J.; Syvänen, Ann-Christine; Tan, Sian-Tsung; Tayo, Bamidele O.; Thorand, Barbara; Thorleifsson, Gudmar; Tyrer, Jonathan P.; Uh, Hae-Won; Vandenput, Liesbeth; Verhulst, Frank C.; Vermeulen, Sita H.; Verweij, Niek; Vonk, Judith M.; Waite, Lindsay L.; Warren, Helen R.; Waterworth, Dawn; Weedon, Michael N.; Wilkens, Lynne R.; Willenborg, Christina; Wilsgaard, Tom; Wojczynski, Mary K.; Wong, Andrew; Wright, Alan F.; Zhang, Qunyuan; Brennan, Eoin P.; Choi, Murim; Dastani, Zari; Drong, Alexander W.; Eriksson, Per; Franco-Cereceda, Anders; Gådin, Jesper R.; Gharavi, Ali G.; Goddard, Michael E.; Handsaker, Robert E.; Huang, Jinyan; Karpe, Fredrik; Kathiresan, Sekar; Keildson, Sarah; Kiryluk, Krzysztof; Kubo, Michiaki; Lee, Jong-Young; Liang, Liming; Lifton, Richard P.; Ma, Baoshan; McCarroll, Steven A.; McKnight, Amy J.; Min, Josine L.; Moffatt, Miriam F.; Montgomery, Grant W.; Murabito, Joanne M.; Nicholson, George; Nyholt, Dale R.; Okada, Yukinori; Perry, John R. B.; Dorajoo, Rajkumar; Reinmaa, Eva; Salem, Rany M.; Sandholm, Niina; Scott, Robert A.; Stolk, Lisette; Takahashi, Atsushi; Tanaka, Toshihiro; van ’t Hooft, Ferdinand M.; Vinkhuyzen, Anna A. E.; Westra, Harm-Jan; Zheng, Wei; Zondervan, Krina T.; Heath, Andrew C.; Arveiler, Dominique; Bakker, Stephan J. L.; Beilby, John; Bergman, Richard N.; Blangero, John; Bovet, Pascal; Campbell, Harry; Caulfield, Mark J.; Cesana, Giancarlo; Chakravarti, Aravinda; Chasman, Daniel I.; Chines, Peter S.; Collins, Francis S.; Crawford, Dana C.; Cupples, L. Adrienne; Cusi, Daniele; Danesh, John; de Faire, Ulf; den Ruijter, Hester M.; Dominiczak, Anna F.; Erbel, Raimund; Erdmann, Jeanette; Eriksson, Johan G.; Farrall, Martin; Felix, Stephan B.; Ferrannini, Ele; Ferrières, Jean; Ford, Ian; Forouhi, Nita G.; Forrester, Terrence; Franco, Oscar H.; Gansevoort, Ron T.; Gejman, Pablo V.; Gieger, Christian; Gottesman, Omri; Gudnason, Vilmundur; Gyllensten, Ulf; Hall, Alistair S.; Harris, Tamara B.; Hattersley, Andrew T.; Hicks, Andrew A.; Hindorff, Lucia A.; Hingorani, Aroon D.; Hofman, Albert; Homuth, Georg; Hovingh, G. Kees; Humphries, Steve E.; Hunt, Steven C.; Hyppönen, Elina; Illig, Thomas; Jacobs, Kevin B.; Jarvelin, Marjo-Riitta; Jöckel, Karl-Heinz; Johansen, Berit; Jousilahti, Pekka; Jukema, J. Wouter; Jula, Antti M.; Kaprio, Jaakko; Kastelein, John J. P.; Keinanen-Kiukaanniemi, Sirkka M.; Kiemeney, Lambertus A.; Knekt, Paul; Kooner, Jaspal S.; Kooperberg, Charles; Kovacs, Peter; Kraja, Aldi T.; Kumari, Meena; Kuusisto, Johanna; Lakka, Timo A.; Langenberg, Claudia; Marchand, Loic Le; Lehtimäki, Terho; Lyssenko, Valeriya; Männistö, Satu; Marette, André; Matise, Tara C.; McKenzie, Colin A.; McKnight, Barbara; Moll, Frans L.; Morris, Andrew D.; Morris, Andrew P.; Murray, Jeffrey C.; Nelis, Mari; Ohlsson, Claes; Oldehinkel, Albertine J.; Ong, Ken K.; Madden, Pamela A. F.; Pasterkamp, Gerard; Peden, John F.; Peters, Annette; Postma, Dirkje S.; Pramstaller, Peter P.; Price, Jackie F.; Qi, Lu; Raitakari, Olli T.; Rankinen, Tuomo; Rao, D. C.; Rice, Treva K.; Ridker, Paul M.; Rioux, John D.; Ritchie, Marylyn D.; Rudan, Igor; Salomaa, Veikko; Samani, Nilesh J.; Saramies, Jouko; Sarzynski, Mark A.; Schunkert, Heribert; Schwarz, Peter E. H.; Sever, Peter; Shuldiner, Alan R.; Sinisalo, Juha; Stolk, Ronald P.; Strauch, Konstantin; Tönjes, Anke; Trégouët, David-Alexandre; Tremblay, Angelo; Tremoli, Elena; Virtamo, Jarmo; Vohl, Marie-Claude; Völker, Uwe; Waeber, Gérard; Willemsen, Gonneke; Witteman, Jacqueline C.; Zillikens, M. Carola; Adair, Linda S.; Amouyel, Philippe; Asselbergs, Folkert W.; Assimes, Themistocles L.; Bochud, Murielle; Boehm, Bernhard O.; Boerwinkle, Eric; Bornstein, Stefan R.; Bottinger, Erwin P.; Bouchard, Claude; Cauchi, Stéphane; Chambers, John C.; Chanock, Stephen J.; Cooper, Richard S.; de Bakker, Paul I. W.; Dedoussis, George; Ferrucci, Luigi; Franks, Paul W.; Froguel, Philippe; Groop, Leif C.; Haiman, Christopher A.; Hamsten, Anders; Hui, Jennie; Hunter, David J.; Hveem, Kristian; Kaplan, Robert C.; Kivimaki, Mika; Kuh, Diana; Laakso, Markku; Liu, Yongmei; Martin, Nicholas G.; März, Winfried; Melbye, Mads; Metspalu, Andres; Moebus, Susanne; Munroe, Patricia B.; Njølstad, Inger; Oostra, Ben A.; Palmer, Colin N. A.; Pedersen, Nancy L.; Perola, Markus; Pérusse, Louis; Peters, Ulrike; Power, Chris; Quertermous, Thomas; Rauramaa, Rainer; Rivadeneira, Fernando; Saaristo, Timo E.; Saleheen, Danish; Sattar, Naveed; Schadt, Eric E.; Schlessinger, David; Slagboom, P. Eline; Snieder, Harold; Spector, Tim D.; Thorsteinsdottir, Unnur; Stumvoll, Michael; Tuomilehto, Jaakko; Uitterlinden, André G.; Uusitupa, Matti; van der Harst, Pim; Walker, Mark; Wallaschofski, Henri; Wareham, Nicholas J.; Watkins, Hugh; Weir, David R.; Wichmann, H-Erich; Wilson, James F.; Zanen, Pieter; Borecki, Ingrid B.; Deloukas, Panos; Fox, Caroline S.; Heid, Iris M.; O’Connell, Jeffrey R.; Strachan, David P.; Stefansson, Kari; van Duijn, Cornelia M.; Abecasis, Gonçalo R.; Franke, Lude; Frayling, Timothy M.; McCarthy, Mark I.; Visscher, Peter M.; Scherag, André; Willer, Cristen J.; Boehnke, Michael; Mohlke, Karen L.; Lindgren, Cecilia M.; Beckmann, Jacques S.; Barroso, Inês; North, Kari E.; Ingelsson, Erik; Hirschhorn, Joel N.; Loos, Ruth J. F.; Speliotes, Elizabeth K.

2015-01-01

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10−8), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ~2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis. PMID:25673413

Novel Sources of Stripe Rust Resistance Identified by Genome-Wide Association Mapping in Ethiopian Durum Wheat (Triticum turgidum ssp. durum)

PubMed Central

Liu, Weizhen; Maccaferri, Marco; Rynearson, Sheri; Letta, Tesfaye; Zegeye, Habtemariam; Tuberosa, Roberto; Chen, Xianming; Pumphrey, Michael

2017-01-01

Stripe rust of wheat, caused by Puccinia striiformis f. sp. tritici (Pst), is a global concern for wheat production, and has been increasingly destructive in Ethiopia, as well as in the United States and in many other countries. As Ethiopia has a long history of stripe rust epidemics, its native wheat germplasm harbors potentially valuable resistance loci. Moreover, the Ethiopian germplasm has been historically underutilized in breeding of modern wheat worldwide and thus the resistance alleles from the Ethiopian germplasm represent potentially novel sources. The objective of this study was to identify loci conferring resistance to predominant Pst races in Ethiopia and the United States. Using a high-density 90 K wheat single nucleotide polymorphism array, a genome-wide association analysis (GWAS) was conducted on 182 durum wheat landrace accessions and contemporary varieties originating from Ethiopia. Landraces were detected to be more resistant at the seedling stage while cultivars were more resistant at the adult-plant stages. GWAS identified 68 loci associated with seedling resistance to one or more races. Six loci on chromosome arms 1AS, 1BS, 3AS, 4BL, and 5BL were associated with resistance against at least two races at the seedling stage, and five loci were previously undocumented. GWAS analysis of field resistance reactions identified 12 loci associated with resistance on chromosomes 1A, 1B, 2BS, 3BL, 4AL, 4B and 5AL, which were detected in at least two of six field screening nurseries at the adult-plant stage. Comparison with previously mapped resistance loci indicates that six of the 12 resistance loci are newly documented. This study reports effective sources of resistance to contemporary races in Ethiopia and the United States and reveals that Ethiopian durum wheat landraces are abundant in novel Pst resistance loci that may be transferred into adapted cultivars to provide resistance against Pst. PMID:28553306

High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci.

PubMed

Kim, Kwangwoo; Bang, So-Young; Lee, Hye-Soon; Cho, Soo-Kyung; Choi, Chan-Bum; Sung, Yoon-Kyoung; Kim, Tae-Hwan; Jun, Jae-Bum; Yoo, Dae Hyun; Kang, Young Mo; Kim, Seong-Kyu; Suh, Chang-Hee; Shim, Seung-Cheol; Lee, Shin-Seok; Lee, Jisoo; Chung, Won Tae; Choe, Jung-Yoon; Shin, Hyoung Doo; Lee, Jong-Young; Han, Bok-Ghee; Nath, Swapan K; Eyre, Steve; Bowes, John; Pappas, Dimitrios A; Kremer, Joel M; Gonzalez-Gay, Miguel A; Rodriguez-Rodriguez, Luis; Ärlestig, Lisbeth; Okada, Yukinori; Diogo, Dorothée; Liao, Katherine P; Karlson, Elizabeth W; Raychaudhuri, Soumya; Rantapää-Dahlqvist, Solbritt; Martin, Javier; Klareskog, Lars; Padyukov, Leonid; Gregersen, Peter K; Worthington, Jane; Greenberg, Jeffrey D; Plenge, Robert M; Bae, Sang-Cheol

2015-03-01

A highly polygenic aetiology and high degree of allele-sharing between ancestries have been well elucidated in genetic studies of rheumatoid arthritis. Recently, the high-density genotyping array Immunochip for immune disease loci identified 14 new rheumatoid arthritis risk loci among individuals of European ancestry. Here, we aimed to identify new rheumatoid arthritis risk loci using Korean-specific Immunochip data. We analysed Korean rheumatoid arthritis case-control samples using the Immunochip and genome-wide association studies (GWAS) array to search for new risk alleles of rheumatoid arthritis with anticitrullinated peptide antibodies. To increase power, we performed a meta-analysis of Korean data with previously published European Immunochip and GWAS data for a total sample size of 9299 Korean and 45,790 European case-control samples. We identified eight new rheumatoid arthritis susceptibility loci (TNFSF4, LBH, EOMES, ETS1-FLI1, COG6, RAD51B, UBASH3A and SYNGR1) that passed a genome-wide significance threshold (p<5×10(-8)), with evidence for three independent risk alleles at 1q25/TNFSF4. The risk alleles from the seven new loci except for the TNFSF4 locus (monomorphic in Koreans), together with risk alleles from previously established RA risk loci, exhibited a high correlation of effect sizes between ancestries. Further, we refined the number of single nucleotide polymorphisms (SNPs) that represent potentially causal variants through a trans-ethnic comparison of densely genotyped SNPs. This study demonstrates the advantage of dense-mapping and trans-ancestral analysis for identification of potentially causal SNPs. In addition, our findings support the importance of T cells in the pathogenesis and the fact of frequent overlap of risk loci among diverse autoimmune diseases. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries

PubMed Central

Guo, Xiuqing; Franceschini, Nora; Cheng, Ching-Yu; Sim, Xueling; Vojinovic, Dina; Marten, Jonathan; Musani, Solomon K.; Li, Changwei; Schwander, Karen; Richard, Melissa A.; Noordam, Raymond; Aschard, Hugues; Bartz, Traci M.; Bielak, Lawrence F.; Dorajoo, Rajkumar; Fisher, Virginia; Hartwig, Fernando P.; Horimoto, Andrea R. V. R.; Lohman, Kurt K.; Manning, Alisa K.; Rankinen, Tuomo; Smith, Albert V.; Wojczynski, Mary K.; Alver, Maris; Boissel, Mathilde; Cai, Qiuyin; Divers, Jasmin; Gao, Chuan; Goel, Anuj; Harris, Sarah E.; He, Meian; Hsu, Fang-Chi; Jackson, Anne U.; Kähönen, Mika; Kasturiratne, Anuradhani; Komulainen, Pirjo; Kühnel, Brigitte; Laguzzi, Federica; Luan, Jian'an; Nolte, Ilja M.; Padmanabhan, Sandosh; Robino, Antonietta; Scott, Robert A.; Sofer, Tamar; Stančáková, Alena; Takeuchi, Fumihiko; Tayo, Bamidele O.; Varga, Tibor V.; Vitart, Veronique; Wang, Yajuan; Warren, Helen R.; Wen, Wanqing; Yanek, Lisa R.; Zhang, Weihua; Zhao, Jing Hua; Afaq, Saima; Amin, Najaf; Arking, Dan E.; Aung, Tin; Boerwinkle, Eric; Borecki, Ingrid; Broeckel, Ulrich; Brown, Morris; Brumat, Marco; Burke, Gregory L.; Chakravarti, Aravinda; Charumathi, Sabanayagam; Ida Chen, Yii-Der; Connell, John M.; Correa, Adolfo; de las Fuentes, Lisa; de Mutsert, Renée; de Silva, H. Janaka; Deng, Xuan; Ding, Jingzhong; Duan, Qing; Eaton, Charles B.; Ehret, Georg; Eppinga, Ruben N.; Faul, Jessica D.; Felix, Stephan B.; Forouhi, Nita G.; Forrester, Terrence; Franco, Oscar H.; Friedlander, Yechiel; Gandin, Ilaria; Gao, He; Ghanbari, Mohsen; Gigante, Bruna; Gu, C. Charles; Gu, Dongfeng; Hagenaars, Saskia P.; Hallmans, Göran; Harris, Tamara B.; He, Jiang; Heng, Chew-Kiat; Hirata, Makoto; Howard, Barbara V.; Ikram, M. Arfan; John, Ulrich; Katsuya, Tomohiro; Khor, Chiea Chuen; Kilpeläinen, Tuomas O.; Koh, Woon-Puay; Krieger, José E.; Kritchevsky, Stephen B.; Kubo, Michiaki; Kuusisto, Johanna; Lakka, Timo A.; Langefeld, Carl D.; Langenberg, Claudia; Launer, Lenore J.; Lehne, Benjamin; Lewis, Cora E.; Li, Yize; Lin, Shiow; Liu, Jianjun; Liu, Jingmin; Loh, Marie; Louie, Tin; Mägi, Reedik; McKenzie, Colin A.; Meitinger, Thomas; Milaneschi, Yuri; Milani, Lili; Mohlke, Karen L.; Momozawa, Yukihide; Nalls, Mike A.; Nelson, Christopher P.; Sotoodehnia, Nona; Norris, Jill M.; O'Connell, Jeff R.; Palmer, Nicholette D.; Perls, Thomas; Pedersen, Nancy L.; Peters, Annette; Peyser, Patricia A.; Poulter, Neil; Raffel, Leslie J.; Raitakari, Olli T.; Roll, Kathryn; Rose, Lynda M.; Rosendaal, Frits R.; Rotter, Jerome I.; Schmidt, Carsten O.; Schreiner, Pamela J.; Schupf, Nicole; Scott, William R.; Shi, Yuan; Sidney, Stephen; Sims, Mario; Sitlani, Colleen M.; Smith, Jennifer A.; Snieder, Harold; Starr, John M.; Strauch, Konstantin; Stringham, Heather M.; Tan, Nicholas Y. Q.; Tang, Hua; Taylor, Kent D.; Teo, Yik Ying; Tham, Yih Chung; Turner, Stephen T.; Uitterlinden, André G.; Vollenweider, Peter; Waldenberger, Melanie; Wang, Lihua; Wang, Ya Xing; Wei, Wen Bin; Williams, Christine; Yao, Jie; Yu, Caizheng; Yuan, Jian-Min; Zhao, Wei; Zonderman, Alan B.; Becker, Diane M.; Boehnke, Michael; Bowden, Donald W.; Chambers, John C.; Deary, Ian J.; Esko, Tõnu; Farrall, Martin; Franks, Paul W.; Freedman, Barry I.; Froguel, Philippe; Gasparini, Paolo; Gieger, Christian; Kamatani, Yoichiro; Kato, Norihiro; Kooner, Jaspal S.; Kutalik, Zoltán; Laakso, Markku; Laurie, Cathy C.; Leander, Karin; Lehtimäki, Terho; Study, Lifelines Cohort; Magnusson, Patrik K. E.; Oldehinkel, Albertine J.; Penninx, Brenda W. J. H.; Polasek, Ozren; Porteous, David J.; Rauramaa, Rainer; Samani, Nilesh J.; Scott, James; Shu, Xiao-Ou; van der Harst, Pim; Wagenknecht, Lynne E.; Watkins, Hugh; Weir, David R.; Wickremasinghe, Ananda R.; Wu, Tangchun; Zheng, Wei; Bouchard, Claude; Christensen, Kaare; Evans, Michele K.; Gudnason, Vilmundur; Horta, Bernardo L.; Kardia, Sharon L. R.; Liu, Yongmei; Pereira, Alexandre C.; Psaty, Bruce M.; Ridker, Paul M.; van Dam, Rob M.; Gauderman, W. James; Zhu, Xiaofeng; Mook-Kanamori, Dennis O.; Fornage, Myriam; Rotimi, Charles N.; Cupples, L. Adrienne; Kelly, Tanika N.; Fox, Ervin R.; Hayward, Caroline; van Duijn, Cornelia M.; Tai, E Shyong; Wong, Tien Yin; Kooperberg, Charles; Palmas, Walter; Morrison, Alanna C.; Caulfield, Mark J.; Munroe, Patricia B.; Rao, Dabeeru C.; Province, Michael A.; Levy, Daniel

2018-01-01

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10−5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10−8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10−8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension. PMID:29912962

Novel genetic associations for blood pressure identified via gene-alcohol interaction in up to 570K individuals across multiple ancestries.

PubMed

Feitosa, Mary F; Kraja, Aldi T; Chasman, Daniel I; Sung, Yun J; Winkler, Thomas W; Ntalla, Ioanna; Guo, Xiuqing; Franceschini, Nora; Cheng, Ching-Yu; Sim, Xueling; Vojinovic, Dina; Marten, Jonathan; Musani, Solomon K; Li, Changwei; Bentley, Amy R; Brown, Michael R; Schwander, Karen; Richard, Melissa A; Noordam, Raymond; Aschard, Hugues; Bartz, Traci M; Bielak, Lawrence F; Dorajoo, Rajkumar; Fisher, Virginia; Hartwig, Fernando P; Horimoto, Andrea R V R; Lohman, Kurt K; Manning, Alisa K; Rankinen, Tuomo; Smith, Albert V; Tajuddin, Salman M; Wojczynski, Mary K; Alver, Maris; Boissel, Mathilde; Cai, Qiuyin; Campbell, Archie; Chai, Jin Fang; Chen, Xu; Divers, Jasmin; Gao, Chuan; Goel, Anuj; Hagemeijer, Yanick; Harris, Sarah E; He, Meian; Hsu, Fang-Chi; Jackson, Anne U; Kähönen, Mika; Kasturiratne, Anuradhani; Komulainen, Pirjo; Kühnel, Brigitte; Laguzzi, Federica; Luan, Jian'an; Matoba, Nana; Nolte, Ilja M; Padmanabhan, Sandosh; Riaz, Muhammad; Rueedi, Rico; Robino, Antonietta; Said, M Abdullah; Scott, Robert A; Sofer, Tamar; Stančáková, Alena; Takeuchi, Fumihiko; Tayo, Bamidele O; van der Most, Peter J; Varga, Tibor V; Vitart, Veronique; Wang, Yajuan; Ware, Erin B; Warren, Helen R; Weiss, Stefan; Wen, Wanqing; Yanek, Lisa R; Zhang, Weihua; Zhao, Jing Hua; Afaq, Saima; Amin, Najaf; Amini, Marzyeh; Arking, Dan E; Aung, Tin; Boerwinkle, Eric; Borecki, Ingrid; Broeckel, Ulrich; Brown, Morris; Brumat, Marco; Burke, Gregory L; Canouil, Mickaël; Chakravarti, Aravinda; Charumathi, Sabanayagam; Ida Chen, Yii-Der; Connell, John M; Correa, Adolfo; de Las Fuentes, Lisa; de Mutsert, Renée; de Silva, H Janaka; Deng, Xuan; Ding, Jingzhong; Duan, Qing; Eaton, Charles B; Ehret, Georg; Eppinga, Ruben N; Evangelou, Evangelos; Faul, Jessica D; Felix, Stephan B; Forouhi, Nita G; Forrester, Terrence; Franco, Oscar H; Friedlander, Yechiel; Gandin, Ilaria; Gao, He; Ghanbari, Mohsen; Gigante, Bruna; Gu, C Charles; Gu, Dongfeng; Hagenaars, Saskia P; Hallmans, Göran; Harris, Tamara B; He, Jiang; Heikkinen, Sami; Heng, Chew-Kiat; Hirata, Makoto; Howard, Barbara V; Ikram, M Arfan; John, Ulrich; Katsuya, Tomohiro; Khor, Chiea Chuen; Kilpeläinen, Tuomas O; Koh, Woon-Puay; Krieger, José E; Kritchevsky, Stephen B; Kubo, Michiaki; Kuusisto, Johanna; Lakka, Timo A; Langefeld, Carl D; Langenberg, Claudia; Launer, Lenore J; Lehne, Benjamin; Lewis, Cora E; Li, Yize; Lin, Shiow; Liu, Jianjun; Liu, Jingmin; Loh, Marie; Louie, Tin; Mägi, Reedik; McKenzie, Colin A; Meitinger, Thomas; Metspalu, Andres; Milaneschi, Yuri; Milani, Lili; Mohlke, Karen L; Momozawa, Yukihide; Nalls, Mike A; Nelson, Christopher P; Sotoodehnia, Nona; Norris, Jill M; O'Connell, Jeff R; Palmer, Nicholette D; Perls, Thomas; Pedersen, Nancy L; Peters, Annette; Peyser, Patricia A; Poulter, Neil; Raffel, Leslie J; Raitakari, Olli T; Roll, Kathryn; Rose, Lynda M; Rosendaal, Frits R; Rotter, Jerome I; Schmidt, Carsten O; Schreiner, Pamela J; Schupf, Nicole; Scott, William R; Sever, Peter S; Shi, Yuan; Sidney, Stephen; Sims, Mario; Sitlani, Colleen M; Smith, Jennifer A; Snieder, Harold; Starr, John M; Strauch, Konstantin; Stringham, Heather M; Tan, Nicholas Y Q; Tang, Hua; Taylor, Kent D; Teo, Yik Ying; Tham, Yih Chung; Turner, Stephen T; Uitterlinden, André G; Vollenweider, Peter; Waldenberger, Melanie; Wang, Lihua; Wang, Ya Xing; Wei, Wen Bin; Williams, Christine; Yao, Jie; Yu, Caizheng; Yuan, Jian-Min; Zhao, Wei; Zonderman, Alan B; Becker, Diane M; Boehnke, Michael; Bowden, Donald W; Chambers, John C; Deary, Ian J; Esko, Tõnu; Farrall, Martin; Franks, Paul W; Freedman, Barry I; Froguel, Philippe; Gasparini, Paolo; Gieger, Christian; Jonas, Jost Bruno; Kamatani, Yoichiro; Kato, Norihiro; Kooner, Jaspal S; Kutalik, Zoltán; Laakso, Markku; Laurie, Cathy C; Leander, Karin; Lehtimäki, Terho; Study, Lifelines Cohort; Magnusson, Patrik K E; Oldehinkel, Albertine J; Penninx, Brenda W J H; Polasek, Ozren; Porteous, David J; Rauramaa, Rainer; Samani, Nilesh J; Scott, James; Shu, Xiao-Ou; van der Harst, Pim; Wagenknecht, Lynne E; Wareham, Nicholas J; Watkins, Hugh; Weir, David R; Wickremasinghe, Ananda R; Wu, Tangchun; Zheng, Wei; Bouchard, Claude; Christensen, Kaare; Evans, Michele K; Gudnason, Vilmundur; Horta, Bernardo L; Kardia, Sharon L R; Liu, Yongmei; Pereira, Alexandre C; Psaty, Bruce M; Ridker, Paul M; van Dam, Rob M; Gauderman, W James; Zhu, Xiaofeng; Mook-Kanamori, Dennis O; Fornage, Myriam; Rotimi, Charles N; Cupples, L Adrienne; Kelly, Tanika N; Fox, Ervin R; Hayward, Caroline; van Duijn, Cornelia M; Tai, E Shyong; Wong, Tien Yin; Kooperberg, Charles; Palmas, Walter; Rice, Kenneth; Morrison, Alanna C; Elliott, Paul; Caulfield, Mark J; Munroe, Patricia B; Rao, Dabeeru C; Province, Michael A; Levy, Daniel

2018-01-01

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

Polymorphic microsatellite DNA markers for the Florida manatee (Trichechus manatus latirostris)

USGS Publications Warehouse

Pause, K.C.; Nourisson, C.; Clark, A.; Kellogg, M.E.; Bonde, R.K.; McGuire, P.M.

2007-01-01

Florida manatees (Trichechus manatus latirostris) are marine mammals that inhabit the coastal waters and rivers of the southeastern USA, primarily Florida. Previous studies have shown that Florida manatees have low mitochondrial DNA variability, suggesting that nuclear DNA loci are necessary for discriminatory analyses. Here we report 10 polymorphic microsatellite loci with an average of 4.2 alleles per locus, and average heterozygosity of 50.1%. These loci have been developed for use in population studies, parentage assignment, and individual identification. ?? 2007 Blackwell Publishing Ltd.

Genome-wide association mapping of canopy wilting in diverse soybean genotypes

USDA-ARS?s Scientific Manuscript database

Drought stress is a major global constraint for crop production, and slow canopy wilting has been shown to be a promising trait for improving drought tolerance. The objective of this study was to identify genetic loci associated with canopy wilting and confirm those loci with previously reported can...

Conservation genetics of bull trout: Geographic distribution of variation at microsatellite loci.

Treesearch

P. Spruell; A.R. Hemmingsen; P.J. Howell; N. Kanda; F.W. Allendorf

2003-01-01

We describe the genetic population structure of 65 bull trout (Salvelinus confluentus) populations from the northwestern United States using four microsatellite loci. The distribution of genetic variation as measured by microsatellites is consistent with previous allozyme and mitochondrial DNA analysis. There is relatively little genetic variation...

Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways.

PubMed

Nair, Rajan P; Duffin, Kristina Callis; Helms, Cynthia; Ding, Jun; Stuart, Philip E; Goldgar, David; Gudjonsson, Johann E; Li, Yun; Tejasvi, Trilokraj; Feng, Bing-Jian; Ruether, Andreas; Schreiber, Stefan; Weichenthal, Michael; Gladman, Dafna; Rahman, Proton; Schrodi, Steven J; Prahalad, Sampath; Guthery, Stephen L; Fischer, Judith; Liao, Wilson; Kwok, Pui-Yan; Menter, Alan; Lathrop, G Mark; Wise, Carol A; Begovich, Ann B; Voorhees, John J; Elder, James T; Krueger, Gerald G; Bowcock, Anne M; Abecasis, Gonçalo R

2009-02-01

Psoriasis is a common immune-mediated disorder that affects the skin, nails and joints. To identify psoriasis susceptibility loci, we genotyped 438,670 SNPs in 1,409 psoriasis cases and 1,436 controls of European ancestry. We followed up 21 promising SNPs in 5,048 psoriasis cases and 5,041 controls. Our results provide strong support for the association of at least seven genetic loci and psoriasis (each with combined P < 5 x 10(-8)). Loci with confirmed association include HLA-C, three genes involved in IL-23 signaling (IL23A, IL23R, IL12B), two genes that act downstream of TNF-alpha and regulate NF-kappaB signaling (TNIP1, TNFAIP3) and two genes involved in the modulation of Th2 immune responses (IL4, IL13). Although the proteins encoded in these loci are known to interact biologically, we found no evidence for epistasis between associated SNPs. Our results expand the catalog of genetic loci implicated in psoriasis susceptibility and suggest priority targets for study in other auto-immune disorders.

Genome-wide association analysis in dogs implicates 99 loci as risk variants for anterior cruciate ligament rupture

PubMed Central

Baker, Lauren A.; Kirkpatrick, Brian; Rosa, Guilherme J. M.; Gianola, Daniel; Valente, Bruno; Sumner, Julia P.; Baltzer, Wendy; Hao, Zhengling; Binversie, Emily E.; Volstad, Nicola; Piazza, Alexander; Sample, Susannah J.

2017-01-01

Anterior cruciate ligament (ACL) rupture is a common condition that can be devastating and life changing, particularly in young adults. A non-contact mechanism is typical. Second ACL ruptures through rupture of the contralateral ACL or rupture of a graft repair is also common. Risk of rupture is increased in females. ACL rupture is also common in dogs. Disease prevalence exceeds 5% in several dog breeds, ~100 fold higher than human beings. We provide insight into the genetic etiology of ACL rupture by genome-wide association study (GWAS) in a high-risk breed using 98 case and 139 control Labrador Retrievers. We identified 129 single nucleotide polymorphisms (SNPs) within 99 risk loci. Associated loci (P<5E-04) explained approximately half of phenotypic variance in the ACL rupture trait. Two of these loci were located in uncharacterized or non-coding regions of the genome. A chromosome 24 locus containing nine genes with diverse functions met genome-wide significance (P = 3.63E-0.6). GWAS pathways were enriched for c-type lectins, a gene set that includes aggrecan, a gene set encoding antimicrobial proteins, and a gene set encoding membrane transport proteins with a variety of physiological functions. Genotypic risk estimated for each dog based on the risk contributed by each GWAS locus showed clear separation of ACL rupture cases and controls. Power analysis of the GWAS data set estimated that ~172 loci explain the genetic contribution to ACL rupture in the Labrador Retriever. Heritability was estimated at 0.48. We conclude ACL rupture is a moderately heritable highly polygenic complex trait. Our results implicate c-type lectin pathways in ACL homeostasis. PMID:28379989

Gene-centric Meta-analysis in 87,736 Individuals of European Ancestry Identifies Multiple Blood-Pressure-Related Loci

PubMed Central

Tragante, Vinicius; Barnes, Michael R.; Ganesh, Santhi K.; Lanktree, Matthew B.; Guo, Wei; Franceschini, Nora; Smith, Erin N.; Johnson, Toby; Holmes, Michael V.; Padmanabhan, Sandosh; Karczewski, Konrad J.; Almoguera, Berta; Barnard, John; Baumert, Jens; Chang, Yen-Pei Christy; Elbers, Clara C.; Farrall, Martin; Fischer, Mary E.; Gaunt, Tom R.; Gho, Johannes M.I.H.; Gieger, Christian; Goel, Anuj; Gong, Yan; Isaacs, Aaron; Kleber, Marcus E.; Leach, Irene Mateo; McDonough, Caitrin W.; Meijs, Matthijs F.L.; Melander, Olle; Nelson, Christopher P.; Nolte, Ilja M.; Pankratz, Nathan; Price, Tom S.; Shaffer, Jonathan; Shah, Sonia; Tomaszewski, Maciej; van der Most, Peter J.; Van Iperen, Erik P.A.; Vonk, Judith M.; Witkowska, Kate; Wong, Caroline O.L.; Zhang, Li; Beitelshees, Amber L.; Berenson, Gerald S.; Bhatt, Deepak L.; Brown, Morris; Burt, Amber; Cooper-DeHoff, Rhonda M.; Connell, John M.; Cruickshanks, Karen J.; Curtis, Sean P.; Davey-Smith, George; Delles, Christian; Gansevoort, Ron T.; Guo, Xiuqing; Haiqing, Shen; Hastie, Claire E.; Hofker, Marten H.; Hovingh, G. Kees; Kim, Daniel S.; Kirkland, Susan A.; Klein, Barbara E.; Klein, Ronald; Li, Yun R.; Maiwald, Steffi; Newton-Cheh, Christopher; O’Brien, Eoin T.; Onland-Moret, N. Charlotte; Palmas, Walter; Parsa, Afshin; Penninx, Brenda W.; Pettinger, Mary; Vasan, Ramachandran S.; Ranchalis, Jane E.; M Ridker, Paul; Rose, Lynda M.; Sever, Peter; Shimbo, Daichi; Steele, Laura; Stolk, Ronald P.; Thorand, Barbara; Trip, Mieke D.; van Duijn, Cornelia M.; Verschuren, W. Monique; Wijmenga, Cisca; Wyatt, Sharon; Young, J. Hunter; Zwinderman, Aeilko H.; Bezzina, Connie R.; Boerwinkle, Eric; Casas, Juan P.; Caulfield, Mark J.; Chakravarti, Aravinda; Chasman, Daniel I.; Davidson, Karina W.; Doevendans, Pieter A.; Dominiczak, Anna F.; FitzGerald, Garret A.; Gums, John G.; Fornage, Myriam; Hakonarson, Hakon; Halder, Indrani; Hillege, Hans L.; Illig, Thomas; Jarvik, Gail P.; Johnson, Julie A.; Kastelein, John J.P.; Koenig, Wolfgang; Kumari, Meena; März, Winfried; Murray, Sarah S.; O’Connell, Jeffery R.; Oldehinkel, Albertine J.; Pankow, James S.; Rader, Daniel J.; Redline, Susan; Reilly, Muredach P.; Schadt, Eric E.; Kottke-Marchant, Kandice; Snieder, Harold; Snyder, Michael; Stanton, Alice V.; Tobin, Martin D.; Uitterlinden, André G.; van der Harst, Pim; van der Schouw, Yvonne T.; Samani, Nilesh J.; Watkins, Hugh; Johnson, Andrew D.; Reiner, Alex P.; Zhu, Xiaofeng; de Bakker, Paul I.W.; Levy, Daniel; Asselbergs, Folkert W.; Munroe, Patricia B.; Keating, Brendan J.

2014-01-01

Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ∼50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10−7) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification. PMID:24560520

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

PubMed

Sawcer, Stephen; Hellenthal, Garrett; Pirinen, Matti; Spencer, Chris C A; Patsopoulos, Nikolaos A; Moutsianas, Loukas; Dilthey, Alexander; Su, Zhan; Freeman, Colin; Hunt, Sarah E; Edkins, Sarah; Gray, Emma; Booth, David R; Potter, Simon C; Goris, An; Band, Gavin; Oturai, Annette Bang; Strange, Amy; Saarela, Janna; Bellenguez, Céline; Fontaine, Bertrand; Gillman, Matthew; Hemmer, Bernhard; Gwilliam, Rhian; Zipp, Frauke; Jayakumar, Alagurevathi; Martin, Roland; Leslie, Stephen; Hawkins, Stanley; Giannoulatou, Eleni; D'alfonso, Sandra; Blackburn, Hannah; Martinelli Boneschi, Filippo; Liddle, Jennifer; Harbo, Hanne F; Perez, Marc L; Spurkland, Anne; Waller, Matthew J; Mycko, Marcin P; Ricketts, Michelle; Comabella, Manuel; Hammond, Naomi; Kockum, Ingrid; McCann, Owen T; Ban, Maria; Whittaker, Pamela; Kemppinen, Anu; Weston, Paul; Hawkins, Clive; Widaa, Sara; Zajicek, John; Dronov, Serge; Robertson, Neil; Bumpstead, Suzannah J; Barcellos, Lisa F; Ravindrarajah, Rathi; Abraham, Roby; Alfredsson, Lars; Ardlie, Kristin; Aubin, Cristin; Baker, Amie; Baker, Katharine; Baranzini, Sergio E; Bergamaschi, Laura; Bergamaschi, Roberto; Bernstein, Allan; Berthele, Achim; Boggild, Mike; Bradfield, Jonathan P; Brassat, David; Broadley, Simon A; Buck, Dorothea; Butzkueven, Helmut; Capra, Ruggero; Carroll, William M; Cavalla, Paola; Celius, Elisabeth G; Cepok, Sabine; Chiavacci, Rosetta; Clerget-Darpoux, Françoise; Clysters, Katleen; Comi, Giancarlo; Cossburn, Mark; Cournu-Rebeix, Isabelle; Cox, Mathew B; Cozen, Wendy; Cree, Bruce A C; Cross, Anne H; Cusi, Daniele; Daly, Mark J; Davis, Emma; de Bakker, Paul I W; Debouverie, Marc; D'hooghe, Marie Beatrice; Dixon, Katherine; Dobosi, Rita; Dubois, Bénédicte; Ellinghaus, David; Elovaara, Irina; Esposito, Federica; Fontenille, Claire; Foote, Simon; Franke, Andre; Galimberti, Daniela; Ghezzi, Angelo; Glessner, Joseph; Gomez, Refujia; Gout, Olivier; Graham, Colin; Grant, Struan F A; Guerini, Franca Rosa; Hakonarson, Hakon; Hall, Per; Hamsten, Anders; Hartung, Hans-Peter; Heard, Rob N; Heath, Simon; Hobart, Jeremy; Hoshi, Muna; Infante-Duarte, Carmen; Ingram, Gillian; Ingram, Wendy; Islam, Talat; Jagodic, Maja; Kabesch, Michael; Kermode, Allan G; Kilpatrick, Trevor J; Kim, Cecilia; Klopp, Norman; Koivisto, Keijo; Larsson, Malin; Lathrop, Mark; Lechner-Scott, Jeannette S; Leone, Maurizio A; Leppä, Virpi; Liljedahl, Ulrika; Bomfim, Izaura Lima; Lincoln, Robin R; Link, Jenny; Liu, Jianjun; Lorentzen, Aslaug R; Lupoli, Sara; Macciardi, Fabio; Mack, Thomas; Marriott, Mark; Martinelli, Vittorio; Mason, Deborah; McCauley, Jacob L; Mentch, Frank; Mero, Inger-Lise; Mihalova, Tania; Montalban, Xavier; Mottershead, John; Myhr, Kjell-Morten; Naldi, Paola; Ollier, William; Page, Alison; Palotie, Aarno; Pelletier, Jean; Piccio, Laura; Pickersgill, Trevor; Piehl, Fredrik; Pobywajlo, Susan; Quach, Hong L; Ramsay, Patricia P; Reunanen, Mauri; Reynolds, Richard; Rioux, John D; Rodegher, Mariaemma; Roesner, Sabine; Rubio, Justin P; Rückert, Ina-Maria; Salvetti, Marco; Salvi, Erika; Santaniello, Adam; Schaefer, Catherine A; Schreiber, Stefan; Schulze, Christian; Scott, Rodney J; Sellebjerg, Finn; Selmaj, Krzysztof W; Sexton, David; Shen, Ling; Simms-Acuna, Brigid; Skidmore, Sheila; Sleiman, Patrick M A; Smestad, Cathrine; Sørensen, Per Soelberg; Søndergaard, Helle Bach; Stankovich, Jim; Strange, Richard C; Sulonen, Anna-Maija; Sundqvist, Emilie; Syvänen, Ann-Christine; Taddeo, Francesca; Taylor, Bruce; Blackwell, Jenefer M; Tienari, Pentti; Bramon, Elvira; Tourbah, Ayman; Brown, Matthew A; Tronczynska, Ewa; Casas, Juan P; Tubridy, Niall; Corvin, Aiden; Vickery, Jane; Jankowski, Janusz; Villoslada, Pablo; Markus, Hugh S; Wang, Kai; Mathew, Christopher G; Wason, James; Palmer, Colin N A; Wichmann, H-Erich; Plomin, Robert; Willoughby, Ernest; Rautanen, Anna; Winkelmann, Juliane; Wittig, Michael; Trembath, Richard C; Yaouanq, Jacqueline; Viswanathan, Ananth C; Zhang, Haitao; Wood, Nicholas W; Zuvich, Rebecca; Deloukas, Panos; Langford, Cordelia; Duncanson, Audrey; Oksenberg, Jorge R; Pericak-Vance, Margaret A; Haines, Jonathan L; Olsson, Tomas; Hillert, Jan; Ivinson, Adrian J; De Jager, Philip L; Peltonen, Leena; Stewart, Graeme J; Hafler, David A; Hauser, Stephen L; McVean, Gil; Donnelly, Peter; Compston, Alastair

2011-08-10

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

Differential Regulation of Cryptic Genetic Variation Shapes the Genetic Interactome Underlying Complex Traits.

PubMed

Yadav, Anupama; Dhole, Kaustubh; Sinha, Himanshu

2016-12-01

Cryptic genetic variation (CGV) refers to genetic variants whose effects are buffered in most conditions but manifest phenotypically upon specific genetic and environmental perturbations. Despite having a central role in adaptation, contribution of CGV to regulation of quantitative traits is unclear. Instead, a relatively simplistic architecture of additive genetic loci is known to regulate phenotypic variation in most traits. In this paper, we investigate the regulation of CGV and its implication on the genetic architecture of quantitative traits at a genome-wide level. We use a previously published dataset of biparental recombinant population of Saccharomyces cerevisiae phenotyped in 34 diverse environments to perform single locus, two-locus, and covariance mapping. We identify loci that have independent additive effects as well as those which regulate the phenotypic manifestation of other genetic variants (variance QTL). We find that whereas additive genetic variance is predominant, a higher order genetic interaction network regulates variation in certain environments. Despite containing pleiotropic loci, with effects across environments, these genetic networks are highly environment specific. CGV is buffered under most allelic combinations of these networks and perturbed only in rare combinations resulting in high phenotypic variance. The presence of such environment specific genetic networks is the underlying cause of abundant gene–environment interactions. We demonstrate that overlaying identified molecular networks on such genetic networks can identify potential candidate genes and underlying mechanisms regulating phenotypic variation. Such an integrated approach applied to human disease datasets has the potential to improve the ability to predict disease predisposition and identify specific therapeutic targets.

Differential Regulation of Cryptic Genetic Variation Shapes the Genetic Interactome Underlying Complex Traits

PubMed Central

Yadav, Anupama; Dhole, Kaustubh

2016-01-01

Cryptic genetic variation (CGV) refers to genetic variants whose effects are buffered in most conditions but manifest phenotypically upon specific genetic and environmental perturbations. Despite having a central role in adaptation, contribution of CGV to regulation of quantitative traits is unclear. Instead, a relatively simplistic architecture of additive genetic loci is known to regulate phenotypic variation in most traits. In this paper, we investigate the regulation of CGV and its implication on the genetic architecture of quantitative traits at a genome-wide level. We use a previously published dataset of biparental recombinant population of Saccharomyces cerevisiae phenotyped in 34 diverse environments to perform single locus, two-locus, and covariance mapping. We identify loci that have independent additive effects as well as those which regulate the phenotypic manifestation of other genetic variants (variance QTL). We find that whereas additive genetic variance is predominant, a higher order genetic interaction network regulates variation in certain environments. Despite containing pleiotropic loci, with effects across environments, these genetic networks are highly environment specific. CGV is buffered under most allelic combinations of these networks and perturbed only in rare combinations resulting in high phenotypic variance. The presence of such environment specific genetic networks is the underlying cause of abundant gene–environment interactions. We demonstrate that overlaying identified molecular networks on such genetic networks can identify potential candidate genes and underlying mechanisms regulating phenotypic variation. Such an integrated approach applied to human disease datasets has the potential to improve the ability to predict disease predisposition and identify specific therapeutic targets. PMID:28172852

A combined analysis of genetically correlated traits identifies 187 loci and a role for neurogenesis and myelination in intelligence.

PubMed

Hill, W D; Marioni, R E; Maghzian, O; Ritchie, S J; Hagenaars, S P; McIntosh, A M; Gale, C R; Davies, G; Deary, I J

2018-01-11

Intelligence, or general cognitive function, is phenotypically and genetically correlated with many traits, including a wide range of physical, and mental health variables. Education is strongly genetically correlated with intelligence (r g  = 0.70). We used these findings as foundations for our use of a novel approach-multi-trait analysis of genome-wide association studies (MTAG; Turley et al. 2017)-to combine two large genome-wide association studies (GWASs) of education and intelligence, increasing statistical power and resulting in the largest GWAS of intelligence yet reported. Our study had four goals: first, to facilitate the discovery of new genetic loci associated with intelligence; second, to add to our understanding of the biology of intelligence differences; third, to examine whether combining genetically correlated traits in this way produces results consistent with the primary phenotype of intelligence; and, finally, to test how well this new meta-analytic data sample on intelligence predicts phenotypic intelligence in an independent sample. By combining datasets using MTAG, our functional sample size increased from 199,242 participants to 248,482. We found 187 independent loci associated with intelligence, implicating 538 genes, using both SNP-based and gene-based GWAS. We found evidence that neurogenesis and myelination-as well as genes expressed in the synapse, and those involved in the regulation of the nervous system-may explain some of the biological differences in intelligence. The results of our combined analysis demonstrated the same pattern of genetic correlations as those from previous GWASs of intelligence, providing support for the meta-analysis of these genetically-related phenotypes.

Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study.

PubMed

2016-02-01

The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading genetic approach to the identification of novel biological pathways underlying diseases in humans. Until recently, GWAS in ischaemic stroke have been limited by small sample sizes and have yielded few loci associated with ischaemic stroke. We did a large-scale GWAS to identify additional susceptibility genes for stroke and its subtypes. To identify genetic loci associated with ischaemic stroke, we did a two-stage GWAS. In the first stage, we included 16 851 cases with state-of-the-art phenotyping data and 32 473 stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtypes of ischaemic stroke were recorded by centrally trained and certified investigators who used the web-based protocol, Causative Classification of Stroke (CCS). We constructed case-control strata by identifying samples that were genotyped on nearly identical arrays and were of similar genetic ancestral background. We cleaned and imputed data by use of dense imputation reference panels generated from whole-genome sequence data. We did genome-wide testing to identify stroke-associated loci within each stratum for each available phenotype, and we combined summary-level results using inverse variance-weighted fixed-effects meta-analysis. In the second stage, we did in-silico lookups of 1372 single nucleotide polymorphisms identified from the first stage GWAS in 20 941 cases and 364 736 unique stroke-free controls. The ischaemic stroke subtypes of these cases had previously been established with the Trial of Org 10 172 in Acute Stroke Treatment (TOAST) classification system, in accordance with local standards. Results from the two stages were then jointly analysed in a final meta-analysis. We identified a novel locus (G allele at rs12122341) at 1p13.2 near TSPAN2 that was associated with large artery atherosclerosis-related stroke (first stage odds ratio [OR] 1·21, 95% CI 1·13-1·30, p=4·50 × 10 -8 ; joint OR 1·19, 1·12-1·26, p=1·30 × 10 -9 ). Our results also supported robust associations with ischaemic stroke for four other loci that have been reported in previous studies, including PITX2 (first stage OR 1·39, 1·29-1·49, p=3·26 × 10 -19 ; joint OR 1·37, 1·30-1·45, p=2·79 × 10 -32 ) and ZFHX3 (first stage OR 1·19, 1·11-1·27, p=2·93 × 10 -7 ; joint OR 1·17, 1·11-1·23, p=2·29 × 10 -10 ) for cardioembolic stroke, and HDAC9 (first stage OR 1·29, 1·18-1·42, p=3·50 × 10 -8 ; joint OR 1·24, 1·15-1·33, p=4·52 × 10 -9 ) for large artery atherosclerosis stroke. The 12q24 locus near ALDH2, which has previously been associated with all ischaemic stroke but not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery stroke (first stage OR 1·20, 1·12-1·28, p=6·82 × 10 -8 ; joint OR 1·17, 1·11-1·23, p=2·92 × 10 -9 ). Other loci associated with stroke in previous studies, including NINJ2, were not confirmed. Our results suggest that all ischaemic stroke-related loci previously implicated by GWAS are subtype specific. We identified a novel gene associated with large artery atherosclerosis stroke susceptibility. Follow-up studies will be necessary to establish whether the locus near TSPAN2 can be a target for a novel therapeutic approach to stroke prevention. In view of the subtype-specificity of the associations detected, the rich phenotyping data available in the Stroke Genetics Network (SiGN) are likely to be crucial for further genetic discoveries related to ischaemic stroke. US National Institute of Neurological Disorders and Stroke, National Institutes of Health. Copyright © 2016 Elsevier Ltd. All rights reserved.

A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinson's disease

PubMed Central

Holmans, Peter; Moskvina, Valentina; Jones, Lesley; Sharma, Manu; Vedernikov, Alexey; Buchel, Finja; Sadd, Mohamad; Bras, Jose M.; Bettella, Francesco; Nicolaou, Nayia; Simón-Sánchez, Javier; Mittag, Florian; Gibbs, J. Raphael; Schulte, Claudia; Durr, Alexandra; Guerreiro, Rita; Hernandez, Dena; Brice, Alexis; Stefánsson, Hreinn; Majamaa, Kari; Gasser, Thomas; Heutink, Peter; Wood, Nicholas W.; Martinez, Maria; Singleton, Andrew B.; Nalls, Michael A.; Hardy, John; Morris, Huw R.; Williams, Nigel M.; Arepalli, Sampath; Barker, Roger; Barrett, Jeffrey; Ben-Shlomo, Yoav; Berendse, Henk W.; Berg, Daniela; Bhatia, Kailash; de Bie, Rob M.A.; Biffi, Alessandro; Bloem, Bas; Brice, Alexis; Bochdanovits, Zoltan; Bonin, Michael; Bras, Jose M.; Brockmann, Kathrin; Brooks, Janet; Burn, David J.; Charlesworth, Gavin; Chen, Honglei; Chinnery, Patrick F.; Chong, Sean; Clarke, Carl E.; Cookson, Mark R.; Cooper, Jonathan M.; Corvol, Jen-Christophe; Counsell, Carl; Damier, Philippe; Dartigues, Jean Francois; Deloukas, Panagiotis; Deuschl, Günther; Dexter, David T.; van Dijk, Karin D.; Dillman, Allissa; Durif, Frank; Durr, Alexandra; Edkins, Sarah; Evans, Jonathan R.; Foltynie, Thomas; Gao, Jianjun; Gardner, Michelle; Gasser, Thomas; Gibbs, J. Raphael; Goate, Alison; Gray, Emma; Guerreiro, Rita; Gústafsson, Ómar; Hardy, John; Harris, Clare; Hernandez, Dena G.; Heutink, Peter; van Hilten, Jacobus J.; Hofman, Albert; Hollenbeck, Albert; Holmans, Peter; Holton, Janice; Hu, Michele; Huber, Heiko; Hudson, Gavin; Hunt, Sarah E.; Huttenlocher, Johanna; Illig, Thomas; Langford, Cordelia; Lees, Andrew; Lesage, Suzanne; Lichtner, Peter; Limousin, Patricia; Lopez, Grisel; Lorenz, Delia; Martinez, Maria; McNeill, Alisdair; Moorby, Catriona; Moore, Matthew; Morris, Huw; Morrison, Karen E.; Moskvina, Valentina; Mudanohwo, Ese; Nalls, Michael A.; Pearson, Justin; Perlmutter, Joel S.; Pétursson, Hjörvar; Plagnol, Vincent; Pollak, Pierre; Post, Bart; Potter, Simon; Ravina, Bernard; Revesz, Tamas; Riess, Olaf; Rivadeneira, Fernando; Rizzu, Patrizia; Ryten, Mina; Saad, Mohamad; Sawcer, Stephen; Schapira, Anthony; Scheffer, Hans; Sharma, Manu; Shaw, Karen; Sheerin, Una-Marie; Shoulson, Ira; Schulte, Claudia; Sidransky, Ellen; Simón-Sánchez, Javier; Singleton, Andrew B.; Smith, Colin; Stefánsson, Hreinn; Stefánsson, Kári; Steinberg, Stacy; Stockton, Joanna D.; Sveinbjornsdottir, Sigurlaug; Talbot, Kevin; Tanner, Carlie M.; Tashakkori-Ghanbaria, Avazeh; Tison, François; Trabzuni, Daniah; Traynor, Bryan J.; Uitterlinden, André G.; Velseboer, Daan; Vidailhet, Marie; Walker, Robert; van de Warrenburg, Bart; Wickremaratchi, Mirdhu; Williams, Nigel; Williams-Gray, Caroline H.; Winder-Rhodes, Sophie; Wood, Nicholas

2013-01-01

Parkinson's disease (PD) is the second most common neurodegenerative disease affecting 1–2% in people >60 and 3–4% in people >80. Genome-wide association (GWA) studies have now implicated significant evidence for association in at least 18 genomic regions. We have studied a large PD-meta analysis and identified a significant excess of SNPs (P < 1 × 10−16) that are associated with PD but fall short of the genome-wide significance threshold. This result was independent of variants at the 18 previously implicated regions and implies the presence of additional polygenic risk alleles. To understand how these loci increase risk of PD, we applied a pathway-based analysis, testing for biological functions that were significantly enriched for genes containing variants associated with PD. Analysing two independent GWA studies, we identified that both had a significant excess in the number of functional categories enriched for PD-associated genes (minimum P = 0.014 and P = 0.006, respectively). Moreover, 58 categories were significantly enriched for associated genes in both GWA studies (P < 0.001), implicating genes involved in the ‘regulation of leucocyte/lymphocyte activity’ and also ‘cytokine-mediated signalling’ as conferring an increased susceptibility to PD. These results were unaltered by the exclusion of all 178 genes that were present at the 18 genomic regions previously reported to be strongly associated with PD (including the HLA locus). Our findings, therefore, provide independent support to the strong association signal at the HLA locus and imply that the immune-related genetic susceptibility to PD is likely to be more widespread in the genome than previously appreciated. PMID:23223016

Identification of a New Susceptibility Locus for Systemic Lupus Erythematosus on Chromosome 12 in Individuals of European Ancestry

PubMed Central

Demirci, F. Yesim; Wang, Xingbin; Kelly, Jennifer A.; Morris, David L.; Barmada, M. Michael; Feingold, Eleanor; Kao, Amy H.; Sivils, Kathy L.; Bernatsky, Sasha; Pineau, Christian; Clarke, Ann; Ramsey-Goldman, Rosalind; Vyse, Timothy J.; Gaffney, Patrick M.; Manzi, Susan; Kamboh, M. Ilyas

2016-01-01

Objective Genome-wide association studies (GWASs) in individuals of European ancestry identified a number of systemic lupus erythematosus (SLE) susceptibility loci using earlier versions of high-density genotyping platforms. Follow-up studies on suggestive GWAS regions using larger samples and more markers identified additional SLE loci in European-descent subjects. Here we report the results of a multi-stage study that we performed to identify novel SLE loci. Methods In Stage 1, we conducted a new GWAS of SLE in a North American case-control sample of European ancestry (n=1,166) genotyped on Affymetrix Genome-Wide Human SNP Array 6.0. In Stage 2, we further investigated top new suggestive GWAS hits by in silico evaluation and meta-analysis using an additional dataset of European-descent subjects (>2,500 individuals), followed by replication of top meta-analysis findings in another dataset of European-descent subjects (>10,000 individuals) in Stage 3. Results As expected, our GWAS revealed most significant associations at the major histocompatibility complex locus (6p21), which easily surpassed genome-wide significance threshold (P<5×10−8). Several other SLE signals/loci previously implicated in Caucasians and/or Asians were also supported in Stage 1 discovery sample and strongest signals were observed at 2q32/STAT4 (P=3.6×10−7) and at 8p23/BLK (P=8.1×10−6). Stage 2 meta-analyses identified a new genome-wide significant SLE locus at 12q12 (meta P=3.1×10−8), which was replicated in Stage 3. Conclusion Our multi-stage study identified and replicated a new SLE locus that warrants further follow-up in additional studies. Publicly available databases suggest that this new SLE signal falls within a functionally relevant genomic region and near biologically important genes. PMID:26316170

Exome sequences of multiplex, multigenerational families reveal schizophrenia risk loci with potential implications for neurocognitive performance.

PubMed

Kos, Mark Z; Carless, Melanie A; Peralta, Juan; Curran, Joanne E; Quillen, Ellen E; Almeida, Marcio; Blackburn, August; Blondell, Lucy; Roalf, David R; Pogue-Geile, Michael F; Gur, Ruben C; Göring, Harald H H; Nimgaonkar, Vishwajit L; Gur, Raquel E; Almasy, Laura

2017-12-01

Schizophrenia is a serious mental illness, involving disruptions in thought and behavior, with a worldwide prevalence of about one percent. Although highly heritable, much of the genetic liability of schizophrenia is yet to be explained. We searched for susceptibility loci in multiplex, multigenerational families affected by schizophrenia, targeting protein-altering variation with in silico predicted functional effects. Exome sequencing was performed on 136 samples from eight European-American families, including 23 individuals diagnosed with schizophrenia or schizoaffective disorder. In total, 11,878 non-synonymous variants from 6,396 genes were tested for their association with schizophrenia spectrum disorders. Pathway enrichment analyses were conducted on gene-based test results, protein-protein interaction (PPI) networks, and epistatic effects. Using a significance threshold of FDR < 0.1, association was detected for rs10941112 (p = 2.1 × 10 -5 ; q-value = 0.073) in AMACR, a gene involved in fatty acid metabolism and previously implicated in schizophrenia, with significant cis effects on gene expression (p = 5.5 × 10 -4 ), including brain tissue data from the Genotype-Tissue Expression project (minimum p = 6.0 × 10 -5 ). A second SNP, rs10378 located in TMEM176A, also shows risk effects in the exome data (p = 2.8 × 10 -5 ; q-value = 0.073). PPIs among our top gene-based association results (p < 0.05; n = 359 genes) reveal significant enrichment of genes involved in NCAM-mediated neurite outgrowth (p = 3.0 × 10 -5 ), while exome-wide SNP-SNP interaction effects for rs10941112 and rs10378 indicate a potential role for kinase-mediated signaling involved in memory and learning. In conclusion, these association results implicate AMACR and TMEM176A in schizophrenia risk, whose effects may be modulated by genes involved in synaptic plasticity and neurocognitive performance. © 2017 Wiley Periodicals, Inc.

Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin.

PubMed

Liu, Ching-Ti; Raghavan, Sridharan; Maruthur, Nisa; Kabagambe, Edmond Kato; Hong, Jaeyoung; Ng, Maggie C Y; Hivert, Marie-France; Lu, Yingchang; An, Ping; Bentley, Amy R; Drolet, Anne M; Gaulton, Kyle J; Guo, Xiuqing; Armstrong, Loren L; Irvin, Marguerite R; Li, Man; Lipovich, Leonard; Rybin, Denis V; Taylor, Kent D; Agyemang, Charles; Palmer, Nicholette D; Cade, Brian E; Chen, Wei-Min; Dauriz, Marco; Delaney, Joseph A C; Edwards, Todd L; Evans, Daniel S; Evans, Michele K; Lange, Leslie A; Leong, Aaron; Liu, Jingmin; Liu, Yongmei; Nayak, Uma; Patel, Sanjay R; Porneala, Bianca C; Rasmussen-Torvik, Laura J; Snijder, Marieke B; Stallings, Sarah C; Tanaka, Toshiko; Yanek, Lisa R; Zhao, Wei; Becker, Diane M; Bielak, Lawrence F; Biggs, Mary L; Bottinger, Erwin P; Bowden, Donald W; Chen, Guanjie; Correa, Adolfo; Couper, David J; Crawford, Dana C; Cushman, Mary; Eicher, John D; Fornage, Myriam; Franceschini, Nora; Fu, Yi-Ping; Goodarzi, Mark O; Gottesman, Omri; Hara, Kazuo; Harris, Tamara B; Jensen, Richard A; Johnson, Andrew D; Jhun, Min A; Karter, Andrew J; Keller, Margaux F; Kho, Abel N; Kizer, Jorge R; Krauss, Ronald M; Langefeld, Carl D; Li, Xiaohui; Liang, Jingling; Liu, Simin; Lowe, William L; Mosley, Thomas H; North, Kari E; Pacheco, Jennifer A; Peyser, Patricia A; Patrick, Alan L; Rice, Kenneth M; Selvin, Elizabeth; Sims, Mario; Smith, Jennifer A; Tajuddin, Salman M; Vaidya, Dhananjay; Wren, Mary P; Yao, Jie; Zhu, Xiaofeng; Ziegler, Julie T; Zmuda, Joseph M; Zonderman, Alan B; Zwinderman, Aeilko H; Adeyemo, Adebowale; Boerwinkle, Eric; Ferrucci, Luigi; Hayes, M Geoffrey; Kardia, Sharon L R; Miljkovic, Iva; Pankow, James S; Rotimi, Charles N; Sale, Michele M; Wagenknecht, Lynne E; Arnett, Donna K; Chen, Yii-Der Ida; Nalls, Michael A; Province, Michael A; Kao, W H Linda; Siscovick, David S; Psaty, Bruce M; Wilson, James G; Loos, Ruth J F; Dupuis, Josée; Rich, Stephen S; Florez, Jose C; Rotter, Jerome I; Morris, Andrew P; Meigs, James B

2016-07-07

Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci. Copyright © 2016 American Society of Human Genetics. All rights reserved.

Mapping of quantitative trait loci for resistance to fall armyworm and southwestern corn borer leaf-feeding damage in maize.

USDA-ARS?s Scientific Manuscript database

Fall armyworm (FAW), Spodoptera frugiperda (J. E. Smith), and southwestern corn borer (SWCB), Diatraea grandiosella Dyar are damaging insect pests of maize resulting in significant yield and economic losses. A previous study identified quantitative trait loci (QTL) that contribute to reduced leaf-fe...

Classification of Korean native pear based on a standard set of microsatellite loci

USDA-ARS?s Scientific Manuscript database

After analysis with 12 microsatellite loci previously selected for use by ECPGR, 34 Korean pear accessions were classified into 3 groups. Group I included 4 Korean pea pears and one accession of P. calleryana. Group II contained 12 cultivars including 7 accessions presumed to belong to P. pyrifolia....

Genome-Wide Meta-Analysis of Myopia and Hyperopia Provides Evidence for Replication of 11 Loci

PubMed Central

Simpson, Claire L.; Wojciechowski, Robert; Oexle, Konrad; Murgia, Federico; Portas, Laura; Li, Xiaohui; Verhoeven, Virginie J. M.; Vitart, Veronique; Schache, Maria; Hosseini, S. Mohsen; Hysi, Pirro G.; Raffel, Leslie J.; Cotch, Mary Frances; Chew, Emily; Klein, Barbara E. K.; Klein, Ronald; Wong, Tien Yin; van Duijn, Cornelia M.; Mitchell, Paul; Saw, Seang Mei; Fossarello, Maurizio; Wang, Jie Jin; Polašek, Ozren; Campbell, Harry; Rudan, Igor; Oostra, Ben A.; Uitterlinden, André G.; Hofman, Albert; Rivadeneira, Fernando; Amin, Najaf; Karssen, Lennart C.; Vingerling, Johannes R.; Döring, Angela; Bettecken, Thomas; Bencic, Goran; Gieger, Christian; Wichmann, H.-Erich; Wilson, James F.; Venturini, Cristina; Fleck, Brian; Cumberland, Phillippa M.; Rahi, Jugnoo S.; Hammond, Chris J.; Hayward, Caroline; Wright, Alan F.; Paterson, Andrew D.; Baird, Paul N.; Klaver, Caroline C. W.; Rotter, Jerome I.; Pirastu, Mario; Meitinger, Thomas; Bailey-Wilson, Joan E.; Stambolian, Dwight

2014-01-01

Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10−8), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10−11) and 8q12 (minimum p value 1.82×10−11) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. “Replication-level” association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution. PMID:25233373

Genome-wide association of body fat distribution in African ancestry populations suggests new loci.

PubMed

Liu, Ching-Ti; Monda, Keri L; Taylor, Kira C; Lange, Leslie; Demerath, Ellen W; Palmas, Walter; Wojczynski, Mary K; Ellis, Jaclyn C; Vitolins, Mara Z; Liu, Simin; Papanicolaou, George J; Irvin, Marguerite R; Xue, Luting; Griffin, Paula J; Nalls, Michael A; Adeyemo, Adebowale; Liu, Jiankang; Li, Guo; Ruiz-Narvaez, Edward A; Chen, Wei-Min; Chen, Fang; Henderson, Brian E; Millikan, Robert C; Ambrosone, Christine B; Strom, Sara S; Guo, Xiuqing; Andrews, Jeanette S; Sun, Yan V; Mosley, Thomas H; Yanek, Lisa R; Shriner, Daniel; Haritunians, Talin; Rotter, Jerome I; Speliotes, Elizabeth K; Smith, Megan; Rosenberg, Lynn; Mychaleckyj, Josyf; Nayak, Uma; Spruill, Ida; Garvey, W Timothy; Pettaway, Curtis; Nyante, Sarah; Bandera, Elisa V; Britton, Angela F; Zonderman, Alan B; Rasmussen-Torvik, Laura J; Chen, Yii-Der Ida; Ding, Jingzhong; Lohman, Kurt; Kritchevsky, Stephen B; Zhao, Wei; Peyser, Patricia A; Kardia, Sharon L R; Kabagambe, Edmond; Broeckel, Ulrich; Chen, Guanjie; Zhou, Jie; Wassertheil-Smoller, Sylvia; Neuhouser, Marian L; Rampersaud, Evadnie; Psaty, Bruce; Kooperberg, Charles; Manson, Joann E; Kuller, Lewis H; Ochs-Balcom, Heather M; Johnson, Karen C; Sucheston, Lara; Ordovas, Jose M; Palmer, Julie R; Haiman, Christopher A; McKnight, Barbara; Howard, Barbara V; Becker, Diane M; Bielak, Lawrence F; Liu, Yongmei; Allison, Matthew A; Grant, Struan F A; Burke, Gregory L; Patel, Sanjay R; Schreiner, Pamela J; Borecki, Ingrid B; Evans, Michele K; Taylor, Herman; Sale, Michele M; Howard, Virginia; Carlson, Christopher S; Rotimi, Charles N; Cushman, Mary; Harris, Tamara B; Reiner, Alexander P; Cupples, L Adrienne; North, Kari E; Fox, Caroline S

2013-01-01

Central obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values<5.0 × 10(-6) were followed-up (stage 2) in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA) WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24×10(-8) for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48×10(-8) for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5 × 10(-8); RREB1: p = 5.7 × 10(-8)). Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region) in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). Further, we observed associations with metabolic traits: rs13389219 at GRB14 associated with HDL-cholesterol, triglycerides, and fasting insulin, and rs13060013 at ADAMTS9 with HDL-cholesterol and fasting insulin. Finally, we observed nominal evidence for sexual dimorphism, with stronger results in AA women at the GRB14 locus (p for interaction = 0.02). In conclusion, we identified two suggestive loci associated with fat distribution in AA populations in addition to confirming 6 loci previously identified in populations of EA. These findings reinforce the concept that there are fat distribution loci that are independent of generalized adiposity.

Genome-wide meta-analysis of myopia and hyperopia provides evidence for replication of 11 loci.

PubMed

Simpson, Claire L; Wojciechowski, Robert; Oexle, Konrad; Murgia, Federico; Portas, Laura; Li, Xiaohui; Verhoeven, Virginie J M; Vitart, Veronique; Schache, Maria; Hosseini, S Mohsen; Hysi, Pirro G; Raffel, Leslie J; Cotch, Mary Frances; Chew, Emily; Klein, Barbara E K; Klein, Ronald; Wong, Tien Yin; van Duijn, Cornelia M; Mitchell, Paul; Saw, Seang Mei; Fossarello, Maurizio; Wang, Jie Jin; Polašek, Ozren; Campbell, Harry; Rudan, Igor; Oostra, Ben A; Uitterlinden, André G; Hofman, Albert; Rivadeneira, Fernando; Amin, Najaf; Karssen, Lennart C; Vingerling, Johannes R; Döring, Angela; Bettecken, Thomas; Bencic, Goran; Gieger, Christian; Wichmann, H-Erich; Wilson, James F; Venturini, Cristina; Fleck, Brian; Cumberland, Phillippa M; Rahi, Jugnoo S; Hammond, Chris J; Hayward, Caroline; Wright, Alan F; Paterson, Andrew D; Baird, Paul N; Klaver, Caroline C W; Rotter, Jerome I; Pirastu, Mario; Meitinger, Thomas; Bailey-Wilson, Joan E; Stambolian, Dwight

2014-01-01

Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10(-8)), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10(-11)) and 8q12 (minimum p value 1.82×10(-11)) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. "Replication-level" association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.

Trans-Ethnic Fine-Mapping of Lipid Loci Identifies Population-Specific Signals and Allelic Heterogeneity That Increases the Trait Variance Explained

PubMed Central

Wu, Ying; Waite, Lindsay L.; Jackson, Anne U.; Sheu, Wayne H-H.; Buyske, Steven; Absher, Devin; Arnett, Donna K.; Boerwinkle, Eric; Bonnycastle, Lori L.; Carty, Cara L.; Cheng, Iona; Cochran, Barbara; Croteau-Chonka, Damien C.; Dumitrescu, Logan; Eaton, Charles B.; Franceschini, Nora; Guo, Xiuqing; Henderson, Brian E.; Hindorff, Lucia A.; Kim, Eric; Kinnunen, Leena; Komulainen, Pirjo; Lee, Wen-Jane; Le Marchand, Loic; Lin, Yi; Lindström, Jaana; Lingaas-Holmen, Oddgeir; Mitchell, Sabrina L.; Narisu, Narisu; Robinson, Jennifer G.; Schumacher, Fred; Stančáková, Alena; Sundvall, Jouko; Sung, Yun-Ju; Swift, Amy J.; Wang, Wen-Chang; Wilkens, Lynne; Wilsgaard, Tom; Young, Alicia M.; Adair, Linda S.; Ballantyne, Christie M.; Bůžková, Petra; Chakravarti, Aravinda; Collins, Francis S.; Duggan, David; Feranil, Alan B.; Ho, Low-Tone; Hung, Yi-Jen; Hunt, Steven C.; Hveem, Kristian; Juang, Jyh-Ming J.; Kesäniemi, Antero Y.; Kuusisto, Johanna; Laakso, Markku; Lakka, Timo A.; Lee, I-Te; Leppert, Mark F.; Matise, Tara C.; Moilanen, Leena; Njølstad, Inger; Peters, Ulrike; Quertermous, Thomas; Rauramaa, Rainer; Rotter, Jerome I.; Saramies, Jouko; Tuomilehto, Jaakko; Uusitupa, Matti; Wang, Tzung-Dau; Mohlke, Karen L.

2013-01-01

Genome-wide association studies (GWAS) have identified ∼100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1×10−4 in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies. PMID:23555291

Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African Ancestry Anthropometry Genetics Consortium.

PubMed

Ng, Maggie C Y; Graff, Mariaelisa; Lu, Yingchang; Justice, Anne E; Mudgal, Poorva; Liu, Ching-Ti; Young, Kristin; Yanek, Lisa R; Feitosa, Mary F; Wojczynski, Mary K; Rand, Kristin; Brody, Jennifer A; Cade, Brian E; Dimitrov, Latchezar; Duan, Qing; Guo, Xiuqing; Lange, Leslie A; Nalls, Michael A; Okut, Hayrettin; Tajuddin, Salman M; Tayo, Bamidele O; Vedantam, Sailaja; Bradfield, Jonathan P; Chen, Guanjie; Chen, Wei-Min; Chesi, Alessandra; Irvin, Marguerite R; Padhukasahasram, Badri; Smith, Jennifer A; Zheng, Wei; Allison, Matthew A; Ambrosone, Christine B; Bandera, Elisa V; Bartz, Traci M; Berndt, Sonja I; Bernstein, Leslie; Blot, William J; Bottinger, Erwin P; Carpten, John; Chanock, Stephen J; Chen, Yii-Der Ida; Conti, David V; Cooper, Richard S; Fornage, Myriam; Freedman, Barry I; Garcia, Melissa; Goodman, Phyllis J; Hsu, Yu-Han H; Hu, Jennifer; Huff, Chad D; Ingles, Sue A; John, Esther M; Kittles, Rick; Klein, Eric; Li, Jin; McKnight, Barbara; Nayak, Uma; Nemesure, Barbara; Ogunniyi, Adesola; Olshan, Andrew; Press, Michael F; Rohde, Rebecca; Rybicki, Benjamin A; Salako, Babatunde; Sanderson, Maureen; Shao, Yaming; Siscovick, David S; Stanford, Janet L; Stevens, Victoria L; Stram, Alex; Strom, Sara S; Vaidya, Dhananjay; Witte, John S; Yao, Jie; Zhu, Xiaofeng; Ziegler, Regina G; Zonderman, Alan B; Adeyemo, Adebowale; Ambs, Stefan; Cushman, Mary; Faul, Jessica D; Hakonarson, Hakon; Levin, Albert M; Nathanson, Katherine L; Ware, Erin B; Weir, David R; Zhao, Wei; Zhi, Degui; Arnett, Donna K; Grant, Struan F A; Kardia, Sharon L R; Oloapde, Olufunmilayo I; Rao, D C; Rotimi, Charles N; Sale, Michele M; Williams, L Keoki; Zemel, Babette S; Becker, Diane M; Borecki, Ingrid B; Evans, Michele K; Harris, Tamara B; Hirschhorn, Joel N; Li, Yun; Patel, Sanjay R; Psaty, Bruce M; Rotter, Jerome I; Wilson, James G; Bowden, Donald W; Cupples, L Adrienne; Haiman, Christopher A; Loos, Ruth J F; North, Kari E

2017-04-01

Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10-8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.

Identification of seven new prostate cancer susceptibility loci through a genome-wide association study

PubMed Central

Eeles, Rosalind A.; Kote-Jarai, Zsofia; Olama, Ali Amin Al; Giles, Graham G.; Guy, Michelle; Severi, Gianluca; Muir, Kenneth; Hopper, John L.; Henderson, Brian E.; Haiman, Christopher A.; Schleutker, Johanna; Hamdy, Freddie C.; Neal, David E.; Donovan, Jenny L.; Stanford, Janet L.; Ostrander, Elaine A.; Ingles, Sue A.; John, Esther M.; Thibodeau, Stephen N.; Schaid, Daniel; Park, Jong Y.; Spurdle, Amanda; Clements, Judith; Dickinson, Joanne L.; Maier, Christiane; Vogel, Walther; Dörk, Thilo; Rebbeck, Timothy R.; Cooney, Kathleen A.; Cannon-Albright, Lisa; Chappuis, Pierre O.; Hutter, Pierre; Zeegers, Maurice; Kaneva, Radka; Zhang, Hong-Wei; Lu, Yong-Jie; Foulkes, William D.; English, Dallas R.; Leongamornlert, Daniel A.; Tymrakiewicz, Malgorzata; Morrison, Jonathan; Ardern-Jones, Audrey T.; Hall, Amanda L.; O’Brien, Lynne T.; Wilkinson, Rosemary A.; Saunders, Edward J.; Page, Elizabeth C.; Sawyer, Emma J.; Edwards, Stephen M.; Dearnaley, David P.; Horwich, Alan; Huddart, Robert A.; Khoo, Vincent S.; Parker, Christopher C.; Van As, Nicholas; Woodhouse, Christopher J.; Thompson, Alan; Christmas, Tim; Ogden, Chris; Cooper, Colin S.; Southey, Melissa C.; Lophatananon, Artitaya; Liu, Jo-Fen; Kolonel, Laurence N.; Le Marchand, Loic; Wahlfors, Tiina; Tammela, Teuvo L.; Auvinen, Anssi; Lewis, Sarah J.; Cox, Angela; FitzGerald, Liesel M.; Koopmeiners, Joseph S.; Karyadi, Danielle M.; Kwon, Erika M.; Stern, Mariana C.; Corral, Roman; Joshi, Amit D.; Shahabi, Ahva; McDonnell, Shannon K.; Sellers, Thomas A; Pow-Sang, Julio; Chambers, Suzanne; Aitken, Joanne; Gardiner, R.A. (Frank); Batra, Jyotsna; Kedda, Mary Anne; Lose, Felicity; Polanowski, Andrea; Patterson, Briony; Serth, Jürgen; Meyer, Andreas; Luedeke, Manuel; Stefflova, Klara; Ray, Anna M.; Lange, Ethan M.; Farnham, Jim; Khan, Humera; Slavov, Chavdar; Mitkova, Atanaska; Cao, Guangwen; Easton, Douglas F.

2010-01-01

Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. To identify common PrCa susceptibility alleles, we have previously conducted a genome-wide association study in which 541, 129 SNPs were genotyped in 1,854 PrCa cases with clinically detected disease and 1,894 controls. We have now evaluated promising associations in a second stage, in which we genotyped 43,671 SNPs in 3,650 PrCa cases and 3,940 controls, and a third stage, involving an additional 16,229 cases and 14,821 controls from 21 studies. In addition to previously identified loci, we identified a further seven new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11, and 22 (P=1.6×10−8 to P=2.7×10−33). PMID:19767753

Identification of five novel modifier loci of ApcMin harbored in the BXH14 recombinant inbred strain

PubMed Central

Siracusa, Linda D.

2012-01-01

Every year thousands of people in the USA are diagnosed with small intestine and colorectal cancers (CRC). Although environmental factors affect disease etiology, uncovering underlying genetic factors is imperative for risk assessment and developing preventative therapies. Familial adenomatous polyposis is a heritable genetic disorder in which individuals carry germ-line mutations in the adenomatous polyposis coli (APC) gene that predisposes them to CRC. The Apc Min mouse model carries a point mutation in the Apc gene and develops polyps along the intestinal tract. Inbred strain background influences polyp phenotypes in Apc Min mice. Several Modifier of Min (Mom) loci that alter tumor phenotypes associated with the Apc Min mutation have been identified to date. We screened BXH recombinant inbred (RI) strains by crossing BXH RI females with C57BL/6J (B6) Apc Min males and quantitating tumor phenotypes in backcross progeny. We found that the BXH14 RI strain harbors five modifier loci that decrease polyp multiplicity. Furthermore, we show that resistance is determined by varying combinations of these modifier loci. Gene interaction network analysis shows that there are multiple networks with proven gene–gene interactions, which contain genes from all five modifier loci. We discuss the implications of this result for studies that define susceptibility loci, namely that multiple networks may be acting concurrently to alter tumor phenotypes. Thus, the significance of this work resides not only with the modifier loci we identified but also with the combinations of loci needed to get maximal protection against polyposis and the impact of this finding on human disease studies. Abbreviations:APCadenomatous polyposis coliGWASgenome-wide association studiesQTLquantitative trait lociSNPsingle-nucleotide polymorphism. PMID:22637734

Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine.

PubMed

Gormley, Padhraig; Anttila, Verneri; Winsvold, Bendik S; Palta, Priit; Esko, Tonu; Pers, Tune H; Farh, Kai-How; Cuenca-Leon, Ester; Muona, Mikko; Furlotte, Nicholas A; Kurth, Tobias; Ingason, Andres; McMahon, George; Ligthart, Lannie; Terwindt, Gisela M; Kallela, Mikko; Freilinger, Tobias M; Ran, Caroline; Gordon, Scott G; Stam, Anine H; Steinberg, Stacy; Borck, Guntram; Koiranen, Markku; Quaye, Lydia; Adams, Hieab H H; Lehtimäki, Terho; Sarin, Antti-Pekka; Wedenoja, Juho; Hinds, David A; Buring, Julie E; Schürks, Markus; Ridker, Paul M; Hrafnsdottir, Maria Gudlaug; Stefansson, Hreinn; Ring, Susan M; Hottenga, Jouke-Jan; Penninx, Brenda W J H; Färkkilä, Markus; Artto, Ville; Kaunisto, Mari; Vepsäläinen, Salli; Malik, Rainer; Heath, Andrew C; Madden, Pamela A F; Martin, Nicholas G; Montgomery, Grant W; Kurki, Mitja I; Kals, Mart; Mägi, Reedik; Pärn, Kalle; Hämäläinen, Eija; Huang, Hailiang; Byrnes, Andrea E; Franke, Lude; Huang, Jie; Stergiakouli, Evie; Lee, Phil H; Sandor, Cynthia; Webber, Caleb; Cader, Zameel; Muller-Myhsok, Bertram; Schreiber, Stefan; Meitinger, Thomas; Eriksson, Johan G; Salomaa, Veikko; Heikkilä, Kauko; Loehrer, Elizabeth; Uitterlinden, Andre G; Hofman, Albert; van Duijn, Cornelia M; Cherkas, Lynn; Pedersen, Linda M; Stubhaug, Audun; Nielsen, Christopher S; Männikkö, Minna; Mihailov, Evelin; Milani, Lili; Göbel, Hartmut; Esserlind, Ann-Louise; Christensen, Anne Francke; Hansen, Thomas Folkmann; Werge, Thomas; Kaprio, Jaakko; Aromaa, Arpo J; Raitakari, Olli; Ikram, M Arfan; Spector, Tim; Järvelin, Marjo-Riitta; Metspalu, Andres; Kubisch, Christian; Strachan, David P; Ferrari, Michel D; Belin, Andrea C; Dichgans, Martin; Wessman, Maija; van den Maagdenberg, Arn M J M; Zwart, John-Anker; Boomsma, Dorret I; Smith, George Davey; Stefansson, Kari; Eriksson, Nicholas; Daly, Mark J; Neale, Benjamin M; Olesen, Jes; Chasman, Daniel I; Nyholt, Dale R; Palotie, Aarno

2016-08-01

Migraine is a debilitating neurological disorder affecting around one in seven people worldwide, but its molecular mechanisms remain poorly understood. There is some debate about whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we carried out a genetic study of migraine on 59,674 affected subjects and 316,078 controls from 22 GWA studies. We identified 44 independent single-nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10(-8)) that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to our knowledge is the first to be identified on chromosome X. In subsequent computational analyses, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.

Blood pressure loci identified with a gene-centric array.

PubMed

Johnson, Toby; Gaunt, Tom R; Newhouse, Stephen J; Padmanabhan, Sandosh; Tomaszewski, Maciej; Kumari, Meena; Morris, Richard W; Tzoulaki, Ioanna; O'Brien, Eoin T; Poulter, Neil R; Sever, Peter; Shields, Denis C; Thom, Simon; Wannamethee, Sasiwarang G; Whincup, Peter H; Brown, Morris J; Connell, John M; Dobson, Richard J; Howard, Philip J; Mein, Charles A; Onipinla, Abiodun; Shaw-Hawkins, Sue; Zhang, Yun; Davey Smith, George; Day, Ian N M; Lawlor, Debbie A; Goodall, Alison H; Fowkes, F Gerald; Abecasis, Gonçalo R; Elliott, Paul; Gateva, Vesela; Braund, Peter S; Burton, Paul R; Nelson, Christopher P; Tobin, Martin D; van der Harst, Pim; Glorioso, Nicola; Neuvrith, Hani; Salvi, Erika; Staessen, Jan A; Stucchi, Andrea; Devos, Nabila; Jeunemaitre, Xavier; Plouin, Pierre-François; Tichet, Jean; Juhanson, Peeter; Org, Elin; Putku, Margus; Sõber, Siim; Veldre, Gudrun; Viigimaa, Margus; Levinsson, Anna; Rosengren, Annika; Thelle, Dag S; Hastie, Claire E; Hedner, Thomas; Lee, Wai K; Melander, Olle; Wahlstrand, Björn; Hardy, Rebecca; Wong, Andrew; Cooper, Jackie A; Palmen, Jutta; Chen, Li; Stewart, Alexandre F R; Wells, George A; Westra, Harm-Jan; Wolfs, Marcel G M; Clarke, Robert; Franzosi, Maria Grazia; Goel, Anuj; Hamsten, Anders; Lathrop, Mark; Peden, John F; Seedorf, Udo; Watkins, Hugh; Ouwehand, Willem H; Sambrook, Jennifer; Stephens, Jonathan; Casas, Juan-Pablo; Drenos, Fotios; Holmes, Michael V; Kivimaki, Mika; Shah, Sonia; Shah, Tina; Talmud, Philippa J; Whittaker, John; Wallace, Chris; Delles, Christian; Laan, Maris; Kuh, Diana; Humphries, Steve E; Nyberg, Fredrik; Cusi, Daniele; Roberts, Robert; Newton-Cheh, Christopher; Franke, Lude; Stanton, Alice V; Dominiczak, Anna F; Farrall, Martin; Hingorani, Aroon D; Samani, Nilesh J; Caulfield, Mark J; Munroe, Patricia B

2011-12-09

Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies. Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

A multi-ethnic genome-wide association study identifies novel loci for non-syndromic cleft lip with or without cleft palate on 2p24.2, 17q23 and 19q13

PubMed Central

Leslie, Elizabeth J.; Carlson, Jenna C.; Shaffer, John R.; Feingold, Eleanor; Wehby, George; Laurie, Cecelia A.; Jain, Deepti; Laurie, Cathy C.; Doheny, Kimberly F.; McHenry, Toby; Resick, Judith; Sanchez, Carla; Jacobs, Jennifer; Emanuele, Beth; Vieira, Alexandre R.; Neiswanger, Katherine; Lidral, Andrew C.; Valencia-Ramirez, Luz Consuelo; Lopez-Palacio, Ana Maria; Valencia, Dora Rivera; Arcos-Burgos, Mauricio; Czeizel, Andrew E.; Field, L. Leigh; Padilla, Carmencita D.; Cutiongco-de la Paz, Eva Maria, C.; Deleyiannis, Frederic; Christensen, Kaare; Munger, Ronald G.; Lie, Rolv T.; Wilcox, Allen; Romitti, Paul A.; Castilla, Eduardo E.; Mereb, Juan C.; Poletta, Fernando A.; Orioli, Iêda M.; Carvalho, Flavia M.; Hecht, Jacqueline T.; Blanton, Susan H.; Buxó, Carmen J.; Butali, Azeez; Mossey, Peter A.; Adeyemo, Wasiu L.; James, Olutayo; Braimah, Ramat O.; Aregbesola, Babatunde S.; Eshete, Mekonen A.; Abate, Fikre; Koruyucu, Mine; Seymen, Figen; Ma, Lian; de Salamanca, Javier Enríquez; Weinberg, Seth M.; Moreno, Lina; Murray, Jeffrey C.; Marazita, Mary L.

2016-01-01

Orofacial clefts (OFCs), which include non-syndromic cleft lip with or without cleft palate (CL/P), are among the most common birth defects in humans, affecting approximately 1 in 700 newborns. CL/P is phenotypically heterogeneous and has a complex etiology caused by genetic and environmental factors. Previous genome-wide association studies (GWASs) have identified at least 15 risk loci for CL/P. As these loci do not account for all of the genetic variance of CL/P, we hypothesized the existence of additional risk loci. We conducted a multiethnic GWAS in 6480 participants (823 unrelated cases, 1700 unrelated controls and 1319 case–parent trios) with European, Asian, African and Central and South American ancestry. Our GWAS revealed novel associations on 2p24 near FAM49A, a gene of unknown function (P = 4.22 × 10−8), and 19q13 near RHPN2, a gene involved in organizing the actin cytoskeleton (P = 4.17 × 10−8). Other regions reaching genome-wide significance were 1p36 (PAX7), 1p22 (ARHGAP29), 1q32 (IRF6), 8q24 and 17p13 (NTN1), all reported in previous GWASs. Stratification by ancestry group revealed a novel association with a region on 17q23 (P = 2.92 × 10−8) among individuals with European ancestry. This region included several promising candidates including TANC2, an oncogene required for development, and DCAF7, a scaffolding protein required for craniofacial development. In the Central and South American ancestry group, significant associations with loci previously identified in Asian or European ancestry groups reflected their admixed ancestry. In summary, we have identified novel CL/P risk loci and suggest new genes involved in craniofacial development, confirming the highly heterogeneous etiology of OFCs. PMID:27033726

An update on alopecia areata.

PubMed

Kos, Liborka; Conlon, Joseph

2009-08-01

Alopecia areata is one of the most frequent organ-restricted autoimmune diseases, yet its pathogenesis is still unclear. In addition, although alopecia areata often results in significant psychological distress, effective treatment is lacking. New potential susceptibility loci have been implicated, but the strongest evidence points to certain class II human leukocyte antigen alleles. There is new evidence for the collapse of hair follicle immune privilege as a key step in the pathogenesis of alopecia areata. There is also new basic science evidence for stress as a contributing factor in the development of alopecia areata. Few treatments for alopecia areata have been well evaluated in randomized trials. Although multiple potential susceptibility loci have been implicated, the genetics of alopecia areata is still unclear. The role of any potential environmental contributors is also unclear. Quality evidence for efficacy of currently used treatments for alopecia areata is lacking.

Discrimination of candidate subgenome-specific loci by linkage map construction with an S1 population of octoploid strawberry (Fragaria × ananassa).

PubMed

Nagano, Soichiro; Shirasawa, Kenta; Hirakawa, Hideki; Maeda, Fumi; Ishikawa, Masami; Isobe, Sachiko N

2017-05-12

The strawberry, Fragaria × ananassa, is an allo-octoploid (2n = 8x = 56) and outcrossing species. Although it is the most widely consumed berry crop in the world, its complex genome structure has hindered its genetic and genomic analysis, and thus discrimination of subgenome-specific loci among the homoeologous chromosomes is needed. In the present study, we identified candidate subgenome-specific single nucleotide polymorphism (SNP) and simple sequence repeat (SSR) loci, and constructed a linkage map using an S 1 mapping population of the cultivar 'Reikou' with an IStraw90 Axiom® SNP array and previously published SSR markers. The 'Reikou' linkage map consisted of 11,574 loci (11,002 SNPs and 572 SSR loci) spanning 2816.5 cM of 31 linkage groups. The 11,574 loci were located on 4738 unique positions (bin) on the linkage map. Of the mapped loci, 8999 (8588 SNPs and 411 SSR loci) showed a 1:2:1 segregation ratio of AA:AB:BB allele, which suggested the possibility of deriving loci from candidate subgenome-specific sequences. In addition, 2575 loci (2414 SNPs and 161 SSR loci) showed a 3:1 segregation of AB:BB allele, indicating they were derived from homoeologous genomic sequences. Comparative analysis of the homoeologous linkage groups revealed differences in genome structure among the subgenomes. Our results suggest that candidate subgenome-specific loci are randomly located across the genomes, and that there are small- to large-scale structural variations among the subgenomes. The mapped SNPs and SSR loci on the linkage map are expected to be seed points for the construction of pseudomolecules in the octoploid strawberry.

Conservation genomics of threatened animal species.

PubMed

Steiner, Cynthia C; Putnam, Andrea S; Hoeck, Paquita E A; Ryder, Oliver A

2013-01-01

The genomics era has opened up exciting possibilities in the field of conservation biology by enabling genomic analyses of threatened species that previously were limited to model organisms. Next-generation sequencing (NGS) and the collection of genome-wide data allow for more robust studies of the demographic history of populations and adaptive variation associated with fitness and local adaptation. Genomic analyses can also advance management efforts for threatened wild and captive populations by identifying loci contributing to inbreeding depression and disease susceptibility, and predicting fitness consequences of introgression. However, the development of genomic tools in wild species still carries multiple challenges, particularly those associated with computational and sampling constraints. This review provides an overview of the most significant applications of NGS and the implications and limitations of genomic studies in conservation.

Genome-wide association mapping of partial resistance to Aphanomyces euteiches in pea.

PubMed

Desgroux, Aurore; L'Anthoëne, Virginie; Roux-Duparque, Martine; Rivière, Jean-Philippe; Aubert, Grégoire; Tayeh, Nadim; Moussart, Anne; Mangin, Pierre; Vetel, Pierrick; Piriou, Christophe; McGee, Rebecca J; Coyne, Clarice J; Burstin, Judith; Baranger, Alain; Manzanares-Dauleux, Maria; Bourion, Virginie; Pilet-Nayel, Marie-Laure

2016-02-20

Genome-wide association (GWA) mapping has recently emerged as a valuable approach for refining the genetic basis of polygenic resistance to plant diseases, which are increasingly used in integrated strategies for durable crop protection. Aphanomyces euteiches is a soil-borne pathogen of pea and other legumes worldwide, which causes yield-damaging root rot. Linkage mapping studies reported quantitative trait loci (QTL) controlling resistance to A. euteiches in pea. However the confidence intervals (CIs) of these QTL remained large and were often linked to undesirable alleles, which limited their application in breeding. The aim of this study was to use a GWA approach to validate and refine CIs of the previously reported Aphanomyces resistance QTL, as well as identify new resistance loci. A pea-Aphanomyces collection of 175 pea lines, enriched in germplasm derived from previously studied resistant sources, was evaluated for resistance to A. euteiches in field infested nurseries in nine environments and with two strains in climatic chambers. The collection was genotyped using 13,204 SNPs from the recently developed GenoPea Infinium® BeadChip. GWA analysis detected a total of 52 QTL of small size-intervals associated with resistance to A. euteiches, using the recently developed Multi-Locus Mixed Model. The analysis validated six of the seven previously reported main Aphanomyces resistance QTL and detected novel resistance loci. It also provided marker haplotypes at 14 consistent QTL regions associated with increased resistance and highlighted accumulation of favourable haplotypes in the most resistant lines. Previous linkages between resistance alleles and undesired late-flowering alleles for dry pea breeding were mostly confirmed, but the linkage between loci controlling resistance and coloured flowers was broken due to the high resolution of the analysis. A high proportion of the putative candidate genes underlying resistance loci encoded stress-related proteins and others suggested that the QTL are involved in diverse functions. This study provides valuable markers, marker haplotypes and germplasm lines to increase levels of partial resistance to A. euteiches in pea breeding.

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.

PubMed

Andlauer, Till F M; Buck, Dorothea; Antony, Gisela; Bayas, Antonios; Bechmann, Lukas; Berthele, Achim; Chan, Andrew; Gasperi, Christiane; Gold, Ralf; Graetz, Christiane; Haas, Jürgen; Hecker, Michael; Infante-Duarte, Carmen; Knop, Matthias; Kümpfel, Tania; Limmroth, Volker; Linker, Ralf A; Loleit, Verena; Luessi, Felix; Meuth, Sven G; Mühlau, Mark; Nischwitz, Sandra; Paul, Friedemann; Pütz, Michael; Ruck, Tobias; Salmen, Anke; Stangel, Martin; Stellmann, Jan-Patrick; Stürner, Klarissa H; Tackenberg, Björn; Then Bergh, Florian; Tumani, Hayrettin; Warnke, Clemens; Weber, Frank; Wiendl, Heinz; Wildemann, Brigitte; Zettl, Uwe K; Ziemann, Ulf; Zipp, Frauke; Arloth, Janine; Weber, Peter; Radivojkov-Blagojevic, Milena; Scheinhardt, Markus O; Dankowski, Theresa; Bettecken, Thomas; Lichtner, Peter; Czamara, Darina; Carrillo-Roa, Tania; Binder, Elisabeth B; Berger, Klaus; Bertram, Lars; Franke, Andre; Gieger, Christian; Herms, Stefan; Homuth, Georg; Ising, Marcus; Jöckel, Karl-Heinz; Kacprowski, Tim; Kloiber, Stefan; Laudes, Matthias; Lieb, Wolfgang; Lill, Christina M; Lucae, Susanne; Meitinger, Thomas; Moebus, Susanne; Müller-Nurasyid, Martina; Nöthen, Markus M; Petersmann, Astrid; Rawal, Rajesh; Schminke, Ulf; Strauch, Konstantin; Völzke, Henry; Waldenberger, Melanie; Wellmann, Jürgen; Porcu, Eleonora; Mulas, Antonella; Pitzalis, Maristella; Sidore, Carlo; Zara, Ilenia; Cucca, Francesco; Zoledziewska, Magdalena; Ziegler, Andreas; Hemmer, Bernhard; Müller-Myhsok, Bertram

2016-06-01

We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis.

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation

PubMed Central

Andlauer, Till F. M.; Buck, Dorothea; Antony, Gisela; Bayas, Antonios; Bechmann, Lukas; Berthele, Achim; Chan, Andrew; Gasperi, Christiane; Gold, Ralf; Graetz, Christiane; Haas, Jürgen; Hecker, Michael; Infante-Duarte, Carmen; Knop, Matthias; Kümpfel, Tania; Limmroth, Volker; Linker, Ralf A.; Loleit, Verena; Luessi, Felix; Meuth, Sven G.; Mühlau, Mark; Nischwitz, Sandra; Paul, Friedemann; Pütz, Michael; Ruck, Tobias; Salmen, Anke; Stangel, Martin; Stellmann, Jan-Patrick; Stürner, Klarissa H.; Tackenberg, Björn; Then Bergh, Florian; Tumani, Hayrettin; Warnke, Clemens; Weber, Frank; Wiendl, Heinz; Wildemann, Brigitte; Zettl, Uwe K.; Ziemann, Ulf; Zipp, Frauke; Arloth, Janine; Weber, Peter; Radivojkov-Blagojevic, Milena; Scheinhardt, Markus O.; Dankowski, Theresa; Bettecken, Thomas; Lichtner, Peter; Czamara, Darina; Carrillo-Roa, Tania; Binder, Elisabeth B.; Berger, Klaus; Bertram, Lars; Franke, Andre; Gieger, Christian; Herms, Stefan; Homuth, Georg; Ising, Marcus; Jöckel, Karl-Heinz; Kacprowski, Tim; Kloiber, Stefan; Laudes, Matthias; Lieb, Wolfgang; Lill, Christina M.; Lucae, Susanne; Meitinger, Thomas; Moebus, Susanne; Müller-Nurasyid, Martina; Nöthen, Markus M.; Petersmann, Astrid; Rawal, Rajesh; Schminke, Ulf; Strauch, Konstantin; Völzke, Henry; Waldenberger, Melanie; Wellmann, Jürgen; Porcu, Eleonora; Mulas, Antonella; Pitzalis, Maristella; Sidore, Carlo; Zara, Ilenia; Cucca, Francesco; Zoledziewska, Magdalena; Ziegler, Andreas; Hemmer, Bernhard; Müller-Myhsok, Bertram

2016-01-01

We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis. PMID:27386562

Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation

PubMed Central

Christophersen, Ingrid E.; Rienstra, Michiel; Roselli, Carolina; Yin, Xiaoyan; Geelhoed, Bastiaan; Barnard, John; Lin, Honghuang; Arking, Dan E.; Smith, Albert V.; Albert, Christine M.; Chaffin, Mark; Tucker, Nathan R.; Li, Molong; Klarin, Derek; Bihlmeyer, Nathan A; Low, Siew-Kee; Weeke, Peter E.; Müller-Nurasyid, Martina; Smith, J. Gustav; Brody, Jennifer A.; Niemeijer, Maartje N.; Dörr, Marcus; Trompet, Stella; Huffman, Jennifer; Gustafsson, Stefan; Schurman, Claudia; Kleber, Marcus E.; Lyytikäinen, Leo-Pekka; Seppälä, Ilkka; Malik, Rainer; Horimoto, Andrea R. V. R.; Perez, Marco; Sinisalo, Juha; Aeschbacher, Stefanie; Thériault, Sébastien; Yao, Jie; Radmanesh, Farid; Weiss, Stefan; Teumer, Alexander; Choi, Seung Hoan; Weng, Lu-Chen; Clauss, Sebastian; Deo, Rajat; Rader, Daniel J.; Shah, Svati; Sun, Albert; Hopewell, Jemma C.; Debette, Stephanie; Chauhan, Ganesh; Yang, Qiong; Worrall, Bradford B.; Paré, Guillaume; Kamatani, Yoichiro; Hagemeijer, Yanick P.; Verweij, Niek; Siland, Joylene E.; Kubo, Michiaki; Smith, Jonathan D.; Van Wagoner, David R.; Bis, Joshua C.; Perz, Siegfried; Psaty, Bruce M.; Ridker, Paul M.; Magnani, Jared W.; Harris, Tamara B.; Launer, Lenore J.; Shoemaker, M. Benjamin; Padmanabhan, Sandosh; Haessler, Jeffrey; Bartz, Traci M.; Waldenberger, Melanie; Lichtner, Peter; Arendt, Marina; Krieger, Jose E.; Kähönen, Mika; Risch, Lorenz; Mansur, Alfredo J.; Peters, Annette; Smith, Blair H.; Lind, Lars; Scott, Stuart A.; Lu, Yingchang; Bottinger, Erwin B.; Hernesniemi, Jussi; Lindgren, Cecilia M.; Wong, Jorge; Huang, Jie; Eskola, Markku; Morris, Andrew P.; Ford, Ian; Reiner, Alex P.; Delgado, Graciela; Chen, Lin Y.; Chen, Yii-Der Ida; Sandhu, Roopinder K.; Li, Man; Boerwinkle, Eric; Eisele, Lewin; Lannfelt, Lars; Rost, Natalia; Anderson, Christopher D.; Taylor, Kent D.; Campbell, Archie; Magnusson, Patrik K.; Porteous, David; Hocking, Lynne J.; Vlachopoulou, Efthymia; Pedersen, Nancy L.; Nikus, Kjell; Orho-Melander, Marju; Hamsten, Anders; Heeringa, Jan; Denny, Joshua C.; Kriebel, Jennifer; Darbar, Dawood; Newton-Cheh, Christopher; Shaffer, Christian; Macfarlane, Peter W.; Heilmann, Stefanie; Almgren, Peter; Huang, Paul L.; Sotoodehnia, Nona; Soliman, Elsayed Z.; Uitterlinden, Andre G.; Hofman, Albert; Franco, Oscar H.; Völker, Uwe; Jöckel, Karl-Heinz; Sinner, Moritz F.; Lin, Henry J.; Guo, Xiuqing; Dichgans, Martin; Ingelsson, Erik; Kooperberg, Charles; Melander, Olle; Loos, Ruth J. F.; Laurikka, Jari; Conen, David; Rosand, Jonathan; van der Harst, Pim; Lokki, Marja-Liisa; Kathiresan, Sekar; Pereira, Alexandre; Jukema, J. Wouter; Hayward, Caroline; Rotter, Jerome I.; März, Winfried; Lehtimäki, Terho; Stricker, Bruno H.; Chung, Mina K.; Felix, Stephan B.; Gudnason, Vilmundur; Alonso, Alvaro; Roden, Dan M.; Kääb, Stefan; Chasman, Daniel I.; Heckbert, Susan R.; Benjamin, Emelia J.; Tanaka, Toshihiro; Lunetta, Kathryn L.; Lubitz, Steven A.; Ellinor, Patrick T.

2017-01-01

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death.1,2 Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups.3–7 To further define the genetic basis of atrial fibrillation, we performed large-scale, multi-racial meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 18,398 individuals with atrial fibrillation and 91,536 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,806 cases and 132,612 referents. We identified 12 novel genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate new potential targets for drug discovery.8 PMID:28416818

Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci.

PubMed

Tragante, Vinicius; Barnes, Michael R; Ganesh, Santhi K; Lanktree, Matthew B; Guo, Wei; Franceschini, Nora; Smith, Erin N; Johnson, Toby; Holmes, Michael V; Padmanabhan, Sandosh; Karczewski, Konrad J; Almoguera, Berta; Barnard, John; Baumert, Jens; Chang, Yen-Pei Christy; Elbers, Clara C; Farrall, Martin; Fischer, Mary E; Gaunt, Tom R; Gho, Johannes M I H; Gieger, Christian; Goel, Anuj; Gong, Yan; Isaacs, Aaron; Kleber, Marcus E; Mateo Leach, Irene; McDonough, Caitrin W; Meijs, Matthijs F L; Melander, Olle; Nelson, Christopher P; Nolte, Ilja M; Pankratz, Nathan; Price, Tom S; Shaffer, Jonathan; Shah, Sonia; Tomaszewski, Maciej; van der Most, Peter J; Van Iperen, Erik P A; Vonk, Judith M; Witkowska, Kate; Wong, Caroline O L; Zhang, Li; Beitelshees, Amber L; Berenson, Gerald S; Bhatt, Deepak L; Brown, Morris; Burt, Amber; Cooper-DeHoff, Rhonda M; Connell, John M; Cruickshanks, Karen J; Curtis, Sean P; Davey-Smith, George; Delles, Christian; Gansevoort, Ron T; Guo, Xiuqing; Haiqing, Shen; Hastie, Claire E; Hofker, Marten H; Hovingh, G Kees; Kim, Daniel S; Kirkland, Susan A; Klein, Barbara E; Klein, Ronald; Li, Yun R; Maiwald, Steffi; Newton-Cheh, Christopher; O'Brien, Eoin T; Onland-Moret, N Charlotte; Palmas, Walter; Parsa, Afshin; Penninx, Brenda W; Pettinger, Mary; Vasan, Ramachandran S; Ranchalis, Jane E; M Ridker, Paul; Rose, Lynda M; Sever, Peter; Shimbo, Daichi; Steele, Laura; Stolk, Ronald P; Thorand, Barbara; Trip, Mieke D; van Duijn, Cornelia M; Verschuren, W Monique; Wijmenga, Cisca; Wyatt, Sharon; Young, J Hunter; Zwinderman, Aeilko H; Bezzina, Connie R; Boerwinkle, Eric; Casas, Juan P; Caulfield, Mark J; Chakravarti, Aravinda; Chasman, Daniel I; Davidson, Karina W; Doevendans, Pieter A; Dominiczak, Anna F; FitzGerald, Garret A; Gums, John G; Fornage, Myriam; Hakonarson, Hakon; Halder, Indrani; Hillege, Hans L; Illig, Thomas; Jarvik, Gail P; Johnson, Julie A; Kastelein, John J P; Koenig, Wolfgang; Kumari, Meena; März, Winfried; Murray, Sarah S; O'Connell, Jeffery R; Oldehinkel, Albertine J; Pankow, James S; Rader, Daniel J; Redline, Susan; Reilly, Muredach P; Schadt, Eric E; Kottke-Marchant, Kandice; Snieder, Harold; Snyder, Michael; Stanton, Alice V; Tobin, Martin D; Uitterlinden, André G; van der Harst, Pim; van der Schouw, Yvonne T; Samani, Nilesh J; Watkins, Hugh; Johnson, Andrew D; Reiner, Alex P; Zhu, Xiaofeng; de Bakker, Paul I W; Levy, Daniel; Asselbergs, Folkert W; Munroe, Patricia B; Keating, Brendan J

2014-03-06

Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ~50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Deep Sequencing of Three Loci Implicated in Large-Scale Genome-Wide Association Study Smoking Meta-Analyses.

PubMed

Clark, Shaunna L; McClay, Joseph L; Adkins, Daniel E; Aberg, Karolina A; Kumar, Gaurav; Nerella, Sri; Xie, Linying; Collins, Ann L; Crowley, James J; Quakenbush, Corey R; Hillard, Christopher E; Gao, Guimin; Shabalin, Andrey A; Peterson, Roseann E; Copeland, William E; Silberg, Judy L; Maes, Hermine; Sullivan, Patrick F; Costello, Elizabeth J; van den Oord, Edwin J

2016-05-01

Genome-wide association study meta-analyses have robustly implicated three loci that affect susceptibility for smoking: CHRNA5\\CHRNA3\\CHRNB4, CHRNB3\\CHRNA6 and EGLN2\\CYP2A6. Functional follow-up studies of these loci are needed to provide insight into biological mechanisms. However, these efforts have been hampered by a lack of knowledge about the specific causal variant(s) involved. In this study, we prioritized variants in terms of the likelihood they account for the reported associations. We employed targeted capture of the CHRNA5\\CHRNA3\\CHRNB4, CHRNB3\\CHRNA6, and EGLN2\\CYP2A6 loci and flanking regions followed by next-generation deep sequencing (mean coverage 78×) to capture genomic variation in 363 individuals. We performed single locus tests to determine if any single variant accounts for the association, and examined if sets of (rare) variants that overlapped with biologically meaningful annotations account for the associations. In total, we investigated 963 variants, of which 71.1% were rare (minor allele frequency < 0.01), 6.02% were insertion/deletions, and 51.7% were catalogued in dbSNP141. The single variant results showed that no variant fully accounts for the association in any region. In the variant set results, CHRNB4 accounts for most of the signal with significant sets consisting of directly damaging variants. CHRNA6 explains most of the signal in the CHRNB3\\CHRNA6 locus with significant sets indicating a regulatory role for CHRNA6. Significant sets in CYP2A6 involved directly damaging variants while the significant variant sets suggested a regulatory role for EGLN2. We found that multiple variants implicating multiple processes explain the signal. Some variants can be prioritized for functional follow-up. © The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Deep Sequencing of Three Loci Implicated in Large-Scale Genome-Wide Association Study Smoking Meta-Analyses

PubMed Central

McClay, Joseph L.; Adkins, Daniel E.; Aberg, Karolina A.; Kumar, Gaurav; Nerella, Sri; Xie, Linying; Collins, Ann L.; Crowley, James J.; Quakenbush, Corey R.; Hillard, Christopher E.; Gao, Guimin; Shabalin, Andrey A.; Peterson, Roseann E.; Copeland, William E.; Silberg, Judy L.; Maes, Hermine; Sullivan, Patrick F.; Costello, Elizabeth J.; van den Oord, Edwin J.

2016-01-01

Abstract Introduction: Genome-wide association study meta-analyses have robustly implicated three loci that affect susceptibility for smoking: CHRNA5\\CHRNA3\\CHRNB4 , CHRNB3\\CHRNA6 and EGLN2\\CYP2A6 . Functional follow-up studies of these loci are needed to provide insight into biological mechanisms. However, these efforts have been hampered by a lack of knowledge about the specific causal variant(s) involved. In this study, we prioritized variants in terms of the likelihood they account for the reported associations. Methods: We employed targeted capture of the CHRNA5\\CHRNA3\\CHRNB4 , CHRNB3\\CHRNA6 , and EGLN2\\CYP2A6 loci and flanking regions followed by next-generation deep sequencing (mean coverage 78×) to capture genomic variation in 363 individuals. We performed single locus tests to determine if any single variant accounts for the association, and examined if sets of (rare) variants that overlapped with biologically meaningful annotations account for the associations. Results: In total, we investigated 963 variants, of which 71.1% were rare (minor allele frequency < 0.01), 6.02% were insertion/deletions, and 51.7% were catalogued in dbSNP141. The single variant results showed that no variant fully accounts for the association in any region. In the variant set results, CHRNB4 accounts for most of the signal with significant sets consisting of directly damaging variants. CHRNA6 explains most of the signal in the CHRNB3\\CHRNA6 locus with significant sets indicating a regulatory role for CHRNA6 . Significant sets in CYP2A6 involved directly damaging variants while the significant variant sets suggested a regulatory role for EGLN2 . Conclusions: We found that multiple variants implicating multiple processes explain the signal. Some variants can be prioritized for functional follow-up. PMID:26283763

New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk.

PubMed

Lu, Yingchang; Day, Felix R; Gustafsson, Stefan; Buchkovich, Martin L; Na, Jianbo; Bataille, Veronique; Cousminer, Diana L; Dastani, Zari; Drong, Alexander W; Esko, Tõnu; Evans, David M; Falchi, Mario; Feitosa, Mary F; Ferreira, Teresa; Hedman, Åsa K; Haring, Robin; Hysi, Pirro G; Iles, Mark M; Justice, Anne E; Kanoni, Stavroula; Lagou, Vasiliki; Li, Rui; Li, Xin; Locke, Adam; Lu, Chen; Mägi, Reedik; Perry, John R B; Pers, Tune H; Qi, Qibin; Sanna, Marianna; Schmidt, Ellen M; Scott, William R; Shungin, Dmitry; Teumer, Alexander; Vinkhuyzen, Anna A E; Walker, Ryan W; Westra, Harm-Jan; Zhang, Mingfeng; Zhang, Weihua; Zhao, Jing Hua; Zhu, Zhihong; Afzal, Uzma; Ahluwalia, Tarunveer Singh; Bakker, Stephan J L; Bellis, Claire; Bonnefond, Amélie; Borodulin, Katja; Buchman, Aron S; Cederholm, Tommy; Choh, Audrey C; Choi, Hyung Jin; Curran, Joanne E; de Groot, Lisette C P G M; De Jager, Philip L; Dhonukshe-Rutten, Rosalie A M; Enneman, Anke W; Eury, Elodie; Evans, Daniel S; Forsen, Tom; Friedrich, Nele; Fumeron, Frédéric; Garcia, Melissa E; Gärtner, Simone; Han, Bok-Ghee; Havulinna, Aki S; Hayward, Caroline; Hernandez, Dena; Hillege, Hans; Ittermann, Till; Kent, Jack W; Kolcic, Ivana; Laatikainen, Tiina; Lahti, Jari; Mateo Leach, Irene; Lee, Christine G; Lee, Jong-Young; Liu, Tian; Liu, Youfang; Lobbens, Stéphane; Loh, Marie; Lyytikäinen, Leo-Pekka; Medina-Gomez, Carolina; Michaëlsson, Karl; Nalls, Mike A; Nielson, Carrie M; Oozageer, Laticia; Pascoe, Laura; Paternoster, Lavinia; Polašek, Ozren; Ripatti, Samuli; Sarzynski, Mark A; Shin, Chan Soo; Narančić, Nina Smolej; Spira, Dominik; Srikanth, Priya; Steinhagen-Thiessen, Elisabeth; Sung, Yun Ju; Swart, Karin M A; Taittonen, Leena; Tanaka, Toshiko; Tikkanen, Emmi; van der Velde, Nathalie; van Schoor, Natasja M; Verweij, Niek; Wright, Alan F; Yu, Lei; Zmuda, Joseph M; Eklund, Niina; Forrester, Terrence; Grarup, Niels; Jackson, Anne U; Kristiansson, Kati; Kuulasmaa, Teemu; Kuusisto, Johanna; Lichtner, Peter; Luan, Jian'an; Mahajan, Anubha; Männistö, Satu; Palmer, Cameron D; Ried, Janina S; Scott, Robert A; Stancáková, Alena; Wagner, Peter J; Demirkan, Ayse; Döring, Angela; Gudnason, Vilmundur; Kiel, Douglas P; Kühnel, Brigitte; Mangino, Massimo; Mcknight, Barbara; Menni, Cristina; O'Connell, Jeffrey R; Oostra, Ben A; Shuldiner, Alan R; Song, Kijoung; Vandenput, Liesbeth; van Duijn, Cornelia M; Vollenweider, Peter; White, Charles C; Boehnke, Michael; Boettcher, Yvonne; Cooper, Richard S; Forouhi, Nita G; Gieger, Christian; Grallert, Harald; Hingorani, Aroon; Jørgensen, Torben; Jousilahti, Pekka; Kivimaki, Mika; Kumari, Meena; Laakso, Markku; Langenberg, Claudia; Linneberg, Allan; Luke, Amy; Mckenzie, Colin A; Palotie, Aarno; Pedersen, Oluf; Peters, Annette; Strauch, Konstantin; Tayo, Bamidele O; Wareham, Nicholas J; Bennett, David A; Bertram, Lars; Blangero, John; Blüher, Matthias; Bouchard, Claude; Campbell, Harry; Cho, Nam H; Cummings, Steven R; Czerwinski, Stefan A; Demuth, Ilja; Eckardt, Rahel; Eriksson, Johan G; Ferrucci, Luigi; Franco, Oscar H; Froguel, Philippe; Gansevoort, Ron T; Hansen, Torben; Harris, Tamara B; Hastie, Nicholas; Heliövaara, Markku; Hofman, Albert; Jordan, Joanne M; Jula, Antti; Kähönen, Mika; Kajantie, Eero; Knekt, Paul B; Koskinen, Seppo; Kovacs, Peter; Lehtimäki, Terho; Lind, Lars; Liu, Yongmei; Orwoll, Eric S; Osmond, Clive; Perola, Markus; Pérusse, Louis; Raitakari, Olli T; Rankinen, Tuomo; Rao, D C; Rice, Treva K; Rivadeneira, Fernando; Rudan, Igor; Salomaa, Veikko; Sørensen, Thorkild I A; Stumvoll, Michael; Tönjes, Anke; Towne, Bradford; Tranah, Gregory J; Tremblay, Angelo; Uitterlinden, André G; van der Harst, Pim; Vartiainen, Erkki; Viikari, Jorma S; Vitart, Veronique; Vohl, Marie-Claude; Völzke, Henry; Walker, Mark; Wallaschofski, Henri; Wild, Sarah; Wilson, James F; Yengo, Loïc; Bishop, D Timothy; Borecki, Ingrid B; Chambers, John C; Cupples, L Adrienne; Dehghan, Abbas; Deloukas, Panos; Fatemifar, Ghazaleh; Fox, Caroline; Furey, Terrence S; Franke, Lude; Han, Jiali; Hunter, David J; Karjalainen, Juha; Karpe, Fredrik; Kaplan, Robert C; Kooner, Jaspal S; McCarthy, Mark I; Murabito, Joanne M; Morris, Andrew P; Bishop, Julia A N; North, Kari E; Ohlsson, Claes; Ong, Ken K; Prokopenko, Inga; Richards, J Brent; Schadt, Eric E; Spector, Tim D; Widén, Elisabeth; Willer, Cristen J; Yang, Jian; Ingelsson, Erik; Mohlke, Karen L; Hirschhorn, Joel N; Pospisilik, John Andrew; Zillikens, M Carola; Lindgren, Cecilia; Kilpeläinen, Tuomas Oskari; Loos, Ruth J F

2016-02-01

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.

Exome Sequence Analysis of 14 Families With High Myopia.

PubMed

Kloss, Bethany A; Tompson, Stuart W; Whisenhunt, Kristina N; Quow, Krystina L; Huang, Samuel J; Pavelec, Derek M; Rosenberg, Thomas; Young, Terri L

2017-04-01

To identify causal gene mutations in 14 families with autosomal dominant (AD) high myopia using exome sequencing. Select individuals from 14 large Caucasian families with high myopia were exome sequenced. Gene variants were filtered to identify potential pathogenic changes. Sanger sequencing was used to confirm variants in original DNA, and to test for disease cosegregation in additional family members. Candidate genes and chromosomal loci previously associated with myopic refractive error and its endophenotypes were comprehensively screened. In 14 high myopia families, we identified 73 rare and 31 novel gene variants as candidates for pathogenicity. In seven of these families, two of the novel and eight of the rare variants were within known myopia loci. A total of 104 heterozygous nonsynonymous rare variants in 104 genes were identified in 10 out of 14 probands. Each variant cosegregated with affection status. No rare variants were identified in genes known to cause myopia or in genes closest to published genome-wide association study association signals for refractive error or its endophenotypes. Whole exome sequencing was performed to determine gene variants implicated in the pathogenesis of AD high myopia. This study provides new genes for consideration in the pathogenesis of high myopia, and may aid in the development of genetic profiling of those at greatest risk for attendant ocular morbidities of this disorder.

Variable promoter methylation contributes to differential expression of key genes in human placenta-derived venous and arterial endothelial cells.

PubMed

Joo, Jihoon E; Hiden, Ursula; Lassance, Luciana; Gordon, Lavinia; Martino, David J; Desoye, Gernot; Saffery, Richard

2013-07-15

The endothelial compartment, comprising arterial, venous and lymphatic cell types, is established prenatally in association with rapid phenotypic and functional changes. The molecular mechanisms underpinning this process in utero have yet to be fully elucidated. The aim of this study was to investigate the potential for DNA methylation to act as a driver of the specific gene expression profiles of arterial and venous endothelial cells. Placenta-derived venous and arterial endothelial cells were collected at birth prior to culturing. DNA methylation was measured at >450,000 CpG sites in parallel with expression measurements taken from 25,000 annotated genes. A consistent set of genomic loci was found to show coordinate differential methylation between the arterial and venous cell types. This included many loci previously not investigated in relation to endothelial function. An inverse relationship was observed between gene expression and promoter methylation levels for a limited subset of genes implicated in endothelial function, including NOS3, encoding endothelial Nitric Oxide Synthase. Endothelial cells derived from the placental vasculature at birth contain widespread methylation of key regulatory genes. These are candidates involved in the specification of different endothelial cell types and represent potential target genes for environmentally mediated epigenetic disruption in utero in association with cardiovascular disease risk later in life.

Convergence of genes and cellular pathways dysregulated in autism spectrum disorders.

PubMed

Pinto, Dalila; Delaby, Elsa; Merico, Daniele; Barbosa, Mafalda; Merikangas, Alison; Klei, Lambertus; Thiruvahindrapuram, Bhooma; Xu, Xiao; Ziman, Robert; Wang, Zhuozhi; Vorstman, Jacob A S; Thompson, Ann; Regan, Regina; Pilorge, Marion; Pellecchia, Giovanna; Pagnamenta, Alistair T; Oliveira, Bárbara; Marshall, Christian R; Magalhaes, Tiago R; Lowe, Jennifer K; Howe, Jennifer L; Griswold, Anthony J; Gilbert, John; Duketis, Eftichia; Dombroski, Beth A; De Jonge, Maretha V; Cuccaro, Michael; Crawford, Emily L; Correia, Catarina T; Conroy, Judith; Conceição, Inês C; Chiocchetti, Andreas G; Casey, Jillian P; Cai, Guiqing; Cabrol, Christelle; Bolshakova, Nadia; Bacchelli, Elena; Anney, Richard; Gallinger, Steven; Cotterchio, Michelle; Casey, Graham; Zwaigenbaum, Lonnie; Wittemeyer, Kerstin; Wing, Kirsty; Wallace, Simon; van Engeland, Herman; Tryfon, Ana; Thomson, Susanne; Soorya, Latha; Rogé, Bernadette; Roberts, Wendy; Poustka, Fritz; Mouga, Susana; Minshew, Nancy; McInnes, L Alison; McGrew, Susan G; Lord, Catherine; Leboyer, Marion; Le Couteur, Ann S; Kolevzon, Alexander; Jiménez González, Patricia; Jacob, Suma; Holt, Richard; Guter, Stephen; Green, Jonathan; Green, Andrew; Gillberg, Christopher; Fernandez, Bridget A; Duque, Frederico; Delorme, Richard; Dawson, Geraldine; Chaste, Pauline; Café, Cátia; Brennan, Sean; Bourgeron, Thomas; Bolton, Patrick F; Bölte, Sven; Bernier, Raphael; Baird, Gillian; Bailey, Anthony J; Anagnostou, Evdokia; Almeida, Joana; Wijsman, Ellen M; Vieland, Veronica J; Vicente, Astrid M; Schellenberg, Gerard D; Pericak-Vance, Margaret; Paterson, Andrew D; Parr, Jeremy R; Oliveira, Guiomar; Nurnberger, John I; Monaco, Anthony P; Maestrini, Elena; Klauck, Sabine M; Hakonarson, Hakon; Haines, Jonathan L; Geschwind, Daniel H; Freitag, Christine M; Folstein, Susan E; Ennis, Sean; Coon, Hilary; Battaglia, Agatino; Szatmari, Peter; Sutcliffe, James S; Hallmayer, Joachim; Gill, Michael; Cook, Edwin H; Buxbaum, Joseph D; Devlin, Bernie; Gallagher, Louise; Betancur, Catalina; Scherer, Stephen W

2014-05-01

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

A high-density consensus map of barley linking DArT markers to SSR, RFLP and STS loci and agricultural traits

PubMed Central

Wenzl, Peter; Li, Haobing; Carling, Jason; Zhou, Meixue; Raman, Harsh; Paul, Edie; Hearnden, Phillippa; Maier, Christina; Xia, Ling; Caig, Vanessa; Ovesná, Jaroslava; Cakir, Mehmet; Poulsen, David; Wang, Junping; Raman, Rosy; Smith, Kevin P; Muehlbauer, Gary J; Chalmers, Ken J; Kleinhofs, Andris; Huttner, Eric; Kilian, Andrzej

2006-01-01

Background Molecular marker technologies are undergoing a transition from largely serial assays measuring DNA fragment sizes to hybridization-based technologies with high multiplexing levels. Diversity Arrays Technology (DArT) is a hybridization-based technology that is increasingly being adopted by barley researchers. There is a need to integrate the information generated by DArT with previous data produced with gel-based marker technologies. The goal of this study was to build a high-density consensus linkage map from the combined datasets of ten populations, most of which were simultaneously typed with DArT and Simple Sequence Repeat (SSR), Restriction Enzyme Fragment Polymorphism (RFLP) and/or Sequence Tagged Site (STS) markers. Results The consensus map, built using a combination of JoinMap 3.0 software and several purpose-built perl scripts, comprised 2,935 loci (2,085 DArT, 850 other loci) and spanned 1,161 cM. It contained a total of 1,629 'bins' (unique loci), with an average inter-bin distance of 0.7 ± 1.0 cM (median = 0.3 cM). More than 98% of the map could be covered with a single DArT assay. The arrangement of loci was very similar to, and almost as optimal as, the arrangement of loci in component maps built for individual populations. The locus order of a synthetic map derived from merging the component maps without considering the segregation data was only slightly inferior. The distribution of loci along chromosomes indicated centromeric suppression of recombination in all chromosomes except 5H. DArT markers appeared to have a moderate tendency toward hypomethylated, gene-rich regions in distal chromosome areas. On the average, 14 ± 9 DArT loci were identified within 5 cM on either side of SSR, RFLP or STS loci previously identified as linked to agricultural traits. Conclusion Our barley consensus map provides a framework for transferring genetic information between different marker systems and for deploying DArT markers in molecular breeding schemes. The study also highlights the need for improved software for building consensus maps from high-density segregation data of multiple populations. PMID:16904008

Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease

PubMed Central

Lambert, Jean-Charles; Ibrahim-Verbaas, Carla A; Harold, Denise; Naj, Adam C; Sims, Rebecca; Bellenguez, Céline; Jun, Gyungah; DeStefano, Anita L; Bis, Joshua C; Beecham, Gary W; Grenier-Boley, Benjamin; Russo, Giancarlo; Thornton-Wells, Tricia A; Jones, Nicola; Smith, Albert V; Chouraki, Vincent; Thomas, Charlene; Ikram, M Arfan; Zelenika, Diana; Vardarajan, Badri N; Kamatani, Yoichiro; Lin, Chiao-Feng; Gerrish, Amy; Schmidt, Helena; Kunkle, Brian; Dunstan, Melanie L; Ruiz, Agustin; Bihoreau, Marie-Thérèse; Choi, Seung-Hoan; Reitz, Christiane; Pasquier, Florence; Hollingworth, Paul; Ramirez, Alfredo; Hanon, Olivier; Fitzpatrick, Annette L; Buxbaum, Joseph D; Campion, Dominique; Crane, Paul K; Baldwin, Clinton; Becker, Tim; Gudnason, Vilmundur; Cruchaga, Carlos; Craig, David; Amin, Najaf; Berr, Claudine; Lopez, Oscar L; De Jager, Philip L; Deramecourt, Vincent; Johnston, Janet A; Evans, Denis; Lovestone, Simon; Letenneur, Luc; Morón, Francisco J; Rubinsztein, David C; Eiriksdottir, Gudny; Sleegers, Kristel; Goate, Alison M; Fiévet, Nathalie; Huentelman, Matthew J; Gill, Michael; Brown, Kristelle; Kamboh, M Ilyas; Keller, Lina; Barberger-Gateau, Pascale; McGuinness, Bernadette; Larson, Eric B; Green, Robert; Myers, Amanda J; Dufouil, Carole; Todd, Stephen; Wallon, David; Love, Seth; Rogaeva, Ekaterina; Gallacher, John; St George-Hyslop, Peter; Clarimon, Jordi; Lleo, Alberto; Bayer, Anthony; Tsuang, Debby W; Yu, Lei; Tsolaki, Magda; Bossù, Paola; Spalletta, Gianfranco; Proitsi, Petroula; Collinge, John; Sorbi, Sandro; Sanchez-Garcia, Florentino; Fox, Nick C; Hardy, John; Deniz Naranjo, Maria Candida; Bosco, Paolo; Clarke, Robert; Brayne, Carol; Galimberti, Daniela; Mancuso, Michelangelo; Matthews, Fiona; Moebus, Susanne; Mecocci, Patrizia; Zompo, Maria Del; Maier, Wolfgang; Hampel, Harald; Pilotto, Alberto; Bullido, Maria; Panza, Francesco; Caffarra, Paolo; Nacmias, Benedetta; Gilbert, John R; Mayhaus, Manuel; Lannfelt, Lars; Hakonarson, Hakon; Pichler, Sabrina; Carrasquillo, Minerva M; Ingelsson, Martin; Beekly, Duane; Alvarez, Victoria; Zou, Fanggeng; Valladares, Otto; Younkin, Steven G; Coto, Eliecer; Hamilton-Nelson, Kara L; Gu, Wei; Razquin, Cristina; Pastor, Pau; Mateo, Ignacio; Owen, Michael J; Faber, Kelley M; Jonsson, Palmi V; Combarros, Onofre; O’Donovan, Michael C; Cantwell, Laura B; Soininen, Hilkka; Blacker, Deborah; Mead, Simon; Mosley, Thomas H; Bennett, David A; Harris, Tamara B; Fratiglioni, Laura; Holmes, Clive; de Bruijn, Renee F A G; Passmore, Peter; Montine, Thomas J; Bettens, Karolien; Rotter, Jerome I; Brice, Alexis; Morgan, Kevin; Foroud, Tatiana M; Kukull, Walter A; Hannequin, Didier; Powell, John F; Nalls, Michael A; Ritchie, Karen; Lunetta, Kathryn L; Kauwe, John S K; Boerwinkle, Eric; Riemenschneider, Matthias; Boada, Mercè; Hiltunen, Mikko; Martin, Eden R; Schmidt, Reinhold; Rujescu, Dan; Wang, Li-san; Dartigues, Jean-François; Mayeux, Richard; Tzourio, Christophe; Hofman, Albert; Nöthen, Markus M; Graff, Caroline; Psaty, Bruce M; Jones, Lesley; Haines, Jonathan L; Holmans, Peter A; Lathrop, Mark; Pericak-Vance, Margaret A; Launer, Lenore J; Farrer, Lindsay A; van Duijn, Cornelia M; Van Broeckhoven, Christine; Moskvina, Valentina; Seshadri, Sudha; Williams, Julie; Schellenberg, Gerard D; Amouyel, Philippe

2013-01-01

Eleven susceptibility loci for late-onset Alzheimer’s disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer’s disease cases and 37,154 controls. In stage 2,11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer’s disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10−8) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer’s disease. PMID:24162737

OzPythonPlex: An optimised forensic STR multiplex assay set for the Australasian carpet python (Morelia spilota).

PubMed

Ciavaglia, Sherryn; Linacre, Adrian

2018-05-01

Reptile species, and in particular snakes, are protected by national and international agreements yet are commonly handled illegally. To aid in the enforcement of such legislation, we report on the development of three 11-plex assays from the genome of the carpet python to type 24 loci of tetra-nucleotide and penta-nucleotide repeat motifs (pure, compound and complex included). The loci range in size between 70 and 550 bp. Seventeen of the loci are newly characterised with the inclusion of seven previously developed loci to facilitate cross-comparison with previous carpet python genotyping studies. Assays were optimised in accordance with human forensic profiling kits using one nanogram template DNA. Three loci are included in all three of the multiplex reactions as quality assurance markers, to ensure sample identity and genotyping accuracy is maintained across the three profiling assays. Allelic ladders have been developed for the three assays to ensure consistent and precise allele designation. A DNA reference database of allele frequencies is presented based on 249 samples collected from throughout the species native range. A small number of validation tests are conducted to demonstrate the utility of these multiplex assays. We suggest further appropriate validation tests that should be conducted prior to the application of the multiplex assays in criminal investigations involving carpet pythons. Copyright © 2018 Elsevier B.V. All rights reserved.

Bone Mineral Density Variation in Men is influenced by Sex-Specific and Non Sex-Specific Quantitative Trait Loci

PubMed Central

Peacock, Munro; Koller, Daniel L.; Lai, Dongbing; Hui, Siu; Foroud, Tatiana; Econs, Michael J.

2009-01-01

Introduction A major predictor of age-related osteoporotic fracture is peak areal bone mineral density (aBMD) which is a highly heritable trait. However, few linkage and association studies have been performed in men to identify the genes contributing to normal variation in aBMD. The aim of this study was to perform a genome wide scan in healthy men to identify quantitative trait loci (QTL) that were significantly linked to aBMD and to test whether any of these might be sex-specific. Methods aBMD at the spine and hip were measured in 515 pairs of brothers, aged 18-61 (405 white pairs, 110 black pairs). Linkage analysis in the brother sample was compared with results in a previously published sample of 774 sister pairs to identify sex-specific quantitative trait loci (QTL). Results A genome wide scan identified significant QTL (LOD>3.6) for aBMD on chromosomes 4q21 (hip), 7q34 (spine), 14q32 (hip), 19p13 (hip), 21q21 (hip), and 22q13 (hip). Analysis suggested that the QTL on chromosome 7q34, 14q32, and 21q21 were male-specific whereas the others were not sex-specific. Conclusions This study demonstrates that six QTL were significantly linked with aBMD in men. One was linked to spine and five were linked to hip. When compared to published data in women from the same geographical region, the QTL on chromosomes 7, 14 and 21 were male-specific. The occurrence of sex-specific genes in humans for aBMD has important implications for the pathogenesis and treatment of osteoporosis. PMID:19427925

Genome-wide association study of sex hormones, gonadotropins and sex hormone-binding protein in Chinese men.

PubMed

Chen, Zhuo; Tao, Sha; Gao, Yong; Zhang, Ju; Hu, Yanling; Mo, Linjian; Kim, Seong-Tae; Yang, Xiaobo; Tan, Aihua; Zhang, Haiying; Qin, Xue; Li, Li; Wu, Yongming; Zhang, Shijun; Zheng, S Lilly; Xu, Jianfeng; Mo, Zengnan; Sun, Jielin

2013-12-01

Sex hormones and gonadotropins exert a wide variety of effects in physiological and pathological processes. Accumulated evidence shows a strong heritable component of circulating concentrations of these hormones. Recently, several genome-wide association studies (GWASs) conducted in Caucasians have identified multiple loci that influence serum levels of sex hormones. However, the genetic determinants remain unknown in Chinese populations. In this study, we aimed to identify genetic variants associated with major sex hormones, gonadotropins, including testosterone, oestradiol, follicle-stimulating hormone (FSH), luteinising hormone (LH) and sex hormone binding globulin (SHBG) in a Chinese population. A two-stage GWAS was conducted in a total of 3495 healthy Chinese men (1999 subjects in the GWAS discovery stage and 1496 in the confirmation stage). We identified a novel genetic region at 15q21.2 (rs2414095 in CYP19A1), which was significantly associated with oestradiol and FSH in the Chinese population at a genome-wide significant level (p=6.54×10(-31) and 1.59×10(-16), respectively). Another single nucleotide polymorphism in CYP19A1 gene was significantly associated with oestradiol level (rs2445762, p=7.75×10(-28)). In addition, we confirmed the previous GWAS-identified locus at 17p13.1 for testosterone (rs2075230, p=1.13×10(-8)) and SHBG level (rs2075230, p=4.75×10(-19)) in the Chinese population. This study is the first GWAS investigation of genetic determinants of FSH and LH. The identification of novel susceptibility loci may provide more biological implications for the synthesis and metabolism of these hormones. More importantly, the confirmation of the genetic loci for testosterone and SHBG suggests common genetic components shared among different ethnicities.

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

PubMed Central

Sawcer, Stephen; Hellenthal, Garrett; Pirinen, Matti; Spencer, Chris C.A.; Patsopoulos, Nikolaos A.; Moutsianas, Loukas; Dilthey, Alexander; Su, Zhan; Freeman, Colin; Hunt, Sarah E.; Edkins, Sarah; Gray, Emma; Booth, David R.; Potter, Simon C.; Goris, An; Band, Gavin; Oturai, Annette Bang; Strange, Amy; Saarela, Janna; Bellenguez, Céline; Fontaine, Bertrand; Gillman, Matthew; Hemmer, Bernhard; Gwilliam, Rhian; Zipp, Frauke; Jayakumar, Alagurevathi; Martin, Roland; Leslie, Stephen; Hawkins, Stanley; Giannoulatou, Eleni; D’alfonso, Sandra; Blackburn, Hannah; Boneschi, Filippo Martinelli; Liddle, Jennifer; Harbo, Hanne F.; Perez, Marc L.; Spurkland, Anne; Waller, Matthew J; Mycko, Marcin P.; Ricketts, Michelle; Comabella, Manuel; Hammond, Naomi; Kockum, Ingrid; McCann, Owen T.; Ban, Maria; Whittaker, Pamela; Kemppinen, Anu; Weston, Paul; Hawkins, Clive; Widaa, Sara; Zajicek, John; Dronov, Serge; Robertson, Neil; Bumpstead, Suzannah J.; Barcellos, Lisa F.; Ravindrarajah, Rathi; Abraham, Roby; Alfredsson, Lars; Ardlie, Kristin; Aubin, Cristin; Baker, Amie; Baker, Katharine; Baranzini, Sergio E.; Bergamaschi, Laura; Bergamaschi, Roberto; Bernstein, Allan; Berthele, Achim; Boggild, Mike; Bradfield, Jonathan P.; Brassat, David; Broadley, Simon A.; Buck, Dorothea; Butzkueven, Helmut; Capra, Ruggero; Carroll, William M.; Cavalla, Paola; Celius, Elisabeth G.; Cepok, Sabine; Chiavacci, Rosetta; Clerget-Darpoux, Françoise; Clysters, Katleen; Comi, Giancarlo; Cossburn, Mark; Cournu-Rebeix, Isabelle; Cox, Mathew B.; Cozen, Wendy; Cree, Bruce A.C.; Cross, Anne H.; Cusi, Daniele; Daly, Mark J.; Davis, Emma; de Bakker, Paul I.W.; Debouverie, Marc; D’hooghe, Marie Beatrice; Dixon, Katherine; Dobosi, Rita; Dubois, Bénédicte; Ellinghaus, David; Elovaara, Irina; Esposito, Federica; Fontenille, Claire; Foote, Simon; Franke, Andre; Galimberti, Daniela; Ghezzi, Angelo; Glessner, Joseph; Gomez, Refujia; Gout, Olivier; Graham, Colin; Grant, Struan F.A.; Guerini, Franca Rosa; Hakonarson, Hakon; Hall, Per; Hamsten, Anders; Hartung, Hans-Peter; Heard, Rob N.; Heath, Simon; Hobart, Jeremy; Hoshi, Muna; Infante-Duarte, Carmen; Ingram, Gillian; Ingram, Wendy; Islam, Talat; Jagodic, Maja; Kabesch, Michael; Kermode, Allan G.; Kilpatrick, Trevor J.; Kim, Cecilia; Klopp, Norman; Koivisto, Keijo; Larsson, Malin; Lathrop, Mark; Lechner-Scott, Jeannette S.; Leone, Maurizio A.; Leppä, Virpi; Liljedahl, Ulrika; Bomfim, Izaura Lima; Lincoln, Robin R.; Link, Jenny; Liu, Jianjun; Lorentzen, Åslaug R.; Lupoli, Sara; Macciardi, Fabio; Mack, Thomas; Marriott, Mark; Martinelli, Vittorio; Mason, Deborah; McCauley, Jacob L.; Mentch, Frank; Mero, Inger-Lise; Mihalova, Tania; Montalban, Xavier; Mottershead, John; Myhr, Kjell-Morten; Naldi, Paola; Ollier, William; Page, Alison; Palotie, Aarno; Pelletier, Jean; Piccio, Laura; Pickersgill, Trevor; Piehl, Fredrik; Pobywajlo, Susan; Quach, Hong L.; Ramsay, Patricia P.; Reunanen, Mauri; Reynolds, Richard; Rioux, John D.; Rodegher, Mariaemma; Roesner, Sabine; Rubio, Justin P.; Rückert, Ina-Maria; Salvetti, Marco; Salvi, Erika; Santaniello, Adam; Schaefer, Catherine A.; Schreiber, Stefan; Schulze, Christian; Scott, Rodney J.; Sellebjerg, Finn; Selmaj, Krzysztof W.; Sexton, David; Shen, Ling; Simms-Acuna, Brigid; Skidmore, Sheila; Sleiman, Patrick M.A.; Smestad, Cathrine; Sørensen, Per Soelberg; Søndergaard, Helle Bach; Stankovich, Jim; Strange, Richard C.; Sulonen, Anna-Maija; Sundqvist, Emilie; Syvänen, Ann-Christine; Taddeo, Francesca; Taylor, Bruce; Blackwell, Jenefer M.; Tienari, Pentti; Bramon, Elvira; Tourbah, Ayman; Brown, Matthew A.; Tronczynska, Ewa; Casas, Juan P.; Tubridy, Niall; Corvin, Aiden; Vickery, Jane; Jankowski, Janusz; Villoslada, Pablo; Markus, Hugh S.; Wang, Kai; Mathew, Christopher G.; Wason, James; Palmer, Colin N.A.; Wichmann, H-Erich; Plomin, Robert; Willoughby, Ernest; Rautanen, Anna; Winkelmann, Juliane; Wittig, Michael; Trembath, Richard C.; Yaouanq, Jacqueline; Viswanathan, Ananth C.; Zhang, Haitao; Wood, Nicholas W.; Zuvich, Rebecca; Deloukas, Panos; Langford, Cordelia; Duncanson, Audrey; Oksenberg, Jorge R.; Pericak-Vance, Margaret A.; Haines, Jonathan L.; Olsson, Tomas; Hillert, Jan; Ivinson, Adrian J.; De Jager, Philip L.; Peltonen, Leena; Stewart, Graeme J.; Hafler, David A.; Hauser, Stephen L.; McVean, Gil; Donnelly, Peter; Compston, Alastair

2011-01-01

Multiple sclerosis (OMIM 126200) is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability.1 Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals;2,3 and systematic attempts to identify linkage in multiplex families have confirmed that variation within the Major Histocompatibility Complex (MHC) exerts the greatest individual effect on risk.4 Modestly powered Genome-Wide Association Studies (GWAS)5-10 have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects play a key role in disease susceptibility.11 Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the Class I region. Immunologically relevant genes are significantly over-represented amongst those mapping close to the identified loci and particularly implicate T helper cell differentiation in the pathogenesis of multiple sclerosis. PMID:21833088

Two whitebacked planthopper resistance genes in rice share the same loci with those for brown planthopper resistance.

PubMed

Tan, G X; Weng, Q M; Ren, X; Huang, Z; Zhu, L L; He, G C

2004-03-01

The whitebacked planthopper (WBPH), Sogatella furcifera, and brown planthopper (BPH) Nilaparvata lugens Stål are important sucking insects of rice (Oryza sativa L.) crops throughout the world. Rice 'B5', which has derived its resistance genes from the wild rice O. officinalis Wall ex Watt, is a line that is highly resistant to both WBPH and BPH. Previously, two resistance genes against BPH, Qbp1, and Qbp2 in 'B5' had been mapped onto chromosome 3 and chromosome 4, respectively. In this study, we employed a mapping population composed of 187 recombinant inbred lines (RILs), produced from a cross between 'B5' and susceptible variety 'Minghui63', to locate the WBPH and BPH resistance genes. A RFLP survey of the bulked extremes from the RIL population identified two genomic regions, one on chromosome 3 and the other on chromosome 4, likely containing the resistance genes to planthoppers. QTL analysis of the RILs further confirmed that two WBPH resistance genes were mapped on the same loci as Qbp1 and Qbp2, using a linkage map with 242 molecular markers distributed on 12 rice chromosomes. Of the two WBPH resistance genes, one designated Wbph7(t) was located within a 1.1-cM region between R1925 and G1318 on chromosome 3, the other designated Wbph8(t) was within a 0.3-cM region flanked by R288 and S11182 on chromosome 4. A two-way analysis of variance showed that two loci acted independently with each other in determining WBPH resistance. The results have significant implications in studying the interactions between sucking insects and plants and in breeding programs of resistance to rice planthoppers.

Development and preliminary validation of the Level of Care Index (LOCI) from the Personality Assessment Inventory (PAI) in a psychiatric sample.

PubMed

Sinclair, Samuel Justin; Slavin-Mulford, Jenelle; Antonius, Daniel; Stein, Michelle B; Siefert, Caleb J; Haggerty, Greg; Malone, Johanna C; O'Keefe, Sheila; Blais, Mark A

2013-06-01

Research over the last decade has been promising in terms of the incremental utility of psychometric tools in predicting important clinical outcomes, such as mental health service utilization and inpatient psychiatric hospitalization. The purpose of this study was to develop and validate a new Level of Care Index (LOCI) from the Personality Assessment Inventory (PAI). Logistic regression was initially used in a development sample (n = 253) of psychiatric patients to identify unique PAI indicators associated with inpatient (n = 75) as opposed to outpatient (n = 178) status. Five PAI variables were ultimately retained (Suicidal Ideation, Antisocial Personality-Stimulus Seeking, Paranoia-Persecution, Negative Impression Management, and Depression-Affective) and were then aggregated into a single LOCI and independently evaluated in a second validation sample (n = 252). Results indicated the LOCI effectively differentiated inpatients from outpatients after controlling for demographic variables and was significantly associated with both internalizing and externalizing risk factors for psychiatric admission (range of ds = 0.46 for history of arrests to 0.88 for history of suicidal ideation). The LOCI was additionally found to be meaningfully associated with measures of normal personality, performance-based tests of psychological functioning, and measures of neurocognitive (executive) functioning. The clinical implications of these findings and potential utility of the LOCI are discussed. PsycINFO Database Record (c) 2013 APA, all rights reserved.

Haplogroup-specific deviation from the stepwise mutation model at the microsatellite loci DYS388 and DYS392.

PubMed

Nebel, A; Filon, D; Hohoff, C; Faerman, M; Brinkmann, B; Oppenheim, A

2001-01-01

Deviation from the stepwise mutation model (SMM) at specific human microsatellite loci has implications for population genetic and forensic investigations. In the present study, data on six Y chromosome-specific microsatellites were pooled for 455 paternally unrelated males from six Middle Eastern populations. All chromosomes were assigned to three haplogroups defined by six binary polymorphisms. Two of the microsatellite loci tested, DYS388 and DYS392, displayed marked haplogroup-specific differences in their allele variability. A bimodal distribution of short and long alleles was observed for DYS388 in haplogroup 1 and for DYS392 in haplogroups 1 and 2. Further investigation showed that the short/long alleles segregated almost completely between genealogically distinct haplogroups defined by additional binary markers. Thus, these two loci have a discriminatory power similar to a binary polymorphism. DYS388 was characterised by an extremely low mutation rate in haplogroups 2 and 3, as was DYS392 in haplogroup 3. Sequence analysis of the repeat regions at the two loci revealed no irregularities, indicating that the triplet expansion in these loci is not controlled by sequence variation at the repeat level. A high frequency of long DYS388 alleles has, so far, been found only in populations originating in the Middle East, suggesting that this microsatellite is useful as a region-specific marker.

Identification of novel genetic risk loci in Maltese dogs with necrotizing meningoencephalitis and evidence of a shared genetic risk across toy dog breeds.

PubMed

Schrauwen, Isabelle; Barber, Renee M; Schatzberg, Scott J; Siniard, Ashley L; Corneveaux, Jason J; Porter, Brian F; Vernau, Karen M; Keesler, Rebekah I; Matiasek, Kaspar; Flegel, Thomas; Miller, Andrew D; Southard, Teresa; Mariani, Christopher L; Johnson, Gayle C; Huentelman, Matthew J

2014-01-01

Necrotizing meningoencephalitis (NME) affects toy and small breed dogs causing progressive, often fatal, inflammation and necrosis in the brain. Genetic risk loci for NME previously were identified in pug dogs, particularly associated with the dog leukocyte antigen (DLA) class II complex on chromosome 12, but have not been investigated in other susceptible breeds. We sought to evaluate Maltese and Chihuahua dogs, in addition to pug dogs, to identify novel or shared genetic risk factors for NME development. Genome-wide association testing of single nucleotide polymorphisms (SNPs) in Maltese dogs with NME identified 2 regions of genome-wide significance on chromosomes 4 (chr4:74522353T>A, p = 8.1×10-7) and 15 (chr15:53338796A>G, p = 1.5×10-7). Haplotype analysis and fine-mapping suggests that ILR7 and FBXW7, respectively, both important for regulation of immune system function, could be the underlying associated genes. Further evaluation of these regions and the previously identified DLA II locus across all three breeds, revealed an enrichment of nominal significant SNPs associated with chromosome 15 in pug dogs and DLA II in Maltese and Chihuahua dogs. Meta-analysis confirmed effect sizes the same direction in all three breeds for both the chromosome 15 and DLA II loci (p = 8.6×10-11 and p = 2.5×10-7, respectively). This suggests a shared genetic background exists between all breeds and confers susceptibility to NME, but effect sizes might be different among breeds. In conclusion, we identified the first genetic risk factors for NME development in the Maltese, chromosome 4 and chromosome 15, and provide evidence for a shared genetic risk between breeds associated with chromosome 15 and DLA II. Last, DLA II and IL7R both have been implicated in human inflammatory diseases of the central nervous system such as multiple sclerosis, suggesting that similar pharmacotherapeutic targets across species should be investigated.

Comprehensive annotated STR physical map of the human Y chromosome: Forensic implications.

PubMed

Hanson, Erin K; Ballantyne, Jack

2006-03-01

A plethora of Y-STR markers from diverse sources have been deposited in public databases and represent potential candidates for incorporation into the next generation of Y-STR multiplexes for forensic use. Here, based upon all of the Y-STR loci that have been deposited in the human genome database (>400), we have sequentially positioned each one along the Y chromosome using the most current human genome sequencing data (NCBI Build 35). The information derived from this work defines the number and relative position of all potentially forensically relevant Y-STR loci, their location within the physical linkage map of the Y chromosome and their relationship to structural genes. We conclude that there exists at present at least 417 separate Y-STR markers available for potential forensic use, although many of these will be found to be unsuitable for other reasons. However, from this data, we were able to identify 28 pairs of duplicated loci that were given separate DYS designations and four pairs of loci with overlapping flanking regions. Removing one locus from each set of duplicates reduced the number of potentially useful loci from 417 to 389. The derived information should be useful for workers who are designing novel Y-STR multiplexes to ensure the presence of non-synonymous loci and, if so desired, to avoid loci that lie within structural genes. It may also be useful for forensic casework practitioners (or molecular anthropologists) to aid in distinguishing between chromosomal rearrangements (such as duplications and deletions) and bona fide DNA admixtures or null alleles caused by primer binding site mutations. We illustrate the practical usefulness of the chromosomal positioning data in the design of eight multiplex systems using 94 Y-STR loci.

Establishing the role of rare coding variants in known Parkinson's disease risk loci.

PubMed

Jansen, Iris E; Gibbs, J Raphael; Nalls, Mike A; Price, T Ryan; Lubbe, Steven; van Rooij, Jeroen; Uitterlinden, André G; Kraaij, Robert; Williams, Nigel M; Brice, Alexis; Hardy, John; Wood, Nicholas W; Morris, Huw R; Gasser, Thomas; Singleton, Andrew B; Heutink, Peter; Sharma, Manu

2017-11-01

Many common genetic factors have been identified to contribute to Parkinson's disease (PD) susceptibility, improving our understanding of the related underlying biological mechanisms. The involvement of rarer variants in these loci has been poorly studied. Using International Parkinson's Disease Genomics Consortium data sets, we performed a comprehensive study to determine the impact of rare variants in 23 previously published genome-wide association studies (GWAS) loci in PD. We applied Prix fixe to select the putative causal genes underneath the GWAS peaks, which was based on underlying functional similarities. The Sequence Kernel Association Test was used to analyze the joint effect of rare, common, or both types of variants on PD susceptibility. All genes were tested simultaneously as a gene set and each gene individually. We observed a moderate association of common variants, confirming the involvement of the known PD risk loci within our genetic data sets. Focusing on rare variants, we identified additional association signals for LRRK2, STBD1, and SPATA19. Our study suggests an involvement of rare variants within several putatively causal genes underneath previously identified PD GWAS peaks. Copyright © 2017 Elsevier Inc. All rights reserved.

The Genetic and Molecular Organization of the Dopa Decarboxylase Gene Cluster of Drosophila Melanogaster

PubMed Central

Stathakis, D. G.; Pentz, E. S.; Freeman, M. E.; Kullman, J.; Hankins, G. R.; Pearlson, N. J.; Wright, TRF.

1995-01-01

We report the complete molecular organization of the Dopa decarboxylase gene cluster. Mutagenesis screens recovered 77 new Df(2L)TW130 recessive lethal mutations. These new alleles combined with 263 previously isolated mutations in the cluster to define 18 essential genes. In addition, seven new deficiencies were isolated and characterized. Deficiency mapping, restriction fragment length polymorphism (RFLP) analysis and P-element-mediated germline transformation experiments determined the gene order for all 18 loci. Genomic and cDNA restriction endonuclease mapping, Northern blot analysis and DNA sequencing provided information on exact gene location, mRNA size and transcriptional direction for most of these loci. In addition, this analysis identified two transcription units that had not previously been identified by extensive mutagenesis screening. Most of the loci are contained within two dense subclusters. We discuss the effectiveness of mutagens and strategies used in our screens, the variable mutability of loci within the genome of Drosophila melanogaster, the cytological and molecular organization of the Ddc gene cluster, the validity of the one band-one gene hypothesis and a possible purpose for the clustering of genes in the Ddc region. PMID:8647399

Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African Ancestry Anthropometry Genetics Consortium

PubMed Central

Lu, Yingchang; Justice, Anne E.; Mudgal, Poorva; Liu, Ching-Ti; Young, Kristin; Feitosa, Mary F.; Rand, Kristin; Dimitrov, Latchezar; Duan, Qing; Guo, Xiuqing; Lange, Leslie A.; Nalls, Michael A.; Okut, Hayrettin; Tayo, Bamidele O.; Vedantam, Sailaja; Bradfield, Jonathan P.; Chen, Guanjie; Chesi, Alessandra; Irvin, Marguerite R.; Padhukasahasram, Badri; Zheng, Wei; Allison, Matthew A.; Ambrosone, Christine B.; Bandera, Elisa V.; Berndt, Sonja I.; Blot, William J.; Bottinger, Erwin P.; Carpten, John; Chanock, Stephen J.; Chen, Yii-Der Ida; Conti, David V.; Cooper, Richard S.; Fornage, Myriam; Freedman, Barry I.; Garcia, Melissa; Goodman, Phyllis J.; Hsu, Yu-Han H.; Hu, Jennifer; Huff, Chad D.; Ingles, Sue A.; John, Esther M.; Kittles, Rick; Klein, Eric; Li, Jin; McKnight, Barbara; Nayak, Uma; Nemesure, Barbara; Olshan, Andrew; Salako, Babatunde; Sanderson, Maureen; Shao, Yaming; Siscovick, David S.; Stanford, Janet L.; Strom, Sara S.; Witte, John S.; Yao, Jie; Zhu, Xiaofeng; Ziegler, Regina G.; Zonderman, Alan B.; Ambs, Stefan; Cushman, Mary; Faul, Jessica D.; Hakonarson, Hakon; Levin, Albert M.; Nathanson, Katherine L.; Weir, David R.; Zhi, Degui; Arnett, Donna K.; Kardia, Sharon L. R.; Oloapde, Olufunmilayo I.; Rao, D. C.; Williams, L. Keoki; Becker, Diane M.; Borecki, Ingrid B.; Evans, Michele K.; Harris, Tamara B.; Hirschhorn, Joel N.; Psaty, Bruce M.; Wilson, James G.; Bowden, Donald W.; Cupples, L. Adrienne; Haiman, Christopher A.; Loos, Ruth J. F.; North, Kari E.

2017-01-01

Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5×10−8: seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained ≤ 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations. PMID:28430825

Genome-wide association studies in East Asians identify new loci for waist-hip ratio and waist circumference

PubMed Central

Wen, Wanqing; Kato, Norihiro; Hwang, Joo-Yeon; Guo, Xingyi; Tabara, Yasuharu; Li, Huaixing; Dorajoo, Rajkumar; Yang, Xiaobo; Tsai, Fuu-Jen; Li, Shengxu; Wu, Ying; Wu, Tangchun; Kim, Soriul; Guo, Xiuqing; Liang, Jun; Shungin, Dmitry; Adair, Linda S.; Akiyama, Koichi; Allison, Matthew; Cai, Qiuyin; Chang, Li-Ching; Chen, Chien-Hsiun; Chen, Yuan-Tsong; Cho, Yoon Shin; Choi, Bo Youl; Gao, Yutang; Go, Min Jin; Gu, Dongfeng; Han, Bok-Ghee; He, Meian; Hixson, James E.; Hu, Yanling; Huang, Tao; Isono, Masato; Jung, Keum Ji; Kang, Daehee; Kim, Young Jin; Kita, Yoshikuni; Lee, Juyoung; Lee, Nanette R.; Lee, Jeannette; Wang, Yiqin; Liu, Jian-Jun; Long, Jirong; Moon, Sanghoon; Nakamura, Yasuyuki; Nakatochi, Masahiro; Ohnaka, Keizo; Rao, Dabeeru; Shi, Jiajun; Sull, Jae Woong; Tan, Aihua; Ueshima, Hirotsugu; Wu, Chen; Xiang, Yong-Bing; Yamamoto, Ken; Yao, Jie; Ye, Xingwang; Yokota, Mitsuhiro; Zhang, Xiaomin; Zheng, Yan; Qi, Lu; Rotter, Jerome I.; Jee, Sun Ha; Lin, Dongxin; Mohlke, Karen L.; He, Jiang; Mo, Zengnan; Wu, Jer-Yuarn; Tai, E. Shyong; Lin, Xu; Miki, Tetsuro; Kim, Bong-Jo; Takeuchi, Fumihiko; Zheng, Wei; Shu, Xiao-Ou

2016-01-01

Sixty genetic loci associated with abdominal obesity, measured by waist circumference (WC) and waist-hip ratio (WHR), have been previously identified, primarily from studies conducted in European-ancestry populations. We conducted a meta-analysis of associations of abdominal obesity with approximately 2.5 million single nucleotide polymorphisms (SNPs) among 53,052 (for WC) and 48,312 (for WHR) individuals of Asian descent, and replicated 33 selected SNPs among 3,762 to 17,110 additional individuals. We identified four novel loci near the EFEMP1, ADAMTSL3 , CNPY2, and GNAS genes that were associated with WC after adjustment for body mass index (BMI); two loci near the NID2 and HLA-DRB5 genes associated with WHR after adjustment for BMI, and three loci near the CEP120, TSC22D2, and SLC22A2 genes associated with WC without adjustment for BMI. Functional enrichment analyses revealed enrichment of corticotropin-releasing hormone signaling, GNRH signaling, and/or CDK5 signaling pathways for those newly-identified loci. Our study provides additional insight on genetic contribution to abdominal obesity. PMID:26785701

Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants.

PubMed

Jin, Ying; Andersen, Genevieve; Yorgov, Daniel; Ferrara, Tracey M; Ben, Songtao; Brownson, Kelly M; Holland, Paulene J; Birlea, Stanca A; Siebert, Janet; Hartmann, Anke; Lienert, Anne; van Geel, Nanja; Lambert, Jo; Luiten, Rosalie M; Wolkerstorfer, Albert; Wietze van der Veen, J P; Bennett, Dorothy C; Taïeb, Alain; Ezzedine, Khaled; Kemp, E Helen; Gawkrodger, David J; Weetman, Anthony P; Kõks, Sulev; Prans, Ele; Kingo, Külli; Karelson, Maire; Wallace, Margaret R; McCormack, Wayne T; Overbeck, Andreas; Moretti, Silvia; Colucci, Roberta; Picardo, Mauro; Silverberg, Nanette B; Olsson, Mats; Valle, Yan; Korobko, Igor; Böhm, Markus; Lim, Henry W; Hamzavi, Iltefat; Zhou, Li; Mi, Qing-Sheng; Fain, Pamela R; Santorico, Stephanie A; Spritz, Richard A

2016-11-01

Vitiligo is an autoimmune disease in which depigmented skin results from the destruction of melanocytes, with epidemiological association with other autoimmune diseases. In previous linkage and genome-wide association studies (GWAS1 and GWAS2), we identified 27 vitiligo susceptibility loci in patients of European ancestry. We carried out a third GWAS (GWAS3) in European-ancestry subjects, with augmented GWAS1 and GWAS2 controls, genome-wide imputation, and meta-analysis of all three GWAS, followed by an independent replication. The combined analyses, with 4,680 cases and 39,586 controls, identified 23 new significantly associated loci and 7 suggestive loci. Most encode immune and apoptotic regulators, with some also associated with other autoimmune diseases, as well as several melanocyte regulators. Bioinformatic analyses indicate a predominance of causal regulatory variation, some of which corresponds to expression quantitative trait loci (eQTLs) at these loci. Together, the identified genes provide a framework for the genetic architecture and pathobiology of vitiligo, highlight relationships with other autoimmune diseases and melanoma, and offer potential targets for treatment.

Development of novel microsatellite markers for the Northern Goshawk (Accipiter gentilis) and their utility in cross-species amplification

USGS Publications Warehouse

Haughey, Christy; Sage, George K.; Degange, Gabriel; Sonsthagen, Sarah A.; Talbot, Sandra L.

2016-01-01

The Northern Goshawk (Accipiter gentilis) is a large forest raptor with a Holarctic distribution and, in some portions of its range, a species of conservation concern. To augment previously reported genetic markers, 13 novel polymorphic microsatellite markers were developed to establish individual identification and familial relationships, to assess levels of genetic diversity, and to identify diagnostic markers. Of the 22 loci tested, 13 were polymorphic, seven were monomorphic, and two failed to amplify. This suite of microsatellite loci yielded a combined probability of parental exclusion of 98%; a single individual sampled from a North American population can be reliably identified using a combination of seven of the 13 polymorphic loci. Cross-species screening in Cooper's Hawks (A. cooperii) and Sharp-shinned Hawks (A. striatus) of the 20 loci that successfully amplified in Northern Goshawks identified 13 loci as polymorphic in each species. Six of these loci (Age1303, Age1308, Age1309, Age1312, and Age1314) appeared to be useful in distinguishing between Accipiter species. These markers will be useful to researchers investigating populations of North American accipiters.

Internal genetic structure and outcrossing rate in a natural population of Araucaria angustifolia (Bert.) O. Kuntze.

PubMed

Mantovani, Adelar; Morellato, L Patrícia C; Dos Reis, Maurício S

2006-01-01

The internal genetic structure and outcrossing rate of a population of Araucaria angustifolia (Bert.) O. Kuntze were investigated using 16 allozyme loci. Estimates of the mean number of alleles per loci (1.6), percentage of polymorphic loci (43.8%), and expected genetic diversity (0.170) were similar to those obtained for other gymnosperms. The analysis of spatial autocorrelation demonstrated the presence of internal structure in the first distance classes (up to 70 m), suggesting the presence of family structure. The outcrossing rate was high (0.956), as expected for a dioecious species. However, it was different from unity, indicating outcrossings between related individuals and corroborating the presence of internal genetic structure. The results of this study have implications for the methodologies used in conservation collections and for the use or analysis of this forest species.

Genome-Wide Association of Body Fat Distribution in African Ancestry Populations Suggests New Loci

PubMed Central

Lange, Leslie; Demerath, Ellen W.; Palmas, Walter; Wojczynski, Mary K.; Ellis, Jaclyn C.; Vitolins, Mara Z.; Liu, Simin; Papanicolaou, George J.; Irvin, Marguerite R.; Xue, Luting; Griffin, Paula J.; Nalls, Michael A.; Adeyemo, Adebowale; Liu, Jiankang; Li, Guo; Ruiz-Narvaez, Edward A.; Chen, Wei-Min; Chen, Fang; Henderson, Brian E.; Millikan, Robert C.; Ambrosone, Christine B.; Strom, Sara S.; Guo, Xiuqing; Andrews, Jeanette S.; Sun, Yan V.; Mosley, Thomas H.; Yanek, Lisa R.; Shriner, Daniel; Haritunians, Talin; Rotter, Jerome I.; Speliotes, Elizabeth K.; Smith, Megan; Rosenberg, Lynn; Mychaleckyj, Josyf; Nayak, Uma; Spruill, Ida; Garvey, W. Timothy; Pettaway, Curtis; Nyante, Sarah; Bandera, Elisa V.; Britton, Angela F.; Zonderman, Alan B.; Rasmussen-Torvik, Laura J.; Chen, Yii-Der Ida; Ding, Jingzhong; Lohman, Kurt; Kritchevsky, Stephen B.; Zhao, Wei; Peyser, Patricia A.; Kardia, Sharon L. R.; Kabagambe, Edmond; Broeckel, Ulrich; Chen, Guanjie; Zhou, Jie; Wassertheil-Smoller, Sylvia; Neuhouser, Marian L.; Rampersaud, Evadnie; Psaty, Bruce; Kooperberg, Charles; Manson, JoAnn E.; Kuller, Lewis H.; Ochs-Balcom, Heather M.; Johnson, Karen C.; Sucheston, Lara; Ordovas, Jose M.; Palmer, Julie R.; Haiman, Christopher A.; McKnight, Barbara; Howard, Barbara V.; Becker, Diane M.; Bielak, Lawrence F.; Liu, Yongmei; Allison, Matthew A.; Grant, Struan F. A.; Burke, Gregory L.; Patel, Sanjay R.; Schreiner, Pamela J.; Borecki, Ingrid B.; Evans, Michele K.; Taylor, Herman; Sale, Michele M.; Howard, Virginia; Carlson, Christopher S.; Rotimi, Charles N.; Cushman, Mary; Harris, Tamara B.; Reiner, Alexander P.; Cupples, L. Adrienne; North, Kari E.; Fox, Caroline S.

2013-01-01

Central obesity, measured by waist circumference (WC) or waist-hip ratio (WHR), is a marker of body fat distribution. Although obesity disproportionately affects minority populations, few studies have conducted genome-wide association study (GWAS) of fat distribution among those of predominantly African ancestry (AA). We performed GWAS of WC and WHR, adjusted and unadjusted for BMI, in up to 33,591 and 27,350 AA individuals, respectively. We identified loci associated with fat distribution in AA individuals using meta-analyses of GWA results for WC and WHR (stage 1). Overall, 25 SNPs with single genomic control (GC)-corrected p-values<5.0×10−6 were followed-up (stage 2) in AA with WC and with WHR. Additionally, we interrogated genomic regions of previously identified European ancestry (EA) WHR loci among AA. In joint analysis of association results including both Stage 1 and 2 cohorts, 2 SNPs demonstrated association, rs2075064 at LHX2, p = 2.24×10−8 for WC-adjusted-for-BMI, and rs6931262 at RREB1, p = 2.48×10−8 for WHR-adjusted-for-BMI. However, neither signal was genome-wide significant after double GC-correction (LHX2: p = 6.5×10−8; RREB1: p = 5.7×10−8). Six of fourteen previously reported loci for waist in EA populations were significant (p<0.05 divided by the number of independent SNPs within the region) in AA studied here (TBX15-WARS2, GRB14, ADAMTS9, LY86, RSPO3, ITPR2-SSPN). Further, we observed associations with metabolic traits: rs13389219 at GRB14 associated with HDL-cholesterol, triglycerides, and fasting insulin, and rs13060013 at ADAMTS9 with HDL-cholesterol and fasting insulin. Finally, we observed nominal evidence for sexual dimorphism, with stronger results in AA women at the GRB14 locus (p for interaction = 0.02). In conclusion, we identified two suggestive loci associated with fat distribution in AA populations in addition to confirming 6 loci previously identified in populations of EA. These findings reinforce the concept that there are fat distribution loci that are independent of generalized adiposity. PMID:23966867

Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behçet's disease susceptibility.

PubMed

Takeuchi, Masaki; Mizuki, Nobuhisa; Meguro, Akira; Ombrello, Michael J; Kirino, Yohei; Satorius, Colleen; Le, Julie; Blake, Mary; Erer, Burak; Kawagoe, Tatsukata; Ustek, Duran; Tugal-Tutkun, Ilknur; Seyahi, Emire; Ozyazgan, Yilmaz; Sousa, Inês; Davatchi, Fereydoun; Francisco, Vânia; Shahram, Farhad; Abdollahi, Bahar Sadeghi; Nadji, Abdolhadi; Shafiee, Niloofar Mojarad; Ghaderibarmi, Fahmida; Ohno, Shigeaki; Ueda, Atsuhisa; Ishigatsubo, Yoshiaki; Gadina, Massimo; Oliveira, Sofia A; Gül, Ahmet; Kastner, Daniel L; Remmers, Elaine F

2017-03-01

We analyzed 1,900 Turkish Behçet's disease cases and 1,779 controls genotyped with the Immunochip. The most significantly associated SNP was rs1050502, a tag SNP for HLA-B*51. In the Turkish discovery set, we identified three new risk loci, IL1A-IL1B, IRF8, and CEBPB-PTPN1, with genome-wide significance (P < 5 × 10 -8 ) by direct genotyping and ADO-EGR2 by imputation. We replicated the ADO-EGR2, IRF8, and CEBPB-PTPN1 loci by genotyping 969 Iranian cases and 826 controls. Imputed data in 608 Japanese cases and 737 controls further replicated ADO-EGR2 and IRF8, and meta-analysis additionally identified RIPK2 and LACC1. The disease-associated allele of rs4402765, the lead marker at IL1A-IL1B, was associated with both decreased IL-1α and increased IL-1β production. ABO non-secretor genotypes for two ancestry-specific FUT2 SNPs showed strong disease association (P = 5.89 × 10 -15 ). Our findings extend the list of susceptibility genes shared with Crohn's disease and leprosy and implicate mucosal factors and the innate immune response to microbial exposure in Behçet's disease susceptibility.

The allele combinations of three loci based on, liver, stomach cancers, hematencephalon, COPD and normal population: A preliminary study.

PubMed

Gai, Liping; Liu, Hui; Cui, Jing-Hui; Yu, Weijian; Ding, Xiao-Dong

2017-03-20

The purpose of this study was to examine the specific allele combinations of three loci connected with the liver cancers, stomach cancers, hematencephalon and patients with chronic obstructive pulmonary disease (COPD) and to explore the feasibility of the research methods. We explored different mathematical methods for statistical analyses to assess the association between the genotype and phenotype. At the same time we still analyses the statistical results of allele combinations of three loci by difference value method and ratio method. All the DNA blood samples were collected from patients with 50 liver cancers, 75 stomach cancers, 50 hematencephalon, 72 COPD and 200 normal populations. All the samples were from Chinese. Alleles from short tandem repeat (STR) loci were determined using the STR Profiler plus PCR amplification kit (15 STR loci). Previous research was based on combinations of single-locus alleles, and combinations of cross-loci (two loci) alleles. Allele combinations of three loci were obtained by computer counting and stronger genetic signal was obtained. The methods of allele combinations of three loci can help to identify the statistically significant differences of allele combinations between liver cancers, stomach cancers, patients with hematencephalon, COPD and the normal population. The probability of illness followed different rules and had apparent specificity. This method can be extended to other diseases and provide reference for early clinical diagnosis. Copyright © 2016. Published by Elsevier B.V.

Epistatic Effects Contribute to Variation in BMD in Fischer 344 × Lewis F2 Rats

PubMed Central

Koller, Daniel L; Liu, Lixiang; Alam, Imranul; Sun, Qiwei; Econs, Michael J; Foroud, Tatiana; Turner, Charles H

2008-01-01

To further delineate the factors underlying the complex genetic architecture of BMD in the rat model, a genome screen for epistatic interactions was conducted. Several significant interactions were identified, involving both previously identified and novel QTLs. Introduction The variation in several of the risk factors for osteoporotic fracture, including BMD, has been shown to be caused largely by genetic differences. However, the genetic architecture of BMD is complex in both humans and in model organisms. We have previously reported quantitative trait locus (QTL) results for BMD from a genome screen of 595 female F2 progeny of Fischer 344 and Lewis rats. These progeny also provide an excellent opportunity to search for epistatic effects, or interaction between genetic loci, that contribute to fracture risk. Materials and Methods Microsatellite marker data from a 20-cM genome screen was analyzed along with weight-adjusted BMD (DXA and pQCT) phenotypic data using the R/qtl software package. Genotype and phenotype data were permuted to determine a genome-wide significance threshold for the epistasis or interaction LOD score corresponding to an α level of 0.01. Results and Conclusions Novel loci on chromosomes 12 and 15 showed a strong epistatic effect on total BMD at the femoral midshaft by pQCT (LOD = 5.4). A previously reported QTL on chromosome 7 was found to interact with a novel locus on chromosome 20 to affect whole lumbar BMD by pQCT (LOD = 6.2). These results provide new information regarding the mode of action of previously identified rat QTLs, as well as identifying novel loci that act in combination with known QTLs or with other novel loci to contribute to the risk factors for osteoporotic fracture. PMID:17907919

Epistatic effects contribute to variation in BMD in Fischer 344 x Lewis F2 rats.

PubMed

Koller, Daniel L; Liu, Lixiang; Alam, Imranul; Sun, Qiwei; Econs, Michael J; Foroud, Tatiana; Turner, Charles H

2008-01-01

To further delineate the factors underlying the complex genetic architecture of BMD in the rat model, a genome screen for epistatic interactions was conducted. Several significant interactions were identified, involving both previously identified and novel QTLs. The variation in several of the risk factors for osteoporotic fracture, including BMD, has been shown to be caused largely by genetic differences. However, the genetic architecture of BMD is complex in both humans and in model organisms. We have previously reported quantitative trait locus (QTL) results for BMD from a genome screen of 595 female F(2) progeny of Fischer 344 and Lewis rats. These progeny also provide an excellent opportunity to search for epistatic effects, or interaction between genetic loci, that contribute to fracture risk. Microsatellite marker data from a 20-cM genome screen was analyzed along with weight-adjusted BMD (DXA and pQCT) phenotypic data using the R/qtl software package. Genotype and phenotype data were permuted to determine a genome-wide significance threshold for the epistasis or interaction LOD score corresponding to an alpha level of 0.01. Novel loci on chromosomes 12 and 15 showed a strong epistatic effect on total BMD at the femoral midshaft by pQCT (LOD = 5.4). A previously reported QTL on chromosome 7 was found to interact with a novel locus on chromosome 20 to affect whole lumbar BMD by pQCT (LOD = 6.2). These results provide new information regarding the mode of action of previously identified rat QTLs, as well as identifying novel loci that act in combination with known QTLs or with other novel loci to contribute to the risk factors for osteoporotic fracture.

A Genome Wide Association Study Identifies Common Variants Associated with Lipid Levels in the Chinese Population

PubMed Central

Wu, Chen; Yang, Handong; Yu, Dianke; Yang, Xiaobo; Zhang, Xiaomin; Wang, Yiqin; Sun, Jielin; Gao, Yong; Tan, Aihua; He, Yunfeng; Zhang, Haiying; Qin, Xue; Zhu, Jingwen; Li, Huaixing; Lin, Xu; Zhu, Jiang; Min, Xinwen; Lang, Mingjian; Li, Dongfeng; Zhai, Kan; Chang, Jiang; Tan, Wen; Yuan, Jing; Chen, Weihong; Wang, Youjie; Wei, Sheng; Miao, Xiaoping; Wang, Feng; Fang, Weimin; Liang, Yuan; Deng, Qifei; Dai, Xiayun; Lin, Dafeng; Huang, Suli; Guo, Huan; Lilly Zheng, S.; Xu, Jianfeng; Lin, Dongxin; Hu, Frank B.; Wu, Tangchun

2013-01-01

Plasma lipid levels are important risk factors for cardiovascular disease and are influenced by genetic and environmental factors. Recent genome wide association studies (GWAS) have identified several lipid-associated loci, but these loci have been identified primarily in European populations. In order to identify genetic markers for lipid levels in a Chinese population and analyze the heterogeneity between Europeans and Asians, especially Chinese, we performed a meta-analysis of two genome wide association studies on four common lipid traits including total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL) and high-density lipoprotein cholesterol (HDL) in a Han Chinese population totaling 3,451 healthy subjects. Replication was performed in an additional 8,830 subjects of Han Chinese ethnicity. We replicated eight loci associated with lipid levels previously reported in a European population. The loci genome wide significantly associated with TC were near DOCK7, HMGCR and ABO; those genome wide significantly associated with TG were near APOA1/C3/A4/A5 and LPL; those genome wide significantly associated with LDL were near HMGCR, ABO and TOMM40; and those genome wide significantly associated with HDL were near LPL, LIPC and CETP. In addition, an additive genotype score of eight SNPs representing the eight loci that were found to be associated with lipid levels was associated with higher TC, TG and LDL levels (P = 5.52×10-16, 1.38×10-6 and 5.59×10-9, respectively). These findings suggest the cumulative effects of multiple genetic loci on plasma lipid levels. Comparisons with previous GWAS of lipids highlight heterogeneity in allele frequency and in effect size for some loci between Chinese and European populations. The results from our GWAS provided comprehensive and convincing evidence of the genetic determinants of plasma lipid levels in a Chinese population. PMID:24386095

Generalization and fine mapping of European ancestry-based central adiposity variants in African ancestry populations

PubMed Central

Yoneyama, Sachiko; Yao, Jie; Guo, Xiuqing; Fernandez-Rhodes, Lindsay; Lim, Unhee; Boston, Jonathan; Buzková, Petra; Carlson, Christopher S.; Cheng, Iona; Cochran, Barbara; Cooper, Richard; Ehret, Georg; Fornage, Myriam; Gong, Jian; Gross, Myron; Gu, C. Charles; Haessler, Jeff; Haiman, Christopher A.; Henderson, Brian; Hindorff, Lucia A.; Houston, Denise; Irvin, Marguerite R.; Jackson, Rebecca; Kuller, Lew; Leppert, Mark; Lewis, Cora E.; Li, Rongling; Le Marchand, Loic; Matise, Tara C.; Nguyen, Khanh-Dung H.; Chakravarti, Aravinda; Pankow, James S.; Pankratz, Nathan; Pooler, Loreall; Ritchie, Marylyn D.; Bien, Stephanie A.; Wassel, Christina L.; Chen, Yii-Der I.; Taylor, Kent D.; Allison, Matthew; Rotter, Jerome I.; Schreiner, Pamela J.; Schumacher, Fredrick; Wilkens, Lynne; Boerwinkle, Eric; Kooperberg, Charles; Peters, Ulrike; Buyske, Steven; Graff, Mariaelisa; North, Kari E.

2016-01-01

Background/Objectives Central adiposity measures such as waist circumference (WC) and waist-to-hip ratio (WHR) are associated with cardiometabolic disorders independently of BMI and are gaining clinically utility. Several studies report genetic variants associated with central adiposity, but most utilize only European ancestry populations. Understanding whether the genetic associations discovered among mainly European descendants are shared with African ancestry populations will help elucidate the biological underpinnings of abdominal fat deposition. Subjects/Methods To identify the underlying functional genetic determinants of body fat distribution, we conducted an array-wide association meta-analysis among persons of African ancestry across seven studies/consortia participating in the Population Architecture using Genomics and Epidemiology (PAGE) consortium. We used the Metabochip array, designed for fine mapping cardiovascular associated loci, to explore novel array-wide associations with WC and WHR among 15 945 African descendants using all and sex-stratified groups. We further interrogated 17 known WHR regions for African ancestry-specific variants. Results Of the 17 WHR loci, eight SNPs located in four loci were replicated in the sex-combined or sex-stratified meta-analyses. Two of these eight independently associated with WHR after conditioning on the known variant in European descendants (rs12096179 in TBX15-WARS2 and rs2059092 in ADAMTS9). In the fine mapping assessment, the putative functional region was reduced across all four loci but to varying degrees (average 40% drop in number of putative SNPs and 20% drop in genomic region). Similar to previous studies, the significant SNPs in the female stratified analysis were stronger than the significant SNPs from the sex-combined analysis. No novel associations were detected in the array-wide analyses. Conclusions Of 17 previously identified loci, four loci replicated in the African ancestry populations of this study. Utilizing different linkage disequilibrium patterns observed between European and African ancestries, we narrowed the suggestive region containing causative variants for all four loci. PMID:27867202

Standing Genetic Variation in Contingency Loci Drives the Rapid Adaptation of Campylobacter jejuni to a Novel Host

PubMed Central

Jerome, John P.; Bell, Julia A.; Plovanich-Jones, Anne E.; Barrick, Jeffrey E.; Brown, C. Titus; Mansfield, Linda S.

2011-01-01

The genome of the food-borne pathogen Campylobacter jejuni contains multiple highly mutable sites, or contingency loci. It has been suggested that standing variation at these loci is a mechanism for rapid adaptation to a novel environment, but this phenomenon has not been shown experimentally. In previous work we showed that the virulence of C. jejuni NCTC11168 increased after serial passage through a C57BL/6 IL-10-/- mouse model of campylobacteriosis. Here we sought to determine the genetic basis of this adaptation during passage. Re-sequencing of the 1.64Mb genome to 200-500X coverage allowed us to define variation in 23 contingency loci to an unprecedented depth both before and after in vivo adaptation. Mutations in the mouse-adapted C. jejuni were largely restricted to the homopolymeric tracts of thirteen contingency loci. These changes cause significant alterations in open reading frames of genes in surface structure biosynthesis loci and in genes with only putative functions. Several loci with open reading frame changes also had altered transcript abundance. The increase in specific phases of contingency loci during in vivo passage of C. jejuni, coupled with the observed virulence increase and the lack of other types of genetic changes, is the first experimental evidence that these variable regions play a significant role in C. jejuni adaptation and virulence in a novel host. PMID:21283682

A matter of phylogenetic scale: Distinguishing incomplete lineage sorting from lateral gene transfer as the cause of gene tree discord in recent versus deep diversification histories.

PubMed

Knowles, L Lacey; Huang, Huateng; Sukumaran, Jeet; Smith, Stephen A

2018-03-01

Discordant gene trees are commonly encountered when sequences from thousands of loci are applied to estimate phylogenetic relationships. Several processes contribute to this discord. Yet, we have no methods that jointly model different sources of conflict when estimating phylogenies. An alternative to analyzing entire genomes or all the sequenced loci is to identify a subset of loci for phylogenetic analysis. If we can identify data partitions that are most likely to reflect descent from a common ancestor (i.e., discordant loci that indeed reflect incomplete lineage sorting [ILS], as opposed to some other process, such as lateral gene transfer [LGT]), we can analyze this subset using powerful coalescent-based species-tree approaches. Test data sets were simulated where discord among loci could arise from ILS and LGT. Data sets where analyzed using the newly developed program CLASSIPHY (Huang et al., ) to assess whether our ability to distinguish the cause of discord among loci varied when ILS and LGT occurred in the recent versus deep past and whether the accuracy of these inferences were affected by the mutational process. We show that accuracy of probabilistic classification of individual loci by the cause of discord differed when ILS and LGT events occurred more recently compared with the distant past and that the signal-to-noise ratio arising from the mutational process contributes to difficulties in inferring LGT data partitions. We discuss our findings in terms of the promise and limitations of identifying subsets of loci for species-tree inference that will not violate the underlying coalescent model (i.e., data partitions in which ILS, and not LGT, contributes to discord). We also discuss the empirical implications of our work given the many recalcitrant nodes in the tree of life (e.g., origins of angiosperms, amniotes, or Neoaves), and recent arguments for concatenating loci. © 2018 Botanical Society of America.

Panx3 links body mass index and tumorigenesis in a genetically heterogeneous mouse model of carcinogen-induced cancer. | Office of Cancer Genomics

Cancer.gov

Body mass index (BMI) has been implicated as a primary factor influencing cancer development. However, understanding the relationship between these two complex traits has been confounded by both environmental and genetic heterogeneity. Analysis of QTL linked to tumorigenesis and BMI identified several loci associated with both phenotypes. Exploring these loci in greater detail revealed a novel relationship between the Pannexin 3 gene (Panx3) and both BMI and tumorigenesis. Panx3 is positively associated with BMI and is strongly tied to a lipid metabolism gene expression network.

A multi-ethnic genome-wide association study identifies novel loci for non-syndromic cleft lip with or without cleft palate on 2p24.2, 17q23 and 19q13.

PubMed

Leslie, Elizabeth J; Carlson, Jenna C; Shaffer, John R; Feingold, Eleanor; Wehby, George; Laurie, Cecelia A; Jain, Deepti; Laurie, Cathy C; Doheny, Kimberly F; McHenry, Toby; Resick, Judith; Sanchez, Carla; Jacobs, Jennifer; Emanuele, Beth; Vieira, Alexandre R; Neiswanger, Katherine; Lidral, Andrew C; Valencia-Ramirez, Luz Consuelo; Lopez-Palacio, Ana Maria; Valencia, Dora Rivera; Arcos-Burgos, Mauricio; Czeizel, Andrew E; Field, L Leigh; Padilla, Carmencita D; Cutiongco-de la Paz, Eva Maria C; Deleyiannis, Frederic; Christensen, Kaare; Munger, Ronald G; Lie, Rolv T; Wilcox, Allen; Romitti, Paul A; Castilla, Eduardo E; Mereb, Juan C; Poletta, Fernando A; Orioli, Iêda M; Carvalho, Flavia M; Hecht, Jacqueline T; Blanton, Susan H; Buxó, Carmen J; Butali, Azeez; Mossey, Peter A; Adeyemo, Wasiu L; James, Olutayo; Braimah, Ramat O; Aregbesola, Babatunde S; Eshete, Mekonen A; Abate, Fikre; Koruyucu, Mine; Seymen, Figen; Ma, Lian; de Salamanca, Javier Enríquez; Weinberg, Seth M; Moreno, Lina; Murray, Jeffrey C; Marazita, Mary L

2016-07-01

Orofacial clefts (OFCs), which include non-syndromic cleft lip with or without cleft palate (CL/P), are among the most common birth defects in humans, affecting approximately 1 in 700 newborns. CL/P is phenotypically heterogeneous and has a complex etiology caused by genetic and environmental factors. Previous genome-wide association studies (GWASs) have identified at least 15 risk loci for CL/P. As these loci do not account for all of the genetic variance of CL/P, we hypothesized the existence of additional risk loci. We conducted a multiethnic GWAS in 6480 participants (823 unrelated cases, 1700 unrelated controls and 1319 case-parent trios) with European, Asian, African and Central and South American ancestry. Our GWAS revealed novel associations on 2p24 near FAM49A, a gene of unknown function (P = 4.22 × 10 -8 ), and 19q13 near RHPN2, a gene involved in organizing the actin cytoskeleton (P = 4.17 × 10 -8 ). Other regions reaching genome-wide significance were 1p36 (PAX7), 1p22 (ARHGAP29), 1q32 (IRF6), 8q24 and 17p13 (NTN1), all reported in previous GWASs. Stratification by ancestry group revealed a novel association with a region on 17q23 (P = 2.92 × 10 -8 ) among individuals with European ancestry. This region included several promising candidates including TANC2, an oncogene required for development, and DCAF7, a scaffolding protein required for craniofacial development. In the Central and South American ancestry group, significant associations with loci previously identified in Asian or European ancestry groups reflected their admixed ancestry. In summary, we have identified novel CL/P risk loci and suggest new genes involved in craniofacial development, confirming the highly heterogeneous etiology of OFCs. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Genome-wide association study identifies novel susceptibility loci for cutaneous squamous cell carcinoma.

PubMed

Chahal, Harvind S; Lin, Yuan; Ransohoff, Katherine J; Hinds, David A; Wu, Wenting; Dai, Hong-Ji; Qureshi, Abrar A; Li, Wen-Qing; Kraft, Peter; Tang, Jean Y; Han, Jiali; Sarin, Kavita Y

2016-07-18

Cutaneous squamous cell carcinoma represents the second most common cutaneous malignancy, affecting 7-11% of Caucasians in the United States. The genetic determinants of susceptibility to cutaneous squamous cell carcinoma remain largely unknown. Here we report the results of a two-stage genome-wide association study of cutaneous squamous cell carcinoma, totalling 7,404 cases and 292,076 controls. Eleven loci reached genome-wide significance (P<5 × 10(-8)) including seven previously confirmed pigmentation-related loci: MC1R, ASIP, TYR, SLC45A2, OCA2, IRF4 and BNC2. We identify an additional four susceptibility loci: 11q23.3 CADM1, a metastasis suppressor gene involved in modifying tumour interaction with cell-mediated immunity; 2p22.3; 7p21.1 AHR, the dioxin receptor involved in anti-apoptotic pathways and melanoma progression; and 9q34.3 SEC16A, a putative oncogene with roles in secretion and cellular proliferation. These susceptibility loci provide deeper insight into the pathogenesis of squamous cell carcinoma.

Short Communication Mendelian inheritance, linkage, and genotypic disequilibrium in microsatellite loci of Hymenaea stigonocarpa Mart. ex Hayne (Fabaceae-Caesalpinioideae).

PubMed

Moraes, M A; Kubota, T Y K; Silva, E C B; Silva, A M; Cambuim, J; Moraes, M L T; Furlani Junior, E; Sebbenn, A M

2016-07-29

Hymenaea stigonocarpa is a deciduous and monoecious Neotropical tree species pollinated by bats. Due to overexploitation and habitat destruction, the population size has drastically diminished in nature. No previous study has investigated Mendelian inheritance, linkage, and genotypic disequilibrium in the available microsatellite markers in this species. So, our aim was to estimate these parameters using six microsatellite loci in a sample of 470 adults and 219 juveniles from two populations of H. stigonocarpa. In addition, 30 seeds per tree from 35 seed-trees were collected. Each seed was kept record of the seed-trees and fruit origin. Based on the six microsatellite loci, we found that only 10.6% of the cases showed significant deviations from Mendelian segregation and 15.3% showed linkage. We detected no evidence of genotypic disequilibrium between the loci in the adult trees or juveniles. Thus, our results suggest that these loci can be used with great accuracy in future genetic analyses of H. stigonocarpa populations.

New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

PubMed Central

Lu, Yingchang; Day, Felix R.; Gustafsson, Stefan; Buchkovich, Martin L.; Na, Jianbo; Bataille, Veronique; Cousminer, Diana L.; Dastani, Zari; Drong, Alexander W.; Esko, Tõnu; Evans, David M.; Falchi, Mario; Feitosa, Mary F.; Ferreira, Teresa; Hedman, Åsa K.; Haring, Robin; Hysi, Pirro G.; Iles, Mark M.; Justice, Anne E.; Kanoni, Stavroula; Lagou, Vasiliki; Li, Rui; Li, Xin; Locke, Adam; Lu, Chen; Mägi, Reedik; Perry, John R. B.; Pers, Tune H.; Qi, Qibin; Sanna, Marianna; Schmidt, Ellen M.; Scott, William R.; Shungin, Dmitry; Teumer, Alexander; Vinkhuyzen, Anna A. E.; Walker, Ryan W.; Westra, Harm-Jan; Zhang, Mingfeng; Zhang, Weihua; Zhao, Jing Hua; Zhu, Zhihong; Afzal, Uzma; Ahluwalia, Tarunveer Singh; Bakker, Stephan J. L.; Bellis, Claire; Bonnefond, Amélie; Borodulin, Katja; Buchman, Aron S.; Cederholm, Tommy; Choh, Audrey C.; Choi, Hyung Jin; Curran, Joanne E.; de Groot, Lisette C. P. G. M.; De Jager, Philip L.; Dhonukshe-Rutten, Rosalie A. M.; Enneman, Anke W.; Eury, Elodie; Evans, Daniel S.; Forsen, Tom; Friedrich, Nele; Fumeron, Frédéric; Garcia, Melissa E.; Gärtner, Simone; Han, Bok-Ghee; Havulinna, Aki S.; Hayward, Caroline; Hernandez, Dena; Hillege, Hans; Ittermann, Till; Kent, Jack W.; Kolcic, Ivana; Laatikainen, Tiina; Lahti, Jari; Leach, Irene Mateo; Lee, Christine G.; Lee, Jong-Young; Liu, Tian; Liu, Youfang; Lobbens, Stéphane; Loh, Marie; Lyytikäinen, Leo-Pekka; Medina-Gomez, Carolina; Michaëlsson, Karl; Nalls, Mike A.; Nielson, Carrie M.; Oozageer, Laticia; Pascoe, Laura; Paternoster, Lavinia; Polašek, Ozren; Ripatti, Samuli; Sarzynski, Mark A.; Shin, Chan Soo; Narančić, Nina Smolej; Spira, Dominik; Srikanth, Priya; Steinhagen-Thiessen, Elisabeth; Sung, Yun Ju; Swart, Karin M. A.; Taittonen, Leena; Tanaka, Toshiko; Tikkanen, Emmi; van der Velde, Nathalie; van Schoor, Natasja M.; Verweij, Niek; Wright, Alan F.; Yu, Lei; Zmuda, Joseph M.; Eklund, Niina; Forrester, Terrence; Grarup, Niels; Jackson, Anne U.; Kristiansson, Kati; Kuulasmaa, Teemu; Kuusisto, Johanna; Lichtner, Peter; Luan, Jian'an; Mahajan, Anubha; Männistö, Satu; Palmer, Cameron D.; Ried, Janina S.; Scott, Robert A.; Stancáková, Alena; Wagner, Peter J.; Demirkan, Ayse; Döring, Angela; Gudnason, Vilmundur; Kiel, Douglas P.; Kühnel, Brigitte; Mangino, Massimo; Mcknight, Barbara; Menni, Cristina; O'Connell, Jeffrey R.; Oostra, Ben A.; Shuldiner, Alan R.; Song, Kijoung; Vandenput, Liesbeth; van Duijn, Cornelia M.; Vollenweider, Peter; White, Charles C.; Boehnke, Michael; Boettcher, Yvonne; Cooper, Richard S.; Forouhi, Nita G.; Gieger, Christian; Grallert, Harald; Hingorani, Aroon; Jørgensen, Torben; Jousilahti, Pekka; Kivimaki, Mika; Kumari, Meena; Laakso, Markku; Langenberg, Claudia; Linneberg, Allan; Luke, Amy; Mckenzie, Colin A.; Palotie, Aarno; Pedersen, Oluf; Peters, Annette; Strauch, Konstantin; Tayo, Bamidele O.; Wareham, Nicholas J.; Bennett, David A.; Bertram, Lars; Blangero, John; Blüher, Matthias; Bouchard, Claude; Campbell, Harry; Cho, Nam H.; Cummings, Steven R.; Czerwinski, Stefan A.; Demuth, Ilja; Eckardt, Rahel; Eriksson, Johan G.; Ferrucci, Luigi; Franco, Oscar H.; Froguel, Philippe; Gansevoort, Ron T.; Hansen, Torben; Harris, Tamara B.; Hastie, Nicholas; Heliövaara, Markku; Hofman, Albert; Jordan, Joanne M.; Jula, Antti; Kähönen, Mika; Kajantie, Eero; Knekt, Paul B.; Koskinen, Seppo; Kovacs, Peter; Lehtimäki, Terho; Lind, Lars; Liu, Yongmei; Orwoll, Eric S.; Osmond, Clive; Perola, Markus; Pérusse, Louis; Raitakari, Olli T.; Rankinen, Tuomo; Rao, D. C.; Rice, Treva K.; Rivadeneira, Fernando; Rudan, Igor; Salomaa, Veikko; Sørensen, Thorkild I. A.; Stumvoll, Michael; Tönjes, Anke; Towne, Bradford; Tranah, Gregory J.; Tremblay, Angelo; Uitterlinden, André G.; van der Harst, Pim; Vartiainen, Erkki; Viikari, Jorma S.; Vitart, Veronique; Vohl, Marie-Claude; Völzke, Henry; Walker, Mark; Wallaschofski, Henri; Wild, Sarah; Wilson, James F.; Yengo, Loïc; Bishop, D. Timothy; Borecki, Ingrid B.; Chambers, John C.; Cupples, L. Adrienne; Dehghan, Abbas; Deloukas, Panos; Fatemifar, Ghazaleh; Fox, Caroline; Furey, Terrence S.; Franke, Lude; Han, Jiali; Hunter, David J.; Karjalainen, Juha; Karpe, Fredrik; Kaplan, Robert C.; Kooner, Jaspal S.; McCarthy, Mark I.; Murabito, Joanne M.; Morris, Andrew P.; Bishop, Julia A. N.; North, Kari E.; Ohlsson, Claes; Ong, Ken K.; Prokopenko, Inga; Richards, J. Brent; Schadt, Eric E.; Spector, Tim D.; Widén, Elisabeth; Willer, Cristen J.; Yang, Jian; Ingelsson, Erik; Mohlke, Karen L.; Hirschhorn, Joel N.; Pospisilik, John Andrew; Zillikens, M. Carola; Lindgren, Cecilia; Kilpeläinen, Tuomas Oskari; Loos, Ruth J. F.

2016-01-01

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10−8), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk. PMID:26833246

Genome-wide association study reveals multiple loci associated with primary tooth development during infancy.

PubMed

Pillas, Demetris; Hoggart, Clive J; Evans, David M; O'Reilly, Paul F; Sipilä, Kirsi; Lähdesmäki, Raija; Millwood, Iona Y; Kaakinen, Marika; Netuveli, Gopalakrishnan; Blane, David; Charoen, Pimphen; Sovio, Ulla; Pouta, Anneli; Freimer, Nelson; Hartikainen, Anna-Liisa; Laitinen, Jaana; Vaara, Sarianna; Glaser, Beate; Crawford, Peter; Timpson, Nicholas J; Ring, Susan M; Deng, Guohong; Zhang, Weihua; McCarthy, Mark I; Deloukas, Panos; Peltonen, Leena; Elliott, Paul; Coin, Lachlan J M; Smith, George Davey; Jarvelin, Marjo-Riitta

2010-02-26

Tooth development is a highly heritable process which relates to other growth and developmental processes, and which interacts with the development of the entire craniofacial complex. Abnormalities of tooth development are common, with tooth agenesis being the most common developmental anomaly in humans. We performed a genome-wide association study of time to first tooth eruption and number of teeth at one year in 4,564 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966) and 1,518 individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC). We identified 5 loci at P<5x10(-8), and 5 with suggestive association (P<5x10(-6)). The loci included several genes with links to tooth and other organ development (KCNJ2, EDA, HOXB2, RAD51L1, IGF2BP1, HMGA2, MSRB3). Genes at four of the identified loci are implicated in the development of cancer. A variant within the HOXB gene cluster associated with occlusion defects requiring orthodontic treatment by age 31 years.

Genome-Wide Association Study Reveals Multiple Loci Associated with Primary Tooth Development during Infancy

PubMed Central

Sipilä, Kirsi; Lähdesmäki, Raija; Millwood, Iona Y.; Kaakinen, Marika; Netuveli, Gopalakrishnan; Blane, David; Charoen, Pimphen; Sovio, Ulla; Pouta, Anneli; Freimer, Nelson; Hartikainen, Anna-Liisa; Laitinen, Jaana; Vaara, Sarianna; Glaser, Beate; Crawford, Peter; Timpson, Nicholas J.; Ring, Susan M.; Deng, Guohong; Zhang, Weihua; McCarthy, Mark I.; Deloukas, Panos; Peltonen, Leena

2010-01-01

Tooth development is a highly heritable process which relates to other growth and developmental processes, and which interacts with the development of the entire craniofacial complex. Abnormalities of tooth development are common, with tooth agenesis being the most common developmental anomaly in humans. We performed a genome-wide association study of time to first tooth eruption and number of teeth at one year in 4,564 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966) and 1,518 individuals from the Avon Longitudinal Study of Parents and Children (ALSPAC). We identified 5 loci at P<5×10−8, and 5 with suggestive association (P<5×10−6). The loci included several genes with links to tooth and other organ development (KCNJ2, EDA, HOXB2, RAD51L1, IGF2BP1, HMGA2, MSRB3). Genes at four of the identified loci are implicated in the development of cancer. A variant within the HOXB gene cluster associated with occlusion defects requiring orthodontic treatment by age 31 years. PMID:20195514

Genomics and introgression: discovery and mapping of thousands of species-diagnostic SNPs using RAD sequencing

USGS Publications Warehouse

Hand, Brian K.; Hether, Tyler D; Kovach, Ryan P.; Muhlfeld, Clint C.; Amish, Stephen J.; Boyer, Matthew C.; O’Rourke, Sean M.; Miller, Michael R.; Lowe, Winsor H.; Hohenlohe, Paul A.; Luikart, Gordon

2015-01-01

Invasive hybridization and introgression pose a serious threat to the persistence of many native species. Understanding the effects of hybridization on native populations (e.g., fitness consequences) requires numerous species-diagnostic loci distributed genome-wide. Here we used RAD sequencing to discover thousands of single-nucleotide polymorphisms (SNPs) that are diagnostic between rainbow trout (RBT, Oncorhynchus mykiss), the world’s most widely introduced fish, and native westslope cutthroat trout (WCT, O. clarkii lewisi) in the northern Rocky Mountains, USA. We advanced previous work that identified 4,914 species-diagnostic loci by using longer sequence reads (100 bp vs. 60 bp) and a larger set of individuals (n = 84). We sequenced RAD libraries for individuals from diverse sampling sources, including native populations of WCT and hatchery broodstocks of WCT and RBT. We also took advantage of a newly released reference genome assembly for RBT to align our RAD loci. In total, we discovered 16,788 putatively diagnostic SNPs, 10,267 of which we mapped to anchored chromosome locations on the RBT genome. A small portion of previously discovered putative diagnostic loci (325 of 4,914) were no longer diagnostic (i.e., fixed between species) based on our wider survey of non-hybridized RBT and WCT individuals. Our study suggests that RAD loci mapped to a draft genome assembly could provide the marker density required to identify genes and chromosomal regions influencing selection in admixed populations of conservation concern and evolutionary interest.

Analysis of MHC class I genes across horse MHC haplotypes

PubMed Central

Tallmadge, Rebecca L.; Campbell, Julie A.; Miller, Donald C.; Antczak, Douglas F.

2010-01-01

The genomic sequences of 15 horse Major Histocompatibility Complex (MHC) class I genes and a collection of MHC class I homozygous horses of five different haplotypes were used to investigate the genomic structure and polymorphism of the equine MHC. A combination of conserved and locus-specific primers was used to amplify horse MHC class I genes with classical and non-classical characteristics. Multiple clones from each haplotype identified three to five classical sequences per homozygous animal, and two to three non-classical sequences. Phylogenetic analysis was applied to these sequences and groups were identified which appear to be allelic series, but some sequences were left ungrouped. Sequences determined from MHC class I heterozygous horses and previously described MHC class I sequences were then added, representing a total of ten horse MHC haplotypes. These results were consistent with those obtained from the MHC homozygous horses alone, and 30 classical sequences were assigned to four previously confirmed loci and three new provisional loci. The non-classical genes had few alleles and the classical genes had higher levels of allelic polymorphism. Alleles for two classical loci with the expected pattern of polymorphism were found in the majority of haplotypes tested, but alleles at two other commonly detected loci had more variation outside of the hypervariable region than within. Our data indicate that the equine Major Histocompatibility Complex is characterized by variation in the complement of class I genes expressed in different haplotypes in addition to the expected allelic polymorphism within loci. PMID:20099063

Characterization of Lipooligosaccharide-Biosynthetic Loci of Campylobacter jejuni Reveals New Lipooligosaccharide Classes: Evidence of Mosaic Organizations▿ †

PubMed Central

Parker, Craig T.; Gilbert, Michel; Yuki, Nobuhiro; Endtz, Hubert P.; Mandrell, Robert E.

2008-01-01

The lipooligosaccharide (LOS) biosynthesis region is one of the more variable genomic regions between strains of Campylobacter jejuni. Indeed, eight classes of LOS biosynthesis loci have been established previously based on gene content and organization. In this study, we characterize additional classes of LOS biosynthesis loci and analyze various mechanisms that result in changes to LOS structures. To gain further insights into the genomic diversity of C. jejuni LOS biosynthesis region, we sequenced the LOS biosynthesis loci of 15 strains that possessed gene content that was distinct from the eight classes. This analysis identified 11 new classes of LOS loci that exhibited examples of deletions and insertions of genes and cassettes of genes found in other LOS classes or capsular biosynthesis loci leading to mosaic LOS loci. The sequence analysis also revealed both missense mutations leading to “allelic” glycosyltransferases and phase-variable and non-phase-variable gene inactivation by the deletion or insertion of bases. Specifically, we demonstrated that gene inactivation is an important mechanism for altering the LOS structures of strains possessing the same class of LOS biosynthesis locus. Together, these observations suggest that LOS biosynthesis region is a hotspot for genetic exchange and variability, often leading to changes in the LOS produced. PMID:18556784

Genetic association study of Age-Related Macular Degeneration in the Spanish population

PubMed Central

Brión, María; Sanchez-Salorio, Manuel; Cortón, Marta; de la Fuente, Maria; Pazos, Belen; Othman, Mohammad; Swaroop, Anand; Abecasis, Goncalo; Sobrino, Beatriz; Carracedo, Angel

2017-01-01

Purpose To investigate new genetic risk factors and replicate reported associations with advanced age related macular degeneration (AMD) in a prospective case - control study developed with a Spanish cohort. Methods Three hundred and fifty-three unrelated patients with advanced AMD (225 with atrophic AMD, 57 with neovascular AMD, and 71 with mixed AMD) and 282 age-matched controls were included. Functional and tagging SNPs in 55 candidate genes were genotyped using the SNPlex™ genotyping system. Single SNP and haplotype association analysis were performed to determine possible genetic associations; interaction effects between SNPs were also investigated. Results In agreement with previous reports, ARMS2 and CFH genes were strongly associated with AMD in the studied Spanish population. Moreover, both loci influenced risk independently giving support to different pathways implicated in AMD pathogenesis. No evidence for association of advanced AMD with other previous reported susceptibility genes, such as CST3, CX3CR1, FBLN5, HMCN1, PON1, SOD2, TLR4, VEGF and VLDLR, was detected. However, two additional genes appear to be candidate markers for the development of advanced AMD. A variant located at the 3´UTR of the FGF2 gene (rs6820411) was highly associated with atrophic AMD, and the functional SNP rs3112831 at ABCA4 showed a marginal association with the disease. Conclusion We performed a large gene association study in advanced AMD in a Spanish population. Our findings show that CFH and ARMS2 genes seem to be the principal risk loci contributing independently to AMD in our cohort. We report new significant associations that could also influence the development of advanced AMD. These findings should be confirmed in further studies with larger cohorts. PMID:21106043

A Genome-Wide Association Study Identifies Five Loci Influencing Facial Morphology in Europeans

PubMed Central

Liu, Fan; van der Lijn, Fedde; Schurmann, Claudia; Zhu, Gu; Chakravarty, M. Mallar; Hysi, Pirro G.; Wollstein, Andreas; Lao, Oscar; de Bruijne, Marleen; Ikram, M. Arfan; van der Lugt, Aad; Rivadeneira, Fernando; Uitterlinden, André G.; Hofman, Albert; Niessen, Wiro J.; Homuth, Georg; de Zubicaray, Greig; McMahon, Katie L.; Thompson, Paul M.; Daboul, Amro; Puls, Ralf; Hegenscheid, Katrin; Bevan, Liisa; Pausova, Zdenka; Medland, Sarah E.; Montgomery, Grant W.; Wright, Margaret J.; Wicking, Carol; Boehringer, Stefan; Spector, Timothy D.; Paus, Tomáš; Martin, Nicholas G.; Biffar, Reiner; Kayser, Manfred

2012-01-01

Inter-individual variation in facial shape is one of the most noticeable phenotypes in humans, and it is clearly under genetic regulation; however, almost nothing is known about the genetic basis of normal human facial morphology. We therefore conducted a genome-wide association study for facial shape phenotypes in multiple discovery and replication cohorts, considering almost ten thousand individuals of European descent from several countries. Phenotyping of facial shape features was based on landmark data obtained from three-dimensional head magnetic resonance images (MRIs) and two-dimensional portrait images. We identified five independent genetic loci associated with different facial phenotypes, suggesting the involvement of five candidate genes—PRDM16, PAX3, TP63, C5orf50, and COL17A1—in the determination of the human face. Three of them have been implicated previously in vertebrate craniofacial development and disease, and the remaining two genes potentially represent novel players in the molecular networks governing facial development. Our finding at PAX3 influencing the position of the nasion replicates a recent GWAS of facial features. In addition to the reported GWA findings, we established links between common DNA variants previously associated with NSCL/P at 2p21, 8q24, 13q31, and 17q22 and normal facial-shape variations based on a candidate gene approach. Overall our study implies that DNA variants in genes essential for craniofacial development contribute with relatively small effect size to the spectrum of normal variation in human facial morphology. This observation has important consequences for future studies aiming to identify more genes involved in the human facial morphology, as well as for potential applications of DNA prediction of facial shape such as in future forensic applications. PMID:23028347

Evaluation of SNP Data from the Malus Infinium Array Identifies Challenges for Genetic Analysis of Complex Genomes of Polyploid Origin.

PubMed

Troggio, Michela; Surbanovski, Nada; Bianco, Luca; Moretto, Marco; Giongo, Lara; Banchi, Elisa; Viola, Roberto; Fernández, Felicdad Fernández; Costa, Fabrizio; Velasco, Riccardo; Cestaro, Alessandro; Sargent, Daniel James

2013-01-01

High throughput arrays for the simultaneous genotyping of thousands of single-nucleotide polymorphisms (SNPs) have made the rapid genetic characterisation of plant genomes and the development of saturated linkage maps a realistic prospect for many plant species of agronomic importance. However, the correct calling of SNP genotypes in divergent polyploid genomes using array technology can be problematic due to paralogy, and to divergence in probe sequences causing changes in probe binding efficiencies. An Illumina Infinium II whole-genome genotyping array was recently developed for the cultivated apple and used to develop a molecular linkage map for an apple rootstock progeny (M432), but a large proportion of segregating SNPs were not mapped in the progeny, due to unexpected genotype clustering patterns. To investigate the causes of this unexpected clustering we performed BLAST analysis of all probe sequences against the 'Golden Delicious' genome sequence and discovered evidence for paralogous annealing sites and probe sequence divergence for a high proportion of probes contained on the array. Following visual re-evaluation of the genotyping data generated for 8,788 SNPs for the M432 progeny using the array, we manually re-scored genotypes at 818 loci and mapped a further 797 markers to the M432 linkage map. The newly mapped markers included the majority of those that could not be mapped previously, as well as loci that were previously scored as monomorphic, but which segregated due to divergence leading to heterozygosity in probe annealing sites. An evaluation of the 8,788 probes in a diverse collection of Malus germplasm showed that more than half the probes returned genotype clustering patterns that were difficult or impossible to interpret reliably, highlighting implications for the use of the array in genome-wide association studies.

An updated evolutionary classification of CRISPR–Cas systems

PubMed Central

Makarova, Kira S.; Wolf, Yuri I.; Alkhnbashi, Omer S.; Costa, Fabrizio; Shah, Shiraz A.; Saunders, Sita J.; Barrangou, Rodolphe; Brouns, Stan J. J.; Charpentier, Emmanuelle; Haft, Daniel H.; Horvath, Philippe; Moineau, Sylvain; Mojica, Francisco J. M.; Terns, Rebecca M.; Terns, Michael P.; White, Malcolm F.; Yakunin, Alexander F.; Garrett, Roger A.; van der Oost, John; Backofen, Rolf; Koonin, Eugene V.

2017-01-01

The evolution of CRISPR–cas loci, which encode adaptive immune systems in archaea and bacteria, involves rapid changes, in particular numerous rearrangements of the locus architecture and horizontal transfer of complete loci or individual modules. These dynamics complicate straightforward phylogenetic classification, but here we present an approach combining the analysis of signature protein families and features of the architecture of cas loci that unambiguously partitions most CRISPR–cas loci into distinct classes, types and subtypes. The new classification retains the overall structure of the previous version but is expanded to now encompass two classes, five types and 16 subtypes. The relative stability of the classification suggests that the most prevalent variants of CRISPR–Cas systems are already known. However, the existence of rare, currently unclassifiable variants implies that additional types and subtypes remain to be characterized. PMID:26411297

19-VNTR loci used in genotyping Chinese clinical Mycobacterium tuberculosis complex strains and in association with spoligotyping.

PubMed

Jiang, Yi; Liu, Hai-can; Zheng, Huajun; Dou, Xiangfeng; Tang, Biao; Zhao, Xiu-qin; Zhu, Yongqiang; Lu, Bing; Wang, Shengyue; Dong, Hai-yan; Zhang, Yuan-yuan; Zhao, Guoping; Wan, Kanglin

2013-07-01

Recently, tandem repeat typing has emerged as a rapid and easy method for the molecular epidemiology of the Mycobacterium tuberculosis (M. tuberculosis) complex. In this study, a collection of 19 VNTRs incorporating 15 previously described loci and 4 newly evaluated markers were used to genotype 206 Chinese M. tuberculosis isolates and 9 BCG strains. The discriminatory power was evaluated and compared with that obtained by Spoligotyping. It turned out that 15-locus VNTR could be very useful in M. tuberculosis complex strains genotyping in China. The 4 newly evaluated loci were proved informative and could be useful for future epidemiology studies, especially in Beijing family strains. In addition, a unique pattern of the latter 4 loci were found in Chinese BCG strains. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Neutral mutation as the source of genetic variation in life history traits.

PubMed

Brcić-Kostić, Krunoslav

2005-08-01

The mechanism underlying the maintenance of adaptive genetic variation is a long-standing question in evolutionary genetics. There are two concepts (mutation-selection balance and balancing selection) which are based on the phenotypic differences between alleles. Mutation - selection balance and balancing selection cannot properly explain the process of gene substitution, i.e. the molecular evolution of quantitative trait loci affecting fitness. I assume that such loci have non-essential functions (small effects on fitness), and that they have the potential to evolve into new functions and acquire new adaptations. Here I show that a high amount of neutral polymorphism at these loci can exist in real populations. Consistent with this, I propose a hypothesis for the maintenance of genetic variation in life history traits which can be efficient for the fixation of alleles with very small selective advantage. The hypothesis is based on neutral polymorphism at quantitative trait loci and both neutral and adaptive gene substitutions. The model of neutral - adaptive conversion (NAC) assumes that neutral alleles are not neutral indefinitely, and that in specific and very rare situations phenotypic (relative fitness) differences between them can appear. In this paper I focus on NAC due to phenotypic plasticity of neutral alleles. The important evolutionary consequence of NAC could be the increased adaptive potential of a population. Loci responsible for adaptation should be fast evolving genes with minimally discernible phenotypic effects, and the recent discovery of genes with such characteristics implicates them as suitable candidates for loci involved in adaptation.

Estimated number of loci for autosomal recessive severe nerve deafness within the Israeli Jewish population, with implications for genetic counseling.

PubMed

Brownstein, Z; Friedlander, Y; Peritz, E; Cohen, T

1991-12-01

Deafness occurs in about 1 per thousand live births, and at least 50% of congenital deafness is hereditary. The aim of this study was to examine the number of loci for recessively inherited severe nerve deafness of early onset within the Israeli population and to compare the results to those obtained in other populations. The Jewish population in Israel originates from many countries and may be divided into Sephardi, Eastern and Ashkenazi Jews, and the matings will be intraethnic or interethnic. Data were obtained on 133 deaf couples who lived in the Tel Aviv area, through the files of the Helen Keller Center. Causes of deafness in the spouses were studied and data on their children were obtained. Among 111 couples who had recessive or possibly recessive deafness and had at least 1 child, there were 12 with only deaf children and 5 with both deaf and hearing children. The number of loci for recessive deafness in the whole group was estimated at 8-9. Intraethnic and interethnic matings gave an estimate of 6.7 and 22.0 loci, respectively, which indicates that within populations fewer loci exist with recessive mutations for deafness than between populations. It could be shown that the sharing of loci between spouses decreased with increasing geographical distance of their origin. The results provide data for genetic counseling in Israel for deaf couples who have no children or have one hearing or one deaf child.

Networks, Trees, and Treeshrews: Assessing Support and Identifying Conflict with Multiple Loci and a Problematic Root

PubMed Central

Roberts, Trina E.; Sargis, Eric J.; Olson, Link E.

2009-01-01

Multiple unlinked genetic loci often provide a more comprehensive picture of evolutionary history than any single gene can, but analyzing multigene data presents particular challenges. Differing rates and patterns of nucleotide substitution, combined with the limited information available in any data set, can make it difficult to specify a model of evolution. In addition, conflict among loci can be the result of real differences in evolutionary process or of stochastic variance and errors in reconstruction. We used 6 presumably unlinked nuclear loci to investigate relationships within the mammalian family Tupaiidae (Scandentia), containing all but one of the extant tupaiid genera. We used a phylogenetic mixture model to analyze the concatenated data and compared this with results using partitioned models. We found that more complex models were not necessarily preferred under tests using Bayes factors and that model complexity affected both tree length and parameter variance. We also compared the results of single-gene and multigene analyses and used splits networks to analyze the source and degree of conflict among genes. Networks can show specific relationships that are inconsistent with each other; these conflicting and minority relationships, which are implicitly ignored or collapsed by traditional consensus methods, can be useful in identifying the underlying causes of topological uncertainty. In our data, conflict is concentrated around particular relationships, not widespread throughout the tree. This pattern is further clarified by considering conflict surrounding the root separately from conflict within the ingroup. Uncertainty in rooting may be because of the apparent evolutionary distance separating these genera and our outgroup, the tupaiid genus Dendrogale. Unlike a previous mitochondrial study, these nuclear data strongly suggest that the genus Tupaia is not monophyletic with respect to the monotypic Urogale, even when uncertainty about rooting is taken into account. These data concur with mitochondrial DNA on other relationships, including the close affinity of Tupaia tana with the enigmatic Tupaia splendidula and of Tupaia belangeri with Tupaia glis. We also discuss the taxonomic and biogeographic implications of these results. PMID:20525582

Multiple independent loci at chromosome 15q25.1 affect smoking quantity: a meta-analysis and comparison with lung cancer and COPD.

PubMed

Saccone, Nancy L; Culverhouse, Robert C; Schwantes-An, Tae-Hwi; Cannon, Dale S; Chen, Xiangning; Cichon, Sven; Giegling, Ina; Han, Shizhong; Han, Younghun; Keskitalo-Vuokko, Kaisu; Kong, Xiangyang; Landi, Maria Teresa; Ma, Jennie Z; Short, Susan E; Stephens, Sarah H; Stevens, Victoria L; Sun, Lingwei; Wang, Yufei; Wenzlaff, Angela S; Aggen, Steven H; Breslau, Naomi; Broderick, Peter; Chatterjee, Nilanjan; Chen, Jingchun; Heath, Andrew C; Heliövaara, Markku; Hoft, Nicole R; Hunter, David J; Jensen, Majken K; Martin, Nicholas G; Montgomery, Grant W; Niu, Tianhua; Payne, Thomas J; Peltonen, Leena; Pergadia, Michele L; Rice, John P; Sherva, Richard; Spitz, Margaret R; Sun, Juzhong; Wang, Jen C; Weiss, Robert B; Wheeler, William; Witt, Stephanie H; Yang, Bao-Zhu; Caporaso, Neil E; Ehringer, Marissa A; Eisen, Tim; Gapstur, Susan M; Gelernter, Joel; Houlston, Richard; Kaprio, Jaakko; Kendler, Kenneth S; Kraft, Peter; Leppert, Mark F; Li, Ming D; Madden, Pamela A F; Nöthen, Markus M; Pillai, Sreekumar; Rietschel, Marcella; Rujescu, Dan; Schwartz, Ann; Amos, Christopher I; Bierut, Laura J

2010-08-05

Recently, genetic association findings for nicotine dependence, smoking behavior, and smoking-related diseases converged to implicate the chromosome 15q25.1 region, which includes the CHRNA5-CHRNA3-CHRNB4 cholinergic nicotinic receptor subunit genes. In particular, association with the nonsynonymous CHRNA5 SNP rs16969968 and correlates has been replicated in several independent studies. Extensive genotyping of this region has suggested additional statistically distinct signals for nicotine dependence, tagged by rs578776 and rs588765. One goal of the Consortium for the Genetic Analysis of Smoking Phenotypes (CGASP) is to elucidate the associations among these markers and dichotomous smoking quantity (heavy versus light smoking), lung cancer, and chronic obstructive pulmonary disease (COPD). We performed a meta-analysis across 34 datasets of European-ancestry subjects, including 38,617 smokers who were assessed for cigarettes-per-day, 7,700 lung cancer cases and 5,914 lung-cancer-free controls (all smokers), and 2,614 COPD cases and 3,568 COPD-free controls (all smokers). We demonstrate statistically independent associations of rs16969968 and rs588765 with smoking (mutually adjusted p-values<10(-35) and <10(-8) respectively). Because the risk alleles at these loci are negatively correlated, their association with smoking is stronger in the joint model than when each SNP is analyzed alone. Rs578776 also demonstrates association with smoking after adjustment for rs16969968 (p<10(-6)). In models adjusting for cigarettes-per-day, we confirm the association between rs16969968 and lung cancer (p<10(-20)) and observe a nominally significant association with COPD (p = 0.01); the other loci are not significantly associated with either lung cancer or COPD after adjusting for rs16969968. This study provides strong evidence that multiple statistically distinct loci in this region affect smoking behavior. This study is also the first report of association between rs588765 (and correlates) and smoking that achieves genome-wide significance; these SNPs have previously been associated with mRNA levels of CHRNA5 in brain and lung tissue.

Reappraisal of known malaria resistance loci in a large multi-centre study

PubMed Central

Rockett, Kirk A.; Clarke, Geraldine M.; Fitzpatrick, Kathryn; Hubbart, Christina; Jeffreys, Anna E.; Rowlands, Kate; Craik, Rachel; Jallow, Muminatou; Conway, David J.; Bojang, Kalifa A.; Pinder, Margaret; Usen, Stanley; Sisay-Joof, Fatoumatta; Sirugo, Giorgio; Toure, Ousmane; Thera, Mahamadou A.; Konate, Salimata; Sissoko, Sibiry; Niangaly, Amadou; Poudiougou, Belco; Mangano, Valentina D.; Bougouma, Edith C.; Sirima, Sodiomon B.; Modiano, David; Amenga-Etego, Lucas N.; Ghansah, Anita; Koram, Kwadwo A.; Wilson, Michael D.; Enimil, Anthony; Evans, Jennifer; Amodu, Olukemi; Olaniyan, Subulade; Apinjoh, Tobias; Mugri, Regina; Ndi, Andre; Ndila, Carolyne M.; Uyoga, Sophie; Macharia, Alexander; Peshu, Norbert; Williams, Thomas N.; Manjurano, Alphaxard; Riley, Eleanor; Drakeley, Chris; Reyburn, Hugh; Nyirongo, Vysaul; Kachala, David; Molyneux, Malcolm; Dunstan, Sarah J.; Phu, Nguyen Hoan; Ngoc Quyen, Nguyen Thi; Thai, Cao Quang; Hien, Tran Tinh; Manning, Laurens; Laman, Moses; Siba, Peter; Karunajeewa, Harin; Allen, Steve; Allen, Angela; Davis, Timothy M. E.; Michon, Pascal; Mueller, Ivo; Green, Angie; Molloy, Sile; Johnson, Kimberly J.; Kerasidou, Angeliki; Cornelius, Victoria; Hart, Lee; Vanderwal, Aaron; SanJoaquin, Miguel; Band, Gavin; Le, Si Quang; Pirinen, Matti; Sepúlveda, Nuno; Spencer, Chris C.A.; Clark, Taane G.; Agbenyega, Tsiri; Achidi, Eric; Doumbo, Ogobara; Farrar, Jeremy; Marsh, Kevin; Taylor, Terrie; Kwiatkowski, Dominic P.

2015-01-01

Many human genetic associations with resistance to malaria have been reported but few have been reliably replicated. We collected data on 11,890 cases of severe malaria due to Plasmodium falciparum and 17,441 controls from 12 locations in Africa, Asia and Oceania. There was strong evidence of association with the HBB, ABO, ATP2B4, G6PD and CD40LG loci but previously reported associations at 22 other loci did not replicate in the multi-centre analysis. The large sample size made it possible to identify authentic genetic effects that are heterogeneous across populations or phenotypes, a striking example being the main African form of G6PD deficiency, which reduced the risk of cerebral malaria but increased the risk of severe malarial anaemia. The finding that G6PD deficiency has opposing effects on different fatal complications of P. falciparum infection indicates that the evolutionary origins of this common human genetic disorder are more complex than previously supposed. PMID:25261933

ImmunoChip Study Implicates Antigen Presentation to T Cells in Narcolepsy

PubMed Central

Kornum, Birgitte Rahbek; Kenny, Eimear E.; Trynka, Gosia; Einen, Mali; Rico, Tom J.; Lichtner, Peter; Dauvilliers, Yves; Arnulf, Isabelle; Lecendreux, Michel; Javidi, Sirous; Geisler, Peter; Mayer, Geert; Pizza, Fabio; Poli, Francesca; Plazzi, Giuseppe; Overeem, Sebastiaan; Lammers, Gert Jan; Kemlink, David; Sonka, Karel; Nevsimalova, Sona; Rouleau, Guy; Desautels, Alex; Montplaisir, Jacques; Frauscher, Birgit; Ehrmann, Laura; Högl, Birgit; Jennum, Poul; Bourgin, Patrice; Peraita-Adrados, Rosa; Iranzo, Alex; Bassetti, Claudio; Chen, Wei-Min; Concannon, Patrick; Thompson, Susan D.; Damotte, Vincent; Fontaine, Bertrand; Breban, Maxime; Gieger, Christian; Klopp, Norman; Deloukas, Panos; Wijmenga, Cisca; Hallmayer, Joachim; Onengut-Gumuscu, Suna; Rich, Stephen S.; Winkelmann, Juliane; Mignot, Emmanuel

2013-01-01

Recent advances in the identification of susceptibility genes and environmental exposures provide broad support for a post-infectious autoimmune basis for narcolepsy/hypocretin (orexin) deficiency. We genotyped loci associated with other autoimmune and inflammatory diseases in 1,886 individuals with hypocretin-deficient narcolepsy and 10,421 controls, all of European ancestry, using a custom genotyping array (ImmunoChip). Three loci located outside the Human Leukocyte Antigen (HLA) region on chromosome 6 were significantly associated with disease risk. In addition to a strong signal in the T cell receptor alpha (TRA@), variants in two additional narcolepsy loci, Cathepsin H (CTSH) and Tumor necrosis factor (ligand) superfamily member 4 (TNFSF4, also called OX40L), attained genome-wide significance. These findings underline the importance of antigen presentation by HLA Class II to T cells in the pathophysiology of this autoimmune disease. PMID:23459209

Overlap of disease susceptibility loci for rheumatoid arthritis and juvenile idiopathic arthritis

PubMed Central

Hinks, Anne; Eyre, Steve; Ke, Xiayi; Barton, Anne; Martin, Paul; Flynn, Edward; Packham, Jon; Worthington, Jane; Thomson, Wendy

2010-01-01

Background Genome-wide association studies (GWAS) have been extremely successful in the search for susceptibility risk factors for complex genetic autoimmune diseases. As more studies are published, evidence is emerging of considerable overlap of loci between these diseases. In juvenile idiopathic arthritis (JIA), another complex genetic autoimmune disease, the strategy of using information from autoimmune disease GWAS or candidate gene studies to help in the search for novel JIA susceptibility loci has been successful, with confirmed association with two genes, PTPN22 and IL2RA. Rheumatoid arthritis (RA) is an autoimmune disease that shares similar clinical and pathological features with JIA and, therefore, recently identified confirmed RA susceptibility loci are also excellent JIA candidate loci. Objective To determine the overlap of disease susceptibility loci for RA and JIA. Methods Fifteen single nucleotide polymorphisms (SNPs) at nine RA-associated loci were genotyped in Caucasian patients with JIA (n=1054) and controls (n=3531) and tested for association with JIA. Allele and genotype frequencies were compared between cases and controls using the genetic analysis software, PLINK. Results Two JIA susceptibility loci were identified, one of which was a novel JIA association (STAT4) and the second confirmed previously published associations of the TRAF1/C5 locus with JIA. Weak evidence of association of JIA with three additional loci (Chr6q23, KIF5A and PRKCQ) was also obtained, which warrants further investigation. Conclusion All these loci are good candidates in view of the known pathogenesis of JIA, as genes within these regions (TRAF1, STAT4, TNFAIP3, PRKCQ) are known to be involved in T-cell receptor signalling or activation pathways. PMID:19674979

Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis.

PubMed

Kraus, William E; Muoio, Deborah M; Stevens, Robert; Craig, Damian; Bain, James R; Grass, Elizabeth; Haynes, Carol; Kwee, Lydia; Qin, Xuejun; Slentz, Dorothy H; Krupp, Deidre; Muehlbauer, Michael; Hauser, Elizabeth R; Gregory, Simon G; Newgard, Christopher B; Shah, Svati H

2015-11-01

Levels of certain circulating short-chain dicarboxylacylcarnitine (SCDA), long-chain dicarboxylacylcarnitine (LCDA) and medium chain acylcarnitine (MCA) metabolites are heritable and predict cardiovascular disease (CVD) events. Little is known about the biological pathways that influence levels of most of these metabolites. Here, we analyzed genetics, epigenetics, and transcriptomics with metabolomics in samples from a large CVD cohort to identify novel genetic markers for CVD and to better understand the role of metabolites in CVD pathogenesis. Using genomewide association in the CATHGEN cohort (N = 1490), we observed associations of several metabolites with genetic loci. Our strongest findings were for SCDA metabolite levels with variants in genes that regulate components of endoplasmic reticulum (ER) stress (USP3, HERC1, STIM1, SEL1L, FBXO25, SUGT1) These findings were validated in a second cohort of CATHGEN subjects (N = 2022, combined p = 8.4x10-6-2.3x10-10). Importantly, variants in these genes independently predicted CVD events. Association of genomewide methylation profiles with SCDA metabolites identified two ER stress genes as differentially methylated (BRSK2 and HOOK2). Expression quantitative trait loci (eQTL) pathway analyses driven by gene variants and SCDA metabolites corroborated perturbations in ER stress and highlighted the ubiquitin proteasome system (UPS) arm. Moreover, culture of human kidney cells in the presence of levels of fatty acids found in individuals with cardiometabolic disease, induced accumulation of SCDA metabolites in parallel with increases in the ER stress marker BiP. Thus, our integrative strategy implicates the UPS arm of the ER stress pathway in CVD pathogenesis, and identifies novel genetic loci associated with CVD event risk.

Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis

PubMed Central

Kraus, William E.; Muoio, Deborah M.; Stevens, Robert; Craig, Damian; Bain, James R.; Grass, Elizabeth; Haynes, Carol; Kwee, Lydia; Qin, Xuejun; Slentz, Dorothy H.; Krupp, Deidre; Muehlbauer, Michael; Hauser, Elizabeth R.; Gregory, Simon G.; Newgard, Christopher B.; Shah, Svati H.

2015-01-01

Levels of certain circulating short-chain dicarboxylacylcarnitine (SCDA), long-chain dicarboxylacylcarnitine (LCDA) and medium chain acylcarnitine (MCA) metabolites are heritable and predict cardiovascular disease (CVD) events. Little is known about the biological pathways that influence levels of most of these metabolites. Here, we analyzed genetics, epigenetics, and transcriptomics with metabolomics in samples from a large CVD cohort to identify novel genetic markers for CVD and to better understand the role of metabolites in CVD pathogenesis. Using genomewide association in the CATHGEN cohort (N = 1490), we observed associations of several metabolites with genetic loci. Our strongest findings were for SCDA metabolite levels with variants in genes that regulate components of endoplasmic reticulum (ER) stress (USP3, HERC1, STIM1, SEL1L, FBXO25, SUGT1) These findings were validated in a second cohort of CATHGEN subjects (N = 2022, combined p = 8.4x10-6–2.3x10-10). Importantly, variants in these genes independently predicted CVD events. Association of genomewide methylation profiles with SCDA metabolites identified two ER stress genes as differentially methylated (BRSK2 and HOOK2). Expression quantitative trait loci (eQTL) pathway analyses driven by gene variants and SCDA metabolites corroborated perturbations in ER stress and highlighted the ubiquitin proteasome system (UPS) arm. Moreover, culture of human kidney cells in the presence of levels of fatty acids found in individuals with cardiometabolic disease, induced accumulation of SCDA metabolites in parallel with increases in the ER stress marker BiP. Thus, our integrative strategy implicates the UPS arm of the ER stress pathway in CVD pathogenesis, and identifies novel genetic loci associated with CVD event risk. PMID:26540294

TAS3 miR390-dependent loci in non-vascular land plants: towards a comprehensive reconstruction of the gene evolutionary history.

PubMed

Morozov, Sergey Y; Milyutina, Irina A; Erokhina, Tatiana N; Ozerova, Liudmila V; Troitsky, Alexey V; Solovyev, Andrey G

2018-01-01

Trans-acting small interfering RNAs (ta-siRNAs) are transcribed from protein non-coding genomic TAS loci and belong to a plant-specific class of endogenous small RNAs. These siRNAs have been found to regulate gene expression in most taxa including seed plants, gymnosperms, ferns and mosses. In this study, bioinformatic and experimental PCR-based approaches were used as tools to analyze TAS3 and TAS6 loci in transcriptomes and genomic DNAs from representatives of evolutionary distant non-vascular plant taxa such as Bryophyta, Marchantiophyta and Anthocerotophyta. We revealed previously undiscovered TAS3 loci in plant classes Sphagnopsida and Anthocerotopsida, as well as TAS6 loci in Bryophyta classes Tetraphidiopsida, Polytrichopsida, Andreaeopsida and Takakiopsida. These data further unveil the evolutionary pathway of the miR390-dependent TAS3 loci in land plants. We also identified charophyte alga sequences coding for SUPPRESSOR OF GENE SILENCING 3 (SGS3), which is required for generation of ta-siRNAs in plants, and hypothesized that the appearance of TAS3-related sequences could take place at a very early step in evolutionary transition from charophyte algae to an earliest common ancestor of land plants.

Comparative mapping reveals quantitative trait loci that affect spawning time in coho salmon (Oncorhynchus kisutch)

PubMed Central

Araneda, Cristian; Díaz, Nelson F.; Gomez, Gilda; López, María Eugenia; Iturra, Patricia

2012-01-01

Spawning time in salmonids is a sex-limited quantitative trait that can be modified by selection. In rainbow trout (Oncorhynchus mykiss), various quantitative trait loci (QTL) that affect the expression of this trait have been discovered. In this study, we describe four microsatellite loci associated with two possible spawning time QTL regions in coho salmon (Oncorhynchus kisutch). The four loci were identified in females from two populations (early and late spawners) produced by divergent selection from the same base population. Three of the loci (OmyFGT34TUF, One2ASC and One19ASC) that were strongly associated with spawning time in coho salmon (p < 0.0002) were previously associated with QTL for the same trait in rainbow trout; a fourth loci (Oki10) with a suggestive association (p = 0.00035) mapped 10 cM from locus OmyFGT34TUF in rainbow trout. The changes in allelic frequency observed after three generations of selection were greater than expected because of genetic drift. This work shows that comparing information from closely-related species is a valid strategy for identifying QTLs for marker-assisted selection in species whose genomes are poorly characterized or lack a saturated genetic map. PMID:22888302

Russian Doll Genes and Complex Chromosome Rearrangements in Oxytricha trifallax

PubMed Central

Braun, Jasper; Nabergall, Lukas; Neme, Rafik; Landweber, Laura F.; Saito, Masahico; Jonoska, Nataša

2018-01-01

Ciliates have two different types of nuclei per cell, with one acting as a somatic, transcriptionally active nucleus (macronucleus; abbr. MAC) and another serving as a germline nucleus (micronucleus; abbr. MIC). Furthermore, Oxytricha trifallax undergoes extensive genome rearrangements during sexual conjugation and post-zygotic development of daughter cells. These rearrangements are necessary because the precursor MIC loci are often both fragmented and scrambled, with respect to the corresponding MAC loci. Such genome architectures are remarkably tolerant of encrypted MIC loci, because RNA-guided processes during MAC development reorganize the gene fragments in the correct order to resemble the parental MAC sequence. Here, we describe the germline organization of several nested and highly scrambled genes in Oxytricha trifallax. These include cases with multiple layers of nesting, plus highly interleaved or tangled precursor loci that appear to deviate from previously described patterns. We present mathematical methods to measure the degree of nesting between precursor MIC loci, and revisit a method for a mathematical description of scrambling. After applying these methods to the chromosome rearrangement maps of O. trifallax we describe cases of nested arrangements with up to five layers of embedded genes, as well as the most scrambled loci in O. trifallax. PMID:29545465

Immunochip Analysis Identifies Multiple Susceptibility Loci for Systemic Sclerosis

PubMed Central

Mayes, Maureen D.; Bossini-Castillo, Lara; Gorlova, Olga; Martin, José Ezequiel; Zhou, Xiaodong; Chen, Wei V.; Assassi, Shervin; Ying, Jun; Tan, Filemon K.; Arnett, Frank C.; Reveille, John D.; Guerra, Sandra; Teruel, María; Carmona, Francisco David; Gregersen, Peter K.; Lee, Annette T.; López-Isac, Elena; Ochoa, Eguzkine; Carreira, Patricia; Simeón, Carmen Pilar; Castellví, Iván; González-Gay, Miguel Ángel; Ortego-Centeno, Norberto; Ríos, Raquel; Callejas, José Luis; Navarrete, Nuria; García Portales, Rosa; Camps, María Teresa; Fernández-Nebro, Antonio; González-Escribano, María F.; Sánchez-Román, Julio; García-Hernández, Francisco José; Castillo, María Jesús; Aguirre, María Ángeles; Gómez-Gracia, Inmaculada; Fernández-Gutiérrez, Benjamín; Rodríguez-Rodríguez, Luis; Vicente, Esther; Andreu, José Luis; Fernández de Castro, Mónica; García de la Peña, Paloma; López-Longo, Francisco Javier; Martínez, Lina; Fonollosa, Vicente; Espinosa, Gerard; Tolosa, Carlos; Pros, Anna; Rodríguez Carballeira, Mónica; Narváez, Francisco Javier; Rubio Rivas, Manel; Ortiz Santamaría, Vera; Díaz, Bernardino; Trapiella, Luis; Freire, María del Carmen; Sousa, Adrián; Egurbide, María Victoria; Fanlo Mateo, Patricia; Sáez-Comet, Luis; Díaz, Federico; Hernández, Vanesa; Beltrán, Emma; Román-Ivorra, José Andrés; Grau, Elena; Alegre Sancho, Juan José; Blanco García, Francisco J.; Oreiro, Natividad; Fernández Sueiro, Luis; Zhernakova, Alexandra; Padyukov, Leonid; Alarcón-Riquelme, Marta; Wijmenga, Cisca; Brown, Matthew; Beretta, Lorenzo; Riemekasten, Gabriela; Witte, Torsten; Hunzelmann, Nicolas; Kreuter, Alexander; Distler, Jörg H.W.; Voskuyl, Alexandre E.; Schuerwegh, Annemie J.; Hesselstrand, Roger; Nordin, Annika; Airó, Paolo; Lunardi, Claudio; Shiels, Paul; van Laar, Jacob M.; Herrick, Ariane; Worthington, Jane; Denton, Christopher; Wigley, Fredrick M.; Hummers, Laura K.; Varga, John; Hinchcliff, Monique E.; Baron, Murray; Hudson, Marie; Pope, Janet E.; Furst, Daniel E.; Khanna, Dinesh; Phillips, Kristin; Schiopu, Elena; Segal, Barbara M.; Molitor, Jerry A.; Silver, Richard M.; Steen, Virginia D.; Simms, Robert W.; Lafyatis, Robert A.; Fessler, Barri J.; Frech, Tracy M.; AlKassab, Firas; Docherty, Peter; Kaminska, Elzbieta; Khalidi, Nader; Jones, Henry Niall; Markland, Janet; Robinson, David; Broen, Jasper; Radstake, Timothy R.D.J.; Fonseca, Carmen; Koeleman, Bobby P.; Martin, Javier

2014-01-01

In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci. PMID:24387989

Expression quantitative trait loci and genetic regulatory network analysis reveals that Gabra2 is involved in stress responses in the mouse.

PubMed

Dai, Jiajuan; Wang, Xusheng; Chen, Ying; Wang, Xiaodong; Zhu, Jun; Lu, Lu

2009-11-01

Previous studies have revealed that the subunit alpha 2 (Gabra2) of the gamma-aminobutyric acid receptor plays a critical role in the stress response. However, little is known about the gentetic regulatory network for Gabra2 and the stress response. We combined gene expression microarray analysis and quantitative trait loci (QTL) mapping to characterize the genetic regulatory network for Gabra2 expression in the hippocampus of BXD recombinant inbred (RI) mice. Our analysis found that the expression level of Gabra2 exhibited much variation in the hippocampus across the BXD RI strains and between the parental strains, C57BL/6J, and DBA/2J. Expression QTL (eQTL) mapping showed three microarray probe sets of Gabra2 to have highly significant linkage likelihood ratio statistic (LRS) scores. Gene co-regulatory network analysis showed that 10 genes, including Gria3, Chka, Drd3, Homer1, Grik2, Odz4, Prkag2, Grm5, Gabrb1, and Nlgn1 are directly or indirectly associated with stress responses. Eleven genes were implicated as Gabra2 downstream genes through mapping joint modulation. The genetical genomics approach demonstrates the importance and the potential power of the eQTL studies in identifying genetic regulatory networks that contribute to complex traits, such as stress responses.

Analysis of four neuroligin genes as candidates for autism.

PubMed

Ylisaukko-oja, Tero; Rehnström, Karola; Auranen, Mari; Vanhala, Raija; Alen, Reija; Kempas, Elli; Ellonen, Pekka; Turunen, Joni A; Makkonen, Ismo; Riikonen, Raili; Nieminen-von Wendt, Taina; von Wendt, Lennart; Peltonen, Leena; Järvelä, Irma

2005-12-01

Neuroligins are cell-adhesion molecules located at the postsynaptic side of the synapse. Neuroligins interact with beta-neurexins and this interaction is involved in the formation of functional synapses. Mutations in two X-linked neuroligin genes, NLGN3 and NLGN4, have recently been implicated in pathogenesis of autism. The neuroligin gene family consists of five members (NLGN1 at 3q26, NLGN2 at 17p13, NLGN3 at Xq13, NLGN4 at Xp22, and NLGN4Y at Yq11), of which NLGN1 and NLGN3 are located within the best loci observed in our previous genome-wide scan for autism in the Finnish sample. Here, we report a detailed molecular genetic analysis of NLGN1, NLGN3, NLGN4, and NLNG4Y in the Finnish autism sample. Mutation analysis of 30 probands selected from families producing linkage evidence for Xq13 and/or 3q26 loci revealed several polymorphisms, but none of these seemed to be functional. Family-based association analysis in 100 families with autism spectrum disorders yielded only modest associations at NLGN1 (rs1488545, P=0.002), NLGN3 (DXS7132, P=0.014), and NLGN4 (DXS996, P=0.031). We conclude that neuroligin mutations most probably represent rare causes of autism and that it is unlikely that the allelic variants in these genes would be major risk factors for autism.

Association between GWAS-identified lung adenocarcinoma susceptibility loci and EGFR mutations in never-smoking Asian women, and comparison with findings from Western populations

PubMed Central

Seow, Wei Jie; Matsuo, Keitaro; Hsiung, Chao Agnes; Shiraishi, Kouya; Song, Minsun; Kim, Hee Nam; Wong, Maria Pik; Hong, Yun-Chul; Hosgood, H. Dean; Wang, Zhaoming; Chang, I-Shou; Wang, Jiu-Cun; Chatterjee, Nilanjan; Tucker, Margaret; Wei, Hu; Mitsudomi, Tetsuya; Zheng, Wei; Kim, Jin Hee; Zhou, Baosen; Caporaso, Neil E.; Albanes, Demetrius; Shin, Min-Ho; Chung, Lap Ping; An, She-Juan; Wang, Ping; Zheng, Hong; Yatabe, Yasushi; Zhang, Xu-Chao; Kim, Young Tae; Shu, Xiao-Ou; Kim, Young-Chul; Bassig, Bryan A.; Chang, Jiang; Ho, James Chung Man; Ji, Bu-Tian; Kubo, Michiaki; Daigo, Yataro; Ito, Hidemi; Momozawa, Yukihide; Ashikawa, Kyota; Kamatani, Yoichiro; Honda, Takayuki; Sakamoto, Hiromi; Kunitoh, Hideo; Tsuta, Koji; Watanabe, Shun-Ichi; Nokihara, Hiroshi; Miyagi, Yohei; Nakayama, Haruhiko; Matsumoto, Shingo; Tsuboi, Masahiro; Goto, Koichi; Yin, Zhihua; Shi, Jianxin; Takahashi, Atsushi; Goto, Akiteru; Minamiya, Yoshihiro; Shimizu, Kimihiro; Tanaka, Kazumi; Wu, Tangchun; Wei, Fusheng; Wong, Jason Y.Y.; Matsuda, Fumihiko; Su, Jian; Kim, Yeul Hong; Oh, In-Jae; Song, Fengju; Lee, Victor Ho Fun; Su, Wu-Chou; Chen, Yuh-Min; Chang, Gee-Chen; Chen, Kuan-Yu; Huang, Ming-Shyan; Yang, Pan-Chyr; Lin, Hsien-Chih; Xiang, Yong-Bing; Seow, Adeline; Park, Jae Yong; Kweon, Sun-Seog; Chen, Chien-Jen; Li, Haixin; Gao, Yu-Tang; Wu, Chen; Qian, Biyun; Lu, Daru; Liu, Jianjun; Jeon, Hyo-Sung; Hsiao, Chin-Fu; Sung, Jae Sook; Tsai, Ying-Huang; Jung, Yoo Jin; Guo, Huan; Hu, Zhibin; Wang, Wen-Chang; Chung, Charles C.; Lawrence, Charles; Burdett, Laurie; Yeager, Meredith; Jacobs, Kevin B.; Hutchinson, Amy; Berndt, Sonja I.; He, Xingzhou; Wu, Wei; Wang, Junwen; Li, Yuqing; Choi, Jin Eun; Park, Kyong Hwa; Sung, Sook Whan; Liu, Li; Kang, Chang Hyun; Hu, Lingmin; Chen, Chung-Hsing; Yang, Tsung-Ying; Xu, Jun; Guan, Peng; Tan, Wen; Wang, Chih-Liang; Sihoe, Alan Dart Loon; Chen, Ying; Choi, Yi Young; Hung, Jen-Yu; Kim, Jun Suk; Yoon, Ho-Il; Cai, Qiuyin; Lin, Chien-Chung; Park, In Kyu; Xu, Ping; Dong, Jing; Kim, Christopher; He, Qincheng; Perng, Reury-Perng; Chen, Chih-Yi; Vermeulen, Roel; Wu, Junjie; Lim, Wei-Yen; Chen, Kun-Chieh; Chan, John K.C.; Chu, Minjie; Li, Yao-Jen; Li, Jihua; Chen, Hongyan; Yu, Chong-Jen; Jin, Li; Lo, Yen-Li; Chen, Ying-Hsiang; Fraumeni, Joseph F.; Liu, Jie; Yamaji, Taiki; Yang, Yang; Hicks, Belynda; Wyatt, Kathleen; Li, Shengchao A.; Dai, Juncheng; Ma, Hongxia; Jin, Guangfu; Song, Bao; Wang, Zhehai; Cheng, Sensen; Li, Xuelian; Ren, Yangwu; Cui, Ping; Iwasaki, Motoki; Shimazu, Taichi; Tsugane, Shoichiro; Zhu, Junjie; Jiang, Gening; Fei, Ke; Wu, Guoping; Chien, Li-Hsin; Chen, Hui-Ling; Su, Yu-Chun; Tsai, Fang-Yu; Chen, Yi-Song; Yu, Jinming; Stevens, Victoria L.; Laird-Offringa, Ite A.; Marconett, Crystal N.; Lin, Dongxin; Chen, Kexin; Wu, Yi-Long; Landi, Maria Teresa; Shen, Hongbing; Rothman, Nathaniel; Kohno, Takashi; Chanock, Stephen J.; Lan, Qing

2017-01-01

Abstract To evaluate associations by EGFR mutation status for lung adenocarcinoma risk among never-smoking Asian women, we conducted a meta-analysis of 11 loci previously identified in genome-wide association studies (GWAS). Genotyping in an additional 10,780 never-smoking cases and 10,938 never-smoking controls from Asia confirmed associations with eight known single nucleotide polymorphisms (SNPs). Two new signals were observed at genome-wide significance (P < 5 × 10−8), namely, rs7216064 (17q24.3, BPTF), for overall lung adenocarcinoma risk, and rs3817963 (6p21.3, BTNL2) which is specific to cases with EGFR mutations. In further sub-analyses by EGFR status, rs9387478 (ROS1/DCBLD1) and rs2179920 (HLA-DPB1) showed stronger estimated associations in EGFR-positive compared to EGFR-negative cases. Comparison of the overall associations with published results in Western populations revealed that the majority of these findings were distinct, underscoring the importance of distinct contributing factors for smoking and non-smoking lung cancer. Our results extend the catalogue of regions associated with lung adenocarcinoma in non-smoking Asian women and highlight the importance of how the germline could inform risk for specific tumour mutation patterns, which could have important translational implications. PMID:28025329

Restriction fragment length polymorphism mapping of quantitative trait loci for malaria parasite susceptibility in the mosquito Aedes aegypti

DOE Office of Scientific and Technical Information (OSTI.GOV)

Severson, D.W.; Thathy, V.; Mori, A.

Susceptibility of the mosquito Aedes aegypti to the malarial parasite Plasmodium gallinaceum was investigated as a quantitative trait using restriction fragment length polymorphisms (RFLP). Two F{sub 2} populations of mosquitoes were independently prepared from pairwise matings between a highly susceptible and a refractory strain of A. aegypti. RFLP were tested for association with oocyst development on the mosquito midgut. Two putative quantitative trait loci (QTL) were identified that significantly affect susceptibility. One QTL, pgs [2,LF98], is located on chromosome 2 and accounted for 65 and 49% of the observed phenotypic variance in the two populations, respectively. A second QTL, pgs[3,MalI],more » is located on chromosome 3 and accounted for 14 and 10% of the observed phenotypic variance in the two populations, respectively. Both QTL exhibit a partial dominance effect on susceptibility, wherein the dominance effect is derived from the refractory parent. No indication of epistasis between these QTL was detected. Evidence suggests that either a tightly linked cluster of independent genes or a single locus affecting susceptibility to various mosquito-borne parasites and pathogens has evolved near the LF98 locus; in addition to P. gallinaceum susceptibility, this general genome region has previously been implicated in susceptibility to the filaria nematode Brugia malayi and the yellow fever virus. 35 refs., 2 figs., 3 tabs.« less

Hip3 interacts with the HIRA proteins Hip1 and Slm9 and is required for transcriptional silencing and accurate chromosome segregation.

PubMed

Greenall, Amanda; Williams, Emma S; Martin, Katherine A; Palmer, Jeremy M; Gray, Joe; Liu, Cong; Whitehall, Simon K

2006-03-31

The fission yeast HIRA proteins Hip1 and Slm9 are members of an evolutionarily conserved family of histone chaperones that are implicated in nucleosome assembly. Here we have used single-step affinity purification and mass spectrometry to identify factors that interact with both Hip1 and Slm9. This analysis identified Hip3, a previously uncharacterized 187-kDa protein, with similarity to S. cerevisiae Hir3. Consistent with this, cells disrupted for hip3+ exhibit a range of growth defects that are similar to those associated with loss of Hip1 and Slm9. These include temperature sensitivity, a cell cycle delay, and synthetic lethality with cdc25-22. Furthermore, genetic analysis also indicates that disruption of hip3+ is epistatic with mutation of hip1+ and slm9+. Mutation of hip3+ alleviates transcriptional silencing at several heterochromatic loci, including in the outer (otr) centromeric repeats, indicating that Hip3 is required for the integrity of pericentric heterochromatin. As a result, loss of Hip3 function leads to high levels of minichromosome loss and an increased frequency of lagging chromosomes during mitosis. Importantly, the function of Hip1, Slm9, and Hip3 is not restricted to constitutive heterochromatic loci, since these proteins also repress the expression of a number of genes, including the Tf2 retrotransposons.

Sequence capture of ultraconserved elements from bird museum specimens.

PubMed

McCormack, John E; Tsai, Whitney L E; Faircloth, Brant C

2016-09-01

New DNA sequencing technologies are allowing researchers to explore the genomes of the millions of natural history specimens collected prior to the molecular era. Yet, we know little about how well specific next-generation sequencing (NGS) techniques work with the degraded DNA typically extracted from museum specimens. Here, we use one type of NGS approach, sequence capture of ultraconserved elements (UCEs), to collect data from bird museum specimens as old as 120 years. We targeted 5060 UCE loci in 27 western scrub-jays (Aphelocoma californica) representing three evolutionary lineages that could be species, and we collected an average of 3749 UCE loci containing 4460 single nucleotide polymorphisms (SNPs). Despite older specimens producing fewer and shorter loci in general, we collected thousands of markers from even the oldest specimens. More sequencing reads per individual helped to boost the number of UCE loci we recovered from older specimens, but more sequencing was not as successful at increasing the length of loci. We detected contamination in some samples and determined that contamination was more prevalent in older samples that were subject to less sequencing. For the phylogeny generated from concatenated UCE loci, contamination led to incorrect placement of some individuals. In contrast, a species tree constructed from SNPs called within UCE loci correctly placed individuals into three monophyletic groups, perhaps because of the stricter analytical procedures used for SNP calling. This study and other recent studies on the genomics of museum specimens have profound implications for natural history collections, where millions of older specimens should now be considered genomic resources. © 2015 The Authors. Molecular Ecology Resources Published by John Wiley & Sons Ltd.

The association of genome-wide significant spirometric loci with chronic obstructive pulmonary disease susceptibility.

PubMed

Castaldi, Peter J; Cho, Michael H; Litonjua, Augusto A; Bakke, Per; Gulsvik, Amund; Lomas, David A; Anderson, Wayne; Beaty, Terri H; Hokanson, John E; Crapo, James D; Laird, Nan; Silverman, Edwin K

2011-12-01

Two recent metaanalyses of genome-wide association studies conducted by the CHARGE and SpiroMeta consortia identified novel loci yielding evidence of association at or near genome-wide significance (GWS) with FEV(1) and FEV(1)/FVC. We hypothesized that a subset of these markers would also be associated with chronic obstructive pulmonary disease (COPD) susceptibility. Thirty-two single-nucleotide polymorphisms (SNPs) in or near 17 genes in 11 previously identified GWS spirometric genomic regions were tested for association with COPD status in four COPD case-control study samples (NETT/NAS, the Norway case-control study, ECLIPSE, and the first 1,000 subjects in COPDGene; total sample size, 3,456 cases and 1,906 controls). In addition to testing the 32 spirometric GWS SNPs, we tested a dense panel of imputed HapMap2 SNP markers from the 17 genes located near the 32 GWS SNPs and in a set of 21 well studied COPD candidate genes. Of the previously identified GWS spirometric genomic regions, three loci harbored SNPs associated with COPD susceptibility at a 5% false discovery rate: the 4q24 locus including FLJ20184/INTS12/GSTCD/NPNT, the 6p21 locus including AGER and PPT2, and the 5q33 locus including ADAM19. In conclusion, markers previously associated at or near GWS with spirometric measures were tested for association with COPD status in data from four COPD case-control studies, and three loci showed evidence of association with COPD susceptibility at a 5% false discovery rate.

Multiple Novel Prostate Cancer Predisposition Loci Confirmed by an International Study: The PRACTICAL Consortium

PubMed Central

Kote-Jarai, Zsofia; Easton, Douglas F.; Stanford, Janet L.; Ostrander, Elaine A.; Schleutker, Johanna; Ingles, Sue A.; Schaid, Daniel; Thibodeau, Stephen; Dörk, Thilo; Neal, David; Cox, Angela; Maier, Christiane; Vogel, Walter; Guy, Michelle; Muir, Kenneth; Lophatananon, Artitaya; Kedda, Mary-Anne; Spurdle, Amanda; Steginga, Suzanne; John, Esther M.; Giles, Graham; Hopper, John; Chappuis, Pierre O.; Hutter, Pierre; Foulkes, William D.; Hamel, Nancy; Salinas, Claudia A.; Koopmeiners, Joseph S.; Karyadi, Danielle M.; Johanneson, Bo; Wahlfors, Tiina; Tammela, Teuvo L.; Stern, Mariana C.; Corral, Roman; McDonnell, Shannon K.; Schürmann, Peter; Meyer, Andreas; Kuefer, Rainer; Leongamornlert, Daniel A.; Tymrakiewicz, Malgorzata; Liu, Jo-fen; O'Mara, Tracy; Gardiner, R.A. (Frank); Aitken, Joanne; Joshi, Amit D.; Severi, Gianluca; English, Dallas R.; Southey, Melissa; Edwards, Stephen M.; Amin Al Olama, Ali; Eeles, Rosalind A.

2009-01-01

A recent genome-wide association study found that genetic variants on chromosomes 3, 6, 7, 10, 11, 19 and X were associated with prostate cancer risk. We evaluated the most significant single-nucleotide polymorphisms (SNP) in these loci using a worldwide consortium of 13 groups (PRACTICAL). Blood DNA from 7,370 prostate cancer cases and 5,742 male controls was analyzed by genotyping assays. Odds ratios (OR) associated with each genotype were estimated using unconditional logistic regression. Six of the seven SNPs showed clear evidence of association with prostate cancer (P = 0.0007-P = 10−17). For each of these six SNPs, the estimated per-allele OR was similar to those previously reported and ranged from 1.12 to 1.29. One SNP on 3p12 (rs2660753) showed a weaker association than previously reported [per-allele OR, 1.08 (95% confidence interval, 1.00-1.16; P = 0.06) versus 1.18 (95% confidence interval, 1.06-1.31)]. The combined risks associated with each pair of SNPs were consistent with a multiplicative risk model. Under this model, and in combination with previously reported SNPs on 8q and 17q, these loci explain 16% of the familial risk of the disease, and men in the top 10% of the risk distribution have a 2.1-fold increased risk relative to general population rates. This study provides strong confirmation of these susceptibility loci in multiple populations and shows that they make an important contribution to prostate cancer risk prediction. PMID:18708398

Interactome-transcriptome analysis discovers signatures complementary to GWAS Loci of Type 2 Diabetes

PubMed Central

Li, Jing-Woei; Lee, Heung-Man; Wang, Ying; Tong, Amy Hin-Yan; Yip, Kevin Y.; Tsui, Stephen Kwok-Wing; Lok, Si; Ozaki, Risa; Luk, Andrea O; Kong, Alice P. S.; So, Wing-Yee; Ma, Ronald C. W.; Chan, Juliana C. N.; Chan, Ting-Fung

2016-01-01

Protein interactions play significant roles in complex diseases. We analyzed peripheral blood mononuclear cells (PBMC) transcriptome using a multi-method strategy. We constructed a tissue-specific interactome (T2Di) and identified 420 molecular signatures associated with T2D-related comorbidity and symptoms, mainly implicated in inflammation, adipogenesis, protein phosphorylation and hormonal secretion. Apart from explaining the residual associations within the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) study, the T2Di signatures were enriched in pathogenic cell type-specific regulatory elements related to fetal development, immunity and expression quantitative trait loci (eQTL). The T2Di revealed a novel locus near a well-established GWAS loci AChE, in which SRRT interacts with JAZF1, a T2D-GWAS gene implicated in pancreatic function. The T2Di also included known anti-diabetic drug targets (e.g. PPARD, MAOB) and identified possible druggable targets (e.g. NCOR2, PDGFR). These T2Di signatures were validated by an independent computational method, and by expression data of pancreatic islet, muscle and liver with some of the signatures (CEBPB, SREBF1, MLST8, SRF, SRRT and SLC12A9) confirmed in PBMC from an independent cohort of 66 T2D and 66 control subjects. By combining prior knowledge and transcriptome analysis, we have constructed an interactome to explain the multi-layered regulatory pathways in T2D. PMID:27752041

Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array

PubMed Central

Eeles, Rosalind A; Olama, Ali Amin Al; Benlloch, Sara; Saunders, Edward J; Leongamornlert, Daniel A; Tymrakiewicz, Malgorzata; Ghoussaini, Maya; Luccarini, Craig; Dennis, Joe; Jugurnauth-Little, Sarah; Dadaev, Tokhir; Neal, David E; Hamdy, Freddie C; Donovan, Jenny L; Muir, Ken; Giles, Graham G; Severi, Gianluca; Wiklund, Fredrik; Gronberg, Henrik; Haiman, Christopher A; Schumacher, Fredrick; Henderson, Brian; Le Marchand, Loic; Lindstrom, Sara; Kraft, Peter; Hunter, David J; Gapstur, Susan; Chanock, Stephen J; Berndt, Sonja I; Albanes, Demetrius; Andriole, Gerald; Schleutker, Johanna; Weischer, Maren; Canzian, Federico; Riboli, Elio; Key, Tim J; Travis, Ruth; Campa, Daniele; Ingles, Sue A; John, Esther M; Hayes, Richard B; Pharoah, Paul DP; Pashayan, Nora; Khaw, Kay-Tee; Stanford, Janet; Ostrander, Elaine A; Signorello, Lisa B; Thibodeau, Stephen N; Schaid, Dan; Maier, Christiane; Vogel, Walther; Kibel, Adam S; Cybulski, Cezary; Lubinski, Jan; Cannon-Albright; Brenner, Hermann; Park, Jong Y; Kaneva, Radka; Batra, Jyotsna; Spurdle, Amanda B; Clements, Judith A; Teixeira, Manuel R; Dicks, Ed; Lee, Andrew; Dunning, Alison; Baynes, Caroline; Conroy, Don; Maranian, Melanie J; Ahmed, Shahana; Govindasami, Koveela; Guy, Michelle; Wilkinson, Rosemary A; Sawyer, Emma J; Morgan, Angela; Dearnaley, David P; Horwich, Alan; Huddart, Robert A; Khoo, Vincent S; Parker, Christopher C; Van As, Nicholas J; Woodhouse, J; Thompson, Alan; Dudderidge, Tim; Ogden, Chris; Cooper, Colin; Lophatananon, Artitaya; Cox, Angela; Southey, Melissa; Hopper, John L; English, Dallas R; Aly, Markus; Adolfsson, Jan; Xu, Jiangfeng; Zheng, Siqun; Yeager, Meredith; Kaaks, Rudolf; Diver, W Ryan; Gaudet, Mia M; Stern, Mariana; Corral, Roman; Joshi, Amit D; Shahabi, Ahva; Wahlfors, Tiina; Tammela, Teuvo J; Auvinen, Anssi; Virtamo, Jarmo; Klarskov, Peter; Nordestgaard, Børge G; Røder, Andreas; Nielsen, Sune F; Bojesen, Stig E; Siddiq, Afshan; FitzGerald, Liesel; Kolb, Suzanne; Kwon, Erika; Karyadi, Danielle; Blot, William J; Zheng, Wei; Cai, Qiuyin; McDonnell, Shannon K; Rinckleb, Antje; Drake, Bettina; Colditz, Graham; Wokolorczyk, Dominika; Stephenson, Robert A; Teerlink, Craig; Muller, Heiko; Rothenbacher, Dietrich; Sellers, Thomas A; Lin, Hui-Yi; Slavov, Chavdar; Mitev, Vanio; Lose, Felicity; Srinivasan, Srilakshmi; Maia, Sofia; Paulo, Paula; Lange, Ethan; Cooney, Kathleen A; Antoniou, Antonis; Vincent, Daniel; Bacot, François; Tessier; Kote-Jarai, Zsofia; Easton, Douglas F

2013-01-01

Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10−8). More than 70 prostate cancer susceptibility loci, explaining ~30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies. PMID:23535732

Investigation of the multifunctional gene AOP3 expands the regulatory network fine-tuning glucosinolate production in Arabidopsis

PubMed Central

Jensen, Lea M.; Kliebenstein, Daniel J.; Burow, Meike

2015-01-01

Quantitative trait loci (QTL) mapping studies enable identification of loci that are part of regulatory networks controlling various phenotypes. Detailed investigations of genes within these loci are required to ultimately understand the function of individual genes and how they interact with other players in the network. In this study, we use transgenic plants in combination with natural variation to investigate the regulatory role of the AOP3 gene found in GS-AOP locus previously suggested to contribute to the regulation of glucosinolate defense compounds. Phenotypic analysis and QTL mapping in F2 populations with different AOP3 transgenes support that the enzymatic function and the AOP3 RNA both play a significant role in controlling glucosinolate accumulation. Furthermore, we find different loci interacting with either the enzymatic activity or the RNA of AOP3 and thereby extend the regulatory network controlling glucosinolate accumulation. PMID:26442075

Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.

PubMed

van der Harst, Pim; Verweij, Niek

2018-02-02

Coronary artery disease (CAD) is a complex phenotype driven by genetic and environmental factors. Ninety-seven genetic risk loci have been identified to date, but the identification of additional susceptibility loci might be important to enhance our understanding of the genetic architecture of CAD. To expand the number of genome-wide significant loci, catalog functional insights, and enhance our understanding of the genetic architecture of CAD. We performed a genome-wide association study in 34 541 CAD cases and 261 984 controls of UK Biobank resource followed by replication in 88 192 cases and 162 544 controls from CARDIoGRAMplusC4D. We identified 75 loci that replicated and were genome-wide significant ( P <5×10 -8 ) in meta-analysis, 13 of which had not been reported previously. Next, to further identify novel loci, we identified all promising ( P <0.0001) loci in the CARDIoGRAMplusC4D data and performed reciprocal replication and meta-analyses with UK Biobank. This led to the identification of 21 additional novel loci reaching genome-wide significance ( P <5×10 -8 ) in meta-analysis. Finally, we performed a genome-wide meta-analysis of all available data revealing 30 additional novel loci ( P <5×10 -8 ) without further replication. The increase in sample size by UK Biobank raised the number of reconstituted gene sets from 4.2% to 13.9% of all gene sets to be involved in CAD. For the 64 novel loci, 155 candidate causal genes were prioritized, many without an obvious connection to CAD. Fine mapping of the 161 CAD loci generated lists of credible sets of single causal variants and genes for functional follow-up. Genetic risk variants of CAD were linked to development of atrial fibrillation, heart failure, and death. We identified 64 novel genetic risk loci for CAD and performed fine mapping of all 161 risk loci to obtain a credible set of causal variants. The large expansion of reconstituted gene sets argues in favor of an expanded omnigenic model view on the genetic architecture of CAD. © 2017 The Authors.

From genome-wide to candidate gene: an investigation of variation at the major histocompatibility complex in common bottlenose dolphins exposed to harmful algal blooms.

PubMed

Cammen, Kristina M; Wilcox, Lynsey A; Rosel, Patricia E; Wells, Randall S; Read, Andrew J

2015-02-01

The role the major histocompatibility complex (MHC) plays in response to exposure to environmental toxins is relatively poorly understood, particularly in comparison to its well-described role in pathogen immunity. We investigated associations between MHC diversity and resistance to brevetoxins in common bottlenose dolphins (Tursiops truncatus). A previous genome-wide association study investigating an apparent difference in harmful algal bloom (HAB) resistance among dolphin populations in the Gulf of Mexico identified genetic variation associated with survival in close genomic proximity to multiple MHC class II loci. Here, we characterized genetic variation at DQA, DQB, DRA, and DRB loci in dolphins from central-west Florida and the Florida Panhandle, including dolphins that died during HABs and dolphins presumed to have survived HAB exposure. We found that DRB and DQB exhibited patterns of genetic differentiation among geographic regions that differed from neutral microsatellite loci. In addition, genetic differentiation at DRB across multiple pairwise comparisons of live and dead dolphins was greater than differentiation observed at neutral loci. Our findings at these MHC loci did not approach the strength of association with survival previously described for a nearby genetic variant. However, the results provide evidence that selective pressures at the MHC vary among dolphin populations that differ in the frequency of HAB exposure and that the overall composition of DRB variants differs between dolphin survivors and non-survivors of HABs. These results may suggest a potential role of MHC diversity in variable survival of bottlenose dolphins exposed to HABs.

A methodological study of genome-wide DNA methylation analyses using matched archival formalin-fixed paraffin embedded and fresh frozen breast tumors.

PubMed

Espinal, Allyson C; Wang, Dan; Yan, Li; Liu, Song; Tang, Li; Hu, Qiang; Morrison, Carl D; Ambrosone, Christine B; Higgins, Michael J; Sucheston-Campbell, Lara E

2017-02-28

DNA from archival formalin-fixed and paraffin embedded (FFPE) tissue is an invaluable resource for genome-wide methylation studies although concerns about poor quality may limit its use. In this study, we compared DNA methylation profiles of breast tumors using DNA from fresh-frozen (FF) tissues and three types of matched FFPE samples. For 9/10 patients, correlation and unsupervised clustering analysis revealed that the FF and FFPE samples were consistently correlated with each other and clustered into distinct subgroups. Greater than 84% of the top 100 loci previously shown to differentiate ER+ and ER- tumors in FF tissues were also FFPE DML. Weighted Correlation Gene Network Analyses (WCGNA) grouped the DML loci into 16 modules in FF tissue, with ~85% of the module membership preserved across tissue types. Restored FFPE and matched FF samples were profiled using the Illumina Infinium HumanMethylation450K platform. Methylation levels (β-values) across all loci and the top 100 loci previously shown to differentiate tumors by estrogen receptor status (ER+ or ER-) in a larger FF study, were compared between matched FF and FFPE samples using Pearson's correlation, hierarchical clustering and WCGNA. Positive predictive values and sensitivity levels for detecting differentially methylated loci (DML) in FF samples were calculated in an independent FFPE cohort. FFPE breast tumors samples show lower overall detection of DMLs versus FF, however FFPE and FF DMLs compare favorably. These results support the emerging consensus that the 450K platform can be employed to investigate epigenetics in large sets of archival FFPE tissues.

Clustering Genes of Common Evolutionary History

PubMed Central

Gori, Kevin; Suchan, Tomasz; Alvarez, Nadir; Goldman, Nick; Dessimoz, Christophe

2016-01-01

Phylogenetic inference can potentially result in a more accurate tree using data from multiple loci. However, if the loci are incongruent—due to events such as incomplete lineage sorting or horizontal gene transfer—it can be misleading to infer a single tree. To address this, many previous contributions have taken a mechanistic approach, by modeling specific processes. Alternatively, one can cluster loci without assuming how these incongruencies might arise. Such “process-agnostic” approaches typically infer a tree for each locus and cluster these. There are, however, many possible combinations of tree distance and clustering methods; their comparative performance in the context of tree incongruence is largely unknown. Furthermore, because standard model selection criteria such as AIC cannot be applied to problems with a variable number of topologies, the issue of inferring the optimal number of clusters is poorly understood. Here, we perform a large-scale simulation study of phylogenetic distances and clustering methods to infer loci of common evolutionary history. We observe that the best-performing combinations are distances accounting for branch lengths followed by spectral clustering or Ward’s method. We also introduce two statistical tests to infer the optimal number of clusters and show that they strongly outperform the silhouette criterion, a general-purpose heuristic. We illustrate the usefulness of the approach by 1) identifying errors in a previous phylogenetic analysis of yeast species and 2) identifying topological incongruence among newly sequenced loci of the globeflower fly genus Chiastocheta. We release treeCl, a new program to cluster genes of common evolutionary history (http://git.io/treeCl). PMID:26893301

An integrative process model of leadership: examining loci, mechanisms, and event cycles.

PubMed

Eberly, Marion B; Johnson, Michael D; Hernandez, Morela; Avolio, Bruce J

2013-09-01

Utilizing the locus (source) and mechanism (transmission) of leadership framework (Hernandez, Eberly, Avolio, & Johnson, 2011), we propose and examine the application of an integrative process model of leadership to help determine the psychological interactive processes that constitute leadership. In particular, we identify the various dynamics involved in generating leadership processes by modeling how the loci and mechanisms interact through a series of leadership event cycles. We discuss the major implications of this model for advancing an integrative understanding of what constitutes leadership and its current and future impact on the field of psychological theory, research, and practice. © 2013 APA, all rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Farahani, Poupak; Chiu, Sally; Bowlus, Christopher L.

Obesity is a complex disease. To date, over 100 chromosomal loci for body weight, body fat, regional white adipose tissue weight, and other obesity-related traits have been identified in humans and in animal models. For most loci, the underlying genes are not yet identified; some of these chromosomal loci will be alleles of known obesity genes, whereas many will represent alleles of unknown genes. Microarray analysis allows simultaneous multiple gene and pathway discovery. cDNA and oligonucleotide arrays are commonly used to identify differentially expressed genes by surveys of large numbers of known and unnamed genes. Two papers previously identified genesmore » differentially expressed in adipose tissue of mouse models of obesity and diabetes by analysis of hybridization to Affymetrix oligonucleotide chips.« less

Exploiting position effects and the gypsy retrovirus insulator to engineer precisely expressed transgenes.

PubMed

Markstein, Michele; Pitsouli, Chrysoula; Villalta, Christians; Celniker, Susan E; Perrimon, Norbert

2008-04-01

A major obstacle to creating precisely expressed transgenes lies in the epigenetic effects of the host chromatin that surrounds them. Here we present a strategy to overcome this problem, employing a Gal4-inducible luciferase assay to systematically quantify position effects of host chromatin and the ability of insulators to counteract these effects at phiC31 integration loci randomly distributed throughout the Drosophila genome. We identify loci that can be exploited to deliver precise doses of transgene expression to specific tissues. Moreover, we uncover a previously unrecognized property of the gypsy retrovirus insulator to boost gene expression to levels severalfold greater than at most or possibly all un-insulated loci, in every tissue tested. These findings provide the first opportunity to create a battery of transgenes that can be reliably expressed at high levels in virtually any tissue by integration at a single locus, and conversely, to engineer a controlled phenotypic allelic series by exploiting several loci. The generality of our approach makes it adaptable to other model systems to identify and modify loci for optimal transgene expression.

Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants

PubMed Central

Jin, Ying; Andersen, Genevieve; Yorgov, Daniel; Ferrara, Tracey M; Ben, Songtao; Brownson, Kelly M; Holland, Paulene J; Birlea, Stanca A; Siebert, Janet; Hartmann, Anke; Lienert, Anne; van Geel, Nanja; Lambert, Jo; Luiten, Rosalie M; Wolkerstorfer, Albert; van der Veen, JP Wietze; Bennett, Dorothy C; Taïeb, Alain; Ezzedine, Khaled; Kemp, E Helen; Gawkrodger, David J; Weetman, Anthony P; Kõks, Sulev; Prans, Ele; Kingo, Külli; Karelson, Maire; Wallace, Margaret R; McCormack, Wayne T; Overbeck, Andreas; Moretti, Silvia; Colucci, Roberta; Picardo, Mauro; Silverberg, Nanette B; Olsson, Mats; Valle, Yan; Korobko, Igor; Böhm, Markus; Lim, Henry W.; Hamzavi, Iltefat; Zhou, Li; Mi, Qing-Sheng; Fain, Pamela R.; Santorico, Stephanie A; Spritz, Richard A

2016-01-01

Vitiligo is an autoimmune disease in which depigmented skin results from destruction of melanocytes1, with epidemiologic association with other autoimmune diseases2. In previous linkage and genome-wide association studies (GWAS1, GWAS2), we identified 27 vitiligo susceptibility loci in patients of European (EUR) ancestry. We carried out a third GWAS (GWAS3) in EUR subjects, with augmented GWAS1 and GWAS2 controls, genome-wide imputation, and meta-analysis of all three GWAS, followed by an independent replication. The combined analyses, with 4,680 cases and 39,586 controls, identified 23 new loci and 7 suggestive loci, most encoding immune and apoptotic regulators, some also associated with other autoimmune diseases, as well as several melanocyte regulators. Bioinformatic analyses indicate a predominance of causal regulatory variation, some corresponding to eQTL at these loci. Together, the identified genes provide a framework for vitiligo genetic architecture and pathobiology, highlight relationships to other autoimmune diseases and melanoma, and offer potential targets for treatment. PMID:27723757

Extremely low nucleotide polymorphism in Pinus krempfii Lecomte, a unique flat needle pine endemic to Vietnam

PubMed Central

Wang, Baosheng; Khalili Mahani, Marjan; Ng, Wei Lun; Kusumi, Junko; Phi, Hai Hong; Inomata, Nobuyuki; Wang, Xiao-Ru; Szmidt, Alfred E

2014-01-01

Pinus krempfii Lecomte is a morphologically and ecologically unique pine, endemic to Vietnam. It is regarded as vulnerable species with distribution limited to just two provinces: Khanh Hoa and Lam Dong. Although a few phylogenetic studies have included this species, almost nothing is known about its genetic features. In particular, there are no studies addressing the levels and patterns of genetic variation in natural populations of P. krempfii. In this study, we sampled 57 individuals from six natural populations of P. krempfii and analyzed their sequence variation in ten nuclear gene regions (approximately 9 kb) and 14 mitochondrial (mt) DNA regions (approximately 10 kb). We also analyzed variation at seven chloroplast (cp) microsatellite (SSR) loci. We found very low haplotype and nucleotide diversity at nuclear loci compared with other pine species. Furthermore, all investigated populations were monomorphic across all mitochondrial DNA (mtDNA) regions included in our study, which are polymorphic in other pine species. Population differentiation at nuclear loci was low (5.2%) but significant. However, structure analysis of nuclear loci did not detect genetically differentiated groups of populations. Approximate Bayesian computation (ABC) using nuclear sequence data and mismatch distribution analysis for cpSSR loci suggested recent expansion of the species. The implications of these findings for the management and conservation of P. krempfii genetic resources were discussed. PMID:25360263

The human lexinome: Genes of language and reading

PubMed Central

Gibson, Christopher J.; Gruen, Jeffrey R.

2008-01-01

Within the human genome, genetic mapping studies have identified ten regions of different chromosomes, known as DYX loci, in genetic linkage with dyslexia, and two, known as SLI loci, in genetic linkage with Specific Language Impairment. Further genetic studies have identified four dyslexia genes within the DYX loci: DYX1C1 on 15q, KIAA0319 and DCDC2 on 6p22, and ROBO1on 13q. FOXP2 on 7q has been implicated in the development of Speech-Language Disorder. No genes for Specific Language impairment have yet been identified within the two SLI loci. Functional studies have shown that all four dyslexia genes play roles in brain development, and ongoing molecular studies are attempting to elucidate how these genes exert their effects at a subcellular level. Taken together, these genes and loci likely represent only a fraction of the human lexinome, a term we introduce here to refer to the collection of all the genetic and protein elements involved in the development of human language, expression, and reading. Learning outcomes The reader will become familiar with (i) methods for identifying genes for complex diseases, (ii) the application of these methods in the elucidation of genes underlying disorders of language and reading, and (iii) the cellular pathways through which polymorphisms in these genes may contribute to the development of the disorders. PMID:18466916

Haplotype diversity of 16 Y-chromosomal STRs in three main ethnic populations (Malays, Chinese and Indians) in Malaysia.

PubMed

Chang, Yuet Meng; Perumal, Revathi; Keat, Phoon Yoong; Kuehn, Daniel L C

2007-03-22

We have analyzed 16 Y-STR loci (DYS456, DYS389I, DYS390, DYS389II, DYS458, DYS19, DYS385a/b, DYS393, DYS391, DYS439, DYS635 or Y-GATA C4, DYS392, Y-GATA H4, DYS437, DYS438 and DYS448) from the non-recombining region of the human Y-chromosome in 980 male individuals from three main ethnic populations in Malaysia (Malay, Chinese, Indian) using the AmpFlSTR((R)) Y-filertrade mark (Applied Biosystems, Foster City, CA). The observed 17-loci haplotypes and the individual allele frequencies for each locus were estimated, whilst the locus diversity, haplotype diversity and discrimination capacity were calculated in the three ethnic populations. Analysis of molecular variance indicated that 88.7% of the haplotypic variation is found within population and 11.3% is between populations (fixation index F(ST)=0.113, p=0.000). This study has revealed Y-chromosomes with null alleles at several Y-loci, namely DYS458, DYS392, DYS389I, DYS389II, DYS439, DYS448 and Y-GATA H4; and several occurrences of duplications at the highly polymorphic DYS385 loci. Some of these deleted loci were in regions of the Y(q) arm that have been implicated in the occurrence of male infertility.

Memory retrieval and the parietal cortex: a review of evidence from a dual-process perspective.

PubMed

Vilberg, Kaia L; Rugg, Michael D

2008-01-01

Although regions of the parietal cortex have been consistently implicated in episodic memory retrieval, the functional roles of these regions remain poorly understood. The present review presents a meta-analysis of findings from event-related fMRI studies reporting the loci of retrieval effects associated with familiarity- and recollection-related recognition judgments. The results of this analysis support previous suggestions that retrieval-related activity in lateral parietal cortex dissociates between superior regions, where activity likely reflects the task relevance of different classes of recognition test items, and more inferior regions where retrieval-related activity appears closely linked to successful recollection. It is proposed that inferior lateral parietal cortex forms part of a neural network supporting the 'episodic buffer' [Baddeley, A. D. (2000). The episodic buffer: A new component of working memory? Trends in Cognitive Sciences, 4, 417-423].

Insights into DDT Resistance from the Drosophila melanogaster Genetic Reference Panel

PubMed Central

Schmidt, Joshua M.; Battlay, Paul; Gledhill-Smith, Rebecca S.; Good, Robert T.; Lumb, Chris; Fournier-Level, Alexandre; Robin, Charles

2017-01-01

Insecticide resistance is considered a classic model of microevolution, where a strong selective agent is applied to a large natural population, resulting in a change in frequency of alleles that confer resistance. While many insecticide resistance variants have been characterized at the gene level, they are typically single genes of large effect identified in highly resistant pest species. In contrast, multiple variants have been implicated in DDT resistance in Drosophila melanogaster; however, only the Cyp6g1 locus has previously been shown to be relevant to field populations. Here we use genome-wide association studies (GWAS) to identify DDT-associated polygenes and use selective sweep analyses to assess their adaptive significance. We identify and verify two candidate DDT resistance loci. A largely uncharacterized gene, CG10737, has a function in muscles that ameliorates the effects of DDT, while a putative detoxifying P450, Cyp6w1, shows compelling evidence of positive selection. PMID:28935691

Genome-wide association mapping reveals a rich genetic architecture of stripe rust resistance loci in emmer wheat (Triticum turgidum ssp. dicoccum).

PubMed

Liu, Weizhen; Maccaferri, Marco; Chen, Xianming; Laghetti, Gaetano; Pignone, Domenico; Pumphrey, Michael; Tuberosa, Roberto

2017-11-01

SNP-based genome scanning in worldwide domesticated emmer germplasm showed high genetic diversity, rapid linkage disequilibrium decay and 51 loci for stripe rust resistance, a large proportion of which were novel. Cultivated emmer wheat (Triticum turgidum ssp. dicoccum), one of the oldest domesticated crops in the world, is a potentially rich reservoir of variation for improvement of resistance/tolerance to biotic and abiotic stresses in wheat. Resistance to stripe rust (Puccinia striiformis f. sp. tritici) in emmer wheat has been under-investigated. Here, we employed genome-wide association (GWAS) mapping with a mixed linear model to dissect effective stripe rust resistance loci in a worldwide collection of 176 cultivated emmer wheat accessions. Adult plants were tested in six environments and seedlings were evaluated with five races from the United States and one from Italy under greenhouse conditions. Five accessions were resistant across all experiments. The panel was genotyped with the wheat 90,000 Illumina iSelect single nucleotide polymorphism (SNP) array and 5106 polymorphic SNP markers with mapped positions were obtained. A high level of genetic diversity and fast linkage disequilibrium decay were observed. In total, we identified 14 loci associated with field resistance in multiple environments. Thirty-seven loci were significantly associated with all-stage (seedling) resistance and six of them were effective against multiple races. Of the 51 total loci, 29 were mapped distantly from previously reported stripe rust resistance genes or quantitative trait loci and represent newly discovered resistance loci. Our results suggest that GWAS is an effective method for characterizing genes in cultivated emmer wheat and confirm that emmer wheat is a rich source of stripe rust resistance loci that can be used for wheat improvement.

Genome wide association mapping for grain shape traits in indica rice.

PubMed

Feng, Yue; Lu, Qing; Zhai, Rongrong; Zhang, Mengchen; Xu, Qun; Yang, Yaolong; Wang, Shan; Yuan, Xiaoping; Yu, Hanyong; Wang, Yiping; Wei, Xinghua

2016-10-01

Using genome-wide association mapping, 47 SNPs within 27 significant loci were identified for four grain shape traits, and 424 candidate genes were predicted from public database. Grain shape is a key determinant of grain yield and quality in rice (Oryza sativa L.). However, our knowledge of genes controlling rice grain shape remains limited. Genome-wide association mapping based on linkage disequilibrium (LD) has recently emerged as an effective approach for identifying genes or quantitative trait loci (QTL) underlying complex traits in plants. In this study, association mapping based on 5291 single nucleotide polymorphisms (SNPs) was conducted to identify significant loci associated with grain shape traits in a global collection of 469 diverse rice accessions. A total of 47 SNPs were located in 27 significant loci for four grain traits, and explained ~44.93-65.90 % of the phenotypic variation for each trait. In total, 424 candidate genes within a 200 kb extension region (±100 kb of each locus) of these loci were predicted. Of them, the cloned genes GS3 and qSW5 showed very strong effects on grain length and grain width in our study. Comparing with previously reported QTLs for grain shape traits, we found 11 novel loci, including 3, 3, 2 and 3 loci for grain length, grain width, grain length-width ratio and thousand grain weight, respectively. Validation of these new loci would be performed in the future studies. These results revealed that besides GS3 and qSW5, multiple novel loci and mechanisms were involved in determining rice grain shape. These findings provided valuable information for understanding of the genetic control of grain shape and molecular marker assistant selection (MAS) breeding in rice.

Development of microsatellite loci exhibiting reverse ascertainment bias and a sexing marker for use in Emperor Geese (Chen canagica)

USGS Publications Warehouse

Gravley, Megan C.; Sage, George K.; Schmutz, Joel A.; Talbot, Sandra L.

2017-01-01

The Alaskan population of Emperor Geese (Chen canagica) nests on the Yukon–Kuskokwim Delta in western Alaska. Numbers of Emperor Geese in Alaska declined from the 1960s to the mid-1980s and since then, their numbers have slowly increased. Low statistical power of microsatellite loci developed in other waterfowl species and used in previous studies of Emperor Geese are unable to confidently assign individual identity. Microsatellite loci for Emperor Goose were therefore developed using shotgun amplification and next-generation sequencing technology. Forty-one microsatellite loci were screened and 14 were found to be polymorphic in Emperor Geese. Only six markers – a combination of four novel loci and two loci developed in other waterfowl species – are needed to identify an individual from among the Alaskan Emperor Goose population. Genetic markers for identifying sex in Emperor Geese were also developed. The 14 novel variable loci and 15 monomorphic loci were screened for polymorphism in four other Arctic-nesting goose species, Black Brant (Branta bernicla nigricans), Greater White-fronted (Anser albifrons), Canada (B. canadensis) and Cackling (B. hutchinsii) Goose. Emperor Goose exhibited the smallest average number of alleles (3.3) and the lowest expected heterozygosity (0.467). Greater White-fronted Geese exhibited the highest average number of alleles (4.7) and Cackling Geese the highest expected heterozygosity (0.599). Six of the monomorphic loci were variable and able to be characterised in the other goose species assayed, a predicted outcome of reverse ascertainment bias. These findings fail to support the hypothesis of ascertainment bias due to selection of microsatellite markers.

De novo and inherited private variants in MAP1B in periventricular nodular heterotopia.

PubMed

Heinzen, Erin L; O'Neill, Adam C; Zhu, Xiaolin; Allen, Andrew S; Bahlo, Melanie; Chelly, Jamel; Chen, Ming Hui; Dobyns, William B; Freytag, Saskia; Guerrini, Renzo; Leventer, Richard J; Poduri, Annapurna; Robertson, Stephen P; Walsh, Christopher A; Zhang, Mengqi

2018-05-01

Periventricular nodular heterotopia (PVNH) is a malformation of cortical development commonly associated with epilepsy. We exome sequenced 202 individuals with sporadic PVNH to identify novel genetic risk loci. We first performed a trio-based analysis and identified 219 de novo variants. Although no novel genes were implicated in this initial analysis, PVNH cases were found overall to have a significant excess of nonsynonymous de novo variants in intolerant genes (p = 3.27x10-7), suggesting a role for rare new alleles in genes yet to be associated with the condition. Using a gene-level collapsing analysis comparing cases and controls, we identified a genome-wide significant signal driven by four ultra-rare loss-of-function heterozygous variants in MAP1B, including one de novo variant. In at least one instance, the MAP1B variant was inherited from a parent with previously undiagnosed PVNH. The PVNH was frontally predominant and associated with perisylvian polymicrogyria. These results implicate MAP1B in PVNH. More broadly, our findings suggest that detrimental mutations likely arising in immediately preceding generations with incomplete penetrance may also be responsible for some apparently sporadic diseases.

Genetic identification of brain cell types underlying schizophrenia.

PubMed

Skene, Nathan G; Bryois, Julien; Bakken, Trygve E; Breen, Gerome; Crowley, James J; Gaspar, Héléna A; Giusti-Rodriguez, Paola; Hodge, Rebecca D; Miller, Jeremy A; Muñoz-Manchado, Ana B; O'Donovan, Michael C; Owen, Michael J; Pardiñas, Antonio F; Ryge, Jesper; Walters, James T R; Linnarsson, Sten; Lein, Ed S; Sullivan, Patrick F; Hjerling-Leffler, Jens

2018-06-01

With few exceptions, the marked advances in knowledge about the genetic basis of schizophrenia have not converged on findings that can be confidently used for precise experimental modeling. By applying knowledge of the cellular taxonomy of the brain from single-cell RNA sequencing, we evaluated whether the genomic loci implicated in schizophrenia map onto specific brain cell types. We found that the common-variant genomic results consistently mapped to pyramidal cells, medium spiny neurons (MSNs) and certain interneurons, but far less consistently to embryonic, progenitor or glial cells. These enrichments were due to sets of genes that were specifically expressed in each of these cell types. We also found that many of the diverse gene sets previously associated with schizophrenia (genes involved in synaptic function, those encoding mRNAs that interact with FMRP, antipsychotic targets, etc.) generally implicated the same brain cell types. Our results suggest a parsimonious explanation: the common-variant genetic results for schizophrenia point at a limited set of neurons, and the gene sets point to the same cells. The genetic risk associated with MSNs did not overlap with that of glutamatergic pyramidal cells and interneurons, suggesting that different cell types have biologically distinct roles in schizophrenia.

Identification of the sex genes in an early diverged fungus.

PubMed

Idnurm, Alexander; Walton, Felicia J; Floyd, Anna; Heitman, Joseph

2008-01-10

Sex determination in fungi is controlled by a small, specialized region of the genome in contrast to the large sex-specific chromosomes of animals and some plants. Different gene combinations reside at these mating-type (MAT) loci and confer sexual identity; invariably they encode homeodomain, alpha-box, or high mobility group (HMG)-domain transcription factors. So far, MAT loci have been characterized from a single monophyletic clade of fungi, the Dikarya (the ascomycetes and basidiomycetes), and the ancestral state and evolutionary history of these loci have remained a mystery. Mating in the basal members of the kingdom has been less well studied, and even their precise taxonomic inter-relationships are still obscure. Here we apply bioinformatic and genetic mapping to identify the sex-determining (sex) region in Phycomyces blakesleeanus (Zygomycota), which represents an early branch within the fungi. Each sex allele contains a single gene that encodes an HMG-domain protein, implicating the HMG-domain proteins as an earlier form of fungal MAT loci. Additionally, one allele also contains a copy of a unique, chromosome-specific repetitive element, suggesting a generalized mechanism for the earliest steps in the evolution of sex determination and sex chromosome structure in eukaryotes.

Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

PubMed Central

Drong, Alexander W; Abbott, James; Wahl, Simone; Tan, Sian-Tsung; Scott, William R; Campanella, Gianluca; Chadeau-Hyam, Marc; Afzal, Uzma; Ahluwalia, Tarunveer S; Bonder, Marc Jan; Chen, Peng; Dehghan, Abbas; Edwards, Todd L; Esko, Tõnu; Go, Min Jin; Harris, Sarah E; Hartiala, Jaana; Kasela, Silva; Kasturiratne, Anuradhani; Khor, Chiea-Chuen; Kleber, Marcus E; Li, Huaixing; Yu Mok, Zuan; Nakatochi, Masahiro; Sapari, Nur Sabrina; Saxena, Richa; Stewart, Alexandre F R; Stolk, Lisette; Tabara, Yasuharu; Teh, Ai Ling; Wu, Ying; Wu, Jer-Yuarn; Zhang, Yi; Aits, Imke; Da Silva Couto Alves, Alexessander; Das, Shikta; Dorajoo, Rajkumar; Hopewell, Jemma C; Kim, Yun Kyoung; Koivula, Robert W; Luan, Jian’an; Lyytikäinen, Leo-Pekka; Nguyen, Quang N; Pereira, Mark A; Postmus, Iris; Raitakari, Olli T; Bryan, Molly Scannell; Scott, Robert A; Sorice, Rossella; Tragante, Vinicius; Traglia, Michela; White, Jon; Yamamoto, Ken; Zhang, Yonghong; Adair, Linda S; Ahmed, Alauddin; Akiyama, Koichi; Asif, Rasheed; Aung, Tin; Barroso, Inês; Bjonnes, Andrew; Braun, Timothy R; Cai, Hui; Chang, Li-Ching; Chen, Chien-Hsiun; Cheng, Ching-Yu; Chong, Yap-Seng; Collins, Rory; Courtney, Regina; Davies, Gail; Delgado, Graciela; Do, Loi D; Doevendans, Pieter A; Gansevoort, Ron T; Gao, Yu-Tang; Grammer, Tanja B; Grarup, Niels; Grewal, Jagvir; Gu, Dongfeng; Wander, Gurpreet S; Hartikainen, Anna-Liisa; Hazen, Stanley L; He, Jing; Heng, Chew-Kiat; Hixson, James E; Hofman, Albert; Hsu, Chris; Huang, Wei; Husemoen, Lise L N; Hwang, Joo-Yeon; Ichihara, Sahoko; Igase, Michiya; Isono, Masato; Justesen, Johanne M; Katsuya, Tomohiro; Kibriya, Muhammad G; Kim, Young Jin; Kishimoto, Miyako; Koh, Woon-Puay; Kohara, Katsuhiko; Kumari, Meena; Kwek, Kenneth; Lee, Nanette R; Lee, Jeannette; Liao, Jiemin; Lieb, Wolfgang; Liewald, David C M; Matsubara, Tatsuaki; Matsushita, Yumi; Meitinger, Thomas; Mihailov, Evelin; Milani, Lili; Mills, Rebecca; Mononen, Nina; Müller-Nurasyid, Martina; Nabika, Toru; Nakashima, Eitaro; Ng, Hong Kiat; Nikus, Kjell; Nutile, Teresa; Ohkubo, Takayoshi; Ohnaka, Keizo; Parish, Sarah; Paternoster, Lavinia; Peng, Hao; Peters, Annette; Pham, Son T; Pinidiyapathirage, Mohitha J; Rahman, Mahfuzar; Rakugi, Hiromi; Rolandsson, Olov; Ann Rozario, Michelle; Ruggiero, Daniela; Sala, Cinzia F; Sarju, Ralhan; Shimokawa, Kazuro; Snieder, Harold; Sparsø, Thomas; Spiering, Wilko; Starr, John M; Stott, David J; Stram, Daniel O; Sugiyama, Takao; Szymczak, Silke; Tang, W H Wilson; Tong, Lin; Trompet, Stella; Turjanmaa, Väinö; Ueshima, Hirotsugu; Uitterlinden, André G; Umemura, Satoshi; Vaarasmaki, Marja; van Dam, Rob M; van Gilst, Wiek H; van Veldhuisen, Dirk J; Viikari, Jorma S; Waldenberger, Melanie; Wang, Yiqin; Wang, Aili; Wilson, Rory; Wong, Tien-Yin; Xiang, Yong-Bing; Yamaguchi, Shuhei; Ye, Xingwang; Young, Robin D; Young, Terri L; Yuan, Jian-Min; Zhou, Xueya; Asselbergs, Folkert W; Ciullo, Marina; Clarke, Robert; Deloukas, Panos; Franke, Andre; Franks, Paul W; Franks, Steve; Friedlander, Yechiel; Gross, Myron D; Guo, Zhirong; Hansen, Torben; Jarvelin, Marjo-Riitta; Jørgensen, Torben; Jukema, J Wouter; kähönen, Mika; Kajio, Hiroshi; Kivimaki, Mika; Lee, Jong-Young; Lehtimäki, Terho; Linneberg, Allan; Miki, Tetsuro; Pedersen, Oluf; Samani, Nilesh J; Sørensen, Thorkild I A; Takayanagi, Ryoichi; Toniolo, Daniela; Ahsan, Habibul; Allayee, Hooman; Chen, Yuan-Tsong; Danesh, John; Deary, Ian J; Franco, Oscar H; Franke, Lude; Heijman, Bastiaan T; Holbrook, Joanna D; Isaacs, Aaron; Kim, Bong-Jo; Lin, Xu; Liu, Jianjun; März, Winfried; Metspalu, Andres; Mohlke, Karen L; Sanghera, Dharambir K; Shu, Xiao-Ou; van Meurs, Joyce B J; Vithana, Eranga; Wickremasinghe, Ananda R; Wijmenga, Cisca; Wolffenbuttel, Bruce H W; Yokota, Mitsuhiro; Zheng, Wei; Zhu, Dingliang; Vineis, Paolo; Kyrtopoulos, Soterios A; Kleinjans, Jos C S; McCarthy, Mark I; Soong, Richie; Gieger, Christian; Scott, James

2016-01-01

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10−11 to 5.0 × 10−21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10−6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation. PMID:26390057

Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation.

PubMed

Kato, Norihiro; Loh, Marie; Takeuchi, Fumihiko; Verweij, Niek; Wang, Xu; Zhang, Weihua; Kelly, Tanika N; Saleheen, Danish; Lehne, Benjamin; Leach, Irene Mateo; Drong, Alexander W; Abbott, James; Wahl, Simone; Tan, Sian-Tsung; Scott, William R; Campanella, Gianluca; Chadeau-Hyam, Marc; Afzal, Uzma; Ahluwalia, Tarunveer S; Bonder, Marc Jan; Chen, Peng; Dehghan, Abbas; Edwards, Todd L; Esko, Tõnu; Go, Min Jin; Harris, Sarah E; Hartiala, Jaana; Kasela, Silva; Kasturiratne, Anuradhani; Khor, Chiea-Chuen; Kleber, Marcus E; Li, Huaixing; Yu Mok, Zuan; Nakatochi, Masahiro; Sapari, Nur Sabrina; Saxena, Richa; Stewart, Alexandre F R; Stolk, Lisette; Tabara, Yasuharu; Teh, Ai Ling; Wu, Ying; Wu, Jer-Yuarn; Zhang, Yi; Aits, Imke; Da Silva Couto Alves, Alexessander; Das, Shikta; Dorajoo, Rajkumar; Hopewell, Jemma C; Kim, Yun Kyoung; Koivula, Robert W; Luan, Jian'an; Lyytikäinen, Leo-Pekka; Nguyen, Quang N; Pereira, Mark A; Postmus, Iris; Raitakari, Olli T; Bryan, Molly Scannell; Scott, Robert A; Sorice, Rossella; Tragante, Vinicius; Traglia, Michela; White, Jon; Yamamoto, Ken; Zhang, Yonghong; Adair, Linda S; Ahmed, Alauddin; Akiyama, Koichi; Asif, Rasheed; Aung, Tin; Barroso, Inês; Bjonnes, Andrew; Braun, Timothy R; Cai, Hui; Chang, Li-Ching; Chen, Chien-Hsiun; Cheng, Ching-Yu; Chong, Yap-Seng; Collins, Rory; Courtney, Regina; Davies, Gail; Delgado, Graciela; Do, Loi D; Doevendans, Pieter A; Gansevoort, Ron T; Gao, Yu-Tang; Grammer, Tanja B; Grarup, Niels; Grewal, Jagvir; Gu, Dongfeng; Wander, Gurpreet S; Hartikainen, Anna-Liisa; Hazen, Stanley L; He, Jing; Heng, Chew-Kiat; Hixson, James E; Hofman, Albert; Hsu, Chris; Huang, Wei; Husemoen, Lise L N; Hwang, Joo-Yeon; Ichihara, Sahoko; Igase, Michiya; Isono, Masato; Justesen, Johanne M; Katsuya, Tomohiro; Kibriya, Muhammad G; Kim, Young Jin; Kishimoto, Miyako; Koh, Woon-Puay; Kohara, Katsuhiko; Kumari, Meena; Kwek, Kenneth; Lee, Nanette R; Lee, Jeannette; Liao, Jiemin; Lieb, Wolfgang; Liewald, David C M; Matsubara, Tatsuaki; Matsushita, Yumi; Meitinger, Thomas; Mihailov, Evelin; Milani, Lili; Mills, Rebecca; Mononen, Nina; Müller-Nurasyid, Martina; Nabika, Toru; Nakashima, Eitaro; Ng, Hong Kiat; Nikus, Kjell; Nutile, Teresa; Ohkubo, Takayoshi; Ohnaka, Keizo; Parish, Sarah; Paternoster, Lavinia; Peng, Hao; Peters, Annette; Pham, Son T; Pinidiyapathirage, Mohitha J; Rahman, Mahfuzar; Rakugi, Hiromi; Rolandsson, Olov; Ann Rozario, Michelle; Ruggiero, Daniela; Sala, Cinzia F; Sarju, Ralhan; Shimokawa, Kazuro; Snieder, Harold; Sparsø, Thomas; Spiering, Wilko; Starr, John M; Stott, David J; Stram, Daniel O; Sugiyama, Takao; Szymczak, Silke; Tang, W H Wilson; Tong, Lin; Trompet, Stella; Turjanmaa, Väinö; Ueshima, Hirotsugu; Uitterlinden, André G; Umemura, Satoshi; Vaarasmaki, Marja; van Dam, Rob M; van Gilst, Wiek H; van Veldhuisen, Dirk J; Viikari, Jorma S; Waldenberger, Melanie; Wang, Yiqin; Wang, Aili; Wilson, Rory; Wong, Tien-Yin; Xiang, Yong-Bing; Yamaguchi, Shuhei; Ye, Xingwang; Young, Robin D; Young, Terri L; Yuan, Jian-Min; Zhou, Xueya; Asselbergs, Folkert W; Ciullo, Marina; Clarke, Robert; Deloukas, Panos; Franke, Andre; Franks, Paul W; Franks, Steve; Friedlander, Yechiel; Gross, Myron D; Guo, Zhirong; Hansen, Torben; Jarvelin, Marjo-Riitta; Jørgensen, Torben; Jukema, J Wouter; Kähönen, Mika; Kajio, Hiroshi; Kivimaki, Mika; Lee, Jong-Young; Lehtimäki, Terho; Linneberg, Allan; Miki, Tetsuro; Pedersen, Oluf; Samani, Nilesh J; Sørensen, Thorkild I A; Takayanagi, Ryoichi; Toniolo, Daniela; Ahsan, Habibul; Allayee, Hooman; Chen, Yuan-Tsong; Danesh, John; Deary, Ian J; Franco, Oscar H; Franke, Lude; Heijman, Bastiaan T; Holbrook, Joanna D; Isaacs, Aaron; Kim, Bong-Jo; Lin, Xu; Liu, Jianjun; März, Winfried; Metspalu, Andres; Mohlke, Karen L; Sanghera, Dharambir K; Shu, Xiao-Ou; van Meurs, Joyce B J; Vithana, Eranga; Wickremasinghe, Ananda R; Wijmenga, Cisca; Wolffenbuttel, Bruce H W; Yokota, Mitsuhiro; Zheng, Wei; Zhu, Dingliang; Vineis, Paolo; Kyrtopoulos, Soterios A; Kleinjans, Jos C S; McCarthy, Mark I; Soong, Richie; Gieger, Christian; Scott, James; Teo, Yik-Ying; He, Jiang; Elliott, Paul; Tai, E Shyong; van der Harst, Pim; Kooner, Jaspal S; Chambers, John C

2015-11-01

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10(-11) to 5.0 × 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.

Genome-Wide Association Scan Meta-Analysis Identifies Three Loci Influencing Adiposity and Fat Distribution

PubMed Central

Qi, Lu; Speliotes, Elizabeth K.; Thorleifsson, Gudmar; Willer, Cristen J.; Herrera, Blanca M.; Jackson, Anne U.; Lim, Noha; Scheet, Paul; Soranzo, Nicole; Amin, Najaf; Aulchenko, Yurii S.; Chambers, John C.; Drong, Alexander; Luan, Jian'an; Lyon, Helen N.; Rivadeneira, Fernando; Sanna, Serena; Timpson, Nicholas J.; Zillikens, M. Carola; Zhao, Jing Hua; Almgren, Peter; Bandinelli, Stefania; Bennett, Amanda J.; Bergman, Richard N.; Bonnycastle, Lori L.; Bumpstead, Suzannah J.; Chanock, Stephen J.; Cherkas, Lynn; Chines, Peter; Coin, Lachlan; Cooper, Cyrus; Crawford, Gabriel; Doering, Angela; Dominiczak, Anna; Doney, Alex S. F.; Ebrahim, Shah; Elliott, Paul; Erdos, Michael R.; Estrada, Karol; Ferrucci, Luigi; Fischer, Guido; Forouhi, Nita G.; Gieger, Christian; Grallert, Harald; Groves, Christopher J.; Grundy, Scott; Guiducci, Candace; Hadley, David; Hamsten, Anders; Havulinna, Aki S.; Hofman, Albert; Holle, Rolf; Holloway, John W.; Illig, Thomas; Isomaa, Bo; Jacobs, Leonie C.; Jameson, Karen; Jousilahti, Pekka; Karpe, Fredrik; Kuusisto, Johanna; Laitinen, Jaana; Lathrop, G. Mark; Lawlor, Debbie A.; Mangino, Massimo; McArdle, Wendy L.; Meitinger, Thomas; Morken, Mario A.; Morris, Andrew P.; Munroe, Patricia; Narisu, Narisu; Nordström, Anna; Nordström, Peter; Oostra, Ben A.; Palmer, Colin N. A.; Payne, Felicity; Peden, John F.; Prokopenko, Inga; Renström, Frida; Ruokonen, Aimo; Salomaa, Veikko; Sandhu, Manjinder S.; Scott, Laura J.; Scuteri, Angelo; Silander, Kaisa; Song, Kijoung; Yuan, Xin; Stringham, Heather M.; Swift, Amy J.; Tuomi, Tiinamaija; Uda, Manuela; Vollenweider, Peter; Waeber, Gerard; Wallace, Chris; Walters, G. Bragi; Weedon, Michael N.; Witteman, Jacqueline C. M.; Zhang, Cuilin; Zhang, Weihua; Caulfield, Mark J.; Collins, Francis S.; Davey Smith, George; Day, Ian N. M.; Franks, Paul W.; Hattersley, Andrew T.; Hu, Frank B.; Jarvelin, Marjo-Riitta; Kong, Augustine; Kooner, Jaspal S.; Laakso, Markku; Lakatta, Edward; Mooser, Vincent; Morris, Andrew D.; Peltonen, Leena; Samani, Nilesh J.; Spector, Timothy D.; Strachan, David P.; Tanaka, Toshiko; Tuomilehto, Jaakko; Uitterlinden, André G.; van Duijn, Cornelia M.; Wareham, Nicholas J.; Watkins for the PROCARDIS consortia, Hugh; Waterworth, Dawn M.; Boehnke, Michael; Deloukas, Panos; Groop, Leif; Hunter, David J.; Thorsteinsdottir, Unnur; Schlessinger, David; Wichmann, H.-Erich; Frayling, Timothy M.; Abecasis, Gonçalo R.; Hirschhorn, Joel N.; Loos, Ruth J. F.; Stefansson, Kari; Mohlke, Karen L.; Barroso, Inês; McCarthy for the GIANT consortium, Mark I.

2009-01-01

To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist–hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9×10−11) and MSRA (WC, P = 8.9×10−9). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6×10−8). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity. PMID:19557161

Isogenic mice exhibit sexually-dimorphic DNA methylation patterns across multiple tissues.

PubMed

McCormick, Helen; Young, Paul E; Hur, Suzy S J; Booher, Keith; Chung, Hunter; Cropley, Jennifer E; Giannoulatou, Eleni; Suter, Catherine M

2017-12-13

Cytosine methylation is a stable epigenetic modification of DNA that plays an important role in both normal physiology and disease. Most diseases exhibit some degree of sexual dimorphism, but the extent to which epigenetic states are influenced by sex is understudied and poorly understood. To address this deficit we studied DNA methylation patterns across multiple reduced representation bisulphite sequencing datasets (from liver, heart, brain, muscle and spleen) derived from isogenic male and female mice. DNA methylation patterns varied significantly from tissue to tissue, as expected, but they also varied between the sexes, with thousands of sexually dimorphic loci identified. The loci affected were largely autonomous to each tissue, even within tissues derived from the same germ layer. At most loci, differences between genders were driven by females exhibiting hypermethylation relative to males; a proportion of these differences were independent of the presence of testosterone in males. Loci harbouring gender differences were clustered in ontologies related to tissue function. Our findings suggest that gender is underwritten in the epigenome in a tissue-specific and potentially sex hormone-independent manner. Gender-specific epigenetic states are likely to have important implications for understanding sexually dimorphic phenotypes in health and disease.

A Multinational Arab Genome-Wide Association Study Identifies New Genetic Associations for Rheumatoid Arthritis.

PubMed

Saxena, Richa; Plenge, Robert M; Bjonnes, Andrew C; Dashti, Hassan S; Okada, Yukinori; Gad El Haq, Wessam; Hammoudeh, Mohammed; Al Emadi, Samar; Masri, Basel K; Halabi, Hussein; Badsha, Humeira; Uthman, Imad W; Margolin, Lauren; Gupta, Namrata; Mahfoud, Ziyad R; Kapiri, Marianthi; Dargham, Soha R; Aranki, Grace; Kazkaz, Layla A; Arayssi, Thurayya

2017-05-01

Genetic factors underlying susceptibility to rheumatoid arthritis (RA) in Arab populations are largely unknown. This genome-wide association study (GWAS) was undertaken to explore the generalizability of previously reported RA loci to Arab subjects and to discover new Arab-specific genetic loci. The Genetics of Rheumatoid Arthritis in Some Arab States Study was designed to examine the genetics and clinical features of RA patients from Jordan, the Kingdom of Saudi Arabia, Lebanon, Qatar, and the United Arab Emirates. In total, >7 million single-nucleotide polymorphisms (SNPs) were tested for association with RA overall and with seropositive or seronegative RA in 511 RA cases and 352 healthy controls. In addition, replication of 15 signals was attempted in 283 RA cases and 221 healthy controls. A genetic risk score of 68 known RA SNPs was also examined in this study population. Three loci (HLA region, intergenic 5q13, and 17p13 at SMTNL2/GGT6) reached genome-wide significance in the analyses of association with RA and with seropositive RA, and for all 3 loci, evidence of independent replication was demonstrated. Consistent with the findings in European and East Asian populations, the association of RA with HLA-DRB1 amino acid position 11 conferred the strongest effect (P = 4.8 × 10 -16 ), and a weighted genetic risk score of previously associated RA loci was found to be associated with RA (P = 3.41 × 10 -5 ) and with seropositive RA (P = 1.48 × 10 -6 ) in this population. In addition, 2 novel associations specific to Arab populations were found at the 5q13 and 17p13 loci. This first RA GWAS in Arab populations confirms that established HLA-region and known RA risk alleles contribute strongly to the risk and severity of disease in some Arab groups, suggesting that the genetic architecture of RA is similar across ethnic groups. Moreover, this study identified 2 novel RA risk loci in Arabs, offering further population-specific insights into the pathophysiology of RA. © 2017, American College of Rheumatology.

Population genetic analysis of oral treponemes by multilocus enzyme electrophoresis.

PubMed

Dahle, U R; Olsen, I; Tronstad, L; Caugant, D A

1995-10-01

Seventeen treponemes recently isolated from necrotic pulps, periodontal and periapical infections and 17 previously well characterized oral treponemal strains were analyzed by multilocus enzyme electrophoresis. Ten genetic loci were characterized on the basis of the electrophoretic mobilities of their enzymatic products. All loci were polymorphic. The average number of alleles per locus was 7.8. The genetic diversity among the electrophoretic types at each locus ranged from 0.624 to 0.836 with a mean genetic diversity per locus of 0.751. The 34 strains represented 34 electrophoretic types, constituting 6 main divisions (I-VI) separated at genetic distances greater than 0.75. Several of the previously characterized treponemes revealed multiple bands of enzyme activity at several loci, indicating that they were not pure. The characterized strains usually clustered within established species, whereas fresh clinical isolates overlapped species borders. There was a large genetic difference between some reference and clinical strains, indicating that the latter may contain undescribed species. Treponema socranskii and Treponema denticola strains clustered in distinct divisions (IV and V, respectively), with the exception of T. denticola strain FDC 51B2 and T. socranskii subsp. paredis strain VPI D46CPE1, both previously well described. This indicated that the taxonomic assignment of these 2 strains should be reconsidered.

Genomewide Linkage Scan for Diabetic Renal Failure and Albuminuria: The FIND Study

PubMed Central

Igo, Robert P.; Iyengar, Sudha K.; Nicholas, Susanne B.; Goddard, Katrina A.B.; Langefeld, Carl D.; Hanson, Robert L.; Duggirala, Ravindranath; Divers, Jasmin; Abboud, Hanna; Adler, Sharon G.; Arar, Nedal H.; Horvath, Amanda; Elston, Robert C.; Bowden, Donald W.; Guo, Xiuqing; Ipp, Eli; Kao, W.H. Linda; Kimmel, Paul L.; Knowler, William C.; Meoni, Lucy A.; Molineros, Julio; Nelson, Robert G.; Pahl, Madeline V.; Parekh, Rulan S.; Rasooly, Rebekah S.; Schelling, Jeffrey R.; Shah, Vallabh O.; Smith, Michael W.; Winkler, Cheryl A.; Zager, Philip G.; Sedor, John R.; Freedman, Barry I.

2011-01-01

Background Diabetic nephropathy (DN) is a leading cause of mortality and morbidity in patients with type 1 and type 2 diabetes. The multicenter FIND consortium aims to identify genes for DN and its associated quantitative traits, e.g. the urine albumin:creatinine ratio (ACR). Herein, the results of whole-genome linkage analysis and a sparse association scan for ACR and a dichotomous DN phenotype are reported in diabetic individuals. Methods A genomewide scan comprising more than 5,500 autosomal single nucleotide polymorphism markers (average spacing of 0.6 cM) was performed on 1,235 nuclear and extended pedigrees (3,972 diabetic participants) ascertained for DN from African-American (AA), American-Indian (AI), European-American (EA) and Mexican-American (MA) populations. Results Strong evidence for linkage to DN was detected on chromosome 6p (p = 8.0 × 10−5, LOD = 3.09) in EA families as well as suggestive evidence for linkage to chromosome 7p in AI families. Regions on chromosomes 3p in AA, 7q in EA, 16q in AA and 22q in MA displayed suggestive evidence of linkage for urine ACR. The linkage peak on chromosome 22q overlaps the MYH9/APOL1 gene region, previously implicated in AA diabetic and nondiabetic nephropathies. Conclusion These results strengthen the evidence for previously identified genomic regions and implicate several novel loci potentially involved in the pathogenesis of DN. PMID:21454968

TAS3 miR390-dependent loci in non-vascular land plants: towards a comprehensive reconstruction of the gene evolutionary history

PubMed Central

Milyutina, Irina A.; Erokhina, Tatiana N.; Ozerova, Liudmila V.; Troitsky, Alexey V.; Solovyev, Andrey G.

2018-01-01

Trans-acting small interfering RNAs (ta-siRNAs) are transcribed from protein non-coding genomic TAS loci and belong to a plant-specific class of endogenous small RNAs. These siRNAs have been found to regulate gene expression in most taxa including seed plants, gymnosperms, ferns and mosses. In this study, bioinformatic and experimental PCR-based approaches were used as tools to analyze TAS3 and TAS6 loci in transcriptomes and genomic DNAs from representatives of evolutionary distant non-vascular plant taxa such as Bryophyta, Marchantiophyta and Anthocerotophyta. We revealed previously undiscovered TAS3 loci in plant classes Sphagnopsida and Anthocerotopsida, as well as TAS6 loci in Bryophyta classes Tetraphidiopsida, Polytrichopsida, Andreaeopsida and Takakiopsida. These data further unveil the evolutionary pathway of the miR390-dependent TAS3 loci in land plants. We also identified charophyte alga sequences coding for SUPPRESSOR OF GENE SILENCING 3 (SGS3), which is required for generation of ta-siRNAs in plants, and hypothesized that the appearance of TAS3-related sequences could take place at a very early step in evolutionary transition from charophyte algae to an earliest common ancestor of land plants. PMID:29682420

Patterns of population structure and environmental associations to aridity across the range of loblolly pine (Pinus taeda L., Pinaceae).

PubMed

Eckert, Andrew J; van Heerwaarden, Joost; Wegrzyn, Jill L; Nelson, C Dana; Ross-Ibarra, Jeffrey; González-Martínez, Santíago C; Neale, David B

2010-07-01

Natural populations of forest trees exhibit striking phenotypic adaptations to diverse environmental gradients, thereby making them appealing subjects for the study of genes underlying ecologically relevant phenotypes. Here, we use a genome-wide data set of single nucleotide polymorphisms genotyped across 3059 functional genes to study patterns of population structure and identify loci associated with aridity across the natural range of loblolly pine (Pinus taeda L.). Overall patterns of population structure, as inferred using principal components and Bayesian cluster analyses, were consistent with three genetic clusters likely resulting from expansions out of Pleistocene refugia located in Mexico and Florida. A novel application of association analysis, which removes the confounding effects of shared ancestry on correlations between genetic and environmental variation, identified five loci correlated with aridity. These loci were primarily involved with abiotic stress response to temperature and drought. A unique set of 24 loci was identified as F(ST) outliers on the basis of the genetic clusters identified previously and after accounting for expansions out of Pleistocene refugia. These loci were involved with a diversity of physiological processes. Identification of nonoverlapping sets of loci highlights the fundamental differences implicit in the use of either method and suggests a pluralistic, yet complementary, approach to the identification of genes underlying ecologically relevant phenotypes.

A Common Missense Variant in the Neuregulin1 Gene is associated with Both Schizophrenia and Sudden Cardiac Death

PubMed Central

Huertas-Vazquez, Adriana; Teodorescu, Carmen; Reinier, Kyndaron; Uy-Evanado, Audrey; Chugh, Harpriya; Jerger, Katherine; Ayala, Jo; Gunson, Karen; Jui, Jonathan; Newton-Cheh, Christopher; Albert, Christine M.; Chugh, Sumeet S.

2013-01-01

Background Both schizophrenia and epilepsy have been linked to increased risk of sudden cardiac death (SCD). We hypothesized that DNA variants within genes previously associated with schizophrenia and epilepsy may contribute to an increased risk of SCD. Objective To investigate the contribution to SCD susceptibility of DNA variants previously implicated in schizophrenia and epilepsy. Methods From the ongoing Oregon Sudden Unexpected Death Study, comparisons were performed among 340 SCD cases presenting with ventricular fibrillation and 342 controls. We tested for association between 17 SNPs mapped to 14 loci previously implicated in schizophrenia and epilepsy using logistic regression, assuming additive, dominant and recessive genetic models. Results The minor allele of the non-synonymous SNP rs10503929 within the Neuregulin 1 gene (NRG1) was associated with SCD under all three investigated models, with the strongest association for the recessive genetic model (recessive P=4.01×10−5, OR= 4.04; additive P=2.84×10−7, OR= 1.9 and dominant P=9.01×10−6, OR= 2.06). To validate our findings, we further explored the association of this variant in the Harvard Cohort SCD study. The SNP rs10503929 was associated with an increased risk of SCD under the recessive genetic model (P=0.0005, OR= 2.7). This missense variation causes a methionine to threonine change and functional effects are currently unknown. Conclusions The observed association between a schizophrenia-related NRG1 variant and SCD may represent the first evidence of coexisting genetic susceptibility between two conditions that have an established clinical overlap. Further investigation is warranted to explore the molecular mechanisms of this variant in the pathogenesis of SCD. PMID:23524320

Discovering genetic variants in Crohn's disease by exploring genomic regions enriched of weak association signals.

PubMed

D'Addabbo, Annarita; Palmieri, Orazio; Maglietta, Rosalia; Latiano, Anna; Mukherjee, Sayan; Annese, Vito; Ancona, Nicola

2011-08-01

A meta-analysis has re-analysed previous genome-wide association scanning definitively confirming eleven genes and further identifying 21 new loci. However, the identified genes/loci still explain only the minority of genetic predisposition of Crohn's disease. To identify genes weakly involved in disease predisposition by analysing chromosomal regions enriched of single nucleotide polymorphisms with modest statistical association. We utilized the WTCCC data set evaluating 1748 CD and 2938 controls. The identification of candidate genes/loci was performed by a two-step procedure: first of all chromosomal regions enriched of weak association signals were localized; subsequently, weak signals clustered in gene regions were identified. The statistical significance was assessed by non parametric permutation tests. The cytoband enrichment analysis highlighted 44 regions (P≤0.05) enriched with single nucleotide polymorphisms significantly associated with the trait including 23 out of 31 previously confirmed and replicated genes. Importantly, we highlight further 20 novel chromosomal regions carrying approximately one hundred genes/loci with modest association. Amongst these we find compelling functional candidate genes such as MAPT, GRB2 and CREM, LCT, and IL12RB2. Our study suggests a different statistical perspective to discover genes weakly associated with a given trait, although further confirmatory functional studies are needed. Copyright © 2011 Editrice Gastroenterologica Italiana S.r.l. All rights reserved.

Genetic basis of delay discounting in frequent gamblers: examination of a priori candidates and exploration of a panel of dopamine-related loci

PubMed Central

Gray, Joshua C; MacKillop, James

2014-01-01

Introduction Delay discounting is a behavioral economic index of impulsivity that reflects preferences for small immediate rewards relative to larger delayed rewards. It has been consistently linked to pathological gambling and other forms of addictive behavior, and has been proposed to be a behavioral characteristic that may link genetic variation and risk of developing addictive disorders (i.e., an endophenotype). Studies to date have revealed significant associations with polymorphisms associated with dopamine neurotransmission. The current study examined associations between delay discounting and both previously linked variants and a novel panel of dopamine-related variants in a sample of frequent gamblers. Methods Participants were 175 weekly gamblers of European ancestry who completed the Monetary Choice Questionnaire to assess delay discounting preferences and provided a DNA via saliva. Results In a priori tests, two loci previously associated with delayed reward discounting (rs1800497 and rs4680) were not replicated, however, the long form of DRD4 VNTR was significantly associated with lower discounting of delayed rewards. Exploratory analysis of the dopamine-related panel revealed 11 additional significant associations in genes associated with dopamine synthesis, breakdown, reuptake, and receptor function (DRD3, SLC6A3, DDC, DBH, and SLC18A2). An aggregate genetic risk score from the nominally significant loci accounted for 17% of the variance in discounting. Mediational analyses largely supported the presence of indirect effects between the associated loci, delay discounting, and pathological gambling severity. Conclusions These findings do not replicate previously reported associations but identify several novel candidates and provide preliminary support for a systems biology approach to understand the genetic basis of delay discounting. PMID:25365808

Reanalysis of BRCA1/2 negative high risk ovarian cancer patients reveals novel germline risk loci and insights into missing heritability

PubMed Central

Dyson, Gregory; Levin, Nancy K.; Chaudhry, Sophia; Rosati, Rita; Kalpage, Hasini; Simon, Michael S.; Tainsky, Michael A.

2017-01-01

While up to 25% of ovarian cancer (OVCA) cases are thought to be due to inherited factors, the majority of genetic risk remains unexplained. To address this gap, we sought to identify previously undescribed OVCA risk variants through the whole exome sequencing (WES) and candidate gene analysis of 48 women with ovarian cancer and selected for high risk of genetic inheritance, yet negative for any known pathogenic variants in either BRCA1 or BRCA2. In silico SNP analysis was employed to identify suspect variants followed by validation using Sanger DNA sequencing. We identified five pathogenic variants in our sample, four of which are in two genes featured on current multi-gene panels; (RAD51D, ATM). In addition, we found a pathogenic FANCM variant (R1931*) which has been recently implicated in familial breast cancer risk. Numerous rare and predicted to be damaging variants of unknown significance were detected in genes on current commercial testing panels, most prominently in ATM (n = 6) and PALB2 (n = 5). The BRCA2 variant p.K3326*, resulting in a 93 amino acid truncation, was overrepresented in our sample (odds ratio = 4.95, p = 0.01) and coexisted in the germline of these women with other deleterious variants, suggesting a possible role as a modifier of genetic penetrance. Furthermore, we detected loss of function variants in non-panel genes involved in OVCA relevant pathways; DNA repair and cell cycle control, including CHEK1, TP53I3, REC8, HMMR, RAD52, RAD1, POLK, POLQ, and MCM4. In summary, our study implicates novel risk loci as well as highlights the clinical utility for retesting BRCA1/2 negative OVCA patients by genomic sequencing and analysis of genes in relevant pathways. PMID:28591191

Genome-wide analysis of copy number variants in attention deficit hyperactivity disorder: the role of rare variants and duplications at 15q13.3.

PubMed

Williams, Nigel M; Franke, Barbara; Mick, Eric; Anney, Richard J L; Freitag, Christine M; Gill, Michael; Thapar, Anita; O'Donovan, Michael C; Owen, Michael J; Holmans, Peter; Kent, Lindsey; Middleton, Frank; Zhang-James, Yanli; Liu, Lu; Meyer, Jobst; Nguyen, Thuy Trang; Romanos, Jasmin; Romanos, Marcel; Seitz, Christiane; Renner, Tobias J; Walitza, Susanne; Warnke, Andreas; Palmason, Haukur; Buitelaar, Jan; Rommelse, Nanda; Vasquez, Alejandro Arias; Hawi, Ziarih; Langley, Kate; Sergeant, Joseph; Steinhausen, Hans-Christoph; Roeyers, Herbert; Biederman, Joseph; Zaharieva, Irina; Hakonarson, Hakon; Elia, Josephine; Lionel, Anath C; Crosbie, Jennifer; Marshall, Christian R; Schachar, Russell; Scherer, Stephen W; Todorov, Alexandre; Smalley, Susan L; Loo, Sandra; Nelson, Stanley; Shtir, Corina; Asherson, Philip; Reif, Andreas; Lesch, Klaus-Peter; Faraone, Stephen V

2012-02-01

Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Because of its multifactorial etiology, however, identifying the genes involved has been difficult. The authors followed up on recent findings suggesting that rare copy number variants (CNVs) may be important for ADHD etiology. The authors performed a genome-wide analysis of large, rare CNVs (<1% population frequency) in children with ADHD (N=896) and comparison subjects (N=2,455) from the IMAGE II Consortium. The authors observed 1,562 individually rare CNVs >100 kb in size, which segregated into 912 independent loci. Overall, the rate of rare CNVs >100 kb was 1.15 times higher in ADHD case subjects relative to comparison subjects, with duplications spanning known genes showing a 1.2-fold enrichment. In accordance with a previous study, rare CNVs >500 kb showed the greatest enrichment (1.28-fold). CNVs identified in ADHD case subjects were significantly enriched for loci implicated in autism and in schizophrenia. Duplications spanning the CHRNA7 gene at chromosome 15q13.3 were associated with ADHD in single-locus analysis. This finding was consistently replicated in an additional 2,242 ADHD case subjects and 8,552 comparison subjects from four independent cohorts from the United Kingdom, the United States, and Canada. Presence of the duplication at 15q13.3 appeared to be associated with comorbid conduct disorder. These findings support the enrichment of large, rare CNVs in ADHD and implicate duplications at 15q13.3 as a novel risk factor for ADHD. With a frequency of 0.6% in the populations investigated and a relatively large effect size (odds ratio=2.22, 95% confidence interval=1.5–3.6), this locus could be an important contributor to ADHD etiology.

Genome-Wide Analysis of Copy Number Variants in Attention Deficit Hyperactivity Disorder: The Role of Rare Variants and Duplications at 15q13.3

PubMed Central

Franke, Barbara; Mick, Eric; Anney, Richard J.L.; Freitag, Christine M.; Gill, Michael; Thapar, Anita; O'Donovan, Michael C.; Owen, Michael J.; Holmans, Peter; Kent, Lindsey; Middleton, Frank; Zhang-James, Yanli; Liu, Lu; Meyer, Jobst; Nguyen, Thuy Trang; Romanos, Jasmin; Romanos, Marcel; Seitz, Christiane; Renner, Tobias J.; Walitza, Susanne; Warnke, Andreas; Palmason, Haukur; Buitelaar, Jan; Rommelse, Nanda; Vasquez, Alejandro Arias; Hawi, Ziarih; Langley, Kate; Sergeant, Joseph; Steinhausen, Hans-Christoph; Roeyers, Herbert; Biederman, Joseph; Zaharieva, Irina; Hakonarson, Hakon; Elia, Josephine; Lionel, Anath C.; Crosbie, Jennifer; Marshall, Christian R.; Schachar, Russell; Scherer, Stephen W.; Todorov, Alexandre; Smalley, Susan L.; Loo, Sandra; Nelson, Stanley; Shtir, Corina; Asherson, Philip; Reif, Andreas; Lesch, Klaus-Peter

2012-01-01

Objective: Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Because of its multifactorial etiology, however, identifying the genes involved has been difficult. The authors followed up on recent findings suggesting that rare copy number variants (CNVs) may be important for ADHD etiology. Method: The authors performed a genome-wide analysis of large, rare CNVs (<1% population frequency) in children with ADHD (N=896) and comparison subjects (N=2,455) from the IMAGE II Consortium. Results: The authors observed 1,562 individually rare CNVs >100 kb in size, which segregated into 912 independent loci. Overall, the rate of rare CNVs >100 kb was 1.15 times higher in ADHD case subjects relative to comparison subjects, with duplications spanning known genes showing a 1.2-fold enrichment. In accordance with a previous study, rare CNVs >500 kb showed the greatest enrichment (1.28-fold). CNVs identified in ADHD case subjects were significantly enriched for loci implicated in autism and in schizophrenia. Duplications spanning the CHRNA7 gene at chromosome 15q13.3 were associated with ADHD in single-locus analysis. This finding was consistently replicated in an additional 2,242 ADHD case subjects and 8,552 comparison subjects from four independent cohorts from the United Kingdom, the United States, and Canada. Presence of the duplication at 15q13.3 appeared to be associated with comorbid conduct disorder. Conclusions: These findings support the enrichment of large, rare CNVs in ADHD and implicate duplications at 15q13.3 as a novel risk factor for ADHD. With a frequency of 0.6% in the populations investigated and a relatively large effect size (odds ratio=2.22, 95% confidence interval=1.5–3.6), this locus could be an important contributor to ADHD etiology. PMID:22420048

A GWA study reveals genetic loci for body conformation traits in Chinese Laiwu pigs and its implications for human BMI.

PubMed

Zhou, Lisheng; Ji, Jiuxiu; Peng, Song; Zhang, Zhen; Fang, Shaoming; Li, Lin; Zhu, Yaling; Huang, Lusheng; Chen, Congying; Ma, Junwu

2016-12-01

Pigs share numerous physiological and phenotypic similarities with human and thus have been considered as a good model in nonrodent mammals for the study of genetic basis of human obesity. Researches on candidate genes for obesity traits have successfully identified some common genes between humans and pigs. However, few studies have assessed how many similarities exist between the genetic architecture of obesity in pigs and humans by large-scale comparative genomics. Here, we performed a genome-wide association study (GWAS) using the porcine 60 K SNP Beadchip for BMI and other four conformation traits at three different ages in a Chinese Laiwu pig population, which shows a large variability in fat deposition. In total, 35 SNPs were found to be significant at Bonferroni-corrected 5 % chromosome-wise level (P = 2.13 × 10 -5 ) and 88 SNPs had suggestive (P < 10 -4 ) association with the conformation traits. Some SNPs showed age-dependent association. Intriguingly, out of 32 regions associated with BMI in pigs, 18 were homologous with the loci for BMI in humans. Furthermore, five closest genes to GWAS peaks including HIF1AN, SMYD3, COX10, SLMAP, and GBE1 have been already associated with BMI in humans, which makes them very promising candidates for these QTLs. The result of GO analysis provided strong support to the fact that mitochondria and synapse play important roles in obesity susceptibility, which is consistent with previous findings on human obesity, and it also implicated new gene sets related to chromatin modification and Ig-like C2-type 5 domain. Therefore, these results not only provide new insights into the genetic architecture of BMI in pigs but also highlight that humans and pigs share the significant overlap of obesity-related genes.

Allozyme variation and possible phylogenetic implications in Abies cephalonica Loudon and some related eastern Mediterranean firs

Treesearch

B. Fady; M. T. Conkle

1993-01-01

A total of 22 loci were assayed in several populations of Abies cephalonica, A. borisii regis, A. bornmuelleriana and A. alba using horizontal starch gel electrophoresis. Within and between-population diversity were analyzed as well as between-species diversity. Mean expected heterozygosity was...

GEOGRAPHIC DISTRIBUTION OF MOLECULAR VARIANCE WITHIN THE BLUE MARLIN (MAKAIRA NIGRICANS): A HIERARCHICAL ANALYSIS OF ALLOZYME, SINGLE-COPY NUCLEAR DNA, AND MITOCHONDRIAL DNA MARKERS.

PubMed

Buonaccorsi, Vincent P; Reece, Kimberly S; Morgan, Lee W; Graves, John E

1999-04-01

This study presents a comparative hierarchical analysis of variance applied to three classes of molecular markers within the blue marlin (Makaira nigricans). Results are reported from analyses of four polymorphic allozyme loci, four polymorphic anonymously chosen single-copy nuclear DNA (scnDNA) loci, and previously reported restriction fragment length polymorphisms (RFLPs) of mitochondrial DNA (mtDNA). Samples were collected within and among the Atlantic and Pacific Oceans over a period of several years. Although moderate levels of genetic variation were detected at both polymorphic allozyme (H = 0.30) and scnDNA loci (H = 0.37), mtDNA markers were much more diverse (h = 0.85). Allele frequencies were significantly different between Atlantic and Pacific Ocean samples at three of four allozyme loci and three of four scnDNA loci. Estimates of allozyme genetic differentiation (θ O ) ranged from 0.00 to 0.15, with a mean of 0.08. The θ O values for scnDNA loci were similar to those of allozymes, ranging from 0.00 to 0.12 with a mean of 0.09. MtDNA RFLP divergence between oceans (θ O = 0.39) was significantly greater than divergence detected at nuclear loci (95% nuclear confidence interval = 0.04-0.11). The fourfold smaller effective population size of mtDNA and male-mediated gene flow may account for the difference observed between nuclear and mitochondrial divergence estimates. © 1999 The Society for the Study of Evolution.

Identification and Validation of Loci Governing Seed Coat Color by Combining Association Mapping and Bulk Segregation Analysis in Soybean

PubMed Central

Ma, Yansong; Tian, Long; Li, Xinxiu; Li, Ying-Hui; Guan, Rongxia; Guo, Yong; Qiu, Li-Juan

2016-01-01

Soybean seed coat exists in a range of colors from yellow, green, brown, black, to bicolor. Classical genetic analysis suggested that soybean seed color was a moderately complex trait controlled by multi-loci. However, only a couple of loci could be detected using a single biparental segregating population. In this study, a combination of association mapping and bulk segregation analysis was employed to identify genes/loci governing this trait in soybean. A total of 14 loci, including nine novel and five previously reported ones, were identified using 176,065 coding SNPs selected from entire SNP dataset among 56 soybean accessions. Four of these loci were confirmed and further mapped using a biparental population developed from the cross between ZP95-5383 (yellow seed color) and NY279 (brown seed color), in which different seed coat colors were further dissected into simple trait pairs (green/yellow, green/black, green/brown, yellow/black, yellow/brown, and black/brown) by continuously developing residual heterozygous lines. By genotyping entire F2 population using flanking markers located in fine-mapping regions, the genetic basis of seed coat color was fully dissected and these four loci could explain all variations of seed colors in this population. These findings will be useful for map-based cloning of genes as well as marker-assisted breeding in soybean. This work also provides an alternative strategy for systematically isolating genes controlling relative complex trait by association analysis followed by biparental mapping. PMID:27404272

Genome-Wide Association Study Identifies Loci for Salt Tolerance during Germination in Autotetraploid Alfalfa (Medicago sativa L.) Using Genotyping-by-Sequencing

PubMed Central

Yu, Long-Xi; Liu, Xinchun; Boge, William; Liu, Xiang-Ping

2016-01-01

Salinity is one of major abiotic stresses limiting alfalfa (Medicago sativa L.) production in the arid and semi-arid regions in US and other counties. In this study, we used a diverse panel of alfalfa accessions previously described by Zhang et al. (2015) to identify molecular markers associated with salt tolerance during germination using genome-wide association study (GWAS) and genotyping-by-sequencing (GBS). Phenotyping was done by germinating alfalfa seeds under different levels of salt stress. Phenotypic data of adjusted germination rates and SNP markers generated by GBS were used for marker-trait association. Thirty six markers were significantly associated with salt tolerance in at least one level of salt treatments. Alignment of sequence tags to the Medicago truncatula genome revealed genetic locations of the markers on all chromosomes except chromosome 3. Most significant markers were found on chromosomes 1, 2, and 4. BLAST search using the flanking sequences of significant markers identified 14 putative candidate genes linked to 23 significant markers. Most of them were repeatedly identified in two or three salt treatments. Several loci identified in the present study had similar genetic locations to the reported QTL associated with salt tolerance in M. truncatula. A locus identified on chromosome 6 by this study overlapped with that by drought in our previous study. To our knowledge, this is the first report on mapping loci associated with salt tolerance during germination in autotetraploid alfalfa. Further investigation on these loci and their linked genes would provide insight into understanding molecular mechanisms by which salt and drought stresses affect alfalfa growth. Functional markers closely linked to the resistance loci would be useful for MAS to improve alfalfa cultivars with enhanced resistance to drought and salt stresses. PMID:27446182

Gene-based meta-analysis of genome-wide association study data identifies independent single-nucleotide polymorphisms in ANXA6 as being associated with systemic lupus erythematosus in Asian populations.

PubMed

Zhang, Jing; Zhang, Lu; Zhang, Yan; Yang, Jing; Guo, Mengbiao; Sun, Liangdan; Pan, Hai-Feng; Hirankarn, Nattiya; Ying, Dingge; Zeng, Shuai; Lee, Tsz Leung; Lau, Chak Sing; Chan, Tak Mao; Leung, Alexander Moon Ho; Mok, Chi Chiu; Wong, Sik Nin; Lee, Ka Wing; Ho, Marco Hok Kung; Lee, Pamela Pui Wah; Chung, Brian Hon-Yin; Chong, Chun Yin; Wong, Raymond Woon Sing; Mok, Mo Yin; Wong, Wilfred Hing Sang; Tong, Kwok Lung; Tse, Niko Kei Chiu; Li, Xiang-Pei; Avihingsanon, Yingyos; Rianthavorn, Pornpimol; Deekajorndej, Thavatchai; Suphapeetiporn, Kanya; Shotelersuk, Vorasuk; Ying, Shirley King Yee; Fung, Samuel Ka Shun; Lai, Wai Ming; Garcia-Barceló, Maria-Mercè; Cherny, Stacey S; Sham, Pak Chung; Cui, Yong; Yang, Sen; Ye, Dong Qing; Zhang, Xue-Jun; Lau, Yu Lung; Yang, Wanling

2015-11-01

Previous genome-wide association studies (GWAS), which were mainly based on single-variant analysis, have identified many systemic lupus erythematosus (SLE) susceptibility loci. However, the genetic architecture of this complex disease is far from being understood. The aim of this study was to investigate whether using a gene-based analysis may help to identify novel loci, by considering global evidence of association from a gene or a genomic region rather than focusing on evidence for individual variants. Based on the results of a meta-analysis of 2 GWAS of SLE conducted in 2 Asian cohorts, we performed an in-depth gene-based analysis followed by replication in a total of 4,626 patients and 7,466 control subjects of Asian ancestry. Differential allelic expression was measured by pyrosequencing. More than one-half of the reported SLE susceptibility loci showed evidence of independent effects, and this finding is important for understanding the mechanisms of association and explaining disease heritability. ANXA6 was detected as a novel SLE susceptibility gene, with several single-nucleotide polymorphisms (SNPs) contributing independently to the association with disease. The risk allele of rs11960458 correlated significantly with increased expression of ANXA6 in peripheral blood mononuclear cells from heterozygous healthy control subjects. Several other associated SNPs may also regulate ANXA6 expression, according to data obtained from public databases. Higher expression of ANXA6 in patients with SLE was also reported previously. Our study demonstrated the merit of using gene-based analysis to identify novel susceptibility loci, especially those with independent effects, and also demonstrated the widespread presence of loci with independent effects in SLE susceptibility genes. © 2015, American College of Rheumatology.

A methodological study of genome-wide DNA methylation analyses using matched archival formalin-fixed paraffin embedded and fresh frozen breast tumors

PubMed Central

Yan, Li; Liu, Song; Tang, Li; Hu, Qiang; Morrison, Carl D.; Ambrosone, Christine B.; Higgins, Michael J.; Sucheston-Campbell, Lara E.

2017-01-01

Background DNA from archival formalin-fixed and paraffin embedded (FFPE) tissue is an invaluable resource for genome-wide methylation studies although concerns about poor quality may limit its use. In this study, we compared DNA methylation profiles of breast tumors using DNA from fresh-frozen (FF) tissues and three types of matched FFPE samples. Results For 9/10 patients, correlation and unsupervised clustering analysis revealed that the FF and FFPE samples were consistently correlated with each other and clustered into distinct subgroups. Greater than 84% of the top 100 loci previously shown to differentiate ER+ and ER– tumors in FF tissues were also FFPE DML. Weighted Correlation Gene Network Analyses (WCGNA) grouped the DML loci into 16 modules in FF tissue, with ~85% of the module membership preserved across tissue types. Materials and Methods Restored FFPE and matched FF samples were profiled using the Illumina Infinium HumanMethylation450K platform. Methylation levels (β-values) across all loci and the top 100 loci previously shown to differentiate tumors by estrogen receptor status (ER+ or ER−) in a larger FF study, were compared between matched FF and FFPE samples using Pearson's correlation, hierarchical clustering and WCGNA. Positive predictive values and sensitivity levels for detecting differentially methylated loci (DML) in FF samples were calculated in an independent FFPE cohort. Conclusions FFPE breast tumors samples show lower overall detection of DMLs versus FF, however FFPE and FF DMLs compare favorably. These results support the emerging consensus that the 450K platform can be employed to investigate epigenetics in large sets of archival FFPE tissues. PMID:28118602

Genome-Wide Association Study Identifies Loci for Salt Tolerance during Germination in Autotetraploid Alfalfa (Medicago sativa L.) Using Genotyping-by-Sequencing.

PubMed

Yu, Long-Xi; Liu, Xinchun; Boge, William; Liu, Xiang-Ping

2016-01-01

Salinity is one of major abiotic stresses limiting alfalfa (Medicago sativa L.) production in the arid and semi-arid regions in US and other counties. In this study, we used a diverse panel of alfalfa accessions previously described by Zhang et al. (2015) to identify molecular markers associated with salt tolerance during germination using genome-wide association study (GWAS) and genotyping-by-sequencing (GBS). Phenotyping was done by germinating alfalfa seeds under different levels of salt stress. Phenotypic data of adjusted germination rates and SNP markers generated by GBS were used for marker-trait association. Thirty six markers were significantly associated with salt tolerance in at least one level of salt treatments. Alignment of sequence tags to the Medicago truncatula genome revealed genetic locations of the markers on all chromosomes except chromosome 3. Most significant markers were found on chromosomes 1, 2, and 4. BLAST search using the flanking sequences of significant markers identified 14 putative candidate genes linked to 23 significant markers. Most of them were repeatedly identified in two or three salt treatments. Several loci identified in the present study had similar genetic locations to the reported QTL associated with salt tolerance in M. truncatula. A locus identified on chromosome 6 by this study overlapped with that by drought in our previous study. To our knowledge, this is the first report on mapping loci associated with salt tolerance during germination in autotetraploid alfalfa. Further investigation on these loci and their linked genes would provide insight into understanding molecular mechanisms by which salt and drought stresses affect alfalfa growth. Functional markers closely linked to the resistance loci would be useful for MAS to improve alfalfa cultivars with enhanced resistance to drought and salt stresses.

Genetic basis of coaggregation receptor polysaccharide biosynthesis in Streptococcus sanguinis and related species.

PubMed

Yang, J; Yoshida, Y; Cisar, J O

2014-02-01

Interbacterial adhesion between streptococci and actinomyces promotes early dental plaque biofilm development. Recognition of coaggregation receptor polysaccharides (RPS) on strains of Streptococcus sanguinis, Streptococcus gordonii and Streptococcus oralis by Actinomyces spp. type 2 fimbriae is the principal mechanism of these interactions. Previous studies of genetic loci for synthesis of RPS (rps) and RPS precursors (rml, galE1 and galE2) in S. gordonii 38 and S. oralis 34 revealed differences between these strains. To determine whether these differences are strain-specific or species-specific, we identified and compared loci for polysaccharide biosynthesis in additional strains of these species and in several strains of the previously unstudied species, S. sanguinis. Genes for synthesis of RPS precursors distinguished the rps loci of different streptococci. Hence, rml genes for synthesis of TDP-L-Rha were in rps loci of S. oralis strains but at other loci in S. gordonii and S. sanguinis. Genes for two distinct galactose epimerases were also distributed differently. Hence, galE1 for epimerization of UDP-Glc and UDP-Gal was in galactose operons of S. gordonii and S. sanguinis strains but surprisingly, this gene was not present in S. oralis. Moreover, galE2 for epimerization of both UDP-Glc and UDP-Gal and UDP-GlcNAc and UDP-GalNAc was at a different locus in each species, including rps operons of S. sanguinis. The findings provide insight into cell surface properties that distinguish different RPS-producing streptococci and open an approach for identifying these bacteria based on the arrangement of genes for synthesis of polysaccharide precursors. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.

Gene Expression Elucidates Functional Impact of Polygenic Risk for Schizophrenia

PubMed Central

Fromer, Menachem; Roussos, Panos; Sieberts, Solveig K; Johnson, Jessica S; Kavanagh, David H; Perumal, Thanneer M; Ruderfer, Douglas M; Oh, Edwin C; Topol, Aaron; Shah, Hardik R; Klei, Lambertus L; Kramer, Robin; Pinto, Dalila; Gümüş, Zeynep H; Cicek, A. Ercument; Dang, Kristen K; Browne, Andrew; Lu, Cong; Xie, Lu; Readhead, Ben; Stahl, Eli A; Parvizi, Mahsa; Hamamsy, Tymor; Fullard, John F; Wang, Ying-Chih; Mahajan, Milind C; Derry, Jonathan M J; Dudley, Joel; Hemby, Scott E; Logsdon, Benjamin A; Talbot, Konrad; Raj, Towfique; Bennett, David A; De Jager, Philip L; Zhu, Jun; Zhang, Bin; Sullivan, Patrick F; Chess, Andrew; Purcell, Shaun M; Shinobu, Leslie A; Mangravite, Lara M; Toyoshiba, Hiroyoshi; Gur, Raquel E; Hahn, Chang-Gyu; Lewis, David A; Haroutunian, Vahram; Peters, Mette A; Lipska, Barbara K; Buxbaum, Joseph D; Schadt, Eric E; Hirai, Keisuke; Roeder, Kathryn; Brennand, Kristen J; Katsanis, Nicholas; Domenici, Enrico; Devlin, Bernie; Sklar, Pamela

2016-01-01

Over 100 genetic loci harbor schizophrenia associated variants, yet how these variants confer liability is uncertain. The CommonMind Consortium sequenced RNA from dorsolateral prefrontal cortex of schizophrenia cases (N = 258) and control subjects (N = 279), creating a resource of gene expression and its genetic regulation. Using this resource, ~20% of schizophrenia loci have variants that could contribute to altered gene expression and liability. In five loci, only a single gene was involved: FURIN, TSNARE1, CNTN4, CLCN3, or SNAP91. Altering expression of FURIN, TSNARE1, or CNTN4 changes neurodevelopment in zebrafish; knockdown of FURIN in human neural progenitor cells yields abnormal migration. Of 693 genes showing significant case/control differential expression, their fold changes are ≤ 1.33, and an independent cohort yields similar results. Gene co-expression implicates a network relevant for schizophrenia. Our findings show schizophrenia is polygenic and highlight the utility of this resource for mechanistic interpretations of genetic liability for brain diseases. PMID:27668389

Gene expression elucidates functional impact of polygenic risk for schizophrenia.

PubMed

Fromer, Menachem; Roussos, Panos; Sieberts, Solveig K; Johnson, Jessica S; Kavanagh, David H; Perumal, Thanneer M; Ruderfer, Douglas M; Oh, Edwin C; Topol, Aaron; Shah, Hardik R; Klei, Lambertus L; Kramer, Robin; Pinto, Dalila; Gümüş, Zeynep H; Cicek, A Ercument; Dang, Kristen K; Browne, Andrew; Lu, Cong; Xie, Lu; Readhead, Ben; Stahl, Eli A; Xiao, Jianqiu; Parvizi, Mahsa; Hamamsy, Tymor; Fullard, John F; Wang, Ying-Chih; Mahajan, Milind C; Derry, Jonathan M J; Dudley, Joel T; Hemby, Scott E; Logsdon, Benjamin A; Talbot, Konrad; Raj, Towfique; Bennett, David A; De Jager, Philip L; Zhu, Jun; Zhang, Bin; Sullivan, Patrick F; Chess, Andrew; Purcell, Shaun M; Shinobu, Leslie A; Mangravite, Lara M; Toyoshiba, Hiroyoshi; Gur, Raquel E; Hahn, Chang-Gyu; Lewis, David A; Haroutunian, Vahram; Peters, Mette A; Lipska, Barbara K; Buxbaum, Joseph D; Schadt, Eric E; Hirai, Keisuke; Roeder, Kathryn; Brennand, Kristen J; Katsanis, Nicholas; Domenici, Enrico; Devlin, Bernie; Sklar, Pamela

2016-11-01

Over 100 genetic loci harbor schizophrenia-associated variants, yet how these variants confer liability is uncertain. The CommonMind Consortium sequenced RNA from dorsolateral prefrontal cortex of people with schizophrenia (N = 258) and control subjects (N = 279), creating a resource of gene expression and its genetic regulation. Using this resource, ∼20% of schizophrenia loci have variants that could contribute to altered gene expression and liability. In five loci, only a single gene was involved: FURIN, TSNARE1, CNTN4, CLCN3 or SNAP91. Altering expression of FURIN, TSNARE1 or CNTN4 changed neurodevelopment in zebrafish; knockdown of FURIN in human neural progenitor cells yielded abnormal migration. Of 693 genes showing significant case-versus-control differential expression, their fold changes were ≤ 1.33, and an independent cohort yielded similar results. Gene co-expression implicates a network relevant for schizophrenia. Our findings show that schizophrenia is polygenic and highlight the utility of this resource for mechanistic interpretations of genetic liability for brain diseases.

Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness.

PubMed

Willems, Sara M; Wright, Daniel J; Day, Felix R; Trajanoska, Katerina; Joshi, Peter K; Morris, John A; Matteini, Amy M; Garton, Fleur C; Grarup, Niels; Oskolkov, Nikolay; Thalamuthu, Anbupalam; Mangino, Massimo; Liu, Jun; Demirkan, Ayse; Lek, Monkol; Xu, Liwen; Wang, Guan; Oldmeadow, Christopher; Gaulton, Kyle J; Lotta, Luca A; Miyamoto-Mikami, Eri; Rivas, Manuel A; White, Tom; Loh, Po-Ru; Aadahl, Mette; Amin, Najaf; Attia, John R; Austin, Krista; Benyamin, Beben; Brage, Søren; Cheng, Yu-Ching; Cięszczyk, Paweł; Derave, Wim; Eriksson, Karl-Fredrik; Eynon, Nir; Linneberg, Allan; Lucia, Alejandro; Massidda, Myosotis; Mitchell, Braxton D; Miyachi, Motohiko; Murakami, Haruka; Padmanabhan, Sandosh; Pandey, Ashutosh; Papadimitriou, Ioannis; Rajpal, Deepak K; Sale, Craig; Schnurr, Theresia M; Sessa, Francesco; Shrine, Nick; Tobin, Martin D; Varley, Ian; Wain, Louise V; Wray, Naomi R; Lindgren, Cecilia M; MacArthur, Daniel G; Waterworth, Dawn M; McCarthy, Mark I; Pedersen, Oluf; Khaw, Kay-Tee; Kiel, Douglas P; Pitsiladis, Yannis; Fuku, Noriyuki; Franks, Paul W; North, Kathryn N; van Duijn, Cornelia M; Mather, Karen A; Hansen, Torben; Hansson, Ola; Spector, Tim; Murabito, Joanne M; Richards, J Brent; Rivadeneira, Fernando; Langenberg, Claudia; Perry, John R B; Wareham, Nick J; Scott, Robert A

2017-07-12

Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P<5 × 10 -8 ) in combined analyses. A number of these loci contain genes implicated in structure and function of skeletal muscle fibres (ACTG1), neuronal maintenance and signal transduction (PEX14, TGFA, SYT1), or monogenic syndromes with involvement of psychomotor impairment (PEX14, LRPPRC and KANSL1). Mendelian randomization analyses are consistent with a causal effect of higher genetically predicted grip strength on lower fracture risk. In conclusion, our findings provide new biological insight into the mechanistic underpinnings of grip strength and the causal role of muscular strength in age-related morbidities and mortality.

Energy required to pinch a DNA plectoneme

NASA Astrophysics Data System (ADS)

Barde, Céline; Destainville, Nicolas; Manghi, Manoel

2018-03-01

DNA supercoiling plays an important role from a biological point of view. One of its consequences at the supramolecular level is the formation of DNA superhelices named plectonemes. Normally separated by a distance on the order of 10 nm, the two opposite double strands of a DNA plectoneme must be brought closer if a protein or protein complex implicated in genetic regulation is to be bound simultaneously to both strands, as if the plectoneme was locally pinched. We propose an analytic calculation of the energetic barrier, of elastic nature, required to bring closer the two loci situated on the opposed double strands. We examine how this energy barrier scales with the DNA supercoiling. For physically relevant values of elastic parameters and of supercoiling density, we show that the energy barrier is in the kBT range under physiological conditions, thus demonstrating that the limiting step to loci encounter is more likely the preceding plectoneme slithering bringing the two loci side by side.

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

PubMed

Strawbridge, Rona J; Dupuis, Josée; Prokopenko, Inga; Barker, Adam; Ahlqvist, Emma; Rybin, Denis; Petrie, John R; Travers, Mary E; Bouatia-Naji, Nabila; Dimas, Antigone S; Nica, Alexandra; Wheeler, Eleanor; Chen, Han; Voight, Benjamin F; Taneera, Jalal; Kanoni, Stavroula; Peden, John F; Turrini, Fabiola; Gustafsson, Stefan; Zabena, Carina; Almgren, Peter; Barker, David J P; Barnes, Daniel; Dennison, Elaine M; Eriksson, Johan G; Eriksson, Per; Eury, Elodie; Folkersen, Lasse; Fox, Caroline S; Frayling, Timothy M; Goel, Anuj; Gu, Harvest F; Horikoshi, Momoko; Isomaa, Bo; Jackson, Anne U; Jameson, Karen A; Kajantie, Eero; Kerr-Conte, Julie; Kuulasmaa, Teemu; Kuusisto, Johanna; Loos, Ruth J F; Luan, Jian'an; Makrilakis, Konstantinos; Manning, Alisa K; Martínez-Larrad, María Teresa; Narisu, Narisu; Nastase Mannila, Maria; Ohrvik, John; Osmond, Clive; Pascoe, Laura; Payne, Felicity; Sayer, Avan A; Sennblad, Bengt; Silveira, Angela; Stancáková, Alena; Stirrups, Kathy; Swift, Amy J; Syvänen, Ann-Christine; Tuomi, Tiinamaija; van 't Hooft, Ferdinand M; Walker, Mark; Weedon, Michael N; Xie, Weijia; Zethelius, Björn; Ongen, Halit; Mälarstig, Anders; Hopewell, Jemma C; Saleheen, Danish; Chambers, John; Parish, Sarah; Danesh, John; Kooner, Jaspal; Ostenson, Claes-Göran; Lind, Lars; Cooper, Cyrus C; Serrano-Ríos, Manuel; Ferrannini, Ele; Forsen, Tom J; Clarke, Robert; Franzosi, Maria Grazia; Seedorf, Udo; Watkins, Hugh; Froguel, Philippe; Johnson, Paul; Deloukas, Panos; Collins, Francis S; Laakso, Markku; Dermitzakis, Emmanouil T; Boehnke, Michael; McCarthy, Mark I; Wareham, Nicholas J; Groop, Leif; Pattou, François; Gloyn, Anna L; Dedoussis, George V; Lyssenko, Valeriya; Meigs, James B; Barroso, Inês; Watanabe, Richard M; Ingelsson, Erik; Langenberg, Claudia; Hamsten, Anders; Florez, Jose C

2011-10-01

Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

Genome-wide significant loci for addiction and anxiety.

PubMed

Hodgson, K; Almasy, L; Knowles, E E M; Kent, J W; Curran, J E; Dyer, T D; Göring, H H H; Olvera, R L; Fox, P T; Pearlson, G D; Krystal, J H; Duggirala, R; Blangero, J; Glahn, D C

2016-08-01

Psychiatric comorbidity is common among individuals with addictive disorders, with patients frequently suffering from anxiety disorders. While the genetic architecture of comorbid addictive and anxiety disorders remains unclear, elucidating the genes involved could provide important insights into the underlying etiology. Here we examine a sample of 1284 Mexican-Americans from randomly selected extended pedigrees. Variance decomposition methods were used to examine the role of genetics in addiction phenotypes (lifetime history of alcohol dependence, drug dependence or chronic smoking) and various forms of clinically relevant anxiety. Genome-wide univariate and bivariate linkage scans were conducted to localize the chromosomal regions influencing these traits. Addiction phenotypes and anxiety were shown to be heritable and univariate genome-wide linkage scans revealed significant quantitative trait loci for drug dependence (14q13.2-q21.2, LOD=3.322) and a broad anxiety phenotype (12q24.32-q24.33, LOD=2.918). Significant positive genetic correlations were observed between anxiety and each of the addiction subtypes (ρg=0.550-0.655) and further investigation with bivariate linkage analyses identified significant pleiotropic signals for alcohol dependence-anxiety (9q33.1-q33.2, LOD=3.054) and drug dependence-anxiety (18p11.23-p11.22, LOD=3.425). This study confirms the shared genetic underpinnings of addiction and anxiety and identifies genomic loci involved in the etiology of these comorbid disorders. The linkage signal for anxiety on 12q24 spans the location of TMEM132D, an emerging gene of interest from previous GWAS of anxiety traits, whilst the bivariate linkage signal identified for anxiety-alcohol on 9q33 peak coincides with a region where rare CNVs have been associated with psychiatric disorders. Other signals identified implicate novel regions of the genome in addiction genetics. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Ancestry-specific and sex-specific risk alleles identified in a genome-wide gene-by-alcohol dependence interaction study of risky sexual behaviors.

PubMed

Polimanti, Renato; Zhao, Hongyu; Farrer, Lindsay A; Kranzler, Henry R; Gelernter, Joel

2017-12-01

We previously mapped loci for the genome-wide association studies (GWAS) and genome-wide gene-by-alcohol dependence interaction (GW-GxAD) analyses of risky sexual behaviors (RSB). This study extends those findings by analyzing the ancestry- and sex-specific AD-stratified effects on RSB. We examined the concordance of findings for the AD-stratified GWAS and the GW-GxAD analysis of RSB, with concordance defined as genome-wide significance in one analysis and at least nominal significance in the second analysis. A total of 2,173 African-American (AA) and 1,751 European-American (EA) subjects were investigated. Information regarding RSB (lifetime experiences of unprotected sex and multiple sexual partners) and DSM-IV diagnosis of lifetime AD were derived from the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA). In our ancestry- and sex-specific analyses, we identified four independent genome-wide significant (GWS) loci (p < 5*10 -8 ) and one suggestive locus (p < 6*10 -8 ). In men, we observed a GWS signal in FAM162A (rs2002594, p = 4.96*10 -8 ). In women, there was a suggestive locus in PLGRKT (rs3824435, p = 5.52*10 -8 ). In AAs, there was a GWS signal in GRK5 (rs1316543, p = 1.25*10 -9 ). In AA men, we observed an intergenic GWS signal (rs12898370, p = 4.49*10 -8 ) near LINGO1. In EA men, there was a GWS signal in CCSER1 (rs62313897; p = 7.93*10 -10 ). The loci identified in this GWAS implicate molecular mechanisms related to psychiatric illness and personality features, suggesting that the interplay between AD and RSB is mediated by alleles associated with behavioral traits. © 2017 Wiley Periodicals, Inc.

Two new loci and gene sets related to sex determination and cancer progression are associated with susceptibility to testicular germ cell tumor.

PubMed

Kristiansen, Wenche; Karlsson, Robert; Rounge, Trine B; Whitington, Thomas; Andreassen, Bettina K; Magnusson, Patrik K; Fosså, Sophie D; Adami, Hans-Olov; Turnbull, Clare; Haugen, Trine B; Grotmol, Tom; Wiklund, Fredrik

2015-07-15

Genome-wide association (GWA) studies have reported 19 distinct susceptibility loci for testicular germ cell tumor (TGCT). A GWA study for TGCT was performed by genotyping 610 240 single-nucleotide polymorphisms (SNPs) in 1326 cases and 6687 controls from Sweden and Norway. No novel genome-wide significant associations were observed in this discovery stage. We put forward 27 SNPs from 15 novel regions and 12 SNPs previously reported, for replication in 710 case-parent triads and 289 cases and 290 controls. Predefined biological pathways and processes, in addition to a custom-built sex-determination gene set, were subject to enrichment analyses using Meta-Analysis Gene Set Enrichment of Variant Associations (M) and Improved Gene Set Enrichment Analysis for Genome-wide Association Study (I). In the combined meta-analysis, we observed genome-wide significant association for rs7501939 on chromosome 17q12 (OR = 0.78, 95% CI = 0.72-0.84, P = 1.1 × 10(-9)) and rs2195987 on chromosome 19p12 (OR = 0.76, 95% CI: 0.69-0.84, P = 3.2 × 10(-8)). The marker rs7501939 on chromosome 17q12 is located in an intron of the HNF1B gene, encoding a member of the homeodomain-containing superfamily of transcription factors. The sex-determination gene set (false discovery rate, FDRM < 0.001, FDRI < 0.001) and pathways related to NF-κB, glycerophospholipid and ether lipid metabolism, as well as cancer and apoptosis, was associated with TGCT (FDR < 0.1). In addition to revealing two new TGCT susceptibility loci, our results continue to support the notion that genes governing normal germ cell development in utero are implicated in the development of TGCT. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Refined mapping of autoimmune disease associated genetic variants with gene expression suggests an important role for non-coding RNAs.

PubMed

Ricaño-Ponce, Isis; Zhernakova, Daria V; Deelen, Patrick; Luo, Oscar; Li, Xingwang; Isaacs, Aaron; Karjalainen, Juha; Di Tommaso, Jennifer; Borek, Zuzanna Agnieszka; Zorro, Maria M; Gutierrez-Achury, Javier; Uitterlinden, Andre G; Hofman, Albert; van Meurs, Joyce; Netea, Mihai G; Jonkers, Iris H; Withoff, Sebo; van Duijn, Cornelia M; Li, Yang; Ruan, Yijun; Franke, Lude; Wijmenga, Cisca; Kumar, Vinod

2016-04-01

Genome-wide association and fine-mapping studies in 14 autoimmune diseases (AID) have implicated more than 250 loci in one or more of these diseases. As more than 90% of AID-associated SNPs are intergenic or intronic, pinpointing the causal genes is challenging. We performed a systematic analysis to link 460 SNPs that are associated with 14 AID to causal genes using transcriptomic data from 629 blood samples. We were able to link 71 (39%) of the AID-SNPs to two or more nearby genes, providing evidence that for part of the AID loci multiple causal genes exist. While 54 of the AID loci are shared by one or more AID, 17% of them do not share candidate causal genes. In addition to finding novel genes such as ULK3, we also implicate novel disease mechanisms and pathways like autophagy in celiac disease pathogenesis. Furthermore, 42 of the AID SNPs specifically affected the expression of 53 non-coding RNA genes. To further understand how the non-coding genome contributes to AID, the SNPs were linked to functional regulatory elements, which suggest a model where AID genes are regulated by network of chromatin looping/non-coding RNAs interactions. The looping model also explains how a causal candidate gene is not necessarily the gene closest to the AID SNP, which was the case in nearly 50% of cases. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

VAV1 and BAFF, via NFκB pathway, are genetic risk factors for myasthenia gravis

PubMed Central

Avidan, Nili; Le Panse, Rozen; Harbo, Hanne F; Bernasconi, Pia; Poulas, Konstantinos; Ginzburg, Elizabeta; Cavalcante, Paola; Colleoni, Lara; Baggi, Fulvio; Antozzi, Carlo; Truffault, Frédérique; Horn-Saban, Shirley; Pöschel, Simone; Zagoriti, Zoi; Maniaol, Angelina; Lie, Benedicte A; Bernard, Isabelle; Saoudi, Abdelhadi; Illes, Zsolt; Casasnovas Pons, Carlos; Melms, Arthur; Tzartos, Socrates; Willcox, Nicholas; Kostera-Pruszczyk, Anna; Tallaksen, Chantal; Mantegazza, Renato; Berrih-Aknin, Sonia; Miller, Ariel

2014-01-01

Objective To identify novel genetic loci that predispose to early-onset myasthenia gravis (EOMG) applying a two-stage association study, exploration, and replication strategy. Methods Thirty-four loci and one confirmation loci, human leukocyte antigen (HLA)-DRA, were selected as candidate genes by team members of groups involved in different research aspects of MG. In the exploration step, these candidate genes were genotyped in 384 EOMG and 384 matched controls and significant difference in allele frequency were found in eight genes. In the replication step, eight candidate genes and one confirmation loci were genotyped in 1177 EOMG patients and 814 controls, from nine European centres. Results Allele frequency differences were found in four novel loci: CD86, AKAP12, VAV1, B-cell activating factor (BAFF), and tumor necrosis factor-alpha (TNF-α), and these differences were consistent in all nine cohorts. Haplotype trend test supported the differences in allele frequencies between cases and controls. In addition, allele frequency difference in female versus male patients at HLA-DRA and TNF-α loci were observed. Interpretation The genetic associations to EOMG outside the HLA complex are novel and of interest as VAV1 is a key signal transducer essential for T- and B-cell activation, and BAFF is a cytokine that plays important roles in the proliferation and differentiation of B-cells. Moreover, we noted striking epistasis between the predisposing VAV1 and BAFF haplotypes; they conferred a greater risk in combination than alone. These, and CD86, share the same signaling pathway, namely nuclear factor-kappaB (NFκB), thus implicating dysregulation of proinflammatory signaling in predisposition to EOMG. PMID:25356403

Genome-wide Analysis of Body Proportion Classifies Height-Associated Variants by Mechanism of Action and Implicates Genes Important for Skeletal Development

PubMed Central

Chan, Yingleong; Salem, Rany M.; Hsu, Yu-Han H.; McMahon, George; Pers, Tune H.; Vedantam, Sailaja; Esko, Tonu; Guo, Michael H.; Lim, Elaine T.; Franke, Lude; Smith, George Davey; Strachan, David P.; Hirschhorn, Joel N.

2015-01-01

Human height is a composite measurement, reflecting the sum of leg, spine, and head lengths. Many common variants influence total height, but the effects of these or other variants on the components of height (body proportion) remain largely unknown. We studied sitting height ratio (SHR), the ratio of sitting height to total height, to identify such effects in 3,545 African Americans and 21,590 individuals of European ancestry. We found that SHR is heritable: 26% and 39% of the total variance of SHR can be explained by common variants in European and African Americans, respectively, and global European admixture is negatively correlated with SHR in African Americans (r2 ≈ 0.03). Six regions reached genome-wide significance (p < 5 × 10−8) for association with SHR and overlapped biological candidate genes, including TBX2 and IGFBP3. We found that 130 of 670 height-associated variants are nominally associated (p < 0.05) with SHR, more than expected by chance (p = 5 × 10−40). At these 130 loci, the height-increasing alleles are associated with either a decrease (71 loci) or increase (59 loci) in SHR, suggesting that different height loci disproportionally affect either leg length or spine/head length. Pathway analyses via DEPICT revealed that height loci affecting SHR, and especially those affecting leg length, show enrichment of different biological pathways (e.g., bone/cartilage/growth plate pathways) than do loci with no effect on SHR (e.g., embryonic development). These results highlight the value of using a pair of related but orthogonal phenotypes, in this case SHR with height, as a prism to dissect the biology underlying genetic associations in polygenic traits and diseases. PMID:25865494

Network-Based Identification and Prioritization of Key Regulators of Coronary Artery Disease Loci

PubMed Central

Zhao, Yuqi; Chen, Jing; Freudenberg, Johannes M.; Meng, Qingying; Rajpal, Deepak K.; Yang, Xia

2017-01-01

Objective Recent genome-wide association studies of coronary artery disease (CAD) have revealed 58 genome-wide significant and 148 suggestive genetic loci. However, the molecular mechanisms through which they contribute to CAD and the clinical implications of these findings remain largely unknown. We aim to retrieve gene subnetworks of the 206 CAD loci and identify and prioritize candidate regulators to better understand the biological mechanisms underlying the genetic associations. Approach and Results We devised a new integrative genomics approach that incorporated (1) candidate genes from the top CAD loci, (2) the complete genetic association results from the 1000 genomes-based CAD genome-wide association studies from the Coronary Artery Disease Genome Wide Replication and Meta-Analysis Plus the Coronary Artery Disease consortium, (3) tissue-specific gene regulatory networks that depict the potential relationship and interactions between genes, and (4) tissue-specific gene expression patterns between CAD patients and controls. The networks and top-ranked regulators according to these data-driven criteria were further queried against literature, experimental evidence, and drug information to evaluate their disease relevance and potential as drug targets. Our analysis uncovered several potential novel regulators of CAD such as LUM and STAT3, which possess properties suitable as drug targets. We also revealed molecular relations and potential mechanisms through which the top CAD loci operate. Furthermore, we found that multiple CAD-relevant biological processes such as extracellular matrix, inflammatory and immune pathways, complement and coagulation cascades, and lipid metabolism interact in the CAD networks. Conclusions Our data-driven integrative genomics framework unraveled tissue-specific relations among the candidate genes of the CAD genome-wide association studies loci and prioritized novel network regulatory genes orchestrating biological processes relevant to CAD. PMID:26966275

Evaluation of European Schizophrenia GWAS Loci in Asian Populations via Comprehensive Meta-Analyses.

PubMed

Xiao, Xiao; Luo, Xiong-Jian; Chang, Hong; Liu, Zichao; Li, Ming

2017-08-01

Schizophrenia is a severe and highly heritable neuropsychiatric disorder. Recent genetic analyses including genome-wide association studies (GWAS) have implicated multiple genome-wide significant variants for schizophrenia among European populations. However, many of these risk variants were not largely validated in other populations of different ancestry such as Asians. To validate whether these European GWAS significant loci are associated with schizophrenia in Asian populations, we conducted a systematic literature search and meta-analyses on 19 single nucleotide polymorphisms (SNPs) in Asian populations by combining all available case-control and family-based samples, including up to 30,000 individuals. We employed classical fixed (or random) effects inverse variance weighted methods to calculate summary odds ratios (ORs) and 95 % confidence intervals (CIs). Among the 19 GWAS loci, we replicated the risk associations of nine markers (e.g., SNPs at VRK2, ITIH3/4, NDST3, NOTCH4) surpassing significance level (two-tailed P < 0.05), and three additional SNPs in MIR137 and ZNF804A also showed trend associations (one-tailed P < 0.05). These risk associations are in the same directions of allelic effects between Asian replication samples and initial European GWAS findings, and the successful replications of these GWAS loci in a different ethnic group provide stronger evidence for their clinical associations with schizophrenia. Further studies, focusing on the molecular mechanisms of these GWAS significant loci, will become increasingly important for understanding of the pathogenesis to schizophrenia.

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

PubMed

Pattaro, Cristian; Teumer, Alexander; Gorski, Mathias; Chu, Audrey Y; Li, Man; Mijatovic, Vladan; Garnaas, Maija; Tin, Adrienne; Sorice, Rossella; Li, Yong; Taliun, Daniel; Olden, Matthias; Foster, Meredith; Yang, Qiong; Chen, Ming-Huei; Pers, Tune H; Johnson, Andrew D; Ko, Yi-An; Fuchsberger, Christian; Tayo, Bamidele; Nalls, Michael; Feitosa, Mary F; Isaacs, Aaron; Dehghan, Abbas; d'Adamo, Pio; Adeyemo, Adebowale; Dieffenbach, Aida Karina; Zonderman, Alan B; Nolte, Ilja M; van der Most, Peter J; Wright, Alan F; Shuldiner, Alan R; Morrison, Alanna C; Hofman, Albert; Smith, Albert V; Dreisbach, Albert W; Franke, Andre; Uitterlinden, Andre G; Metspalu, Andres; Tonjes, Anke; Lupo, Antonio; Robino, Antonietta; Johansson, Åsa; Demirkan, Ayse; Kollerits, Barbara; Freedman, Barry I; Ponte, Belen; Oostra, Ben A; Paulweber, Bernhard; Krämer, Bernhard K; Mitchell, Braxton D; Buckley, Brendan M; Peralta, Carmen A; Hayward, Caroline; Helmer, Catherine; Rotimi, Charles N; Shaffer, Christian M; Müller, Christian; Sala, Cinzia; van Duijn, Cornelia M; Saint-Pierre, Aude; Ackermann, Daniel; Shriner, Daniel; Ruggiero, Daniela; Toniolo, Daniela; Lu, Yingchang; Cusi, Daniele; Czamara, Darina; Ellinghaus, David; Siscovick, David S; Ruderfer, Douglas; Gieger, Christian; Grallert, Harald; Rochtchina, Elena; Atkinson, Elizabeth J; Holliday, Elizabeth G; Boerwinkle, Eric; Salvi, Erika; Bottinger, Erwin P; Murgia, Federico; Rivadeneira, Fernando; Ernst, Florian; Kronenberg, Florian; Hu, Frank B; Navis, Gerjan J; Curhan, Gary C; Ehret, George B; Homuth, Georg; Coassin, Stefan; Thun, Gian-Andri; Pistis, Giorgio; Gambaro, Giovanni; Malerba, Giovanni; Montgomery, Grant W; Eiriksdottir, Gudny; Jacobs, Gunnar; Li, Guo; Wichmann, H-Erich; Campbell, Harry; Schmidt, Helena; Wallaschofski, Henri; Völzke, Henry; Brenner, Hermann; Kroemer, Heyo K; Kramer, Holly; Lin, Honghuang; Leach, I Mateo; Ford, Ian; Guessous, Idris; Rudan, Igor; Prokopenko, Inga; Borecki, Ingrid; Heid, Iris M; Kolcic, Ivana; Persico, Ivana; Jukema, J Wouter; Wilson, James F; Felix, Janine F; Divers, Jasmin; Lambert, Jean-Charles; Stafford, Jeanette M; Gaspoz, Jean-Michel; Smith, Jennifer A; Faul, Jessica D; Wang, Jie Jin; Ding, Jingzhong; Hirschhorn, Joel N; Attia, John; Whitfield, John B; Chalmers, John; Viikari, Jorma; Coresh, Josef; Denny, Joshua C; Karjalainen, Juha; Fernandes, Jyotika K; Endlich, Karlhans; Butterbach, Katja; Keene, Keith L; Lohman, Kurt; Portas, Laura; Launer, Lenore J; Lyytikäinen, Leo-Pekka; Yengo, Loic; Franke, Lude; Ferrucci, Luigi; Rose, Lynda M; Kedenko, Lyudmyla; Rao, Madhumathi; Struchalin, Maksim; Kleber, Marcus E; Cavalieri, Margherita; Haun, Margot; Cornelis, Marilyn C; Ciullo, Marina; Pirastu, Mario; de Andrade, Mariza; McEvoy, Mark A; Woodward, Mark; Adam, Martin; Cocca, Massimiliano; Nauck, Matthias; Imboden, Medea; Waldenberger, Melanie; Pruijm, Menno; Metzger, Marie; Stumvoll, Michael; Evans, Michele K; Sale, Michele M; Kähönen, Mika; Boban, Mladen; Bochud, Murielle; Rheinberger, Myriam; Verweij, Niek; Bouatia-Naji, Nabila; Martin, Nicholas G; Hastie, Nick; Probst-Hensch, Nicole; Soranzo, Nicole; Devuyst, Olivier; Raitakari, Olli; Gottesman, Omri; Franco, Oscar H; Polasek, Ozren; Gasparini, Paolo; Munroe, Patricia B; Ridker, Paul M; Mitchell, Paul; Muntner, Paul; Meisinger, Christa; Smit, Johannes H; Kovacs, Peter; Wild, Philipp S; Froguel, Philippe; Rettig, Rainer; Mägi, Reedik; Biffar, Reiner; Schmidt, Reinhold; Middelberg, Rita P S; Carroll, Robert J; Penninx, Brenda W; Scott, Rodney J; Katz, Ronit; Sedaghat, Sanaz; Wild, Sarah H; Kardia, Sharon L R; Ulivi, Sheila; Hwang, Shih-Jen; Enroth, Stefan; Kloiber, Stefan; Trompet, Stella; Stengel, Benedicte; Hancock, Stephen J; Turner, Stephen T; Rosas, Sylvia E; Stracke, Sylvia; Harris, Tamara B; Zeller, Tanja; Zemunik, Tatijana; Lehtimäki, Terho; Illig, Thomas; Aspelund, Thor; Nikopensius, Tiit; Esko, Tonu; Tanaka, Toshiko; Gyllensten, Ulf; Völker, Uwe; Emilsson, Valur; Vitart, Veronique; Aalto, Ville; Gudnason, Vilmundur; Chouraki, Vincent; Chen, Wei-Min; Igl, Wilmar; März, Winfried; Koenig, Wolfgang; Lieb, Wolfgang; Loos, Ruth J F; Liu, Yongmei; Snieder, Harold; Pramstaller, Peter P; Parsa, Afshin; O'Connell, Jeffrey R; Susztak, Katalin; Hamet, Pavel; Tremblay, Johanne; de Boer, Ian H; Böger, Carsten A; Goessling, Wolfram; Chasman, Daniel I; Köttgen, Anna; Kao, W H Linda; Fox, Caroline S

2016-01-21

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.

Genetic analysis of eight loci tightly linked to neurofibromatosis 1

PubMed Central

Stephens, Karen; Green, Philip; Riccardi, Vincent M.; Ng, Siu; Rising, Marcia; Barker, David; Darby, John K.; Falls, Kathleen M.; Collins, Francis S.; Willard, Huntington F.; Donis-Keller, Helen

1989-01-01

The genetic locus for neurofibromatosis 1 (NF1) has recently been mapped to the pericentromeric region of chromosome 17. We have genotyped eight previously identified RFLP probes on 50 NF1 families to determine the placement of the NF1 locus relative to the RFLP loci. Thirty-eight recombination events in the pericentromeric region were identified, eight involving crossovers between NF1 and loci on either chromosomal arm. Multipoint linkage analysis resulted in the unique placement of six loci at odds >100:1 in the order of pter–A10-41–EW301–NF1–EW207–CRI-L581–CRI-L946–qter. Owing to insufficient crossovers, three loci–D17Z1, EW206, and EW203–could not be uniquely localized. In this region female recombination rates were significantly higher than those of males. These data were part of a joint study aimed at the localization of both NF1 and tightly linked pericentromeric markers for chromosome 17. PMID:2491775

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

PubMed Central

Pattaro, Cristian; Teumer, Alexander; Gorski, Mathias; Chu, Audrey Y.; Li, Man; Mijatovic, Vladan; Garnaas, Maija; Tin, Adrienne; Sorice, Rossella; Li, Yong; Taliun, Daniel; Olden, Matthias; Foster, Meredith; Yang, Qiong; Chen, Ming-Huei; Pers, Tune H.; Johnson, Andrew D.; Ko, Yi-An; Fuchsberger, Christian; Tayo, Bamidele; Nalls, Michael; Feitosa, Mary F.; Isaacs, Aaron; Dehghan, Abbas; d'Adamo, Pio; Adeyemo, Adebowale; Dieffenbach, Aida Karina; Zonderman, Alan B.; Nolte, Ilja M.; van der Most, Peter J.; Wright, Alan F.; Shuldiner, Alan R.; Morrison, Alanna C.; Hofman, Albert; Smith, Albert V.; Dreisbach, Albert W.; Franke, Andre; Uitterlinden, Andre G.; Metspalu, Andres; Tonjes, Anke; Lupo, Antonio; Robino, Antonietta; Johansson, Åsa; Demirkan, Ayse; Kollerits, Barbara; Freedman, Barry I.; Ponte, Belen; Oostra, Ben A.; Paulweber, Bernhard; Krämer, Bernhard K.; Mitchell, Braxton D.; Buckley, Brendan M.; Peralta, Carmen A.; Hayward, Caroline; Helmer, Catherine; Rotimi, Charles N.; Shaffer, Christian M.; Müller, Christian; Sala, Cinzia; van Duijn, Cornelia M.; Saint-Pierre, Aude; Ackermann, Daniel; Shriner, Daniel; Ruggiero, Daniela; Toniolo, Daniela; Lu, Yingchang; Cusi, Daniele; Czamara, Darina; Ellinghaus, David; Siscovick, David S.; Ruderfer, Douglas; Gieger, Christian; Grallert, Harald; Rochtchina, Elena; Atkinson, Elizabeth J.; Holliday, Elizabeth G.; Boerwinkle, Eric; Salvi, Erika; Bottinger, Erwin P.; Murgia, Federico; Rivadeneira, Fernando; Ernst, Florian; Kronenberg, Florian; Hu, Frank B.; Navis, Gerjan J.; Curhan, Gary C.; Ehret, George B.; Homuth, Georg; Coassin, Stefan; Thun, Gian-Andri; Pistis, Giorgio; Gambaro, Giovanni; Malerba, Giovanni; Montgomery, Grant W.; Eiriksdottir, Gudny; Jacobs, Gunnar; Li, Guo; Wichmann, H-Erich; Campbell, Harry; Schmidt, Helena; Wallaschofski, Henri; Völzke, Henry; Brenner, Hermann; Kroemer, Heyo K.; Kramer, Holly; Lin, Honghuang; Leach, I. Mateo; Ford, Ian; Guessous, Idris; Rudan, Igor; Prokopenko, Inga; Borecki, Ingrid; Heid, Iris M.; Kolcic, Ivana; Persico, Ivana; Jukema, J. Wouter; Wilson, James F.; Felix, Janine F.; Divers, Jasmin; Lambert, Jean-Charles; Stafford, Jeanette M.; Gaspoz, Jean-Michel; Smith, Jennifer A.; Faul, Jessica D.; Wang, Jie Jin; Ding, Jingzhong; Hirschhorn, Joel N.; Attia, John; Whitfield, John B.; Chalmers, John; Viikari, Jorma; Coresh, Josef; Denny, Joshua C.; Karjalainen, Juha; Fernandes, Jyotika K.; Endlich, Karlhans; Butterbach, Katja; Keene, Keith L.; Lohman, Kurt; Portas, Laura; Launer, Lenore J.; Lyytikäinen, Leo-Pekka; Yengo, Loic; Franke, Lude; Ferrucci, Luigi; Rose, Lynda M.; Kedenko, Lyudmyla; Rao, Madhumathi; Struchalin, Maksim; Kleber, Marcus E.; Cavalieri, Margherita; Haun, Margot; Cornelis, Marilyn C.; Ciullo, Marina; Pirastu, Mario; de Andrade, Mariza; McEvoy, Mark A.; Woodward, Mark; Adam, Martin; Cocca, Massimiliano; Nauck, Matthias; Imboden, Medea; Waldenberger, Melanie; Pruijm, Menno; Metzger, Marie; Stumvoll, Michael; Evans, Michele K.; Sale, Michele M.; Kähönen, Mika; Boban, Mladen; Bochud, Murielle; Rheinberger, Myriam; Verweij, Niek; Bouatia-Naji, Nabila; Martin, Nicholas G.; Hastie, Nick; Probst-Hensch, Nicole; Soranzo, Nicole; Devuyst, Olivier; Raitakari, Olli; Gottesman, Omri; Franco, Oscar H.; Polasek, Ozren; Gasparini, Paolo; Munroe, Patricia B.; Ridker, Paul M.; Mitchell, Paul; Muntner, Paul; Meisinger, Christa; Smit, Johannes H.; Abecasis, Goncalo R.; Adair, Linda S.; Alexander, Myriam; Altshuler, David; Amin, Najaf; Arking, Dan E.; Arora, Pankaj; Aulchenko, Yurii; Bakker, Stephan J. L.; Bandinelli, Stefania; Barroso, Ines; Beckmann, Jacques S.; Beilby, John P.; Bergman, Richard N.; Bergmann, Sven; Bis, Joshua C.; Boehnke, Michael; Bonnycastle, Lori L.; Bornstein, Stefan R.; Bots, Michiel L.; Bragg-Gresham, Jennifer L.; Brand, Stefan-Martin; Brand, Eva; Braund, Peter S.; Brown, Morris J.; Burton, Paul R.; Casas, Juan P.; Caulfield, Mark J.; Chakravarti, Aravinda; Chambers, John C.; Chandak, Giriraj R.; Chang, Yen-Pei C.; Charchar, Fadi J.; Chaturvedi, Nish; Shin Cho, Yoon; Clarke, Robert; Collins, Francis S.; Collins, Rory; Connell, John M.; Cooper, Jackie A.; Cooper, Matthew N.; Cooper, Richard S.; Corsi, Anna Maria; Dörr, Marcus; Dahgam, Santosh; Danesh, John; Smith, George Davey; Day, Ian N. M.; Deloukas, Panos; Denniff, Matthew; Dominiczak, Anna F.; Dong, Yanbin; Doumatey, Ayo; Elliott, Paul; Elosua, Roberto; Erdmann, Jeanette; Eyheramendy, Susana; Farrall, Martin; Fava, Cristiano; Forrester, Terrence; Fowkes, F. Gerald R.; Fox, Ervin R.; Frayling, Timothy M.; Galan, Pilar; Ganesh, Santhi K.; Garcia, Melissa; Gaunt, Tom R.; Glazer, Nicole L.; Go, Min Jin; Goel, Anuj; Grässler, Jürgen; Grobbee, Diederick E.; Groop, Leif; Guarrera, Simonetta; Guo, Xiuqing; Hadley, David; Hamsten, Anders; Han, Bok-Ghee; Hardy, Rebecca; Hartikainen, Anna-Liisa; Heath, Simon; Heckbert, Susan R.; Hedblad, Bo; Hercberg, Serge; Hernandez, Dena; Hicks, Andrew A.; Hilton, Gina; Hingorani, Aroon D.; Bolton, Judith A Hoffman; Hopewell, Jemma C.; Howard, Philip; Humphries, Steve E.; Hunt, Steven C.; Hveem, Kristian; Ikram, M. Arfan; Islam, Muhammad; Iwai, Naoharu; Jarvelin, Marjo-Riitta; Jackson, Anne U.; Jafar, Tazeen H.; Janipalli, Charles S.; Johnson, Toby; Kathiresan, Sekar; Khaw, Kay-Tee; Kim, Hyung-Lae; Kinra, Sanjay; Kita, Yoshikuni; Kivimaki, Mika; Kooner, Jaspal S.; Kumar, M. J. Kranthi; Kuh, Diana; Kulkarni, Smita R.; Kumari, Meena; Kuusisto, Johanna; Kuznetsova, Tatiana; Laakso, Markku; Laan, Maris; Laitinen, Jaana; Lakatta, Edward G.; Langefeld, Carl D.; Larson, Martin G.; Lathrop, Mark; Lawlor, Debbie A.; Lawrence, Robert W.; Lee, Jong-Young; Lee, Nanette R.; Levy, Daniel; Li, Yali; Longstreth, Will T.; Luan, Jian'an; Lucas, Gavin; Ludwig, Barbara; Mangino, Massimo; Mani, K. Radha; Marmot, Michael G.; Mattace-Raso, Francesco U. S.; Matullo, Giuseppe; McArdle, Wendy L.; McKenzie, Colin A.; Meitinger, Thomas; Melander, Olle; Meneton, Pierre; Meschia, James F.; Miki, Tetsuro; Milaneschi, Yuri; Mohlke, Karen L.; Mooser, Vincent; Morken, Mario A.; Morris, Richard W.; Mosley, Thomas H.; Najjar, Samer; Narisu, Narisu; Newton-Cheh, Christopher; Nguyen, Khanh-Dung Hoang; Nilsson, Peter; Nyberg, Fredrik; O'Donnell, Christopher J.; Ogihara, Toshio; Ohkubo, Takayoshi; Okamura, Tomonori; Ong, RickTwee-Hee; Ongen, Halit; Onland-Moret, N. Charlotte; O'Reilly, Paul F.; Org, Elin; Orru, Marco; Palmas, Walter; Palmen, Jutta; Palmer, Lyle J.; Palmer, Nicholette D.; Parker, Alex N.; Peden, John F.; Peltonen, Leena; Perola, Markus; Pihur, Vasyl; Platou, Carl G. P.; Plump, Andrew; Prabhakaran, Dorairajan; Psaty, Bruce M.; Raffel, Leslie J.; Rao, Dabeeru C.; Rasheed, Asif; Ricceri, Fulvio; Rice, Kenneth M.; Rosengren, Annika; Rotter, Jerome I.; Rudock, Megan E.; Sõber, Siim; Salako, Tunde; Saleheen, Danish; Salomaa, Veikko; Samani, Nilesh J.; Schwartz, Steven M.; Schwarz, Peter E. H.; Scott, Laura J.; Scott, James; Scuteri, Angelo; Sehmi, Joban S.; Seielstad, Mark; Seshadri, Sudha; Sharma, Pankaj; Shaw-Hawkins, Sue; Shi, Gang; Shrine, Nick R. G.; Sijbrands, Eric J. G.; Sim, Xueling; Singleton, Andrew; Sjögren, Marketa; Smith, Nicholas L.; Artigas, Maria Soler; Spector, Tim D.; Staessen, Jan A.; Stancakova, Alena; Steinle, Nanette I.; Strachan, David P.; Stringham, Heather M.; Sun, Yan V.; Swift, Amy J.; Tabara, Yasuharu; Tai, E-Shyong; Talmud, Philippa J.; Taylor, Andrew; Terzic, Janos; Thelle, Dag S.; Tobin, Martin D.; Tomaszewski, Maciej; Tripathy, Vikal; Tuomilehto, Jaakko; Tzoulaki, Ioanna; Uda, Manuela; Ueshima, Hirotsugu; Uiterwaal, Cuno S. P. M.; Umemura, Satoshi; van der Harst, Pim; van der Schouw, Yvonne T.; van Gilst, Wiek H.; Vartiainen, Erkki; Vasan, Ramachandran S.; Veldre, Gudrun; Verwoert, Germaine C.; Viigimaa, Margus; Vinay, D. G.; Vineis, Paolo; Voight, Benjamin F.; Vollenweider, Peter; Wagenknecht, Lynne E.; Wain, Louise V.; Wang, Xiaoling; Wang, Thomas J.; Wareham, Nicholas J.; Watkins, Hugh; Weder, Alan B.; Whincup, Peter H.; Wiggins, Kerri L.; Witteman, Jacqueline C. M.; Wong, Andrew; Wu, Ying; Yajnik, Chittaranjan S.; Yao, Jie; Young, J. H.; Zelenika, Diana; Zhai, Guangju; Zhang, Weihua; Zhang, Feng; Zhao, Jing Hua; Zhu, Haidong; Zhu, Xiaofeng; Zitting, Paavo; Zukowska-Szczechowska, Ewa; Okada, Yukinori; Wu, Jer-Yuarn; Gu, Dongfeng; Takeuchi, Fumihiko; Takahashi, Atsushi; Maeda, Shiro; Tsunoda, Tatsuhiko; Chen, Peng; Lim, Su-Chi; Wong, Tien-Yin; Liu, Jianjun; Young, Terri L.; Aung, Tin; Teo, Yik-Ying; Kim, Young Jin; Kang, Daehee; Chen, Chien-Hsiun; Tsai, Fuu-Jen; Chang, Li-Ching; Fann, S. -J. Cathy; Mei, Hao; Hixson, James E.; Chen, Shufeng; Katsuya, Tomohiro; Isono, Masato; Albrecht, Eva; Yamamoto, Kazuhiko; Kubo, Michiaki; Nakamura, Yusuke; Kamatani, Naoyuki; Kato, Norihiro; He, Jiang; Chen, Yuan-Tsong; Tanaka, Toshihiro; Reilly, Muredach P; Schunkert, Heribert; Assimes, Themistocles L.; Hall, Alistair; Hengstenberg, Christian; König, Inke R.; Laaksonen, Reijo; McPherson, Ruth; Thompson, John R.; Thorsteinsdottir, Unnur; Ziegler, Andreas; Absher, Devin; Chen, Li; Cupples13, L. Adrienne; Halperin, Eran; Li, Mingyao; Musunuru, Kiran; Preuss, Michael; Schillert, Arne; Thorleifsson, Gudmar; Wells, George A.; Holm, Hilma; Roberts, Robert; Stewart, Alexandre F. R.; Fortmann, Stephen; Go, Alan; Hlatky, Mark; Iribarren, Carlos; Knowles, Joshua; Myers, Richard; Quertermous, Thomas; Sidney, Steven; Risch, Neil; Tang, Hua; Blankenberg, Stefan; Schnabel, Renate; Sinning, Christoph; Lackner, Karl J.; Tiret, Laurence; Nicaud, Viviane; Cambien, Francois; Bickel, Christoph; Rupprecht, Hans J.; Perret, Claire; Proust, Carole; Münzel, Thomas F.; Barbalic, Maja; Chen, Ida Yii-Der; Demissie-Banjaw, Serkalem; Folsom, Aaron; Lumley, Thomas; Marciante, Kristin; Taylor, Kent D.; Volcik, Kelly; Gretarsdottir, Solveig; Gulcher, Jeffrey R.; Kong, Augustine; Stefansson, Kari; Thorgeirsson, Gudmundur; Andersen, Karl; Fischer, Marcus; Grosshennig, Anika; Linsel-Nitschke, Patrick; Stark, Klaus; Schreiber, Stefan; Aherrahrou, Zouhair; Bruse, Petra; Doering, Angela; Klopp, Norman; Diemert, Patrick; Loley, Christina; Medack, Anja; Nahrstedt, Janja; Peters, Annette; Wagner, Arnika K.; Willenborg, Christina; Böhm, Bernhard O.; Dobnig, Harald; Grammer, Tanja B.; Hoffmann, Michael M.; Meinitzer, Andreas; Winkelmann, Bernhard R.; Pilz, Stefan; Renner, Wilfried; Scharnagl, Hubert; Stojakovic, Tatjana; Tomaschitz, Andreas; Winkler, Karl; Guiducci, Candace; Burtt, Noel; Gabriel, Stacey B.; Dandona, Sonny; Jarinova, Olga; Qu, Liming; Wilensky, Robert; Matthai, William; Hakonarson, Hakon H.; Devaney, Joe; Burnett, Mary Susan; Pichard, Augusto D.; Kent, Kenneth M.; Satler, Lowell; Lindsay, Joseph M.; Waksman, Ron; Knouff, Christopher W.; Waterworth, Dawn M.; Walker, Max C.; Epstein, Stephen E.; Rader, Daniel J.; Nelson, Christopher P.; Wright, Benjamin J.; Balmforth, Anthony J.; Ball, Stephen G.; Loehr, Laura R.; Rosamond, Wayne D.; Benjamin, Emelia; Haritunians, Talin; Couper, David; Murabito, Joanne; Wang, Ying A.; Stricker, Bruno H.; Chang, Patricia P.; Willerson, James T.; Felix, Stephan B.; Watzinger, Norbert; Aragam, Jayashri; Zweiker, Robert; Lind, Lars; Rodeheffer, Richard J.; Greiser, Karin Halina; Deckers, Jaap W.; Stritzke, Jan; Ingelsson, Erik; Kullo, Iftikhar; Haerting, Johannes; Reffelmann, Thorsten; Redfield, Margaret M.; Werdan, Karl; Mitchell, Gary F.; Arnett, Donna K.; Gottdiener, John S.; Blettner, Maria; Friedrich, Nele; Kovacs, Peter; Wild, Philipp S.; Froguel, Philippe; Rettig, Rainer; Mägi, Reedik; Biffar, Reiner; Schmidt, Reinhold; Middelberg, Rita P. S.; Carroll, Robert J.; Penninx, Brenda W.; Scott, Rodney J.; Katz, Ronit; Sedaghat, Sanaz; Wild, Sarah H.; Kardia, Sharon L. R.; Ulivi, Sheila; Hwang, Shih-Jen; Enroth, Stefan; Kloiber, Stefan; Trompet, Stella; Stengel, Benedicte; Hancock, Stephen J.; Turner, Stephen T.; Rosas, Sylvia E.; Stracke, Sylvia; Harris, Tamara B.; Zeller, Tanja; Zemunik, Tatijana; Lehtimäki, Terho; Illig, Thomas; Aspelund, Thor; Nikopensius, Tiit; Esko, Tonu; Tanaka, Toshiko; Gyllensten, Ulf; Völker, Uwe; Emilsson, Valur; Vitart, Veronique; Aalto, Ville; Gudnason, Vilmundur; Chouraki, Vincent; Chen, Wei-Min; Igl, Wilmar; März, Winfried; Koenig, Wolfgang; Lieb, Wolfgang; Loos, Ruth J. F.; Liu, Yongmei; Snieder, Harold; Pramstaller, Peter P.; Parsa, Afshin; O'Connell, Jeffrey R.; Susztak, Katalin; Hamet, Pavel; Tremblay, Johanne; de Boer, Ian H.; Böger, Carsten A.; Goessling, Wolfram; Chasman, Daniel I.; Köttgen, Anna; Kao, W. H. Linda; Fox, Caroline S.

2016-01-01

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways. PMID:26831199

Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders.

PubMed

den Hoed, Marcel; Eijgelsheim, Mark; Esko, Tõnu; Brundel, Bianca J J M; Peal, David S; Evans, David M; Nolte, Ilja M; Segrè, Ayellet V; Holm, Hilma; Handsaker, Robert E; Westra, Harm-Jan; Johnson, Toby; Isaacs, Aaron; Yang, Jian; Lundby, Alicia; Zhao, Jing Hua; Kim, Young Jin; Go, Min Jin; Almgren, Peter; Bochud, Murielle; Boucher, Gabrielle; Cornelis, Marilyn C; Gudbjartsson, Daniel; Hadley, David; van der Harst, Pim; Hayward, Caroline; den Heijer, Martin; Igl, Wilmar; Jackson, Anne U; Kutalik, Zoltán; Luan, Jian'an; Kemp, John P; Kristiansson, Kati; Ladenvall, Claes; Lorentzon, Mattias; Montasser, May E; Njajou, Omer T; O'Reilly, Paul F; Padmanabhan, Sandosh; St Pourcain, Beate; Rankinen, Tuomo; Salo, Perttu; Tanaka, Toshiko; Timpson, Nicholas J; Vitart, Veronique; Waite, Lindsay; Wheeler, William; Zhang, Weihua; Draisma, Harmen H M; Feitosa, Mary F; Kerr, Kathleen F; Lind, Penelope A; Mihailov, Evelin; Onland-Moret, N Charlotte; Song, Ci; Weedon, Michael N; Xie, Weijia; Yengo, Loic; Absher, Devin; Albert, Christine M; Alonso, Alvaro; Arking, Dan E; de Bakker, Paul I W; Balkau, Beverley; Barlassina, Cristina; Benaglio, Paola; Bis, Joshua C; Bouatia-Naji, Nabila; Brage, Søren; Chanock, Stephen J; Chines, Peter S; Chung, Mina; Darbar, Dawood; Dina, Christian; Dörr, Marcus; Elliott, Paul; Felix, Stephan B; Fischer, Krista; Fuchsberger, Christian; de Geus, Eco J C; Goyette, Philippe; Gudnason, Vilmundur; Harris, Tamara B; Hartikainen, Anna-Liisa; Havulinna, Aki S; Heckbert, Susan R; Hicks, Andrew A; Hofman, Albert; Holewijn, Suzanne; Hoogstra-Berends, Femke; Hottenga, Jouke-Jan; Jensen, Majken K; Johansson, Asa; Junttila, Juhani; Kääb, Stefan; Kanon, Bart; Ketkar, Shamika; Khaw, Kay-Tee; Knowles, Joshua W; Kooner, Angrad S; Kors, Jan A; Kumari, Meena; Milani, Lili; Laiho, Päivi; Lakatta, Edward G; Langenberg, Claudia; Leusink, Maarten; Liu, Yongmei; Luben, Robert N; Lunetta, Kathryn L; Lynch, Stacey N; Markus, Marcello R P; Marques-Vidal, Pedro; Mateo Leach, Irene; McArdle, Wendy L; McCarroll, Steven A; Medland, Sarah E; Miller, Kathryn A; Montgomery, Grant W; Morrison, Alanna C; Müller-Nurasyid, Martina; Navarro, Pau; Nelis, Mari; O'Connell, Jeffrey R; O'Donnell, Christopher J; Ong, Ken K; Newman, Anne B; Peters, Annette; Polasek, Ozren; Pouta, Anneli; Pramstaller, Peter P; Psaty, Bruce M; Rao, Dabeeru C; Ring, Susan M; Rossin, Elizabeth J; Rudan, Diana; Sanna, Serena; Scott, Robert A; Sehmi, Jaban S; Sharp, Stephen; Shin, Jordan T; Singleton, Andrew B; Smith, Albert V; Soranzo, Nicole; Spector, Tim D; Stewart, Chip; Stringham, Heather M; Tarasov, Kirill V; Uitterlinden, André G; Vandenput, Liesbeth; Hwang, Shih-Jen; Whitfield, John B; Wijmenga, Cisca; Wild, Sarah H; Willemsen, Gonneke; Wilson, James F; Witteman, Jacqueline C M; Wong, Andrew; Wong, Quenna; Jamshidi, Yalda; Zitting, Paavo; Boer, Jolanda M A; Boomsma, Dorret I; Borecki, Ingrid B; van Duijn, Cornelia M; Ekelund, Ulf; Forouhi, Nita G; Froguel, Philippe; Hingorani, Aroon; Ingelsson, Erik; Kivimaki, Mika; Kronmal, Richard A; Kuh, Diana; Lind, Lars; Martin, Nicholas G; Oostra, Ben A; Pedersen, Nancy L; Quertermous, Thomas; Rotter, Jerome I; van der Schouw, Yvonne T; Verschuren, W M Monique; Walker, Mark; Albanes, Demetrius; Arnar, David O; Assimes, Themistocles L; Bandinelli, Stefania; Boehnke, Michael; de Boer, Rudolf A; Bouchard, Claude; Caulfield, W L Mark; Chambers, John C; Curhan, Gary; Cusi, Daniele; Eriksson, Johan; Ferrucci, Luigi; van Gilst, Wiek H; Glorioso, Nicola; de Graaf, Jacqueline; Groop, Leif; Gyllensten, Ulf; Hsueh, Wen-Chi; Hu, Frank B; Huikuri, Heikki V; Hunter, David J; Iribarren, Carlos; Isomaa, Bo; Jarvelin, Marjo-Riitta; Jula, Antti; Kähönen, Mika; Kiemeney, Lambertus A; van der Klauw, Melanie M; Kooner, Jaspal S; Kraft, Peter; Iacoviello, Licia; Lehtimäki, Terho; Lokki, Marja-Liisa L; Mitchell, Braxton D; Navis, Gerjan; Nieminen, Markku S; Ohlsson, Claes; Poulter, Neil R; Qi, Lu; Raitakari, Olli T; Rimm, Eric B; Rioux, John D; Rizzi, Federica; Rudan, Igor; Salomaa, Veikko; Sever, Peter S; Shields, Denis C; Shuldiner, Alan R; Sinisalo, Juha; Stanton, Alice V; Stolk, Ronald P; Strachan, David P; Tardif, Jean-Claude; Thorsteinsdottir, Unnur; Tuomilehto, Jaako; van Veldhuisen, Dirk J; Virtamo, Jarmo; Viikari, Jorma; Vollenweider, Peter; Waeber, Gérard; Widen, Elisabeth; Cho, Yoon Shin; Olsen, Jesper V; Visscher, Peter M; Willer, Cristen; Franke, Lude; Erdmann, Jeanette; Thompson, John R; Pfeufer, Arne; Sotoodehnia, Nona; Newton-Cheh, Christopher; Ellinor, Patrick T; Stricker, Bruno H Ch; Metspalu, Andres; Perola, Markus; Beckmann, Jacques S; Smith, George Davey; Stefansson, Kari; Wareham, Nicholas J; Munroe, Patricia B; Sibon, Ody C M; Milan, David J; Snieder, Harold; Samani, Nilesh J; Loos, Ruth J F

2013-06-01

Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

Novel genetic loci underlying human intracranial volume identified through genome-wide association.

PubMed

Adams, Hieab H H; Hibar, Derrek P; Chouraki, Vincent; Stein, Jason L; Nyquist, Paul A; Rentería, Miguel E; Trompet, Stella; Arias-Vasquez, Alejandro; Seshadri, Sudha; Desrivières, Sylvane; Beecham, Ashley H; Jahanshad, Neda; Wittfeld, Katharina; Van der Lee, Sven J; Abramovic, Lucija; Alhusaini, Saud; Amin, Najaf; Andersson, Micael; Arfanakis, Konstantinos; Aribisala, Benjamin S; Armstrong, Nicola J; Athanasiu, Lavinia; Axelsson, Tomas; Beiser, Alexa; Bernard, Manon; Bis, Joshua C; Blanken, Laura M E; Blanton, Susan H; Bohlken, Marc M; Boks, Marco P; Bralten, Janita; Brickman, Adam M; Carmichael, Owen; Chakravarty, M Mallar; Chauhan, Ganesh; Chen, Qiang; Ching, Christopher R K; Cuellar-Partida, Gabriel; Braber, Anouk Den; Doan, Nhat Trung; Ehrlich, Stefan; Filippi, Irina; Ge, Tian; Giddaluru, Sudheer; Goldman, Aaron L; Gottesman, Rebecca F; Greven, Corina U; Grimm, Oliver; Griswold, Michael E; Guadalupe, Tulio; Hass, Johanna; Haukvik, Unn K; Hilal, Saima; Hofer, Edith; Hoehn, David; Holmes, Avram J; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Kasperaviciute, Dalia; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H; Liao, Jiemin; Liewald, David C M; Lopez, Lorna M; Luciano, Michelle; Macare, Christine; Marquand, Andre; Matarin, Mar; Mather, Karen A; Mattheisen, Manuel; Mazoyer, Bernard; McKay, David R; McWhirter, Rebekah; Milaneschi, Yuri; Mirza-Schreiber, Nazanin; Muetzel, Ryan L; Maniega, Susana Muñoz; Nho, Kwangsik; Nugent, Allison C; Loohuis, Loes M Olde; Oosterlaan, Jaap; Papmeyer, Martina; Pappa, Irene; Pirpamer, Lukas; Pudas, Sara; Pütz, Benno; Rajan, Kumar B; Ramasamy, Adaikalavan; Richards, Jennifer S; Risacher, Shannon L; Roiz-Santiañez, Roberto; Rommelse, Nanda; Rose, Emma J; Royle, Natalie A; Rundek, Tatjana; Sämann, Philipp G; Satizabal, Claudia L; Schmaal, Lianne; Schork, Andrew J; Shen, Li; Shin, Jean; Shumskaya, Elena; Smith, Albert V; Sprooten, Emma; Strike, Lachlan T; Teumer, Alexander; Thomson, Russell; Tordesillas-Gutierrez, Diana; Toro, Roberto; Trabzuni, Daniah; Vaidya, Dhananjay; Van der Grond, Jeroen; Van der Meer, Dennis; Van Donkelaar, Marjolein M J; Van Eijk, Kristel R; Van Erp, Theo G M; Van Rooij, Daan; Walton, Esther; Westlye, Lars T; Whelan, Christopher D; Windham, Beverly G; Winkler, Anderson M; Woldehawariat, Girma; Wolf, Christiane; Wolfers, Thomas; Xu, Bing; Yanek, Lisa R; Yang, Jingyun; Zijdenbos, Alex; Zwiers, Marcel P; Agartz, Ingrid; Aggarwal, Neelum T; Almasy, Laura; Ames, David; Amouyel, Philippe; Andreassen, Ole A; Arepalli, Sampath; Assareh, Amelia A; Barral, Sandra; Bastin, Mark E; Becker, Diane M; Becker, James T; Bennett, David A; Blangero, John; van Bokhoven, Hans; Boomsma, Dorret I; Brodaty, Henry; Brouwer, Rachel M; Brunner, Han G; Buckner, Randy L; Buitelaar, Jan K; Bulayeva, Kazima B; Cahn, Wiepke; Calhoun, Vince D; Cannon, Dara M; Cavalleri, Gianpiero L; Chen, Christopher; Cheng, Ching-Yu; Cichon, Sven; Cookson, Mark R; Corvin, Aiden; Crespo-Facorro, Benedicto; Curran, Joanne E; Czisch, Michael; Dale, Anders M; Davies, Gareth E; De Geus, Eco J C; De Jager, Philip L; de Zubicaray, Greig I; Delanty, Norman; Depondt, Chantal; DeStefano, Anita L; Dillman, Allissa; Djurovic, Srdjan; Donohoe, Gary; Drevets, Wayne C; Duggirala, Ravi; Dyer, Thomas D; Erk, Susanne; Espeseth, Thomas; Evans, Denis A; Fedko, Iryna O; Fernández, Guillén; Ferrucci, Luigi; Fisher, Simon E; Fleischman, Debra A; Ford, Ian; Foroud, Tatiana M; Fox, Peter T; Francks, Clyde; Fukunaga, Masaki; Gibbs, J Raphael; Glahn, David C; Gollub, Randy L; Göring, Harald H H; Grabe, Hans J; Green, Robert C; Gruber, Oliver; Gudnason, Vilmundur; Guelfi, Sebastian; Hansell, Narelle K; Hardy, John; Hartman, Catharina A; Hashimoto, Ryota; Hegenscheid, Katrin; Heinz, Andreas; Le Hellard, Stephanie; Hernandez, Dena G; Heslenfeld, Dirk J; Ho, Beng-Choon; Hoekstra, Pieter J; Hoffmann, Wolfgang; Hofman, Albert; Holsboer, Florian; Homuth, Georg; Hosten, Norbert; Hottenga, Jouke-Jan; Hulshoff Pol, Hilleke E; Ikeda, Masashi; Ikram, M Kamran; Jack, Clifford R; Jenkinson, Mark; Johnson, Robert; Jönsson, Erik G; Jukema, J Wouter; Kahn, René S; Kanai, Ryota; Kloszewska, Iwona; Knopman, David S; Kochunov, Peter; Kwok, John B; Lawrie, Stephen M; Lemaître, Hervé; Liu, Xinmin; Longo, Dan L; Longstreth, W T; Lopez, Oscar L; Lovestone, Simon; Martinez, Oliver; Martinot, Jean-Luc; Mattay, Venkata S; McDonald, Colm; McIntosh, Andrew M; McMahon, Katie L; McMahon, Francis J; Mecocci, Patrizia; Melle, Ingrid; Meyer-Lindenberg, Andreas; Mohnke, Sebastian; Montgomery, Grant W; Morris, Derek W; Mosley, Thomas H; Mühleisen, Thomas W; Müller-Myhsok, Bertram; Nalls, Michael A; Nauck, Matthias; Nichols, Thomas E; Niessen, Wiro J; Nöthen, Markus M; Nyberg, Lars; Ohi, Kazutaka; Olvera, Rene L; Ophoff, Roel A; Pandolfo, Massimo; Paus, Tomas; Pausova, Zdenka; Penninx, Brenda W J H; Pike, G Bruce; Potkin, Steven G; Psaty, Bruce M; Reppermund, Simone; Rietschel, Marcella; Roffman, Joshua L; Romanczuk-Seiferth, Nina; Rotter, Jerome I; Ryten, Mina; Sacco, Ralph L; Sachdev, Perminder S; Saykin, Andrew J; Schmidt, Reinhold; Schofield, Peter R; Sigurdsson, Sigurdur; Simmons, Andy; Singleton, Andrew; Sisodiya, Sanjay M; Smith, Colin; Smoller, Jordan W; Soininen, Hilkka; Srikanth, Velandai; Steen, Vidar M; Stott, David J; Sussmann, Jessika E; Thalamuthu, Anbupalam; Tiemeier, Henning; Toga, Arthur W; Traynor, Bryan J; Troncoso, Juan; Turner, Jessica A; Tzourio, Christophe; Uitterlinden, Andre G; Hernández, Maria C Valdés; Van der Brug, Marcel; Van der Lugt, Aad; Van der Wee, Nic J A; Van Duijn, Cornelia M; Van Haren, Neeltje E M; Van T Ent, Dennis; Van Tol, Marie-Jose; Vardarajan, Badri N; Veltman, Dick J; Vernooij, Meike W; Völzke, Henry; Walter, Henrik; Wardlaw, Joanna M; Wassink, Thomas H; Weale, Michael E; Weinberger, Daniel R; Weiner, Michael W; Wen, Wei; Westman, Eric; White, Tonya; Wong, Tien Y; Wright, Clinton B; Zielke, H Ronald; Zonderman, Alan B; Deary, Ian J; DeCarli, Charles; Schmidt, Helena; Martin, Nicholas G; De Craen, Anton J M; Wright, Margaret J; Launer, Lenore J; Schumann, Gunter; Fornage, Myriam; Franke, Barbara; Debette, Stéphanie; Medland, Sarah E; Ikram, M Arfan; Thompson, Paul M

2016-12-01

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρ genetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (N combined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.

Identification of heart rate–associated loci and their effects on cardiac conduction and rhythm disorders

PubMed Central

den Hoed, Marcel; Eijgelsheim, Mark; Esko, Tõnu; Brundel, Bianca J J M; Peal, David S; Evans, David M; Nolte, Ilja M; Segrè, Ayellet V; Holm, Hilma; Handsaker, Robert E; Westra, Harm-Jan; Johnson, Toby; Isaacs, Aaron; Yang, Jian; Lundby, Alicia; Zhao, Jing Hua; Kim, Young Jin; Go, Min Jin; Almgren, Peter; Bochud, Murielle; Boucher, Gabrielle; Cornelis, Marilyn C; Gudbjartsson, Daniel; Hadley, David; Van Der Harst, Pim; Hayward, Caroline; Heijer, Martin Den; Igl, Wilmar; Jackson, Anne U; Kutalik, Zoltán; Luan, Jian’an; Kemp, John P; Kristiansson, Kati; Ladenvall, Claes; Lorentzon, Mattias; Montasser, May E; Njajou, Omer T; O’Reilly, Paul F; Padmanabhan, Sandosh; Pourcain, Beate St.; Rankinen, Tuomo; Salo, Perttu; Tanaka, Toshiko; Timpson, Nicholas J; Vitart, Veronique; Waite, Lindsay; Wheeler, William; Zhang, Weihua; Draisma, Harmen H M; Feitosa, Mary F; Kerr, Kathleen F; Lind, Penelope A; Mihailov, Evelin; Onland-Moret, N Charlotte; Song, Ci; Weedon, Michael N; Xie, Weijia; Yengo, Loic; Absher, Devin; Albert, Christine M; Alonso, Alvaro; Arking, Dan E; de Bakker, Paul I W; Balkau, Beverley; Barlassina, Cristina; Benaglio, Paola; Bis, Joshua C; Bouatia-Naji, Nabila; Brage, Søren; Chanock, Stephen J; Chines, Peter S; Chung, Mina; Darbar, Dawood; Dina, Christian; Dörr, Marcus; Elliott, Paul; Felix, Stephan B; Fischer, Krista; Fuchsberger, Christian; de Geus, Eco J C; Goyette, Philippe; Gudnason, Vilmundur; Harris, Tamara B; Hartikainen, Anna-liisa; Havulinna, Aki S; Heckbert, Susan R; Hicks, Andrew A; Hofman, Albert; Holewijn, Suzanne; Hoogstra-Berends, Femke; Hottenga, Jouke-Jan; Jensen, Majken K; Johansson, Åsa; Junttila, Juhani; Kääb, Stefan; Kanon, Bart; Ketkar, Shamika; Khaw, Kay-Tee; Knowles, Joshua W; Kooner, Angrad S; Kors, Jan A; Kumari, Meena; Milani, Lili; Laiho, Päivi; Lakatta, Edward G; Langenberg, Claudia; Leusink, Maarten; Liu, Yongmei; Luben, Robert N; Lunetta, Kathryn L; Lynch, Stacey N; Markus, Marcello R P; Marques-Vidal, Pedro; Leach, Irene Mateo; McArdle, Wendy L; McCarroll, Steven A; Medland, Sarah E; Miller, Kathryn A; Montgomery, Grant W; Morrison, Alanna C; Müller-Nurasyid, Martina; Navarro, Pau; Nelis, Mari; O’Connell, Jeffrey R; O’Donnell, Christopher J; Ong, Ken K; Newman, Anne B; Peters, Annette; Polasek, Ozren; Pouta, Anneli; Pramstaller, Peter P; Psaty, Bruce M; Rao, Dabeeru C; Ring, Susan M; Rossin, Elizabeth J; Rudan, Diana; Sanna, Serena; Scott, Robert A; Sehmi, Jaban S; Sharp, Stephen; Shin, Jordan T; Singleton, Andrew B; Smith, Albert V; Soranzo, Nicole; Spector, Tim D; Stewart, Chip; Stringham, Heather M; Tarasov, Kirill V; Uitterlinden, André G; Vandenput, Liesbeth; Hwang, Shih-Jen; Whitfield, John B; Wijmenga, Cisca; Wild, Sarah H; Willemsen, Gonneke; Wilson, James F; Witteman, Jacqueline C M; Wong, Andrew; Wong, Quenna; Jamshidi, Yalda; Zitting, Paavo; Boer, Jolanda M A; Boomsma, Dorret I; Borecki, Ingrid B; Van Duijn, Cornelia M; Ekelund, Ulf; Forouhi, Nita G; Froguel, Philippe; Hingorani, Aroon; Ingelsson, Erik; Kivimaki, Mika; Kronmal, Richard A; Kuh, Diana; Lind, Lars; Martin, Nicholas G; Oostra, Ben A; Pedersen, Nancy L; Quertermous, Thomas; Rotter, Jerome I; van der Schouw, Yvonne T; Verschuren, W M Monique; Walker, Mark; Albanes, Demetrius; Arnar, David O; Assimes, Themistocles L; Bandinelli, Stefania; Boehnke, Michael; de Boer, Rudolf A; Bouchard, Claude; Caulfield, W L Mark; Chambers, John C; Curhan, Gary; Cusi, Daniele; Eriksson, Johan; Ferrucci, Luigi; van Gilst, Wiek H; Glorioso, Nicola; de Graaf, Jacqueline; Groop, Leif; Gyllensten, Ulf; Hsueh, Wen-Chi; Hu, Frank B; Huikuri, Heikki V; Hunter, David J; Iribarren, Carlos; Isomaa, Bo; Jarvelin, Marjo-Riitta; Jula, Antti; Kähönen, Mika; Kiemeney, Lambertus A; van der Klauw, Melanie M; Kooner, Jaspal S; Kraft, Peter; Iacoviello, Licia; Lehtimäki, Terho; Lokki, Marja-Liisa L; Mitchell, Braxton D; Navis, Gerjan; Nieminen, Markku S; Ohlsson, Claes; Poulter, Neil R; Qi, Lu; Raitakari, Olli T; Rimm, Eric B; Rioux, John D; Rizzi, Federica; Rudan, Igor; Salomaa, Veikko; Sever, Peter S; Shields, Denis C; Shuldiner, Alan R; Sinisalo, Juha; Stanton, Alice V; Stolk, Ronald P; Strachan, David P; Tardif, Jean-Claude; Thorsteinsdottir, Unnur; Tuomilehto, Jaako; van Veldhuisen, Dirk J; Virtamo, Jarmo; Viikari, Jorma; Vollenweider, Peter; Waeber, Gérard; Widen, Elisabeth; Cho, Yoon Shin; Olsen, Jesper V; Visscher, Peter M; Willer, Cristen; Franke, Lude; Erdmann, Jeanette; Thompson, John R; Pfeufer, Arne; Sotoodehnia, Nona; Newton-Cheh, Christopher; Ellinor, Patrick T; Stricker, Bruno H Ch; Metspalu, Andres; Perola, Markus; Beckmann, Jacques S; Smith, George Davey; Stefansson, Kari; Wareham, Nicholas J; Munroe, Patricia B; Sibon, Ody C M; Milan, David J; Snieder, Harold; Samani, Nilesh J; Loos, Ruth J F

2013-01-01

Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate–increasing and heart rate–decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets. PMID:23583979

A novel eQTL-based analysis reveals the biology of breast cancer risk loci

PubMed Central

Li, Qiyuan; Seo, Ji-Heui; Stranger, Barbara; McKenna, Aaron; Pe'er, Itsik; LaFramboise, Thomas; Brown, Myles; Tyekucheva, Svitlana; Freedman, Matthew L.

2014-01-01

Summary Germline determinants of gene expression in tumors are less studied due to the complexity of transcript regulation caused by somatically acquired alterations. We performed expression quantitative trait locus (eQTL) based analyses using the multi-level information provided in The Cancer Genome Atlas (TCGA). Of the factors we measured, cis-acting eQTL saccounted for 1.2% of the total variation of tumor gene expression, while somatic copy number alteration and CpG methylation accounted for 7.3% and 3.3%, respectively. eQTL analyses of 15 previously reported breast cancer risk loci resulted in discovery of three variants that are significantly associated with transcript levels (FDR<0.1). In a novel trans- based analysis, an additional three risk loci were identified to act through ESR1, MYC, and KLF4. These findings provide a more comprehensive picture of gene expression determinants in breast cancer as well as insights into the underlying biology of breast cancer risk loci. PMID:23374354

Nine Loci for Ocular Axial Length Identified through Genome-wide Association Studies, Including Shared Loci with Refractive Error

PubMed Central

Cheng, Ching-Yu; Schache, Maria; Ikram, M. Kamran; Young, Terri L.; Guggenheim, Jeremy A.; Vitart, Veronique; MacGregor, Stuart; Verhoeven, Virginie J.M.; Barathi, Veluchamy A.; Liao, Jiemin; Hysi, Pirro G.; Bailey-Wilson, Joan E.; St. Pourcain, Beate; Kemp, John P.; McMahon, George; Timpson, Nicholas J.; Evans, David M.; Montgomery, Grant W.; Mishra, Aniket; Wang, Ya Xing; Wang, Jie Jin; Rochtchina, Elena; Polasek, Ozren; Wright, Alan F.; Amin, Najaf; van Leeuwen, Elisabeth M.; Wilson, James F.; Pennell, Craig E.; van Duijn, Cornelia M.; de Jong, Paulus T.V.M.; Vingerling, Johannes R.; Zhou, Xin; Chen, Peng; Li, Ruoying; Tay, Wan-Ting; Zheng, Yingfeng; Chew, Merwyn; Rahi, Jugnoo S.; Hysi, Pirro G.; Yoshimura, Nagahisa; Yamashiro, Kenji; Miyake, Masahiro; Delcourt, Cécile; Maubaret, Cecilia; Williams, Cathy; Guggenheim, Jeremy A.; Northstone, Kate; Ring, Susan M.; Davey-Smith, George; Craig, Jamie E.; Burdon, Kathryn P.; Fogarty, Rhys D.; Iyengar, Sudha K.; Igo, Robert P.; Chew, Emily; Janmahasathian, Sarayut; Iyengar, Sudha K.; Igo, Robert P.; Chew, Emily; Janmahasathian, Sarayut; Stambolian, Dwight; Wilson, Joan E. Bailey; MacGregor, Stuart; Lu, Yi; Jonas, Jost B.; Xu, Liang; Saw, Seang-Mei; Baird, Paul N.; Rochtchina, Elena; Mitchell, Paul; Wang, Jie Jin; Jonas, Jost B.; Nangia, Vinay; Hayward, Caroline; Wright, Alan F.; Vitart, Veronique; Polasek, Ozren; Campbell, Harry; Vitart, Veronique; Rudan, Igor; Vatavuk, Zoran; Vitart, Veronique; Paterson, Andrew D.; Hosseini, S. Mohsen; Iyengar, Sudha K.; Igo, Robert P.; Fondran, Jeremy R.; Young, Terri L.; Feng, Sheng; Verhoeven, Virginie J.M.; Klaver, Caroline C.; van Duijn, Cornelia M.; Metspalu, Andres; Haller, Toomas; Mihailov, Evelin; Pärssinen, Olavi; Wedenoja, Juho; Wilson, Joan E. Bailey; Wojciechowski, Robert; Baird, Paul N.; Schache, Maria; Pfeiffer, Norbert; Höhn, René; Pang, Chi Pui; Chen, Peng; Meitinger, Thomas; Oexle, Konrad; Wegner, Aharon; Yoshimura, Nagahisa; Yamashiro, Kenji; Miyake, Masahiro; Pärssinen, Olavi; Yip, Shea Ping; Ho, Daniel W.H.; Pirastu, Mario; Murgia, Federico; Portas, Laura; Biino, Genevra; Wilson, James F.; Fleck, Brian; Vitart, Veronique; Stambolian, Dwight; Wilson, Joan E. Bailey; Hewitt, Alex W.; Ang, Wei; Verhoeven, Virginie J.M.; Klaver, Caroline C.; van Duijn, Cornelia M.; Saw, Seang-Mei; Wong, Tien-Yin; Teo, Yik-Ying; Fan, Qiao; Cheng, Ching-Yu; Zhou, Xin; Ikram, M. Kamran; Saw, Seang-Mei; Teo, Yik-Ying; Fan, Qiao; Cheng, Ching-Yu; Zhou, Xin; Ikram, M. Kamran; Saw, Seang-Mei; Wong, Tien-Yin; Teo, Yik-Ying; Fan, Qiao; Cheng, Ching-Yu; Zhou, Xin; Ikram, M. Kamran; Saw, Seang-Mei; Wong, Tien-Yin; Teo, Yik-Ying; Fan, Qiao; Cheng, Ching-Yu; Zhou, Xin; Ikram, M. Kamran; Saw, Seang-Mei; Tai, E-Shyong; Teo, Yik-Ying; Fan, Qiao; Cheng, Ching-Yu; Zhou, Xin; Ikram, M. Kamran; Saw, Seang-Mei; Teo, Yik-Ying; Fan, Qiao; Cheng, Ching-Yu; Zhou, Xin; Ikram, M. Kamran; Mackey, David A.; MacGregor, Stuart; Hammond, Christopher J.; Hysi, Pirro G.; Deangelis, Margaret M.; Morrison, Margaux; Zhou, Xiangtian; Chen, Wei; Paterson, Andrew D.; Hosseini, S. Mohsen; Mizuki, Nobuhisa; Meguro, Akira; Lehtimäki, Terho; Mäkelä, Kari-Matti; Raitakari, Olli; Kähönen, Mika; Burdon, Kathryn P.; Craig, Jamie E.; Iyengar, Sudha K.; Igo, Robert P.; Lass, Jonathan H.; Reinhart, William; Belin, Michael W.; Schultze, Robert L.; Morason, Todd; Sugar, Alan; Mian, Shahzad; Soong, Hunson Kaz; Colby, Kathryn; Jurkunas, Ula; Yee, Richard; Vital, Mark; Alfonso, Eduardo; Karp, Carol; Lee, Yunhee; Yoo, Sonia; Hammersmith, Kristin; Cohen, Elisabeth; Laibson, Peter; Rapuano, Christopher; Ayres, Brandon; Croasdale, Christopher; Caudill, James; Patel, Sanjay; Baratz, Keith; Bourne, William; Maguire, Leo; Sugar, Joel; Tu, Elmer; Djalilian, Ali; Mootha, Vinod; McCulley, James; Bowman, Wayne; Cavanaugh, H. Dwight; Verity, Steven; Verdier, David; Renucci, Ann; Oliva, Matt; Rotkis, Walter; Hardten, David R.; Fahmy, Ahmad; Brown, Marlene; Reeves, Sherman; Davis, Elizabeth A.; Lindstrom, Richard; Hauswirth, Scott; Hamilton, Stephen; Lee, W. Barry; Price, Francis; Price, Marianne; Kelly, Kathleen; Peters, Faye; Shaughnessy, Michael; Steinemann, Thomas; Dupps, B.J.; Meisler, David M.; Mifflin, Mark; Olson, Randal; Aldave, Anthony; Holland, Gary; Mondino, Bartly J.; Rosenwasser, George; Gorovoy, Mark; Dunn, Steven P.; Heidemann, David G.; Terry, Mark; Shamie, Neda; Rosenfeld, Steven I.; Suedekum, Brandon; Hwang, David; Stone, Donald; Chodosh, James; Galentine, Paul G.; Bardenstein, David; Goddard, Katrina; Chin, Hemin; Mannis, Mark; Varma, Rohit; Borecki, Ingrid; Chew, Emily Y.; Haller, Toomas; Mihailov, Evelin; Metspalu, Andres; Wedenoja, Juho; Simpson, Claire L.; Wojciechowski, Robert; Höhn, René; Mirshahi, Alireza; Zeller, Tanja; Pfeiffer, Norbert; Lackner, Karl J.; Donnelly, Peter; Barroso, Ines; Blackwell, Jenefer M.; Bramon, Elvira; Brown, Matthew A.; Casas, Juan P.; Corvin, Aiden; Deloukas, Panos; Duncanson, Audrey; Jankowski, Janusz; Markus, Hugh S.; Mathew, Christopher G.; Palmer, Colin N.A.; Plomin, Robert; Rautanen, Anna; Sawcer, Stephen J.; Trembath, Richard C.; Viswanathan, Ananth C.; Wood, Nicholas W.; Spencer, Chris C.A.; Band, Gavin; Bellenguez, Céline; Freeman, Colin; Hellenthal, Garrett; Giannoulatou, Eleni; Pirinen, Matti; Pearson, Richard; Strange, Amy; Su, Zhan; Vukcevic, Damjan; Donnelly, Peter; Langford, Cordelia; Hunt, Sarah E.; Edkins, Sarah; Gwilliam, Rhian; Blackburn, Hannah; Bumpstead, Suzannah J.; Dronov, Serge; Gillman, Matthew; Gray, Emma; Hammond, Naomi; Jayakumar, Alagurevathi; McCann, Owen T.; Liddle, Jennifer; Potter, Simon C.; Ravindrarajah, Radhi; Ricketts, Michelle; Waller, Matthew; Weston, Paul; Widaa, Sara; Whittaker, Pamela; Barroso, Ines; Deloukas, Panos; Mathew, Christopher G.; Blackwell, Jenefer M.; Brown, Matthew A.; Corvin, Aiden; Spencer, Chris C.A.; Bettecken, Thomas; Meitinger, Thomas; Oexle, Konrad; Pirastu, Mario; Portas, Laura; Nag, Abhishek; Williams, Katie M.; Yonova-Doing, Ekaterina; Klein, Ronald; Klein, Barbara E.; Hosseini, S. Mohsen; Paterson, Andrew D.; Genuth, S.; Nathan, D.M.; Zinman, B.; Crofford, O.; Crandall, J.; Reid, M.; Brown-Friday, J.; Engel, S.; Sheindlin, J.; Martinez, H.; Shamoon, H.; Engel, H.; Phillips, M.; Gubitosi-Klug, R.; Mayer, L.; Pendegast, S.; Zegarra, H.; Miller, D.; Singerman, L.; Smith-Brewer, S.; Novak, M.; Quin, J.; Dahms, W.; Genuth, Saul; Palmert, M.; Brillon, D.; Lackaye, M.E.; Kiss, S.; Chan, R.; Reppucci, V.; Lee, T.; Heinemann, M.; Whitehouse, F.; Kruger, D.; Jones, J.K.; McLellan, M.; Carey, J.D.; Angus, E.; Thomas, A.; Galprin, A.; Bergenstal, R.; Johnson, M.; Spencer, M.; Morgan, K.; Etzwiler, D.; Kendall, D.; Aiello, Lloyd Paul; Golden, E.; Jacobson, A.; Beaser, R.; Ganda, O.; Hamdy, O.; Wolpert, H.; Sharuk, G.; Arrigg, P.; Schlossman, D.; Rosenzwieg, J.; Rand, L.; Nathan, D.M.; Larkin, M.; Ong, M.; Godine, J.; Cagliero, E.; Lou, P.; Folino, K.; Fritz, S.; Crowell, S.; Hansen, K.; Gauthier-Kelly, C.; Service, J.; Ziegler, G.; Luttrell, L.; Caulder, S.; Lopes-Virella, M.; Colwell, J.; Soule, J.; Fernandes, J.; Hermayer, K.; Kwon, S.; Brabham, M.; Blevins, A.; Parker, J.; Lee, D.; Patel, N.; Pittman, C.; Lindsey, P.; Bracey, M.; Lee, K.; Nutaitis, M.; Farr, A.; Elsing, S.; Thompson, T.; Selby, J.; Lyons, T.; Yacoub-Wasef, S.; Szpiech, M.; Wood, D.; Mayfield, R.; Molitch, M.; Schaefer, B.; Jampol, L.; Lyon, A.; Gill, M.; Strugula, Z.; Kaminski, L.; Mirza, R.; Simjanoski, E.; Ryan, D.; Kolterman, O.; Lorenzi, G.; Goldbaum, M.; Sivitz, W.; Bayless, M.; Counts, D.; Johnsonbaugh, S.; Hebdon, M.; Salemi, P.; Liss, R.; Donner, T.; Gordon, J.; Hemady, R.; Kowarski, A.; Ostrowski, D.; Steidl, S.; Jones, B.; Herman, W.H.; Martin, C.L.; Pop-Busui, R.; Sarma, A.; Albers, J.; Feldman, E.; Kim, K.; Elner, S.; Comer, G.; Gardner, T.; Hackel, R.; Prusak, R.; Goings, L.; Smith, A.; Gothrup, J.; Titus, P.; Lee, J.; Brandle, M.; Prosser, L.; Greene, D.A.; Stevens, M.J.; Vine, A.K.; Bantle, J.; Wimmergren, N.; Cochrane, A.; Olsen, T.; Steuer, E.; Rath, P.; Rogness, B.; Hainsworth, D.; Goldstein, D.; Hitt, S.; Giangiacomo, J.; Schade, D.S.; Canady, J.L.; Chapin, J.E.; Ketai, L.H.; Braunstein, C.S.; Bourne, P.A.; Schwartz, S.; Brucker, A.; Maschak-Carey, B.J.; Baker, L.; Orchard, T.; Silvers, N.; Ryan, C.; Songer, T.; Doft, B.; Olson, S.; Bergren, R.L.; Lobes, L.; Rath, P. Paczan; Becker, D.; Rubinstein, D.; Conrad, P.W.; Yalamanchi, S.; Drash, A.; Morrison, A.; Bernal, M.L.; Vaccaro-Kish, J.; Malone, J.; Pavan, P.R.; Grove, N.; Iyer, M.N.; Burrows, A.F.; Tanaka, E.A.; Gstalder, R.; Dagogo-Jack, S.; Wigley, C.; Ricks, H.; Kitabchi, A.; Murphy, M.B.; Moser, S.; Meyer, D.; Iannacone, A.; Chaum, E.; Yoser, S.; Bryer-Ash, M.; Schussler, S.; Lambeth, H.; Raskin, P.; Strowig, S.; Zinman, B.; Barnie, A.; Devenyi, R.; Mandelcorn, M.; Brent, M.; Rogers, S.; Gordon, A.; Palmer, J.; Catton, S.; Brunzell, J.; Wessells, H.; de Boer, I.H.; Hokanson, J.; Purnell, J.; Ginsberg, J.; Kinyoun, J.; Deeb, S.; Weiss, M.; Meekins, G.; Distad, J.; Van Ottingham, L.; Dupre, J.; Harth, J.; Nicolle, D.; Driscoll, M.; Mahon, J.; Canny, C.; May, M.; Lipps, J.; Agarwal, A.; Adkins, T.; Survant, L.; Pate, R.L.; Munn, G.E.; Lorenz, R.; Feman, S.; White, N.; Levandoski, L.; Boniuk, I.; Grand, G.; Thomas, M.; Joseph, D.D.; Blinder, K.; Shah, G.; Boniuk; Burgess; Santiago, J.; Tamborlane, W.; Gatcomb, P.; Stoessel, K.; Taylor, K.; Goldstein, J.; Novella, S.; Mojibian, H.; Cornfeld, D.; Lima, J.; Bluemke, D.; Turkbey, E.; van der Geest, R.J.; Liu, C.; Malayeri, A.; Jain, A.; Miao, C.; Chahal, H.; Jarboe, R.; Maynard, J.; Gubitosi-Klug, R.; Quin, J.; Gaston, P.; Palmert, M.; Trail, R.; Dahms, W.; Lachin, J.; Cleary, P.; Backlund, J.; Sun, W.; Braffett, B.; Klumpp, K.; Chan, K.; Diminick, L.; Rosenberg, D.; Petty, B.; Determan, A.; Kenny, D.; Rutledge, B.; Younes, Naji; Dews, L.; Hawkins, M.; Cowie, C.; Fradkin, J.; Siebert, C.; Eastman, R.; Danis, R.; Gangaputra, S.; Neill, S.; Davis, M.; Hubbard, L.; Wabers, H.; Burger, M.; Dingledine, J.; Gama, V.; Sussman, R.; Steffes, M.; Bucksa, J.; Nowicki, M.; Chavers, B.; O’Leary, D.; Polak, J.; Harrington, A.; Funk, L.; Crow, R.; Gloeb, B.; Thomas, S.; O’Donnell, C.; Soliman, E.; Zhang, Z.M.; Prineas, R.; Campbell, C.; Ryan, C.; Sandstrom, D.; Williams, T.; Geckle, M.; Cupelli, E.; Thoma, F.; Burzuk, B.; Woodfill, T.; Low, P.; Sommer, C.; Nickander, K.; Budoff, M.; Detrano, R.; Wong, N.; Fox, M.; Kim, L.; Oudiz, R.; Weir, G.; Espeland, M.; Manolio, T.; Rand, L.; Singer, D.; Stern, M.; Boulton, A.E.; Clark, C.; D’Agostino, R.; Lopes-Virella, M.; Garvey, W.T.; Lyons, T.J.; Jenkins, A.; Virella, G.; Jaffa, A.; Carter, Rickey; Lackland, D.; Brabham, M.; McGee, D.; Zheng, D.; Mayfield, R.K.; Boright, A.; Bull, S.; Sun, L.; Scherer, S.; Zinman, B.; Natarajan, R.; Miao, F.; Zhang, L.; Chen;, Z.; Nathan, D.M.; Makela, Kari-Matti; Lehtimaki, Terho; Kahonen, Mika; Raitakari, Olli; Yoshimura, Nagahisa; Matsuda, Fumihiko; Chen, Li Jia; Pang, Chi Pui; Yip, Shea Ping; Yap, Maurice K.H.; Meguro, Akira; Mizuki, Nobuhisa; Inoko, Hidetoshi; Foster, Paul J.; Zhao, Jing Hua; Vithana, Eranga; Tai, E-Shyong; Fan, Qiao; Xu, Liang; Campbell, Harry; Fleck, Brian; Rudan, Igor; Aung, Tin; Hofman, Albert; Uitterlinden, André G.; Bencic, Goran; Khor, Chiea-Chuen; Forward, Hannah; Pärssinen, Olavi; Mitchell, Paul; Rivadeneira, Fernando; Hewitt, Alex W.; Williams, Cathy; Oostra, Ben A.; Teo, Yik-Ying; Hammond, Christopher J.; Stambolian, Dwight; Mackey, David A.; Klaver, Caroline C.W.; Wong, Tien-Yin; Saw, Seang-Mei; Baird, Paul N.

2013-01-01

Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways. PMID:24144296

Application of logistic regression to case-control association studies involving two causative loci.

PubMed

North, Bernard V; Curtis, David; Sham, Pak C

2005-01-01

Models in which two susceptibility loci jointly influence the risk of developing disease can be explored using logistic regression analysis. Comparison of likelihoods of models incorporating different sets of disease model parameters allows inferences to be drawn regarding the nature of the joint effect of the loci. We have simulated case-control samples generated assuming different two-locus models and then analysed them using logistic regression. We show that this method is practicable and that, for the models we have used, it can be expected to allow useful inferences to be drawn from sample sizes consisting of hundreds of subjects. Interactions between loci can be explored, but interactive effects do not exactly correspond with classical definitions of epistasis. We have particularly examined the issue of the extent to which it is helpful to utilise information from a previously identified locus when investigating a second, unknown locus. We show that for some models conditional analysis can have substantially greater power while for others unconditional analysis can be more powerful. Hence we conclude that in general both conditional and unconditional analyses should be performed when searching for additional loci.

Genetic dissection of hybrid incompatibilities between Drosophila simulans and D. mauritiana. II. Mapping hybrid male sterility loci on the third chromosome.

PubMed

Tao, Yun; Zeng, Zhao-Bang; Li, Jian; Hartl, Daniel L; Laurie, Cathy C

2003-08-01

Hybrid male sterility (HMS) is a rapidly evolving mechanism of reproductive isolation in Drosophila. Here we report a genetic analysis of HMS in third-chromosome segments of Drosophila mauritiana that were introgressed into a D. simulans background. Qualitative genetic mapping was used to localize 10 loci on 3R and a quantitative trait locus (QTL) procedure (multiple-interval mapping) was used to identify 19 loci on the entire chromosome. These genetic incompatibilities often show dominance and complex patterns of epistasis. Most of the HMS loci have relatively small effects and generally at least two or three of them are required to produce complete sterility. Only one small region of the third chromosome of D. mauritiana by itself causes a high level of infertility when introgressed into D. simulans. By comparison with previous studies of the X chromosome, we infer that HMS loci are only approximately 40% as dense on this autosome as they are on the X chromosome. These results are consistent with the gradual evolution of hybrid incompatibilities as a by-product of genetic divergence in allopatric populations.

Genetic dissection of hybrid incompatibilities between Drosophila simulans and D. mauritiana. II. Mapping hybrid male sterility loci on the third chromosome.

PubMed Central

Tao, Yun; Zeng, Zhao-Bang; Li, Jian; Hartl, Daniel L; Laurie, Cathy C

2003-01-01

Hybrid male sterility (HMS) is a rapidly evolving mechanism of reproductive isolation in Drosophila. Here we report a genetic analysis of HMS in third-chromosome segments of Drosophila mauritiana that were introgressed into a D. simulans background. Qualitative genetic mapping was used to localize 10 loci on 3R and a quantitative trait locus (QTL) procedure (multiple-interval mapping) was used to identify 19 loci on the entire chromosome. These genetic incompatibilities often show dominance and complex patterns of epistasis. Most of the HMS loci have relatively small effects and generally at least two or three of them are required to produce complete sterility. Only one small region of the third chromosome of D. mauritiana by itself causes a high level of infertility when introgressed into D. simulans. By comparison with previous studies of the X chromosome, we infer that HMS loci are only approximately 40% as dense on this autosome as they are on the X chromosome. These results are consistent with the gradual evolution of hybrid incompatibilities as a by-product of genetic divergence in allopatric populations. PMID:12930748

A phenotype-sensitizing Apoe-deficient genetic background reveals novel atherosclerosis predisposition loci in the mouse.

PubMed Central

Dansky, Hayes M; Shu, Pei; Donavan, M; Montagno, Jill; Nagle, Deborah L; Smutko, John S; Roy, Natalie; Whiteing, S; Barrios, Judith; McBride, T J; Smith, Jonathan D; Duyk, Geoffrey; Breslow, Jan L; Moore, Karen J

2002-01-01

Therapeutic intervention for atherosclerosis has predominantly concentrated on regulating cholesterol levels; however, these therapeutics are not efficacious for all patients, suggesting that other factors are involved. This study was initiated to identify mechanisms that regulate atherosclerosis predisposition in mice other than cholesterol level regulation. To do so we performed quantitative trait locus analysis using two inbred strains that each carry the atherosclerosis phenotype-sensitizing Apoe deficiency and that have been shown to have widely disparate predilection to atherosclerotic lesion formation. One highly significant locus on chromosome 10 (LOD = 7.8) accounted for 19% of the variance in lesion area independent of cholesterol. Two additional suggestive loci were identified on chromosomes 14 (LOD = 3.2) and 19 (LOD = 3.2), each accounting for 7-8% of the lesion variance. In all, five statistically significant and suggestive loci affecting lesion size but not lipoprotein levels were identified. Many of these were recapitulated in an independent confirmatory cross. In summary, two independently performed crosses between C57BL/6 and FVB/N Apoe-deficient mice have revealed several previously unreported atherosclerosis susceptibility loci that are distinct from loci linked to lipoprotein levels. PMID:11973313

Immunochip analysis identification of 6 additional susceptibility loci for Crohn's disease in Koreans.

PubMed

Yang, Suk-Kyun; Hong, Myunghee; Choi, Hyunchul; Zhao, Wanting; Jung, Yusun; Haritunians, Talin; Ye, Byong Duk; Kim, Kyung-Jo; Park, Sang Hyoung; Lee, Inchul; Kim, Won Ho; Cheon, Jae Hee; Kim, Young-Ho; Jang, Byung Ik; Kim, Hyun-Soo; Choi, Jai Hyun; Koo, Ja Seol; Lee, Ji Hyun; Jung, Sung-Ae; Shin, Hyoung Doo; Kang, Daehee; Youn, Hee-Shang; Taylor, Kent D; Rotter, Jerome I; Liu, Jianjun; McGovern, Dermot P B; Song, Kyuyoung

2015-01-01

Crohn's disease (CD) is an intractable inflammatory bowel disease of unknown cause. Recent genome-wide association studies of CD in Korean and Japanese populations suggested marginal sharing of susceptibility loci between Caucasian and Asian populations. As the 7 identified loci altogether explain 5.31% of the risk for CD, the objective of this study was to identify additional CD susceptibility loci in the Korean population. Using the ImmunoChip custom single-nucleotide polymorphism array designed for dense genotyping of 186 loci identified through GWAS, we analyzed 722 individuals with CD and 461 controls for 96,048 SNP markers in the discovery stage, followed by validation in an additional 948 affected individuals and 977 controls. We confirmed 6 previously reported loci in Caucasian: GPR35 at 2q37 (rs3749172; P = 5.30 × 10, odds ratio [OR] = 1.45), ZNF365 at 10q21 (rs224143; P = 2.20 × 10, OR = 1.38), ZMIZ1 at 10q22 (rs1250569; P = 3.05 × 10, OR = 1.30), NKX2-3 at 10q24 (rs4409764; P = 7.93 × 10, OR = 1.32), PTPN2 at 18p11 (rs514000; P = 9.00 × 10, OR = 1.33), and USP25 at 21q11 (rs2823256; P = 2.49 × 10, OR = 1.35), bringing the number of known CD loci (including 3 in the HLA) in Koreans to 15. The 6 additional loci increased the total genetic variance for CD risk from 5.31% to 7.27% in Koreans. Although the different genetic backgrounds of CD between Asian and Western countries has been well established for the major susceptibility genes, our findings of overlapping associations offer new insights into the genetic architecture of CD.

Possible involvement of SINEs in mammalian-specific brain formation

PubMed Central

Sasaki, Takeshi; Nishihara, Hidenori; Hirakawa, Mika; Fujimura, Koji; Tanaka, Mikiko; Kokubo, Nobuhiro; Kimura-Yoshida, Chiharu; Matsuo, Isao; Sumiyama, Kenta; Saitou, Naruya; Shimogori, Tomomi; Okada, Norihiro

2008-01-01

Retroposons, such as short interspersed elements (SINEs) and long interspersed elements (LINEs), are the major constituents of higher vertebrate genomes. Although there are many examples of retroposons' acquiring function, none has been implicated in the morphological innovations specific to a certain taxonomic group. We previously characterized a SINE family, AmnSINE1, members of which constitute a part of conserved noncoding elements (CNEs) in mammalian genomes. We proposed that this family acquired genomic functionality or was exapted after retropositioning in a mammalian ancestor. Here we identified 53 new AmnSINE1 loci and refined 124 total loci, two of which were further analyzed. Using a mouse enhancer assay, we demonstrate that one SINE locus, AS071, 178 kbp from the gene FGF8 (fibroblast growth factor 8), is an enhancer that recapitulates FGF8 expression in two regions of the developing forebrain, namely the diencephalon and the hypothalamus. Our gain-of-function analysis revealed that FGF8 expression in the diencephalon controls patterning of thalamic nuclei, which act as a relay center of the neocortex, suggesting a role for FGF8 in mammalian-specific forebrain patterning. Furthermore, we demonstrated that the locus, AS021, 392 kbp from the gene SATB2, controls gene expression in the lateral telencephalon, which is thought to be a signaling center during development. These results suggest important roles for SINEs in the development of the mammalian neuronal network, a part of which was initiated with the exaptation of AmnSINE1 in a common mammalian ancestor. PMID:18334644

Possible involvement of SINEs in mammalian-specific brain formation.

PubMed

Sasaki, Takeshi; Nishihara, Hidenori; Hirakawa, Mika; Fujimura, Koji; Tanaka, Mikiko; Kokubo, Nobuhiro; Kimura-Yoshida, Chiharu; Matsuo, Isao; Sumiyama, Kenta; Saitou, Naruya; Shimogori, Tomomi; Okada, Norihiro

2008-03-18

Retroposons, such as short interspersed elements (SINEs) and long interspersed elements (LINEs), are the major constituents of higher vertebrate genomes. Although there are many examples of retroposons' acquiring function, none has been implicated in the morphological innovations specific to a certain taxonomic group. We previously characterized a SINE family, AmnSINE1, members of which constitute a part of conserved noncoding elements (CNEs) in mammalian genomes. We proposed that this family acquired genomic functionality or was exapted after retropositioning in a mammalian ancestor. Here we identified 53 new AmnSINE1 loci and refined 124 total loci, two of which were further analyzed. Using a mouse enhancer assay, we demonstrate that one SINE locus, AS071, 178 kbp from the gene FGF8 (fibroblast growth factor 8), is an enhancer that recapitulates FGF8 expression in two regions of the developing forebrain, namely the diencephalon and the hypothalamus. Our gain-of-function analysis revealed that FGF8 expression in the diencephalon controls patterning of thalamic nuclei, which act as a relay center of the neocortex, suggesting a role for FGF8 in mammalian-specific forebrain patterning. Furthermore, we demonstrated that the locus, AS021, 392 kbp from the gene SATB2, controls gene expression in the lateral telencephalon, which is thought to be a signaling center during development. These results suggest important roles for SINEs in the development of the mammalian neuronal network, a part of which was initiated with the exaptation of AmnSINE1 in a common mammalian ancestor.

Incipient balancing selection through adaptive loss of aquaporins in natural Saccharomyces cerevisiae populations.

PubMed

Will, Jessica L; Kim, Hyun Seok; Clarke, Jessica; Painter, John C; Fay, Justin C; Gasch, Audrey P

2010-04-01

A major goal in evolutionary biology is to understand how adaptive evolution has influenced natural variation, but identifying loci subject to positive selection has been a challenge. Here we present the adaptive loss of a pair of paralogous genes in specific Saccharomyces cerevisiae subpopulations. We mapped natural variation in freeze-thaw tolerance to two water transporters, AQY1 and AQY2, previously implicated in freeze-thaw survival. However, whereas freeze-thaw-tolerant strains harbor functional aquaporin genes, the set of sensitive strains lost aquaporin function at least 6 independent times. Several genomic signatures at AQY1 and/or AQY2 reveal low variation surrounding these loci within strains of the same haplotype, but high variation between strain groups. This is consistent with recent adaptive loss of aquaporins in subgroups of strains, leading to incipient balancing selection. We show that, although aquaporins are critical for surviving freeze-thaw stress, loss of both genes provides a major fitness advantage on high-sugar substrates common to many strains' natural niche. Strikingly, strains with non-functional alleles have also lost the ancestral requirement for aquaporins during spore formation. Thus, the antagonistic effect of aquaporin function-providing an advantage in freeze-thaw tolerance but a fitness defect for growth in high-sugar environments-contributes to the maintenance of both functional and nonfunctional alleles in S. cerevisiae. This work also shows that gene loss through multiple missense and nonsense mutations, hallmarks of pseudogenization presumed to emerge after loss of constraint, can arise through positive selection.

Chromosomal Locations of 5S and 45S rDNA in Gossypium Genus and Its Phylogenetic Implications Revealed by FISH

PubMed Central

Gan, Yimei; Liu, Fang; Chen, Dan; Wu, Qiong; Qin, Qin; Wang, Chunying; Li, Shaohui; Zhang, Xiangdi; Wang, Yuhong; Wang, Kunbo

2013-01-01

We investigated the locations of 5S and 45S rDNA in Gossypium diploid A, B, D, E, F, G genomes and tetraploid genome (AD) using multi-probe fluorescent in situ hybridization (FISH) for evolution analysis in Gossypium genus. The rDNA numbers and sizes, and synteny relationships between 5S and 45S were revealed using 5S and 45S as double-probe for all species, and the rDNA-bearing chromosomes were identified for A, D and AD genomes with one more probe that is single-chromosome-specific BAC clone from G. hirsutum (A1D1). Two to four 45S and one 5S loci were found in diploid-species except two 5S loci in G . incanum (E4), the same as that in tetraploid species. The 45S on the 7th and 9th chromosomes and the 5S on the 9th chromosomes seemed to be conserved in A, D and AD genomes. In the species of B, E, F and G genomes, the rDNA numbers, sizes, and synteny relationships were first reported in this paper. The rDNA pattern agrees with previously reported phylogenetic history with some disagreements. Combined with the whole-genome sequencing data from G . raimondii (D5) and the conserved cotton karyotype, it is suggested that the expansion, decrease and transposition of rDNA other than chromosome rearrangements might occur during the Gossypium evolution. PMID:23826377

Chromosomal Locations of 5S and 45S rDNA in Gossypium Genus and Its Phylogenetic Implications Revealed by FISH.

PubMed

Gan, Yimei; Liu, Fang; Chen, Dan; Wu, Qiong; Qin, Qin; Wang, Chunying; Li, Shaohui; Zhang, Xiangdi; Wang, Yuhong; Wang, Kunbo

2013-01-01

We investigated the locations of 5S and 45S rDNA in Gossypium diploid A, B, D, E, F, G genomes and tetraploid genome (AD) using multi-probe fluorescent in situ hybridization (FISH) for evolution analysis in Gossypium genus. The rDNA numbers and sizes, and synteny relationships between 5S and 45S were revealed using 5S and 45S as double-probe for all species, and the rDNA-bearing chromosomes were identified for A, D and AD genomes with one more probe that is single-chromosome-specific BAC clone from G. hirsutum (A1D1). Two to four 45S and one 5S loci were found in diploid-species except two 5S loci in G. incanum (E4), the same as that in tetraploid species. The 45S on the 7th and 9th chromosomes and the 5S on the 9th chromosomes seemed to be conserved in A, D and AD genomes. In the species of B, E, F and G genomes, the rDNA numbers, sizes, and synteny relationships were first reported in this paper. The rDNA pattern agrees with previously reported phylogenetic history with some disagreements. Combined with the whole-genome sequencing data from G. raimondii (D5) and the conserved cotton karyotype, it is suggested that the expansion, decrease and transposition of rDNA other than chromosome rearrangements might occur during the Gossypium evolution.

Association between GWAS-identified lung adenocarcinoma susceptibility loci and EGFR mutations in never-smoking Asian women, and comparison with findings from Western populations.

PubMed

Seow, Wei Jie; Matsuo, Keitaro; Hsiung, Chao Agnes; Shiraishi, Kouya; Song, Minsun; Kim, Hee Nam; Wong, Maria Pik; Hong, Yun-Chul; Hosgood, H Dean; Wang, Zhaoming; Chang, I-Shou; Wang, Jiu-Cun; Chatterjee, Nilanjan; Tucker, Margaret; Wei, Hu; Mitsudomi, Tetsuya; Zheng, Wei; Kim, Jin Hee; Zhou, Baosen; Caporaso, Neil E; Albanes, Demetrius; Shin, Min-Ho; Chung, Lap Ping; An, She-Juan; Wang, Ping; Zheng, Hong; Yatabe, Yasushi; Zhang, Xu-Chao; Kim, Young Tae; Shu, Xiao-Ou; Kim, Young-Chul; Bassig, Bryan A; Chang, Jiang; Ho, James Chung Man; Ji, Bu-Tian; Kubo, Michiaki; Daigo, Yataro; Ito, Hidemi; Momozawa, Yukihide; Ashikawa, Kyota; Kamatani, Yoichiro; Honda, Takayuki; Sakamoto, Hiromi; Kunitoh, Hideo; Tsuta, Koji; Watanabe, Shun-Ichi; Nokihara, Hiroshi; Miyagi, Yohei; Nakayama, Haruhiko; Matsumoto, Shingo; Tsuboi, Masahiro; Goto, Koichi; Yin, Zhihua; Shi, Jianxin; Takahashi, Atsushi; Goto, Akiteru; Minamiya, Yoshihiro; Shimizu, Kimihiro; Tanaka, Kazumi; Wu, Tangchun; Wei, Fusheng; Wong, Jason Y Y; Matsuda, Fumihiko; Su, Jian; Kim, Yeul Hong; Oh, In-Jae; Song, Fengju; Lee, Victor Ho Fun; Su, Wu-Chou; Chen, Yuh-Min; Chang, Gee-Chen; Chen, Kuan-Yu; Huang, Ming-Shyan; Yang, Pan-Chyr; Lin, Hsien-Chih; Xiang, Yong-Bing; Seow, Adeline; Park, Jae Yong; Kweon, Sun-Seog; Chen, Chien-Jen; Li, Haixin; Gao, Yu-Tang; Wu, Chen; Qian, Biyun; Lu, Daru; Liu, Jianjun; Jeon, Hyo-Sung; Hsiao, Chin-Fu; Sung, Jae Sook; Tsai, Ying-Huang; Jung, Yoo Jin; Guo, Huan; Hu, Zhibin; Wang, Wen-Chang; Chung, Charles C; Lawrence, Charles; Burdett, Laurie; Yeager, Meredith; Jacobs, Kevin B; Hutchinson, Amy; Berndt, Sonja I; He, Xingzhou; Wu, Wei; Wang, Junwen; Li, Yuqing; Choi, Jin Eun; Park, Kyong Hwa; Sung, Sook Whan; Liu, Li; Kang, Chang Hyun; Hu, Lingmin; Chen, Chung-Hsing; Yang, Tsung-Ying; Xu, Jun; Guan, Peng; Tan, Wen; Wang, Chih-Liang; Sihoe, Alan Dart Loon; Chen, Ying; Choi, Yi Young; Hung, Jen-Yu; Kim, Jun Suk; Yoon, Ho-Il; Cai, Qiuyin; Lin, Chien-Chung; Park, In Kyu; Xu, Ping; Dong, Jing; Kim, Christopher; He, Qincheng; Perng, Reury-Perng; Chen, Chih-Yi; Vermeulen, Roel; Wu, Junjie; Lim, Wei-Yen; Chen, Kun-Chieh; Chan, John K C; Chu, Minjie; Li, Yao-Jen; Li, Jihua; Chen, Hongyan; Yu, Chong-Jen; Jin, Li; Lo, Yen-Li; Chen, Ying-Hsiang; Fraumeni, Joseph F; Liu, Jie; Yamaji, Taiki; Yang, Yang; Hicks, Belynda; Wyatt, Kathleen; Li, Shengchao A; Dai, Juncheng; Ma, Hongxia; Jin, Guangfu; Song, Bao; Wang, Zhehai; Cheng, Sensen; Li, Xuelian; Ren, Yangwu; Cui, Ping; Iwasaki, Motoki; Shimazu, Taichi; Tsugane, Shoichiro; Zhu, Junjie; Jiang, Gening; Fei, Ke; Wu, Guoping; Chien, Li-Hsin; Chen, Hui-Ling; Su, Yu-Chun; Tsai, Fang-Yu; Chen, Yi-Song; Yu, Jinming; Stevens, Victoria L; Laird-Offringa, Ite A; Marconett, Crystal N; Lin, Dongxin; Chen, Kexin; Wu, Yi-Long; Landi, Maria Teresa; Shen, Hongbing; Rothman, Nathaniel; Kohno, Takashi; Chanock, Stephen J; Lan, Qing

2017-01-15

To evaluate associations by EGFR mutation status for lung adenocarcinoma risk among never-smoking Asian women, we conducted a meta-analysis of 11 loci previously identified in genome-wide association studies (GWAS). Genotyping in an additional 10,780 never-smoking cases and 10,938 never-smoking controls from Asia confirmed associations with eight known single nucleotide polymorphisms (SNPs). Two new signals were observed at genome-wide significance (P < 5 × 10-8), namely, rs7216064 (17q24.3, BPTF), for overall lung adenocarcinoma risk, and rs3817963 (6p21.3, BTNL2) which is specific to cases with EGFR mutations. In further sub-analyses by EGFR status, rs9387478 (ROS1/DCBLD1) and rs2179920 (HLA-DPB1) showed stronger estimated associations in EGFR-positive compared to EGFR-negative cases. Comparison of the overall associations with published results in Western populations revealed that the majority of these findings were distinct, underscoring the importance of distinct contributing factors for smoking and non-smoking lung cancer. Our results extend the catalogue of regions associated with lung adenocarcinoma in non-smoking Asian women and highlight the importance of how the germline could inform risk for specific tumour mutation patterns, which could have important translational implications. Published by Oxford University Press 2016. This work is written by US Government employees and is in the public domain in the US.

Implication of a chromosome 15q15.2 locus in regulating UBR1 and predisposing smokers to MGMT methylation in lung

PubMed Central

Leng, Shuguang; Wu, Guodong; Collins, Leonard B.; Thomas, Cynthia L.; Tellez, Carmen S.; Jauregui, Andrew R.; Picchi, Maria A.; Zhang, Xiequn; Juri, Daniel E.; Desai, Dhimant; Amin, Shantu G.; Crowell, Richard E.; Stidley, Christine A.; Liu, Yushi; Swenberg, James A.; Lin, Yong; Wathelet, Marc G.; Gilliland, Frank D.; Belinsky, Steven A.

2015-01-01

O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that protects cells from carcinogenic effects of alkylating agents; however, MGMT is silenced by promoter hypermethylation during carcinogenesis. A single nucleotide polymorphism (SNP) in an enhancer in the MGMT promoter was previously identified to be highly significantly associated with risk for MGMT methylation in lung cancer and sputum from smokers. To further genetic investigations, a genome-wide association and replication study was conducted in two smoker cohorts to identify novel loci for MGMT methylation in sputum that were independent of the MGMT enhancer polymorphism. Two novel trans-acting loci (15q15.2 and 17q24.3) that were identified acted together with the enhancer SNP to empower risk prediction for MGMT methylation. We found that the predisposition to MGMT methylation arising from the 15q15.2 locus involved regulation of the ubiquitin protein ligase E3 component UBR1. UBR1 attenuation reduced turnover of MGMT protein and increased repair of O6-methylguanine in nitrosomethylurea-treated human bronchial epithelial cells (HBEC), while also reducing MGMT promoter activity and abolishing MGMT induction. Overall, our results substantiate reduced gene transcription as a major mechanism for predisposition to MGMT methylation in the lungs of smokers, and support the importance of UBR1 in regulating MGMT homeostasis and DNA repair of alkylated DNA adducts in cells. PMID:26183928

Meta-analysis of genome-wide association studies in East Asian-ancestry populations identifies four new loci for body mass index

PubMed Central

Wen, Wanqing; Zheng, Wei; Okada, Yukinori; Takeuchi, Fumihiko; Tabara, Yasuharu; Hwang, Joo-Yeon; Dorajoo, Rajkumar; Li, Huaixing; Tsai, Fuu-Jen; Yang, Xiaobo; He, Jiang; Wu, Ying; He, Meian; Zhang, Yi; Liang, Jun; Guo, Xiuqing; Sheu, Wayne Huey-Herng; Delahanty, Ryan; Guo, Xingyi; Kubo, Michiaki; Yamamoto, Ken; Ohkubo, Takayoshi; Go, Min Jin; Liu, Jian Jun; Gan, Wei; Chen, Ching-Chu; Gao, Yong; Li, Shengxu; Lee, Nanette R.; Wu, Chen; Zhou, Xueya; Song, Huaidong; Yao, Jie; Lee, I-Te; Long, Jirong; Tsunoda, Tatsuhiko; Akiyama, Koichi; Takashima, Naoyuki; Cho, Yoon Shin; Ong, Rick TH; Lu, Ling; Chen, Chien-Hsiun; Tan, Aihua; Rice, Treva K; Adair, Linda S.; Gui, Lixuan; Allison, Matthew; Lee, Wen-Jane; Cai, Qiuyin; Isomura, Minoru; Umemura, Satoshi; Kim, Young Jin; Seielstad, Mark; Hixson, James; Xiang, Yong-Bing; Isono, Masato; Kim, Bong-Jo; Sim, Xueling; Lu, Wei; Nabika, Toru; Lee, Juyoung; Lim, Wei-Yen; Gao, Yu-Tang; Takayanagi, Ryoichi; Kang, Dae-Hee; Wong, Tien Yin; Hsiung, Chao Agnes; Wu, I-Chien; Juang, Jyh-Ming Jimmy; Shi, Jiajun; Choi, Bo Youl; Aung, Tin; Hu, Frank; Kim, Mi Kyung; Lim, Wei Yen; Wang, Tzung-Dao; Shin, Min-Ho; Lee, Jeannette; Ji, Bu-Tian; Lee, Young-Hoon; Young, Terri L.; Shin, Dong Hoon; Chun, Byung-Yeol; Cho, Myeong-Chan; Han, Bok-Ghee; Hwu, Chii-Min; Assimes, Themistocles L.; Absher, Devin; Yan, Xiaofei; Kim, Eric; Kuo, Jane Z.; Kwon, Soonil; Taylor, Kent D.; Chen, Yii-Der I.; Rotter, Jerome I.; Qi, Lu; Zhu, Dingliang; Wu, Tangchun; Mohlke, Karen L.; Gu, Dongfeng; Mo, Zengnan; Wu, Jer-Yuarn; Lin, Xu; Miki, Tetsuro; Tai, E. Shyong; Lee, Jong-Young; Kato, Norihiro; Shu, Xiao-Ou; Tanaka, Toshihiro

2014-01-01

Recent genetic association studies have identified 55 genetic loci associated with obesity or body mass index (BMI). The vast majority, 51 loci, however, were identified in European-ancestry populations. We conducted a meta-analysis of associations between BMI and ∼2.5 million genotyped or imputed single nucleotide polymorphisms among 86 757 individuals of Asian ancestry, followed by in silico and de novo replication among 7488–47 352 additional Asian-ancestry individuals. We identified four novel BMI-associated loci near the KCNQ1 (rs2237892, P = 9.29 × 10−13), ALDH2/MYL2 (rs671, P = 3.40 × 10−11; rs12229654, P = 4.56 × 10−9), ITIH4 (rs2535633, P = 1.77 × 10−10) and NT5C2 (rs11191580, P = 3.83 × 10−8) genes. The association of BMI with rs2237892, rs671 and rs12229654 was significantly stronger among men than among women. Of the 51 BMI-associated loci initially identified in European-ancestry populations, we confirmed eight loci at the genome-wide significance level (P < 5.0 × 10−8) and an additional 14 at P < 1.0 × 10−3 with the same direction of effect as reported previously. Findings from this analysis expand our knowledge of the genetic basis of obesity. PMID:24861553

SSR allelic variation in almond (Prunus dulcis Mill.).

PubMed

Xie, Hua; Sui, Yi; Chang, Feng-Qi; Xu, Yong; Ma, Rong-Cai

2006-01-01

Sixteen SSR markers including eight EST-SSR and eight genomic SSRs were used for genetic diversity analysis of 23 Chinese and 15 international almond cultivars. EST- and genomic SSR markers previously reported in species of Prunus, mainly peach, proved to be useful for almond genetic analysis. DNA sequences of 117 alleles of six of the 16 SSR loci were analysed to reveal sequence variation among the 38 almond accessions. For the four SSR loci with AG/CT repeats, no insertions or deletions were observed in the flanking regions of the 98 alleles sequenced. Allelic size variation of these loci resulted exclusively from differences in the structures of repeat motifs, which involved interruptions or occurrences of new motif repeats in addition to varying number of AG/CT repeats. Some alleles had a high number of uninterrupted repeat motifs, indicating that SSR mutational patterns differ among alleles at a given SSR locus within the almond species. Allelic homoplasy was observed in the SSR loci because of base substitutions, interruptions or compound repeat motifs. Substitutions in the repeat regions were found at two SSR loci, suggesting that point mutations operate on SSRs and hinder the further SSR expansion by introducing repeat interruptions to stabilize SSR loci. Furthermore, it was shown that some potential point mutations in the flanking regions are linked with new SSR repeat motif variation in almond and peach.

Patterns of Population Structure and Environmental Associations to Aridity Across the Range of Loblolly Pine (Pinus taeda L., Pinaceae)

PubMed Central

Eckert, Andrew J.; van Heerwaarden, Joost; Wegrzyn, Jill L.; Nelson, C. Dana; Ross-Ibarra, Jeffrey; González-Martínez, Santíago C.; Neale, David. B.

2010-01-01

Natural populations of forest trees exhibit striking phenotypic adaptations to diverse environmental gradients, thereby making them appealing subjects for the study of genes underlying ecologically relevant phenotypes. Here, we use a genome-wide data set of single nucleotide polymorphisms genotyped across 3059 functional genes to study patterns of population structure and identify loci associated with aridity across the natural range of loblolly pine (Pinus taeda L.). Overall patterns of population structure, as inferred using principal components and Bayesian cluster analyses, were consistent with three genetic clusters likely resulting from expansions out of Pleistocene refugia located in Mexico and Florida. A novel application of association analysis, which removes the confounding effects of shared ancestry on correlations between genetic and environmental variation, identified five loci correlated with aridity. These loci were primarily involved with abiotic stress response to temperature and drought. A unique set of 24 loci was identified as FST outliers on the basis of the genetic clusters identified previously and after accounting for expansions out of Pleistocene refugia. These loci were involved with a diversity of physiological processes. Identification of nonoverlapping sets of loci highlights the fundamental differences implicit in the use of either method and suggests a pluralistic, yet complementary, approach to the identification of genes underlying ecologically relevant phenotypes. PMID:20439779

Recapitulation of genome-wide association studies on body mass index in the Korean population.

PubMed

Hong, K W; Oh, B

2012-08-01

Obesity is a risk factor for multiple disorders such as diabetes and cardiovascular disease. Recently, a genome-wide association study for body mass index (BMI) was conducted in 249 796 individuals of European ancestry by the Genetic Investigation of Anthropometric Traits (GIANT) consortium. They identified 14 known obesity susceptibility loci and 18 new loci associated with BMI at the genome-wide significance level (P<5 × 10⁻⁸). Because the prevalence and severity of obesity vary among ethnic groups, it is worthy to investigate these results in another ethnic population. We examined the BMI association of 19 single-nucleotide polymorphisms (SNPs) out of the 32 in 8842 individuals from the Korean Association Resource data, and found 12 SNPs to be associated with BMI in the Korean population. Eight loci, rs10968576 (BDNF), rs3817334 (MTCH2), rs1558902 (FTO), rs571312 (MC4R), rs543874 (SEC16B), rs987237 (TFAP2B), rs2867125 (TMEM18) and rs7138803 (FAIM2), were previously known obesity susceptibility loci, and the remaining four loci, rs1514175 (TNNI3K), rs206936 (NUDT3), rs4771122 (MTIF3) and rs2241423 (MAP2K5), were newly identified as BMI loci by the GIANT study. Further, all 12 SNPs showed the same direction of effect on BMI between the two ethnic groups, suggesting a similar genetic architecture governing the obesity.

Genome-wide Meta-analyses of Breast, Ovarian and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by At Least Two Cancer Types

PubMed Central

Kar, Siddhartha P.; Beesley, Jonathan; Al Olama, Ali Amin; Michailidou, Kyriaki; Tyrer, Jonathan; Kote-Jarai, ZSofia; Lawrenson, Kate; Lindstrom, Sara; Ramus, Susan J.; Thompson, Deborah J.; Kibel, Adam S.; Dansonka-Mieszkowska, Agnieszka; Michael, Agnieszka; Dieffenbach, Aida K.; Gentry-Maharaj, Aleksandra; Whittemore, Alice S.; Wolk, Alicja; Monteiro, Alvaro; Peixoto, Ana; Kierzek, Andrzej; Cox, Angela; Rudolph, Anja; Gonzalez-Neira, Anna; Wu, Anna H.; Lindblom, Annika; Swerdlow, Anthony; Ziogas, Argyrios; Ekici, Arif B.; Burwinkel, Barbara; Karlan, Beth Y.; Nordestgaard, Børge G.; Blomqvist, Carl; Phelan, Catherine; McLean, Catriona; Pearce, Celeste Leigh; Vachon, Celine; Cybulski, Cezary; Slavov, Chavdar; Stegmaier, Christa; Maier, Christiane; Ambrosone, Christine B.; Høgdall, Claus K.; Teerlink, Craig C.; Kang, Daehee; Tessier, Daniel C.; Schaid, Daniel J.; Stram, Daniel O.; Cramer, Daniel W.; Neal, David E.; Eccles, Diana; Flesch-Janys, Dieter; Velez Edwards, Digna R.; Wokozorczyk, Dominika; Levine, Douglas A.; Yannoukakos, Drakoulis; Sawyer, Elinor J.; Bandera, Elisa V.; Poole, Elizabeth M.; Goode, Ellen L.; Khusnutdinova, Elza; Høgdall, Estrid; Song, Fengju; Bruinsma, Fiona; Heitz, Florian; Modugno, Francesmary; Hamdy, Freddie C.; Wiklund, Fredrik; Giles, Graham G.; Olsson, Håkan; Wildiers, Hans; Ulmer, Hans-Ulrich; Pandha, Hardev; Risch, Harvey A.; Darabi, Hatef; Salvesen, Helga B.; Nevanlinna, Heli; Gronberg, Henrik; Brenner, Hermann; Brauch, Hiltrud; Anton-Culver, Hoda; Song, Honglin; Lim, Hui-Yi; McNeish, Iain; Campbell, Ian; Vergote, Ignace; Gronwald, Jacek; Lubiński, Jan; Stanford, Janet L.; Benítez, Javier; Doherty, Jennifer A.; Permuth, Jennifer B.; Chang-Claude, Jenny; Donovan, Jenny L.; Dennis, Joe; Schildkraut, Joellen M.; Schleutker, Johanna; Hopper, John L.; Kupryjanczyk, Jolanta; Park, Jong Y.; Figueroa, Jonine; Clements, Judith A.; Knight, Julia A.; Peto, Julian; Cunningham, Julie M.; Pow-Sang, Julio; Batra, Jyotsna; Czene, Kamila; Lu, Karen H.; Herkommer, Kathleen; Khaw, Kay-Tee; Matsuo, Keitaro; Muir, Kenneth; Offitt, Kenneth; Chen, Kexin; Moysich, Kirsten B.; Aittomäki, Kristiina; Odunsi, Kunle; Kiemeney, Lambertus A.; Massuger, Leon F.A.G.; Fitzgerald, Liesel M.; Cook, Linda S.; Cannon-Albright, Lisa; Hooning, Maartje J.; Pike, Malcolm C.; Bolla, Manjeet K.; Luedeke, Manuel; Teixeira, Manuel R.; Goodman, Marc T.; Schmidt, Marjanka K.; Riggan, Marjorie; Aly, Markus; Rossing, Mary Anne; Beckmann, Matthias W.; Moisse, Matthieu; Sanderson, Maureen; Southey, Melissa C.; Jones, Michael; Lush, Michael; Hildebrandt, Michelle A. T.; Hou, Ming-Feng; Schoemaker, Minouk J.; Garcia-Closas, Montserrat; Bogdanova, Natalia; Rahman, Nazneen; Le, Nhu D.; Orr, Nick; Wentzensen, Nicolas; Pashayan, Nora; Peterlongo, Paolo; Guénel, Pascal; Brennan, Paul; Paulo, Paula; Webb, Penelope M.; Broberg, Per; Fasching, Peter A.; Devilee, Peter; Wang, Qin; Cai, Qiuyin; Li, Qiyuan; Kaneva, Radka; Butzow, Ralf; Kopperud, Reidun Kristin; Schmutzler, Rita K.; Stephenson, Robert A.; MacInnis, Robert J.; Hoover, Robert N.; Winqvist, Robert; Ness, Roberta; Milne, Roger L.; Travis, Ruth C.; Benlloch, Sara; Olson, Sara H.; McDonnell, Shannon K.; Tworoger, Shelley S.; Maia, Sofia; Berndt, Sonja; Lee, Soo Chin; Teo, Soo-Hwang; Thibodeau, Stephen N.; Bojesen, Stig E.; Gapstur, Susan M.; Kjær, Susanne Krüger; Pejovic, Tanja; Tammela, Teuvo L.J.; Dörk, Thilo; Brüning, Thomas; Wahlfors, Tiina; Key, Tim J.; Edwards, Todd L.; Menon, Usha; Hamann, Ute; Mitev, Vanio; Kosma, Veli-Matti; Setiawan, Veronica Wendy; Kristensen, Vessela; Arndt, Volker; Vogel, Walther; Zheng, Wei; Sieh, Weiva; Blot, William J.; Kluzniak, Wojciech; Shu, Xiao-Ou; Gao, Yu-Tang; Schumacher, Fredrick; Freedman, Matthew L.; Berchuck, Andrew; Dunning, Alison M.; Simard, Jacques; Haiman, Christopher A.; Spurdle, Amanda; Sellers, Thomas A.; Hunter, David J.; Henderson, Brian E.; Kraft, Peter; Chanock, Stephen J.; Couch, Fergus J.; Hall, Per; Gayther, Simon A.; Easton, Douglas F.; Chenevix-Trench, Georgia; Eeles, Rosalind; Pharoah, Paul D.P.; Lambrechts, Diether

2016-01-01

Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10−8 seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10−5 in the three-cancer meta-analysis. PMID:27432226

Transferability and Fine-Mapping of Genome-Wide Associated Loci for Adult Height across Human Populations

PubMed Central

Shriner, Daniel; Adeyemo, Adebowale; Gerry, Norman P.; Herbert, Alan; Chen, Guanjie; Doumatey, Ayo; Huang, Hanxia; Zhou, Jie; Christman, Michael F.; Rotimi, Charles N.

2009-01-01

Human height is the prototypical polygenic quantitative trait. Recently, several genetic variants influencing adult height were identified, primarily in individuals of East Asian (Chinese Han or Korean) or European ancestry. Here, we examined 152 genetic variants representing 107 independent loci previously associated with adult height for transferability in a well-powered sample of 1,016 unrelated African Americans. When we tested just the reported variants originally identified as associated with adult height in individuals of East Asian or European ancestry, only 8.3% of these loci transferred (p-values≤0.05 under an additive genetic model with directionally consistent effects) to our African American sample. However, when we comprehensively evaluated all HapMap variants in linkage disequilibrium (r 2≥0.3) with the reported variants, the transferability rate increased to 54.1%. The transferability rate was 70.8% for associations originally reported as genome-wide significant and 38.0% for associations originally reported as suggestive. An additional 23 loci were significantly associated but failed to transfer because of directionally inconsistent effects. Six loci were associated with adult height in all three groups. Using differences in linkage disequilibrium patterns between HapMap CEU or CHB reference data and our African American sample, we fine-mapped these six loci, improving both the localization and the annotation of these transferable associations. PMID:20027299

The genetics of celiac disease: A comprehensive review of clinical implications.

PubMed

Dieli-Crimi, Romina; Cénit, M Carmen; Núñez, Concepción

2015-11-01

Celiac disease (CD) is a complex immune-related disease with a very strong genetic component. Multiple genetic findings over the last decade have added to the already known MHC influence numerous genetic variants associated to CD susceptibility. Currently, it is well-established that 6 MHC and 39 non-MHC loci, including a higher number of independent genetic variants, are associated to disease risk. Moreover, additional regions have been recently implicated in the disease, which would increase the number of involved loci. Together, the firmly described genetic variants account for roughly 31% of CD heritability, being 25% explained by the MHC influence. These new variants represent markers of disease risk and turn the identification of the causal genes and the causal variants inside the associated loci, as well as their precise biological role on the disease, into a major challenge in CD research. Numerous studies have been developed with this aim showing the high impact of risk variants on gene expression. These studies also indicate a central role of CD4(+) T cells in CD pathogenesis and point to B cells as important players, which is in accordance with the key steps highlighted by the immunological models of pathogenesis. We comprehensively summarize the current knowledge about the genetic architecture of CD, characterized by multiple low-risk variants located within diverse loci which are most likely affecting genes with immune-related functions. These findings are leading to a better understanding of CD pathogenesis and helping in the design of new treatments. The repertoire of potential drug targets for CD has largely broadened last years, bringing us closer to get alternative or complementary treatments to the life-long gluten-free diet, the only effective treatment so far. Epigenetics and microbiota are emerging as potent factors modulating disease risk and putatively affecting disease manifestation, which are also being explored as therapeutic targets. Copyright © 2015 Elsevier Ltd. All rights reserved.

Genetic susceptibility to type 2 diabetes and obesity: follow-up of findings from genome-wide association studies.

PubMed

Basile, Kevin J; Johnson, Matthew E; Xia, Qianghua; Grant, Struan F A

2014-01-01

Elucidating the underlying genetic variations influencing various complex diseases is one of the major challenges currently facing clinical genetic research. Although these variations are often difficult to uncover, approaches such as genome-wide association studies (GWASs) have been successful at finding statistically significant associations between specific genomic loci and disease susceptibility. GWAS has been especially successful in elucidating genetic variants that influence type 2 diabetes (T2D) and obesity/body mass index (BMI). Specifically, several GWASs have confirmed that a variant in transcription factor 7-like 2 (TCF7L2) confers risk for T2D, while a variant in fat mass and obesity-associated protein (FTO) confers risk for obesity/BMI; indeed both of these signals are considered the most statistically associated loci discovered for these respective traits to date. The discovery of these two key loci in this context has been invaluable for providing novel insight into mechanisms of heritability and disease pathogenesis. As follow-up studies of TCF7L2 and FTO have typically lead the way in how to follow up a GWAS discovery, we outline what has been learned from such investigations and how they have implications for the myriad of other loci that have been subsequently reported in this disease context.

Detecting Selection on Temporal and Spatial Scales: A Genomic Time-Series Assessment of Selective Responses to Devil Facial Tumor Disease

PubMed Central

Brüniche-Olsen, Anna; Austin, Jeremy J.; Jones, Menna E.; Holland, Barbara R.; Burridge, Christopher P.

2016-01-01

Detecting loci under selection is an important task in evolutionary biology. In conservation genetics detecting selection is key to investigating adaptation to the spread of infectious disease. Loci under selection can be detected on a spatial scale, accounting for differences in demographic history among populations, or on a temporal scale, tracing changes in allele frequencies over time. Here we use these two approaches to investigate selective responses to the spread of an infectious cancer—devil facial tumor disease (DFTD)—that since 1996 has ravaged the Tasmanian devil (Sarcophilus harrisii). Using time-series ‘restriction site associated DNA’ (RAD) markers from populations pre- and post DFTD arrival, and DFTD free populations, we infer loci under selection due to DFTD and investigate signatures of selection that are incongruent among methods, populations, and times. The lack of congruence among populations influenced by DFTD with respect to inferred loci under selection, and the direction of that selection, fail to implicate a consistent selective role for DFTD. Instead genetic drift is more likely driving the observed allele frequency changes over time. Our study illustrates the importance of applying methods with different performance optima e.g. accounting for population structure and background selection, and assessing congruence of the results. PMID:26930198

Genetic dissection of adaptive form and function in rapidly speciating cichlid fishes.

PubMed

Henning, Frederico; Machado-Schiaffino, Gonzalo; Baumgarten, Lukas; Meyer, Axel

2017-05-01

Genes of major phenotypic effects and strong genetic correlations can facilitate adaptation, direct selective responses, and potentially lead to phenotypic convergence. However, the preponderance of this type of genetic architecture in repeatedly evolved adaptations remains unknown. Using hybrids between Haplochromis chilotes (thick-lipped) and Pundamilia nyererei (thin-lipped) we investigated the genetics underlying hypertrophied lips and elongated heads, traits that evolved repeatedly in cichlids. At least 25 loci of small-to-moderate and mainly additive effects were detected. Phenotypic variation in lip and head morphology was largely independent. Although several QTL overlapped for lip and head morphology traits, they were often of opposite effects. The distribution of effect signs suggests strong selection on lips. The fitness implications of several detected loci were demonstrated using a laboratory assay testing for the association between genotype and variation in foraging performance. The persistence of low fitness alleles in head morphology appears to be maintained through antagonistic pleiotropy/close linkage with positive-effect lip morphology alleles. Rather than being based on few major loci with strong positive genetic correlations, our results indicate that the evolution of the Lake Victoria thick-lipped ecomorph is the result of selection on numerous loci distributed throughout the genome. © 2017 The Author(s). Evolution © 2017 The Society for the Study of Evolution.

Identification of nine new susceptibility loci for testicular cancer, including variants near DAZL and PRDM14

PubMed Central

Ruark, Elise; Seal, Sheila; McDonald, Heather; Zhang, Feng; Elliot, Anna; Lau, KingWai; Perdeaux, Elizabeth; Rapley, Elizabeth; Eeles, Rosalind; Peto, Julian; Kote-Jarai, Zsofia; Muir, Kenneth; Nsengimana, Jeremie; Shipley, Janet; Bishop, D. Timothy; Stratton, Michael R; Easton, Douglas F; Huddart, Robert A; Rahman, Nazneen; Turnbull, Clare

2013-01-01

Testicular germ cell tumor (TGCT) is the most common cancer in young men and is notable for its high familial risks1,2. To date, six loci associated with TGCT have been reported3-7. From GWAS analysis of 307,291 SNPs in 986 cases and 4,946 controls, we selected for follow-up 694 SNPs, which we genotyped in a further 1,064 TGCT cases and 10,082 controls from the UK. We identified SNPs at nine new loci showing association with TGCT (P<5×10−8), at 1q22, 1q24.1, 3p24.3, 4q24, 5q31.1, 8q13.3, 16q12.1, 17q22 and 21q22.3, which together account for an additional 4-6% of the familial risk of TGCT. The loci include genes plausibly related to TGCT development. PRDM14, at 8q13.3, is essential for early germ cell specification8 whilst DAZL, at 3p24.3, is required for regulation of germ cell development9. Furthermore, PITX1, at 5q31.1 regulates TERT expression, and is the third TGCT locus implicated in telomerase regulation10. PMID:23666240

Locus-dependent selection in crop-wild hybrids of lettuce under field conditions and its implication for GM crop development

PubMed Central

Hooftman, Danny A P; Flavell, Andrew J; Jansen, Hans; den Nijs, Hans C M; Syed, Naeem H; Sørensen, Anker P; Orozco-ter Wengel, Pablo; van de Wiel, Clemens C M

2011-01-01

Gene escape from crops has gained much attention in the last two decades, as transgenes introgressing into wild populations could affect the latter's ecological characteristics. However, different genes have different likelihoods of introgression. The mixture of selective forces provided by natural conditions creates an adaptive mosaic of alleles from both parental species. We investigated segregation patterns after hybridization between lettuce (Lactuca sativa) and its wild relative, L. serriola. Three generations of hybrids (S1, BC1, and BC1S1) were grown in habitats mimicking the wild parent's habitat. As control, we harvested S1 seedlings grown under controlled conditions, providing very limited possibility for selection. We used 89 AFLP loci, as well as more recently developed dominant markers, 115 retrotransposon markers (SSAP), and 28 NBS loci linked to resistance genes. For many loci, allele frequencies were biased in plants exposed to natural field conditions, including over-representation of crop alleles for various loci. Furthermore, Linkage disequilibrium was locally changed, allegedly by selection caused by the natural field conditions, providing ample opportunity for genetic hitchhiking. Our study indicates that when developing genetically modified crops, a judicious selection of insertion sites, based on knowledge of selective (dis)advantages of the surrounding crop genome under field conditions, could diminish transgene persistence. PMID:25568012

Locus-dependent selection in crop-wild hybrids of lettuce under field conditions and its implication for GM crop development.

PubMed

Hooftman, Danny A P; Flavell, Andrew J; Jansen, Hans; den Nijs, Hans C M; Syed, Naeem H; Sørensen, Anker P; Orozco-Ter Wengel, Pablo; van de Wiel, Clemens C M

2011-09-01

Gene escape from crops has gained much attention in the last two decades, as transgenes introgressing into wild populations could affect the latter's ecological characteristics. However, different genes have different likelihoods of introgression. The mixture of selective forces provided by natural conditions creates an adaptive mosaic of alleles from both parental species. We investigated segregation patterns after hybridization between lettuce (Lactuca sativa) and its wild relative, L. serriola. Three generations of hybrids (S1, BC1, and BC1S1) were grown in habitats mimicking the wild parent's habitat. As control, we harvested S1 seedlings grown under controlled conditions, providing very limited possibility for selection. We used 89 AFLP loci, as well as more recently developed dominant markers, 115 retrotransposon markers (SSAP), and 28 NBS loci linked to resistance genes. For many loci, allele frequencies were biased in plants exposed to natural field conditions, including over-representation of crop alleles for various loci. Furthermore, Linkage disequilibrium was locally changed, allegedly by selection caused by the natural field conditions, providing ample opportunity for genetic hitchhiking. Our study indicates that when developing genetically modified crops, a judicious selection of insertion sites, based on knowledge of selective (dis)advantages of the surrounding crop genome under field conditions, could diminish transgene persistence.

Multi-ethnic genome-wide association study identifies novel locus for type 2 diabetes susceptibility

PubMed Central

Cook, James P; Morris, Andrew P

2016-01-01

Genome-wide association studies (GWAS) have traditionally been undertaken in homogeneous populations from the same ancestry group. However, with the increasing availability of GWAS in large-scale multi-ethnic cohorts, we have evaluated a framework for detecting association of genetic variants with complex traits, allowing for population structure, and developed a powerful test of heterogeneity in allelic effects between ancestry groups. We have applied the methodology to identify and characterise loci associated with susceptibility to type 2 diabetes (T2D) using GWAS data from the Resource for Genetic Epidemiology on Adult Health and Aging, a large multi-ethnic population-based cohort, created for investigating the genetic and environmental basis of age-related diseases. We identified a novel locus for T2D susceptibility at genome-wide significance (P<5 × 10−8) that maps to TOMM40-APOE, a region previously implicated in lipid metabolism and Alzheimer's disease. We have also confirmed previous reports that single-nucleotide polymorphisms at the TCF7L2 locus demonstrate the greatest extent of heterogeneity in allelic effects between ethnic groups, with the lowest risk observed in populations of East Asian ancestry. PMID:27189021

Temporal changes in genetic variation of boll weevil (Coleoptera: Curculionidae) populations, and implications for population assignment in eradication zones

USDA-ARS?s Scientific Manuscript database

Genetic differentiation among 10 populations of boll weevil, Anthonomus grandis grandis, sampled in 2009, in Texas and Mexico, was determined using ten microsatellite loci. In addition, temporal changes in genetic composition were examined in the eight populations for which samples were available fr...

Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets.

PubMed

Lam, Max; Trampush, Joey W; Yu, Jin; Knowles, Emma; Davies, Gail; Liewald, David C; Starr, John M; Djurovic, Srdjan; Melle, Ingrid; Sundet, Kjetil; Christoforou, Andrea; Reinvang, Ivar; DeRosse, Pamela; Lundervold, Astri J; Steen, Vidar M; Espeseth, Thomas; Räikkönen, Katri; Widen, Elisabeth; Palotie, Aarno; Eriksson, Johan G; Giegling, Ina; Konte, Bettina; Roussos, Panos; Giakoumaki, Stella; Burdick, Katherine E; Payton, Antony; Ollier, William; Chiba-Falek, Ornit; Attix, Deborah K; Need, Anna C; Cirulli, Elizabeth T; Voineskos, Aristotle N; Stefanis, Nikos C; Avramopoulos, Dimitrios; Hatzimanolis, Alex; Arking, Dan E; Smyrnis, Nikolaos; Bilder, Robert M; Freimer, Nelson A; Cannon, Tyrone D; London, Edythe; Poldrack, Russell A; Sabb, Fred W; Congdon, Eliza; Conley, Emily Drabant; Scult, Matthew A; Dickinson, Dwight; Straub, Richard E; Donohoe, Gary; Morris, Derek; Corvin, Aiden; Gill, Michael; Hariri, Ahmad R; Weinberger, Daniel R; Pendleton, Neil; Bitsios, Panos; Rujescu, Dan; Lahti, Jari; Le Hellard, Stephanie; Keller, Matthew C; Andreassen, Ole A; Deary, Ian J; Glahn, David C; Malhotra, Anil K; Lencz, Todd

2017-11-28

Here, we present a large (n = 107,207) genome-wide association study (GWAS) of general cognitive ability ("g"), further enhanced by combining results with a large-scale GWAS of educational attainment. We identified 70 independent genomic loci associated with general cognitive ability. Results showed significant enrichment for genes causing Mendelian disorders with an intellectual disability phenotype. Competitive pathway analysis implicated the biological processes of neurogenesis and synaptic regulation, as well as the gene targets of two pharmacologic agents: cinnarizine, a T-type calcium channel blocker, and LY97241, a potassium channel inhibitor. Transcriptome-wide and epigenome-wide analysis revealed that the implicated loci were enriched for genes expressed across all brain regions (most strongly in the cerebellum). Enrichment was exclusive to genes expressed in neurons but not oligodendrocytes or astrocytes. Finally, we report genetic correlations between cognitive ability and disparate phenotypes including psychiatric disorders, several autoimmune disorders, longevity, and maternal age at first birth. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Simultaneous Differentiation and Typing of Entamoeba histolytica and Entamoeba dispar

PubMed Central

Zaki, Mehreen; Meelu, Parool; Sun, Wei; Clark, C. Graham

2002-01-01

Sequences corresponding to some of the polymorphic loci previously reported from Entamoeba histolytica have been detected in Entamoeba dispar. Comparison of nucleotide sequences of two loci between E. dispar strain SAW760 and E. histolytica strain HM-1:IMSS revealed significant differences in both repeat and flanking regions. The tandem repeat units varied not only in sequence but also in number and arrangement between the two species at both the loci. Using the sequences obtained, primer pairs aimed at amplifying species-specific products were designed and tested on a variety of E. histolytica and E. dispar samples. Amplification results were in complete agreement with the original species classification in all cases, and the PCR products displayed discernible size and pattern variations among the isolates. PMID:11923344

Genetic diversity analysis in the section Caulorrhizae (genus Arachis) using microsatellite markers.

PubMed

Palmieri, Darío A; Bechara, Marcelo D; Curi, Rogério A; Monteiro, Jomar P; Valente, Sérgio E S; Gimenes, Marcos A; Lopes, Catalina R

2010-01-01

Diversity in 26 microsatellite loci from section Caulorrhizae germplasm was evaluated by using 33 accessions of A. pintoi Krapov. & W.C. Gregory and ten accessions of Arachis repens Handro. Twenty loci proved to be polymorphic and a total of 196 alleles were detected with an average of 9.8 alleles per locus. The variability found in those loci was greater than the variability found using morphological characters, seed storage proteins and RAPD markers previously used in this germplasm. The high potential of these markers to detect species-specific alleles and discriminate among accessions was demonstrated. The set of microsatellite primer pairs developed by our group for A. pintoi are useful molecular tools for evaluating Section Caulorrhizae germplasm, as well as that of species belonging to other Arachis sections.

Genetic diversity analysis in the section Caulorrhizae (genus Arachis) using microsatellite markers

PubMed Central

2010-01-01

Diversity in 26 microsatellite loci from section Caulorrhizae germplasm was evaluated by using 33 accessions of A. pintoi Krapov. & W.C. Gregory and ten accessions of Arachis repens Handro. Twenty loci proved to be polymorphic and a total of 196 alleles were detected with an average of 9.8 alleles per locus. The variability found in those loci was greater than the variability found using morphological characters, seed storage proteins and RAPD markers previously used in this germplasm. The high potential of these markers to detect species-specific alleles and discriminate among accessions was demonstrated. The set of microsatellite primer pairs developed by our group for A. pintoi are useful molecular tools for evaluating Section Caulorrhizae germplasm, as well as that of species belonging to other Arachis sections. PMID:21637613

Seven newly identified loci for autoimmune thyroid disease.

PubMed

Cooper, Jason D; Simmonds, Matthew J; Walker, Neil M; Burren, Oliver; Brand, Oliver J; Guo, Hui; Wallace, Chris; Stevens, Helen; Coleman, Gillian; Franklyn, Jayne A; Todd, John A; Gough, Stephen C L

2012-12-01

Autoimmune thyroid disease (AITD), including Graves' disease (GD) and Hashimoto's thyroiditis (HT), is one of the most common of the immune-mediated diseases. To further investigate the genetic determinants of AITD, we conducted an association study using a custom-made single-nucleotide polymorphism (SNP) array, the ImmunoChip. The SNP array contains all known and genotype-able SNPs across 186 distinct susceptibility loci associated with one or more immune-mediated diseases. After stringent quality control, we analysed 103 875 common SNPs (minor allele frequency >0.05) in 2285 GD and 462 HT patients and 9364 controls. We found evidence for seven new AITD risk loci (P < 1.12 × 10(-6); a permutation test derived significance threshold), five at locations previously associated and two at locations awaiting confirmation, with other immune-mediated diseases.

Fine mapping of the Darier's disease locus on chromosome 12q.

PubMed

Richard, G; Wright, A R; Harris, S; Doyle, S Z; Korge, B; Mazzanti, C; Tanaka, T; Harth, W; McBride, O W; Compton, J G; Bale, S J; DiGiovanna, J J

1994-11-01

Darier's disease (DD) is an autosomal dominant genodermatosis characterized by epidermal acantholysis and dyskeratosis. We have performed genetic linkage studies in 10 families with DD (34 affected) by analyzing 14 polymorphic microsatellite markers. Our results confirm recent reports mapping the DD gene to chromosome 12q23-q24.1. Haplotype analysis of recombinant chromosomes in our families, along with previously reported data, narrow the location of the DD gene to a 5 cM interval flanked by the loci D12S354 and D12S84/D12S105. This localization allowed exclusion of two known genes, PLA2A and PAH, as candidate loci for DD. Three other gene loci (PPP1C, PMCH, PMCA1), mapping in 12q21-q24, remain potential candidates.

Mapping of a novel QTL for resistance to cereal cyst nematode in wheat.

PubMed

Williams, K J; Willsmore, K L; Olson, S; Matic, M; Kuchel, H

2006-05-01

Cereal cyst nematode (CCN; Heterodera avenae Woll.) is a root pathogen of cereals that can cause severe yield losses in intolerant wheat cultivars. Loci for resistance to CCN, measured by a seedling bioassay, were identified by creating a genetic map based on a Trident/Molineux doubled haploid population of 182 lines. A novel locus accounting for up to 14% of the resistance to CCN was mapped to chromosome 1B of Molineux by association with microsatellite marker loci Xwmc719 and Xgwm140. This locus acts additively with the previously identified CCN resistance loci identified on chromosomes 6B (Cre8) and 2A (Cre5 on the VPM1 segment) in this population to explain 44% of the genetic variance for this major wheat pathogen.

Mutation rates at 42 Y chromosomal short tandem repeats in Chinese Han population in Eastern China.

PubMed

Wu, Weiwei; Ren, Wenyan; Hao, Honglei; Nan, Hailun; He, Xin; Liu, Qiuling; Lu, Dejian

2018-01-31

Mutation analysis of 42 Y chromosomal short tandem repeats (Y-STRs) loci was performed using a sample of 1160 father-son pairs from the Chinese Han population in Eastern China. The results showed that the average mutation rate across the 42 Y-STR loci was 0.0041 (95% CI 0.0036-0.0047) per locus per generation. The locus-specific mutation rates varied from 0.000 to 0.0190. No mutation was found at DYS388, DYS437, DYS448, DYS531, and GATA_H4. DYS627, DYS570, DYS576, and DYS449 could be classified as rapidly mutating Y-STRs, with mutation rates higher than 1.0 × 10 -2 . DYS458, DYS630, and DYS518 were moderately mutating Y-STRs, with mutation rates ranging from 8 × 10 -3 to 1 × 10 -2 . Although the characteristics of the Y-STR mutations were consistent with those in previous studies, mutation rate differences between our data and previous published data were found at some rapidly mutating Y-STRs. The single-copy loci located on the short arm of the Y chromosome (Yp) showed relatively higher mutation rates more frequently than the multi-copy loci. These results will not only extend the data for Y-STR mutations but also be important for kinship analysis, paternal lineage identification, and family relationship reconstruction in forensic Y-STR analysis.

Alu expression in human cell lines and their retrotranspositional potential.

PubMed

Oler, Andrew J; Traina-Dorge, Stephen; Derbes, Rebecca S; Canella, Donatella; Cairns, Brad R; Roy-Engel, Astrid M

2012-06-20

The vast majority of the 1.1 million Alu elements are retrotranspositionally inactive, where only a few loci referred to as 'source elements' can generate new Alu insertions. The first step in identifying the active Alu sources is to determine the loci transcribed by RNA polymerase III (pol III). Previous genome-wide analyses from normal and transformed cell lines identified multiple Alu loci occupied by pol III factors, making them candidate source elements. Analysis of the data from these genome-wide studies determined that the majority of pol III-bound Alus belonged to the older subfamilies Alu S and Alu J, which varied between cell lines from 62.5% to 98.7% of the identified loci. The pol III-bound Alus were further scored for estimated retrotransposition potential (ERP) based on the absence or presence of selected sequence features associated with Alu retrotransposition capability. Our analyses indicate that most of the pol III-bound Alu loci candidates identified lack the sequence characteristics important for retrotransposition. These data suggest that Alu expression likely varies by cell type, growth conditions and transformation state. This variation could extend to where the same cell lines in different laboratories present different Alu expression patterns. The vast majority of Alu loci potentially transcribed by RNA pol III lack important sequence features for retrotransposition and the majority of potentially active Alu loci in the genome (scored high ERP) belong to young Alu subfamilies. Our observations suggest that in an in vivo scenario, the contribution of Alu activity on somatic genetic damage may significantly vary between individuals and tissues.

Chaperone-Usher Pili Loci of Colonization Factor-Negative Human Enterotoxigenic Escherichia coli

PubMed Central

Del Canto, Felipe; O'Ryan, Miguel; Pardo, Mirka; Torres, Alexia; Gutiérrez, Daniela; Cádiz, Leandro; Valdés, Raul; Mansilla, Aquiles; Martínez, Rodrigo; Hernández, Daniela; Caro, Benjamin; Levine, Myron M.; Rasko, David A.; Hill, Christopher M.; Pop, Mihai; Stine, O. Colin; Vidal, Roberto

2017-01-01

Enterotoxigenic Escherichia coli (ETEC) is one of the most common causes of diarrhea worldwide. Among the 25 different ETEC adhesins, 22 are known as “colonization factors” (CFs), of which 17 are assembled by the chaperone-usher (CU) mechanism. Currently, there is no preventive therapy against ETEC, and CFs have been proposed as components for vaccine development. However, studies of diarrhea-causing ETEC strains worldwide indicate that between 15 and 50% of these are negative for known CFs, hindering the selection of the most widespread structures and suggesting that unknown adhesins remain to be identified. Here, we report the result of a comprehensive analysis of 35 draft genomes of ETEC strains which do not carry known adhesin genes; our goal was to find new CU pili loci. The phylogenetic profiles and serogroups of these strains were highly diverse, a majority of which produced only the heat-labile toxin. We identified 10 pili loci belonging to CU families β (1 locus), γ2 (7 loci), κ (1 locus), and π (1 locus), all of which contained the required number of open reading frames (ORFs) to encode functional structures. Three loci were variants of previously-known clusters, three had been only-partially described, and four are novel loci. Intra-loci genetic variability identified would allow the synthesis of up to 14 different structures. Clusters of putative γ2-CU pili were most common (23 strains), followed by putative β-CU pili (12 strains), which have not yet been fully characterized. Overall, our findings significantly increase the number of ETEC adhesion genes associated with human infections. PMID:28111618

Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.

PubMed

Randall, Joshua C; Winkler, Thomas W; Kutalik, Zoltán; Berndt, Sonja I; Jackson, Anne U; Monda, Keri L; Kilpeläinen, Tuomas O; Esko, Tõnu; Mägi, Reedik; Li, Shengxu; Workalemahu, Tsegaselassie; Feitosa, Mary F; Croteau-Chonka, Damien C; Day, Felix R; Fall, Tove; Ferreira, Teresa; Gustafsson, Stefan; Locke, Adam E; Mathieson, Iain; Scherag, Andre; Vedantam, Sailaja; Wood, Andrew R; Liang, Liming; Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Dermitzakis, Emmanouil T; Dimas, Antigone S; Karpe, Fredrik; Min, Josine L; Nicholson, George; Clegg, Deborah J; Person, Thomas; Krohn, Jon P; Bauer, Sabrina; Buechler, Christa; Eisinger, Kristina; Bonnefond, Amélie; Froguel, Philippe; Hottenga, Jouke-Jan; Prokopenko, Inga; Waite, Lindsay L; Harris, Tamara B; Smith, Albert Vernon; Shuldiner, Alan R; McArdle, Wendy L; Caulfield, Mark J; Munroe, Patricia B; Grönberg, Henrik; Chen, Yii-Der Ida; Li, Guo; Beckmann, Jacques S; Johnson, Toby; Thorsteinsdottir, Unnur; Teder-Laving, Maris; Khaw, Kay-Tee; Wareham, Nicholas J; Zhao, Jing Hua; Amin, Najaf; Oostra, Ben A; Kraja, Aldi T; Province, Michael A; Cupples, L Adrienne; Heard-Costa, Nancy L; Kaprio, Jaakko; Ripatti, Samuli; Surakka, Ida; Collins, Francis S; Saramies, Jouko; Tuomilehto, Jaakko; Jula, Antti; Salomaa, Veikko; Erdmann, Jeanette; Hengstenberg, Christian; Loley, Christina; Schunkert, Heribert; Lamina, Claudia; Wichmann, H Erich; Albrecht, Eva; Gieger, Christian; Hicks, Andrew A; Johansson, Asa; Pramstaller, Peter P; Kathiresan, Sekar; Speliotes, Elizabeth K; Penninx, Brenda; Hartikainen, Anna-Liisa; Jarvelin, Marjo-Riitta; Gyllensten, Ulf; Boomsma, Dorret I; Campbell, Harry; Wilson, James F; Chanock, Stephen J; Farrall, Martin; Goel, Anuj; Medina-Gomez, Carolina; Rivadeneira, Fernando; Estrada, Karol; Uitterlinden, André G; Hofman, Albert; Zillikens, M Carola; den Heijer, Martin; Kiemeney, Lambertus A; Maschio, Andrea; Hall, Per; Tyrer, Jonathan; Teumer, Alexander; Völzke, Henry; Kovacs, Peter; Tönjes, Anke; Mangino, Massimo; Spector, Tim D; Hayward, Caroline; Rudan, Igor; Hall, Alistair S; Samani, Nilesh J; Attwood, Antony Paul; Sambrook, Jennifer G; Hung, Joseph; Palmer, Lyle J; Lokki, Marja-Liisa; Sinisalo, Juha; Boucher, Gabrielle; Huikuri, Heikki; Lorentzon, Mattias; Ohlsson, Claes; Eklund, Niina; Eriksson, Johan G; Barlassina, Cristina; Rivolta, Carlo; Nolte, Ilja M; Snieder, Harold; Van der Klauw, Melanie M; Van Vliet-Ostaptchouk, Jana V; Gejman, Pablo V; Shi, Jianxin; Jacobs, Kevin B; Wang, Zhaoming; Bakker, Stephan J L; Mateo Leach, Irene; Navis, Gerjan; van der Harst, Pim; Martin, Nicholas G; Medland, Sarah E; Montgomery, Grant W; Yang, Jian; Chasman, Daniel I; Ridker, Paul M; Rose, Lynda M; Lehtimäki, Terho; Raitakari, Olli; Absher, Devin; Iribarren, Carlos; Basart, Hanneke; Hovingh, Kees G; Hyppönen, Elina; Power, Chris; Anderson, Denise; Beilby, John P; Hui, Jennie; Jolley, Jennifer; Sager, Hendrik; Bornstein, Stefan R; Schwarz, Peter E H; Kristiansson, Kati; Perola, Markus; Lindström, Jaana; Swift, Amy J; Uusitupa, Matti; Atalay, Mustafa; Lakka, Timo A; Rauramaa, Rainer; Bolton, Jennifer L; Fowkes, Gerry; Fraser, Ross M; Price, Jackie F; Fischer, Krista; Krjutå Kov, Kaarel; Metspalu, Andres; Mihailov, Evelin; Langenberg, Claudia; Luan, Jian'an; Ong, Ken K; Chines, Peter S; Keinanen-Kiukaanniemi, Sirkka M; Saaristo, Timo E; Edkins, Sarah; Franks, Paul W; Hallmans, Göran; Shungin, Dmitry; Morris, Andrew David; Palmer, Colin N A; Erbel, Raimund; Moebus, Susanne; Nöthen, Markus M; Pechlivanis, Sonali; Hveem, Kristian; Narisu, Narisu; Hamsten, Anders; Humphries, Steve E; Strawbridge, Rona J; Tremoli, Elena; Grallert, Harald; Thorand, Barbara; Illig, Thomas; Koenig, Wolfgang; Müller-Nurasyid, Martina; Peters, Annette; Boehm, Bernhard O; Kleber, Marcus E; März, Winfried; Winkelmann, Bernhard R; Kuusisto, Johanna; Laakso, Markku; Arveiler, Dominique; Cesana, Giancarlo; Kuulasmaa, Kari; Virtamo, Jarmo; Yarnell, John W G; Kuh, Diana; Wong, Andrew; Lind, Lars; de Faire, Ulf; Gigante, Bruna; Magnusson, Patrik K E; Pedersen, Nancy L; Dedoussis, George; Dimitriou, Maria; Kolovou, Genovefa; Kanoni, Stavroula; Stirrups, Kathleen; Bonnycastle, Lori L; Njølstad, Inger; Wilsgaard, Tom; Ganna, Andrea; Rehnberg, Emil; Hingorani, Aroon; Kivimaki, Mika; Kumari, Meena; Assimes, Themistocles L; Barroso, Inês; Boehnke, Michael; Borecki, Ingrid B; Deloukas, Panos; Fox, Caroline S; Frayling, Timothy; Groop, Leif C; Haritunians, Talin; Hunter, David; Ingelsson, Erik; Kaplan, Robert; Mohlke, Karen L; O'Connell, Jeffrey R; Schlessinger, David; Strachan, David P; Stefansson, Kari; van Duijn, Cornelia M; Abecasis, Gonçalo R; McCarthy, Mark I; Hirschhorn, Joel N; Qi, Lu; Loos, Ruth J F; Lindgren, Cecilia M; North, Kari E; Heid, Iris M

2013-06-01

Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.

Sex-stratified Genome-wide Association Studies Including 270,000 Individuals Show Sexual Dimorphism in Genetic Loci for Anthropometric Traits

PubMed Central

Jackson, Anne U.; Monda, Keri L.; Kilpeläinen, Tuomas O.; Esko, Tõnu; Mägi, Reedik; Li, Shengxu; Workalemahu, Tsegaselassie; Feitosa, Mary F.; Croteau-Chonka, Damien C.; Day, Felix R.; Fall, Tove; Ferreira, Teresa; Gustafsson, Stefan; Locke, Adam E.; Mathieson, Iain; Scherag, Andre; Vedantam, Sailaja; Wood, Andrew R.; Liang, Liming; Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Dermitzakis, Emmanouil T.; Dimas, Antigone S.; Karpe, Fredrik; Min, Josine L.; Nicholson, George; Clegg, Deborah J.; Person, Thomas; Krohn, Jon P.; Bauer, Sabrina; Buechler, Christa; Eisinger, Kristina; Bonnefond, Amélie; Froguel, Philippe; Hottenga, Jouke-Jan; Prokopenko, Inga; Waite, Lindsay L.; Harris, Tamara B.; Smith, Albert Vernon; Shuldiner, Alan R.; McArdle, Wendy L.; Caulfield, Mark J.; Munroe, Patricia B.; Grönberg, Henrik; Chen, Yii-Der Ida; Li, Guo; Beckmann, Jacques S.; Johnson, Toby; Thorsteinsdottir, Unnur; Teder-Laving, Maris; Khaw, Kay-Tee; Wareham, Nicholas J.; Zhao, Jing Hua; Amin, Najaf; Oostra, Ben A.; Kraja, Aldi T.; Province, Michael A.; Cupples, L. Adrienne; Heard-Costa, Nancy L.; Kaprio, Jaakko; Ripatti, Samuli; Surakka, Ida; Collins, Francis S.; Saramies, Jouko; Tuomilehto, Jaakko; Jula, Antti; Salomaa, Veikko; Erdmann, Jeanette; Hengstenberg, Christian; Loley, Christina; Schunkert, Heribert; Lamina, Claudia; Wichmann, H. Erich; Albrecht, Eva; Gieger, Christian; Hicks, Andrew A.; Johansson, Åsa; Pramstaller, Peter P.; Kathiresan, Sekar; Speliotes, Elizabeth K.; Penninx, Brenda; Hartikainen, Anna-Liisa; Jarvelin, Marjo-Riitta; Gyllensten, Ulf; Boomsma, Dorret I.; Campbell, Harry; Wilson, James F.; Chanock, Stephen J.; Farrall, Martin; Goel, Anuj; Medina-Gomez, Carolina; Rivadeneira, Fernando; Estrada, Karol; Uitterlinden, André G.; Hofman, Albert; Zillikens, M. Carola; den Heijer, Martin; Kiemeney, Lambertus A.; Maschio, Andrea; Hall, Per; Tyrer, Jonathan; Teumer, Alexander; Völzke, Henry; Kovacs, Peter; Tönjes, Anke; Mangino, Massimo; Spector, Tim D.; Hayward, Caroline; Rudan, Igor; Hall, Alistair S.; Samani, Nilesh J.; Attwood, Antony Paul; Sambrook, Jennifer G.; Hung, Joseph; Palmer, Lyle J.; Lokki, Marja-Liisa; Sinisalo, Juha; Boucher, Gabrielle; Huikuri, Heikki; Lorentzon, Mattias; Ohlsson, Claes; Eklund, Niina; Eriksson, Johan G.; Barlassina, Cristina; Rivolta, Carlo; Nolte, Ilja M.; Snieder, Harold; Van der Klauw, Melanie M.; Van Vliet-Ostaptchouk, Jana V.; Gejman, Pablo V.; Shi, Jianxin; Jacobs, Kevin B.; Wang, Zhaoming; Bakker, Stephan J. L.; Mateo Leach, Irene; Navis, Gerjan; van der Harst, Pim; Martin, Nicholas G.; Medland, Sarah E.; Montgomery, Grant W.; Yang, Jian; Chasman, Daniel I.; Ridker, Paul M.; Rose, Lynda M.; Lehtimäki, Terho; Raitakari, Olli; Absher, Devin; Iribarren, Carlos; Basart, Hanneke; Hovingh, Kees G.; Hyppönen, Elina; Power, Chris; Anderson, Denise; Beilby, John P.; Hui, Jennie; Jolley, Jennifer; Sager, Hendrik; Bornstein, Stefan R.; Schwarz, Peter E. H.; Kristiansson, Kati; Perola, Markus; Lindström, Jaana; Swift, Amy J.; Uusitupa, Matti; Atalay, Mustafa; Lakka, Timo A.; Rauramaa, Rainer; Bolton, Jennifer L.; Fowkes, Gerry; Fraser, Ross M.; Price, Jackie F.; Fischer, Krista; KrjutÅ¡kov, Kaarel; Metspalu, Andres; Mihailov, Evelin; Langenberg, Claudia; Luan, Jian'an; Ong, Ken K.; Chines, Peter S.; Keinanen-Kiukaanniemi, Sirkka M.; Saaristo, Timo E.; Edkins, Sarah; Franks, Paul W.; Hallmans, Göran; Shungin, Dmitry; Morris, Andrew David; Palmer, Colin N. A.; Erbel, Raimund; Moebus, Susanne; Nöthen, Markus M.; Pechlivanis, Sonali; Hveem, Kristian; Narisu, Narisu; Hamsten, Anders; Humphries, Steve E.; Strawbridge, Rona J.; Tremoli, Elena; Grallert, Harald; Thorand, Barbara; Illig, Thomas; Koenig, Wolfgang; Müller-Nurasyid, Martina; Peters, Annette; Boehm, Bernhard O.; Kleber, Marcus E.; März, Winfried; Winkelmann, Bernhard R.; Kuusisto, Johanna; Laakso, Markku; Arveiler, Dominique; Cesana, Giancarlo; Kuulasmaa, Kari; Virtamo, Jarmo; Yarnell, John W. G.; Kuh, Diana; Wong, Andrew; Lind, Lars; de Faire, Ulf; Gigante, Bruna; Magnusson, Patrik K. E.; Pedersen, Nancy L.; Dedoussis, George; Dimitriou, Maria; Kolovou, Genovefa; Kanoni, Stavroula; Stirrups, Kathleen; Bonnycastle, Lori L.; Njølstad, Inger; Wilsgaard, Tom; Ganna, Andrea; Rehnberg, Emil; Hingorani, Aroon; Kivimaki, Mika; Kumari, Meena; Assimes, Themistocles L.; Barroso, Inês; Boehnke, Michael; Borecki, Ingrid B.; Deloukas, Panos; Fox, Caroline S.; Frayling, Timothy; Groop, Leif C.; Haritunians, Talin; Hunter, David; Ingelsson, Erik; Kaplan, Robert; Mohlke, Karen L.; O'Connell, Jeffrey R.; Schlessinger, David; Strachan, David P.; Stefansson, Kari; van Duijn, Cornelia M.; Abecasis, Gonçalo R.; McCarthy, Mark I.; Hirschhorn, Joel N.; Qi, Lu; Loos, Ruth J. F.; Lindgren, Cecilia M.; North, Kari E.; Heid, Iris M.

2013-01-01

Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10−8), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits. PMID:23754948

Genetic architecture of natural variation in Drosophila melanogaster aggressive behavior

PubMed Central

Shorter, John; Couch, Charlene; Huang, Wen; Carbone, Mary Anna; Peiffer, Jason; Anholt, Robert R. H.; Mackay, Trudy F. C.

2015-01-01

Aggression is an evolutionarily conserved complex behavior essential for survival and the organization of social hierarchies. With the exception of genetic variants associated with bioamine signaling, which have been implicated in aggression in many species, the genetic basis of natural variation in aggression is largely unknown. Drosophila melanogaster is a favorable model system for exploring the genetic basis of natural variation in aggression. Here, we performed genome-wide association analyses using the inbred, sequenced lines of the Drosophila melanogaster Genetic Reference Panel (DGRP) and replicate advanced intercross populations derived from the most and least aggressive DGRP lines. We identified genes that have been previously implicated in aggressive behavior as well as many novel loci, including gustatory receptor 63a (Gr63a), which encodes a subunit of the receptor for CO2, and genes associated with development and function of the nervous system. Although genes from the two association analyses were largely nonoverlapping, they mapped onto a genetic interaction network inferred from an analysis of pairwise epistasis in the DGRP. We used mutations and RNAi knock-down alleles to functionally validate 79% of the candidate genes and 75% of the candidate epistatic interactions tested. Epistasis for aggressive behavior causes cryptic genetic variation in the DGRP that is revealed by changing allele frequencies in the outbred populations derived from extreme DGRP lines. This phenomenon may pertain to other fitness traits and species, with implications for evolution, applied breeding, and human genetics. PMID:26100892

IL1RN Variation Influences both Disease Susceptibility and Response to Human Recombinant IL-1RA Therapy in Systemic Juvenile Idiopathic Arthritis.

PubMed

Arthur, Victoria L; Shuldiner, Emily; Remmers, Elaine F; Hinks, Anne; Grom, Alexei A; Foell, Dirk; Martini, Alberto; Gattorno, Marco; Özen, Seza; Prahalad, Sampath; Zeft, Andrew S; Bohnsack, John F; Ilowite, Norman T; Mellins, Elizabeth D; Russo, Ricardo; Len, Claudio; Oliveira, Sheila; Yeung, Rae S M; Rosenberg, Alan M; Wedderburn, Lucy R; Anton, Jordi; Haas, Johannes-Peter; Rösen-Wolff, Angela; Minden, Kirsten; Szymanski, Ann Marie; Thomson, Wendy; Kastner, Daniel L; Woo, Patricia; Ombrello, Michael J

2018-04-02

To determine whether systemic juvenile idiopathic arthritis (sJIA) susceptibility loci identified by candidate gene studies demonstrated association with sJIA in the largest study population assembled to date. Single nucleotide polymorphisms (SNPs) from 11 previously reported sJIA risk loci were examined for association in 9 populations, including 770 sJIA cases and 6947 control subjects. The effect of sJIA-associated SNPs on gene expression was evaluated in silico in paired whole genome and RNA sequencing data from lymphoblastoid cell lines (LCL) of 373 European 1000 Genomes Project subjects. The relationship between sJIA-associated SNPs and response to anakinra treatment was evaluated in 38 US patients for whom treatment response data were available. We found no association of the 26 SNPs previously reported as sJIA-associated. Expanded analysis of the regions containing the 26 SNPs revealed only one significant association, the promoter region of IL1RN (p<1E-4). sJIA-associated SNPs correlated with IL1RN expression in LCLs, with an inverse correlation between sJIA risk and IL1RN expression. The presence of homozygous IL1RN high expression alleles correlated strongly with non-response to anakinra therapy (OR 28.7 [3.2, 255.8]). IL1RN was the only candidate locus associated with sJIA in our study. The implicated SNPs are among the strongest known determinants of IL1RN and IL1RA levels, linking low expression with increased sJIA risk. Homozygous high expression alleles predicted non-response to anakinra therapy, nominating them as candidate biomarkers to guide sJIA treatment. This is an important first step towards the personalized treatment of sJIA. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Evaluation of SNP Data from the Malus Infinium Array Identifies Challenges for Genetic Analysis of Complex Genomes of Polyploid Origin

PubMed Central

Troggio, Michela; Šurbanovski, Nada; Bianco, Luca; Moretto, Marco; Giongo, Lara; Banchi, Elisa; Viola, Roberto; Fernández, Felicdad Fernández; Costa, Fabrizio; Velasco, Riccardo; Cestaro, Alessandro; Sargent, Daniel James

2013-01-01

High throughput arrays for the simultaneous genotyping of thousands of single-nucleotide polymorphisms (SNPs) have made the rapid genetic characterisation of plant genomes and the development of saturated linkage maps a realistic prospect for many plant species of agronomic importance. However, the correct calling of SNP genotypes in divergent polyploid genomes using array technology can be problematic due to paralogy, and to divergence in probe sequences causing changes in probe binding efficiencies. An Illumina Infinium II whole-genome genotyping array was recently developed for the cultivated apple and used to develop a molecular linkage map for an apple rootstock progeny (M432), but a large proportion of segregating SNPs were not mapped in the progeny, due to unexpected genotype clustering patterns. To investigate the causes of this unexpected clustering we performed BLAST analysis of all probe sequences against the ‘Golden Delicious’ genome sequence and discovered evidence for paralogous annealing sites and probe sequence divergence for a high proportion of probes contained on the array. Following visual re-evaluation of the genotyping data generated for 8,788 SNPs for the M432 progeny using the array, we manually re-scored genotypes at 818 loci and mapped a further 797 markers to the M432 linkage map. The newly mapped markers included the majority of those that could not be mapped previously, as well as loci that were previously scored as monomorphic, but which segregated due to divergence leading to heterozygosity in probe annealing sites. An evaluation of the 8,788 probes in a diverse collection of Malus germplasm showed that more than half the probes returned genotype clustering patterns that were difficult or impossible to interpret reliably, highlighting implications for the use of the array in genome-wide association studies. PMID:23826289

Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci

PubMed Central

Glubb, Dylan M.; Johnatty, Sharon E.; Quinn, Michael C.J.; O’Mara, Tracy A.; Tyrer, Jonathan P.; Gao, Bo; Fasching, Peter A.; Beckmann, Matthias W.; Lambrechts, Diether; Vergote, Ignace; Velez Edwards, Digna R.; Beeghly-Fadiel, Alicia; Benitez, Javier; Garcia, Maria J.; Goodman, Marc T.; Thompson, Pamela J.; Dörk, Thilo; Dürst, Matthias; Modungo, Francesmary; Moysich, Kirsten; Heitz, Florian; du Bois, Andreas; Pfisterer, Jacobus; Hillemanns, Peter; Karlan, Beth Y.; Lester, Jenny; Goode, Ellen L.; Cunningham, Julie M.; Winham, Stacey J.; Larson, Melissa C.; McCauley, Bryan M.; Kjær, Susanne Krüger; Jensen, Allan; Schildkraut, Joellen M.; Berchuck, Andrew; Cramer, Daniel W.; Terry, Kathryn L.; Salvesen, Helga B.; Bjorge, Line; Webb, Penny M.; Grant, Peter; Pejovic, Tanja; Moffitt, Melissa; Hogdall, Claus K.; Hogdall, Estrid; Paul, James; Glasspool, Rosalind; Bernardini, Marcus; Tone, Alicia; Huntsman, David; Woo, Michelle; Group, AOCS; deFazio, Anna; Kennedy, Catherine J.; Pharoah, Paul D.P.; MacGregor, Stuart; Chenevix-Trench, Georgia

2017-01-01

We previously identified associations with ovarian cancer outcome at five genetic loci. To identify putatively causal genetic variants and target genes, we prioritized two ovarian outcome loci (1q22 and 19p12) for further study. Bioinformatic and functional genetic analyses indicated that MEF2D and ZNF100 are targets of candidate outcome variants at 1q22 and 19p12, respectively. At 19p12, the chromatin interaction of a putative regulatory element with the ZNF100 promoter region correlated with candidate outcome variants. At 1q22, putative regulatory elements enhanced MEF2D promoter activity and haplotypes containing candidate outcome variants modulated these effects. In a public dataset, MEF2D and ZNF100 expression were both associated with ovarian cancer progression-free or overall survival time. In an extended set of 6,162 epithelial ovarian cancer patients, we found that functional candidates at the 1q22 and 19p12 loci, as well as other regional variants, were nominally associated with patient outcome; however, no associations reached our threshold for statistical significance (p<1×10-5). Larger patient numbers will be needed to convincingly identify any true associations at these loci. PMID:29029385

Substructure of a Tunisian Berber population as inferred from 15 autosomal short tandem repeat loci.

PubMed

Khodjet-El-Khil, Houssein; Fadhlaoui-Zid, Karima; Gusmão, Leonor; Alves, Cíntia; Benammar-Elgaaied, Amel; Amorim, Antonio

2008-08-01

Currently, language and cultural practices are the only criteria to distinguish between Berber autochthonous Tunisian populations. To evaluate these populations' possible genetic structure and differentiation, we have analyzed 15 autosomal short tandem repeat loci (CSF1PO, D3S1358, D5S818, D7S820, D8S1179, D13S317, D16S539, D18S51, D21S11, FGA, TH01, TPOX, VWA, D2S1338, and D19S433) in three southern Tunisian Berber groups: Sened, Matmata, and Chenini-Douiret. The exact test of population differentiation based on allele frequencies at the 15 loci shows significant P values at 7 loci between Chenini-Douiret and both Sened and Matmata, whereas just 5 loci show significant P values between Sened and Matmata. Comparative analyses between the three Berber groups based on genetic distances show that P values for F(ST) distances are significant between the three Berber groups. Population analysis performed using Structure shows a clear differentiation between these Berber groups, with strong genetic isolation of Chenini-Douiret. These results confirm at the autosomal level the high degree of heterogeneity of Tunisian Berber populations that had been previously reported for uniparental markers.

Nine loci for ocular axial length identified through genome-wide association studies, including shared loci with refractive error.

PubMed

Cheng, Ching-Yu; Schache, Maria; Ikram, M Kamran; Young, Terri L; Guggenheim, Jeremy A; Vitart, Veronique; MacGregor, Stuart; Verhoeven, Virginie J M; Barathi, Veluchamy A; Liao, Jiemin; Hysi, Pirro G; Bailey-Wilson, Joan E; St Pourcain, Beate; Kemp, John P; McMahon, George; Timpson, Nicholas J; Evans, David M; Montgomery, Grant W; Mishra, Aniket; Wang, Ya Xing; Wang, Jie Jin; Rochtchina, Elena; Polasek, Ozren; Wright, Alan F; Amin, Najaf; van Leeuwen, Elisabeth M; Wilson, James F; Pennell, Craig E; van Duijn, Cornelia M; de Jong, Paulus T V M; Vingerling, Johannes R; Zhou, Xin; Chen, Peng; Li, Ruoying; Tay, Wan-Ting; Zheng, Yingfeng; Chew, Merwyn; Burdon, Kathryn P; Craig, Jamie E; Iyengar, Sudha K; Igo, Robert P; Lass, Jonathan H; Chew, Emily Y; Haller, Toomas; Mihailov, Evelin; Metspalu, Andres; Wedenoja, Juho; Simpson, Claire L; Wojciechowski, Robert; Höhn, René; Mirshahi, Alireza; Zeller, Tanja; Pfeiffer, Norbert; Lackner, Karl J; Bettecken, Thomas; Meitinger, Thomas; Oexle, Konrad; Pirastu, Mario; Portas, Laura; Nag, Abhishek; Williams, Katie M; Yonova-Doing, Ekaterina; Klein, Ronald; Klein, Barbara E; Hosseini, S Mohsen; Paterson, Andrew D; Makela, Kari-Matti; Lehtimaki, Terho; Kahonen, Mika; Raitakari, Olli; Yoshimura, Nagahisa; Matsuda, Fumihiko; Chen, Li Jia; Pang, Chi Pui; Yip, Shea Ping; Yap, Maurice K H; Meguro, Akira; Mizuki, Nobuhisa; Inoko, Hidetoshi; Foster, Paul J; Zhao, Jing Hua; Vithana, Eranga; Tai, E-Shyong; Fan, Qiao; Xu, Liang; Campbell, Harry; Fleck, Brian; Rudan, Igor; Aung, Tin; Hofman, Albert; Uitterlinden, André G; Bencic, Goran; Khor, Chiea-Chuen; Forward, Hannah; Pärssinen, Olavi; Mitchell, Paul; Rivadeneira, Fernando; Hewitt, Alex W; Williams, Cathy; Oostra, Ben A; Teo, Yik-Ying; Hammond, Christopher J; Stambolian, Dwight; Mackey, David A; Klaver, Caroline C W; Wong, Tien-Yin; Saw, Seang-Mei; Baird, Paul N

2013-08-08

Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Genetic variation associated with cardiovascular risk in autoimmune diseases

PubMed Central

Perrotti, Pedro P.; Aterido, Adrià; Fernández-Nebro, Antonio; Cañete, Juan D.; Ferrándiz, Carlos; Tornero, Jesús; Gisbert, Javier P.; Domènech, Eugeni; Fernández-Gutiérrez, Benjamín; Gomollón, Fernando; García-Planella, Esther; Fernández, Emilia; Sanmartí, Raimon; Gratacós, Jordi; Martínez-Taboada, Víctor Manuel; Rodríguez-Rodríguez, Luís; Palau, Núria; Tortosa, Raül; Corbeto, Mireia L.; Lasanta, María L.; Marsal, Sara; Julià, Antonio

2017-01-01

Autoimmune diseases have a higher prevalence of cardiovascular events compared to the general population. The objective of this study was to investigate the genetic basis of cardiovascular disease (CVD) risk in autoimmunity. We analyzed genome-wide genotyping data from 6,485 patients from six autoimmune diseases that are associated with a high socio-economic impact. First, for each disease, we tested the association of established CVD risk loci. Second, we analyzed the association of autoimmune disease susceptibility loci with CVD. Finally, to identify genetic patterns associated with CVD risk, we applied the cross-phenotype meta-analysis approach (CPMA) on the genome-wide data. A total of 17 established CVD risk loci were significantly associated with CVD in the autoimmune patient cohorts. From these, four loci were found to have significantly different genetic effects across autoimmune diseases. Six autoimmune susceptibility loci were also found to be associated with CVD risk. Genome-wide CPMA analysis identified 10 genetic clusters strongly associated with CVD risk across all autoimmune diseases. Two of these clusters are highly enriched in pathways previously associated with autoimmune disease etiology (TNFα and IFNγ cytokine pathways). The results of this study support the presence of specific genetic variation associated with the increase of CVD risk observed in autoimmunity. PMID:28982122

Analysis of microsatellite instability in CRISPR/Cas9 editing mice.

PubMed

Huo, Xueyun; Du, Yating; Lu, Jing; Guo, Meng; Li, Zhenkun; Zhang, Shuangyue; Li, Xiaohong; Chen, Zhenwen; Du, Xiaoyan

2017-03-01

Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR- associated (Cas) protein 9 system is a novel and powerful tool which is widely used for genome editing. CRISPR/Cas9 is RNA-guided and can lead to desired genomic modifications. However, whether the CRISPR/Cas9-mediated genome editing causes genomic alterations and genomic instability, such as microsatellite instability (MSI), is still unknown. Here we detected MSI in 21 CRISPR/Cas9 mouse strains using a panel of 42 microsatellite loci which were selected from our previous studies. Surprisingly, MSI occurrence was common in CRISPR/Cas9 modified genome, and most of the strains (19/21, 90.5%) examined showed MSI. Of 42 loci examined, 8 loci (8/42, 19.05%) exhibited MSI in the Cas9 editing mice. The Ttll9 (4/42, 9.5%) were the most unstable strains, and D10Mit3 and D10Mit198 (9/21, 42.9%) were considered to be the most "hot" loci in the Cas9 strains we tested. Through analyzing the mutation of microsatellite loci, we provide new insights into the genomic alterations of CRISPR/Cas9 models and it will help us for a better understanding of this powerful technology. Copyright © 2017 Elsevier B.V. All rights reserved.

Meta-analysis of genome-wide association studies of adult height in East Asians identifies 17 novel loci.

PubMed

He, Meian; Xu, Min; Zhang, Ben; Liang, Jun; Chen, Peng; Lee, Jong-Young; Johnson, Todd A; Li, Huaixing; Yang, Xiaobo; Dai, Juncheng; Liang, Liming; Gui, Lixuan; Qi, Qibin; Huang, Jinyan; Li, Yanping; Adair, Linda S; Aung, Tin; Cai, Qiuyin; Cheng, Ching-Yu; Cho, Myeong-Chan; Cho, Yoon Shin; Chu, Minjie; Cui, Bin; Gao, Yu-Tang; Go, Min Jin; Gu, Dongfeng; Gu, Weiqiong; Guo, Huan; Hao, Yongchen; Hong, Jie; Hu, Zhibin; Hu, Yanling; Huang, Jianfeng; Hwang, Joo-Yeon; Ikram, Mohammad Kamran; Jin, Guangfu; Kang, Dae-Hee; Khor, Chiea Chuen; Kim, Bong-Jo; Kim, Hung Tae; Kubo, Michiaki; Lee, Jeannette; Lee, Juyoung; Lee, Nanette R; Li, Ruoying; Li, Jun; Liu, JianJun; Longe, Jirong; Lu, Wei; Lu, Xiangfeng; Miao, Xiaoping; Okada, Yukinori; Ong, Rick Twee-Hee; Qiu, Gaokun; Seielstad, Mark; Sim, Xueling; Song, Huaidong; Takeuchi, Fumihiko; Tanaka, Toshihiro; Taylor, Phil R; Wang, Laiyuan; Wang, Weiqing; Wang, Yiqin; Wu, Chen; Wu, Ying; Xiang, Yong-Bing; Yamamoto, Ken; Yang, Handong; Liao, Ming; Yokota, Mitsuhiro; Young, Terri; Zhang, Xiaomin; Kato, Norihiro; Wang, Qing K; Zheng, Wei; Hu, Frank B; Lin, Dongxin; Shen, Hongbing; Teo, Yik Ying; Mo, Zengnan; Wong, Tien Yin; Lin, Xu; Mohlke, Karen L; Ning, Guang; Tsunoda, Tatsuhiko; Han, Bok-Ghee; Shu, Xiao-Ou; Tai, E Shyong; Wu, Tangchun; Qi, Lu

2015-03-15

Human height is associated with risk of multiple diseases and is profoundly determined by an individual's genetic makeup and shows a high degree of ethnic heterogeneity. Large-scale genome-wide association (GWA) analyses of adult height in Europeans have identified nearly 180 genetic loci. A recent study showed high replicability of results from Europeans-based GWA studies in Asians; however, population-specific loci may exist due to distinct linkage disequilibrium patterns. We carried out a GWA meta-analysis in 93 926 individuals from East Asia. We identified 98 loci, including 17 novel and 81 previously reported loci, associated with height at P < 5 × 10(-8), together explaining 8.89% of phenotypic variance. Among the newly identified variants, 10 are commonly distributed (minor allele frequency, MAF > 5%) in Europeans, with comparable frequencies with in Asians, and 7 single-nucleotide polymorphisms are with low frequency (MAF < 5%) in Europeans. In addition, our data suggest that novel biological pathway such as the protein tyrosine phosphatase family is involved in regulation of height. The findings from this study considerably expand our knowledge of the genetic architecture of human height in Asians. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Comparison of taxon-specific versus general locus sets for targeted sequence capture in plant phylogenomics.

PubMed

Chau, John H; Rahfeldt, Wolfgang A; Olmstead, Richard G

2018-03-01

Targeted sequence capture can be used to efficiently gather sequence data for large numbers of loci, such as single-copy nuclear loci. Most published studies in plants have used taxon-specific locus sets developed individually for a clade using multiple genomic and transcriptomic resources. General locus sets can also be developed from loci that have been identified as single-copy and have orthologs in large clades of plants. We identify and compare a taxon-specific locus set and three general locus sets (conserved ortholog set [COSII], shared single-copy nuclear [APVO SSC] genes, and pentatricopeptide repeat [PPR] genes) for targeted sequence capture in Buddleja (Scrophulariaceae) and outgroups. We evaluate their performance in terms of assembly success, sequence variability, and resolution and support of inferred phylogenetic trees. The taxon-specific locus set had the most target loci. Assembly success was high for all locus sets in Buddleja samples. For outgroups, general locus sets had greater assembly success. Taxon-specific and PPR loci had the highest average variability. The taxon-specific data set produced the best-supported tree, but all data sets showed improved resolution over previous non-sequence capture data sets. General locus sets can be a useful source of sequence capture targets, especially if multiple genomic resources are not available for a taxon.

A systemic sclerosis and systemic lupus erythematosus pan-meta-GWAS reveals new shared susceptibility loci

PubMed Central

Martin, Jose-Ezequiel; Assassi, Shervin; Diaz-Gallo, Lina-Marcela; Broen, Jasper C.; Simeon, Carmen P.; Castellvi, Ivan; Vicente-Rabaneda, Esther; Fonollosa, Vicente; Ortego-Centeno, Norberto; González-Gay, Miguel A.; Espinosa, Gerard; Carreira, Patricia; Camps, Mayte; Sabio, Jose M.; D'alfonso, Sandra; Vonk, Madelon C.; Voskuyl, Alexandre E.; Schuerwegh, Annemie J.; Kreuter, Alexander; Witte, Torsten; Riemekasten, Gabriella; Hunzelmann, Nicolas; Airo, Paolo; Beretta, Lorenzo; Scorza, Raffaella; Lunardi, Claudio; Van Laar, Jacob; Chee, Meng May; Worthington, Jane; Herrick, Arianne; Denton, Christopher; Fonseca, Carmen; Tan, Filemon K.; Arnett, Frank; Zhou, Xiaodong; Reveille, John D.; Gorlova, Olga; Koeleman, Bobby P.C.; Radstake, Timothy R.D.J.; Vyse, Timothy; Mayes, Maureen D.; Alarcón-Riquelme, Marta E.; Martin, Javier

2013-01-01

Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are two archetypal systemic autoimmune diseases which have been shown to share multiple genetic susceptibility loci. In order to gain insight into the genetic basis of these diseases, we performed a pan-meta-analysis of two genome-wide association studies (GWASs) together with a replication stage including additional SSc and SLE cohorts. This increased the sample size to a total of 21 109 (6835 cases and 14 274 controls). We selected for replication 19 SNPs from the GWAS data. We were able to validate KIAA0319L (P = 3.31 × 10−11, OR = 1.49) as novel susceptibility loci for SSc and SLE. Furthermore, we also determined that the previously described SLE susceptibility loci PXK (P = 3.27 × 10−11, OR = 1.20) and JAZF1 (P = 1.11 × 10−8, OR = 1.13) are shared with SSc. Supporting these new discoveries, we observed that KIAA0319L was overexpressed in peripheral blood cells of SSc and SLE patients compared with healthy controls. With these, we add three (KIAA0319L, PXK and JAZF1) and one (KIAA0319L) new susceptibility loci for SSc and SLE, respectively, increasing significantly the knowledge of the genetic basis of autoimmunity. PMID:23740937

Type 2 Diabetes Susceptibility in the Greek-Cypriot Population: Replication of Associations with TCF7L2, FTO, HHEX, SLC30A8 and IGF2BP2 Polymorphisms

PubMed Central

Votsi, Christina; Toufexis, Costas; Michailidou, Kyriaki; Antoniades, Athos; Skordis, Nicos; Karaolis, Minas; Pattichis, Constantinos S.; Christodoulou, Kyproula

2017-01-01

Type 2 diabetes (T2D) has been the subject of numerous genetic studies in recent years which revealed associations of the disease with a large number of susceptibility loci. We hereby initiate the evaluation of T2D susceptibility loci in the Greek-Cypriot population by performing a replication case-control study. One thousand and eighteen individuals (528 T2D patients, 490 controls) were genotyped at 21 T2D susceptibility loci, using the allelic discrimination method. Statistically significant associations of T2D with five of the tested single nucleotide polymorphisms (SNPs) (TCF7L2 rs7901695, FTO rs8050136, HHEX rs5015480, SLC30A8 rs13266634 and IGF2BP2 rs4402960) were observed in this study population. Furthermore, 14 of the tested SNPs had odds ratios (ORs) in the same direction as the previously published studies, suggesting that these variants can potentially be used in the Greek-Cypriot population for predictive testing of T2D. In conclusion, our findings expand the genetic assessment of T2D susceptibility loci and reconfirm five of the worldwide established loci in a distinct, relatively small, newly investigated population. PMID:28067832

Homologous Chromosome Pairing in Drosophila melanogaster Proceeds through Multiple Independent Initiations

PubMed Central

Fung, Jennifer C.; Marshall, Wallace F.; Dernburg, Abby; Agard, David A.; Sedat, John W.

1998-01-01

The dynamics by which homologous chromosomes pair is currently unknown. Here, we use fluorescence in situ hybridization in combination with three-dimensional optical microscopy to show that homologous pairing of the somatic chromosome arm 2L in Drosophila occurs by independent initiation of pairing at discrete loci rather than by a processive zippering of sites along the length of chromosome. By evaluating the pairing frequencies of 11 loci on chromosome arm 2L over several timepoints during Drosophila embryonic development, we show that all 11 loci are paired very early in Drosophila development, within 13 h after egg deposition. To elucidate whether such pairing occurs by directed or undirected motion, we analyzed the pairing kinetics of histone loci during nuclear cycle 14. By measuring changes of nuclear length and correlating these changes with progression of time during cycle 14, we were able to express the pairing frequency and distance between homologous loci as a function of time. Comparing the experimentally determined dynamics of pairing to simulations based on previously proposed models of pairing motion, we show that the observed pairing kinetics are most consistent with a constrained random walk model and not consistent with a directed motion model. Thus, we conclude that simple random contacts through diffusion could suffice to allow pairing of homologous sites. PMID:9531544

Homologous chromosome pairing in Drosophila melanogaster proceeds through multiple independent initiations.

PubMed

Fung, J C; Marshall, W F; Dernburg, A; Agard, D A; Sedat, J W

1998-04-06

The dynamics by which homologous chromosomes pair is currently unknown. Here, we use fluorescence in situ hybridization in combination with three-dimensional optical microscopy to show that homologous pairing of the somatic chromosome arm 2L in Drosophila occurs by independent initiation of pairing at discrete loci rather than by a processive zippering of sites along the length of chromosome. By evaluating the pairing frequencies of 11 loci on chromosome arm 2L over several timepoints during Drosophila embryonic development, we show that all 11 loci are paired very early in Drosophila development, within 13 h after egg deposition. To elucidate whether such pairing occurs by directed or undirected motion, we analyzed the pairing kinetics of histone loci during nuclear cycle 14. By measuring changes of nuclear length and correlating these changes with progression of time during cycle 14, we were able to express the pairing frequency and distance between homologous loci as a function of time. Comparing the experimentally determined dynamics of pairing to simulations based on previously proposed models of pairing motion, we show that the observed pairing kinetics are most consistent with a constrained random walk model and not consistent with a directed motion model. Thus, we conclude that simple random contacts through diffusion could suffice to allow pairing of homologous sites.

Meta-Analysis of Genome-Wide Association Studies for Abdominal Aortic Aneurysm Identifies Four New Disease-Specific Risk Loci

PubMed Central

Tromp, Gerard; Kuivaniemi, Helena; Gretarsdottir, Solveig; Baas, Annette F.; Giusti, Betti; Strauss, Ewa; van‘t Hof, Femke N.G.; Webb, Thomas R.; Erdman, Robert; Ritchie, Marylyn D.; Elmore, James R.; Verma, Anurag; Pendergrass, Sarah; Kullo, Iftikhar J.; Ye, Zi; Peissig, Peggy L.; Gottesman, Omri; Verma, Shefali S.; Malinowski, Jennifer; Rasmussen-Torvik, Laura J.; Borthwick, Kenneth M.; Smelser, Diane T.; Crosslin, David R.; de Andrade, Mariza; Ryer, Evan J.; McCarty, Catherine A.; Böttinger, Erwin P.; Pacheco, Jennifer A.; Crawford, Dana C.; Carrell, David S.; Gerhard, Glenn S.; Franklin, David P.; Carey, David J.; Phillips, Victoria L.; Williams, Michael J.A.; Wei, Wenhua; Blair, Ross; Hill, Andrew A.; Vasudevan, Thodor M.; Lewis, David R.; Thomson, Ian A.; Krysa, Jo; Hill, Geraldine B.; Roake, Justin; Merriman, Tony R.; Oszkinis, Grzegorz; Galora, Silvia; Saracini, Claudia; Abbate, Rosanna; Pulli, Raffaele; Pratesi, Carlo; Saratzis, Athanasios; Verissimo, Ana R.; Bumpstead, Suzannah; Badger, Stephen A.; Clough, Rachel E.; Cockerill, Gillian; Hafez, Hany; Scott, D. Julian A.; Futers, T. Simon; Romaine, Simon P.R.; Bridge, Katherine; Griffin, Kathryn J.; Bailey, Marc A.; Smith, Alberto; Thompson, Matthew M.; van Bockxmeer, Frank M.; Matthiasson, Stefan E.; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Blankensteijn, Jan D.; Teijink, Joep A.W.; Wijmenga, Cisca; de Graaf, Jacqueline; Kiemeney, Lambertus A.; Lindholt, Jes S.; Hughes, Anne; Bradley, Declan T.; Stirrups, Kathleen; Golledge, Jonathan; Norman, Paul E.; Powell, Janet T.; Humphries, Steve E.; Hamby, Stephen E.; Goodall, Alison H.; Nelson, Christopher P.; Sakalihasan, Natzi; Courtois, Audrey; Ferrell, Robert E.; Eriksson, Per; Folkersen, Lasse; Franco-Cereceda, Anders; Eicher, John D.; Johnson, Andrew D.; Betsholtz, Christer; Ruusalepp, Arno; Franzén, Oscar; Schadt, Eric E.; Björkegren, Johan L.M.; Lipovich, Leonard; Drolet, Anne M.; Verhoeven, Eric L.; Zeebregts, Clark J.; Geelkerken, Robert H.; van Sambeek, Marc R.; van Sterkenburg, Steven M.; de Vries, Jean-Paul; Stefansson, Kari; Thompson, John R.; de Bakker, Paul I.W.; Deloukas, Panos; Sayers, Robert D.; Harrison, Seamus C.; van Rij, Andre M.; Samani, Nilesh J.

2017-01-01

Rationale: Abdominal aortic aneurysm (AAA) is a complex disease with both genetic and environmental risk factors. Together, 6 previously identified risk loci only explain a small proportion of the heritability of AAA. Objective: To identify additional AAA risk loci using data from all available genome-wide association studies. Methods and Results: Through a meta-analysis of 6 genome-wide association study data sets and a validation study totaling 10 204 cases and 107 766 controls, we identified 4 new AAA risk loci: 1q32.3 (SMYD2), 13q12.11 (LINC00540), 20q13.12 (near PCIF1/MMP9/ZNF335), and 21q22.2 (ERG). In various database searches, we observed no new associations between the lead AAA single nucleotide polymorphisms and coronary artery disease, blood pressure, lipids, or diabetes mellitus. Network analyses identified ERG, IL6R, and LDLR as modifiers of MMP9, with a direct interaction between ERG and MMP9. Conclusions: The 4 new risk loci for AAA seem to be specific for AAA compared with other cardiovascular diseases and related traits suggesting that traditional cardiovascular risk factor management may only have limited value in preventing the progression of aneurysmal disease. PMID:27899403

A systemic sclerosis and systemic lupus erythematosus pan-meta-GWAS reveals new shared susceptibility loci.

PubMed

Martin, Jose-Ezequiel; Assassi, Shervin; Diaz-Gallo, Lina-Marcela; Broen, Jasper C; Simeon, Carmen P; Castellvi, Ivan; Vicente-Rabaneda, Esther; Fonollosa, Vicente; Ortego-Centeno, Norberto; González-Gay, Miguel A; Espinosa, Gerard; Carreira, Patricia; Camps, Mayte; Sabio, Jose M; D'alfonso, Sandra; Vonk, Madelon C; Voskuyl, Alexandre E; Schuerwegh, Annemie J; Kreuter, Alexander; Witte, Torsten; Riemekasten, Gabriella; Hunzelmann, Nicolas; Airo, Paolo; Beretta, Lorenzo; Scorza, Raffaella; Lunardi, Claudio; Van Laar, Jacob; Chee, Meng May; Worthington, Jane; Herrick, Arianne; Denton, Christopher; Fonseca, Carmen; Tan, Filemon K; Arnett, Frank; Zhou, Xiaodong; Reveille, John D; Gorlova, Olga; Koeleman, Bobby P C; Radstake, Timothy R D J; Vyse, Timothy; Mayes, Maureen D; Alarcón-Riquelme, Marta E; Martin, Javier

2013-10-01

Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are two archetypal systemic autoimmune diseases which have been shown to share multiple genetic susceptibility loci. In order to gain insight into the genetic basis of these diseases, we performed a pan-meta-analysis of two genome-wide association studies (GWASs) together with a replication stage including additional SSc and SLE cohorts. This increased the sample size to a total of 21,109 (6835 cases and 14,274 controls). We selected for replication 19 SNPs from the GWAS data. We were able to validate KIAA0319L (P = 3.31 × 10(-11), OR = 1.49) as novel susceptibility loci for SSc and SLE. Furthermore, we also determined that the previously described SLE susceptibility loci PXK (P = 3.27 × 10(-11), OR = 1.20) and JAZF1 (P = 1.11 × 10(-8), OR = 1.13) are shared with SSc. Supporting these new discoveries, we observed that KIAA0319L was overexpressed in peripheral blood cells of SSc and SLE patients compared with healthy controls. With these, we add three (KIAA0319L, PXK and JAZF1) and one (KIAA0319L) new susceptibility loci for SSc and SLE, respectively, increasing significantly the knowledge of the genetic basis of autoimmunity.

Genetic Susceptibility to Vitiligo: GWAS Approaches for Identifying Vitiligo Susceptibility Genes and Loci

PubMed Central

Shen, Changbing; Gao, Jing; Sheng, Yujun; Dou, Jinfa; Zhou, Fusheng; Zheng, Xiaodong; Ko, Randy; Tang, Xianfa; Zhu, Caihong; Yin, Xianyong; Sun, Liangdan; Cui, Yong; Zhang, Xuejun

2016-01-01

Vitiligo is an autoimmune disease with a strong genetic component, characterized by areas of depigmented skin resulting from loss of epidermal melanocytes. Genetic factors are known to play key roles in vitiligo through discoveries in association studies and family studies. Previously, vitiligo susceptibility genes were mainly revealed through linkage analysis and candidate gene studies. Recently, our understanding of the genetic basis of vitiligo has been rapidly advancing through genome-wide association study (GWAS). More than 40 robust susceptible loci have been identified and confirmed to be associated with vitiligo by using GWAS. Most of these associated genes participate in important pathways involved in the pathogenesis of vitiligo. Many susceptible loci with unknown functions in the pathogenesis of vitiligo have also been identified, indicating that additional molecular mechanisms may contribute to the risk of developing vitiligo. In this review, we summarize the key loci that are of genome-wide significance, which have been shown to influence vitiligo risk. These genetic loci may help build the foundation for genetic diagnosis and personalize treatment for patients with vitiligo in the future. However, substantial additional studies, including gene-targeted and functional studies, are required to confirm the causality of the genetic variants and their biological relevance in the development of vitiligo. PMID:26870082

Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.

PubMed

Kilpeläinen, Tuomas O; Carli, Jayne F Martin; Skowronski, Alicja A; Sun, Qi; Kriebel, Jennifer; Feitosa, Mary F; Hedman, Åsa K; Drong, Alexander W; Hayes, James E; Zhao, Jinghua; Pers, Tune H; Schick, Ursula; Grarup, Niels; Kutalik, Zoltán; Trompet, Stella; Mangino, Massimo; Kristiansson, Kati; Beekman, Marian; Lyytikäinen, Leo-Pekka; Eriksson, Joel; Henneman, Peter; Lahti, Jari; Tanaka, Toshiko; Luan, Jian'an; Del Greco M, Fabiola; Pasko, Dorota; Renström, Frida; Willems, Sara M; Mahajan, Anubha; Rose, Lynda M; Guo, Xiuqing; Liu, Yongmei; Kleber, Marcus E; Pérusse, Louis; Gaunt, Tom; Ahluwalia, Tarunveer S; Ju Sung, Yun; Ramos, Yolande F; Amin, Najaf; Amuzu, Antoinette; Barroso, Inês; Bellis, Claire; Blangero, John; Buckley, Brendan M; Böhringer, Stefan; I Chen, Yii-Der; de Craen, Anton J N; Crosslin, David R; Dale, Caroline E; Dastani, Zari; Day, Felix R; Deelen, Joris; Delgado, Graciela E; Demirkan, Ayse; Finucane, Francis M; Ford, Ian; Garcia, Melissa E; Gieger, Christian; Gustafsson, Stefan; Hallmans, Göran; Hankinson, Susan E; Havulinna, Aki S; Herder, Christian; Hernandez, Dena; Hicks, Andrew A; Hunter, David J; Illig, Thomas; Ingelsson, Erik; Ioan-Facsinay, Andreea; Jansson, John-Olov; Jenny, Nancy S; Jørgensen, Marit E; Jørgensen, Torben; Karlsson, Magnus; Koenig, Wolfgang; Kraft, Peter; Kwekkeboom, Joanneke; Laatikainen, Tiina; Ladwig, Karl-Heinz; LeDuc, Charles A; Lowe, Gordon; Lu, Yingchang; Marques-Vidal, Pedro; Meisinger, Christa; Menni, Cristina; Morris, Andrew P; Myers, Richard H; Männistö, Satu; Nalls, Mike A; Paternoster, Lavinia; Peters, Annette; Pradhan, Aruna D; Rankinen, Tuomo; Rasmussen-Torvik, Laura J; Rathmann, Wolfgang; Rice, Treva K; Brent Richards, J; Ridker, Paul M; Sattar, Naveed; Savage, David B; Söderberg, Stefan; Timpson, Nicholas J; Vandenput, Liesbeth; van Heemst, Diana; Uh, Hae-Won; Vohl, Marie-Claude; Walker, Mark; Wichmann, Heinz-Erich; Widén, Elisabeth; Wood, Andrew R; Yao, Jie; Zeller, Tanja; Zhang, Yiying; Meulenbelt, Ingrid; Kloppenburg, Margreet; Astrup, Arne; Sørensen, Thorkild I A; Sarzynski, Mark A; Rao, D C; Jousilahti, Pekka; Vartiainen, Erkki; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, André G; Kajantie, Eero; Osmond, Clive; Palotie, Aarno; Eriksson, Johan G; Heliövaara, Markku; Knekt, Paul B; Koskinen, Seppo; Jula, Antti; Perola, Markus; Huupponen, Risto K; Viikari, Jorma S; Kähönen, Mika; Lehtimäki, Terho; Raitakari, Olli T; Mellström, Dan; Lorentzon, Mattias; Casas, Juan P; Bandinelli, Stefanie; März, Winfried; Isaacs, Aaron; van Dijk, Ko W; van Duijn, Cornelia M; Harris, Tamara B; Bouchard, Claude; Allison, Matthew A; Chasman, Daniel I; Ohlsson, Claes; Lind, Lars; Scott, Robert A; Langenberg, Claudia; Wareham, Nicholas J; Ferrucci, Luigi; Frayling, Timothy M; Pramstaller, Peter P; Borecki, Ingrid B; Waterworth, Dawn M; Bergmann, Sven; Waeber, Gérard; Vollenweider, Peter; Vestergaard, Henrik; Hansen, Torben; Pedersen, Oluf; Hu, Frank B; Eline Slagboom, P; Grallert, Harald; Spector, Tim D; Jukema, J W; Klein, Robert J; Schadt, Erik E; Franks, Paul W; Lindgren, Cecilia M; Leibel, Rudolph L; Loos, Ruth J F

2016-02-01

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.

Longitudinal genomic surveillance of Plasmodium falciparum malaria parasites reveals complex genomic architecture of emerging artemisinin resistance.

PubMed

Cerqueira, Gustavo C; Cheeseman, Ian H; Schaffner, Steve F; Nair, Shalini; McDew-White, Marina; Phyo, Aung Pyae; Ashley, Elizabeth A; Melnikov, Alexandre; Rogov, Peter; Birren, Bruce W; Nosten, François; Anderson, Timothy J C; Neafsey, Daniel E

2017-04-28

Artemisinin-based combination therapies are the first line of treatment for Plasmodium falciparum infections worldwide, but artemisinin resistance has risen rapidly in Southeast Asia over the past decade. Mutations in the kelch13 gene have been implicated in this resistance. We used longitudinal genomic surveillance to detect signals in kelch13 and other loci that contribute to artemisinin or partner drug resistance. We retrospectively sequenced the genomes of 194 P. falciparum isolates from five sites in Northwest Thailand, over the period of a rapid increase in the emergence of artemisinin resistance (2001-2014). We evaluate statistical metrics for temporal change in the frequency of individual SNPs, assuming that SNPs associated with resistance increase in frequency over this period. After Kelch13-C580Y, the strongest temporal change is seen at a SNP in phosphatidylinositol 4-kinase, which is involved in a pathway recently implicated in artemisinin resistance. Furthermore, other loci exhibit strong temporal signatures which warrant further investigation for involvement in artemisinin resistance evolution. Through genome-wide association analysis we identify a variant in a kelch domain-containing gene on chromosome 10 that may epistatically modulate artemisinin resistance. This analysis demonstrates the potential of a longitudinal genomic surveillance approach to detect resistance-associated gene loci to improve our mechanistic understanding of how resistance develops. Evidence for additional genomic regions outside of the kelch13 locus associated with artemisinin-resistant parasites may yield new molecular markers for resistance surveillance, which may be useful in efforts to reduce the emergence or spread of artemisinin resistance in African parasite populations.

Microevolution of the Direct Repeat Locus of Mycobacterium tuberculosis in a Strain Prevalent in San Francisco

PubMed Central

Aga, Roxanne S.; Fair, Elizabeth; Abernethy, Neil F.; DeRiemer, Kathryn; Paz, E. Antonio; Kawamura, L. Masae; Small, Peter M.; Kato-Maeda, Midori

2006-01-01

We describe a microevolutionary event of a prevalent strain of Mycobacterium tuberculosis that caused two outbreaks in San Francisco. During the second outbreak, a direct variable repeat was lost. We discuss the mechanisms of this change and the implications of analyzing multiple genetic loci in this context. PMID:16597893

Analysis of Mycobacterium avium subsp. paratuberculosis mutant libraries reveals loci-dependent transcription biases and strategies to novel mutant discovery

USDA-ARS?s Scientific Manuscript database

Mycobacterium avium subsp. paratuberculosis (MAP) is the etiologic agent of Johne’s disease in ruminants and it has been implicated as a cause of Crohn’s disease in humans. The generation of comprehensive random mutant banks by transposon mutagenesis is a fundamental wide genomic technology utilized...

Genetic subpopulation structuring and its implications in a mature eastern white pine stand

Treesearch

Samuel E. Nijensohn; Paul G. Schaberg; Gary J. Hawley; Donald H. DeHayes; Donald H. DeHayes

2005-01-01

We examined patterns of genetic structuring within a mature eastern white pine (Pinus strobus L.) forest, using geographic information system (GIS)-based data and maps that combined genetic (isozyme analysis of 46 loci) and other tree-specific information (e.g., size, growth, age, and location) for 220 trees in Jericho, Vermont. Interconnections between genotypic...

Genetics of United States Populations of Western Corn Rootworm ( Diabrotica virgifera virgifera) and Implications for Bacillus thuringiensis (Bt) Corn Management

USDA-ARS?s Scientific Manuscript database

Western corn rootworm (Diabrotica virgifera virgifera; WCR) were sampled from across much of their US range for population genetic analyses. We assayed allelic variation at microsatellite loci, including markers within a cadherin-like gene, a locus shown to be correlated with resistance to Bacillus...

Systematics of Plant-Pathogenic and Related Streptomyces Species Based on Phylogenetic Analyses of Multiple Gene Loci

USDA-ARS?s Scientific Manuscript database

The 10 species of Streptomyces implicated as the etiological agents in scab disease of potatoes or soft rot disease of sweet potatoes are distributed among 7 different phylogenetic clades in analyses based on 16S rRNA gene sequences, but high sequence similarity of this gene among Streptomyces speci...

AFLPs and Mitochondrial Haplotypes Reveal Local Adaptation to Extreme Thermal Environments in a Freshwater Gastropod

PubMed Central

Quintela, María; Johansson, Magnus P.; Kristjánsson, Bjarni K.; Barreiro, Rodolfo; Laurila, Anssi

2014-01-01

The way environmental variation shapes neutral and adaptive genetic variation in natural populations is a key issue in evolutionary biology. Genome scans allow the identification of the genetic basis of local adaptation without previous knowledge of genetic variation or traits under selection. Candidate loci for divergent adaptation are expected to show higher FST than neutral loci influenced solely by random genetic drift, migration and mutation. The comparison of spatial patterns of neutral markers and loci under selection may help disentangle the effects of gene flow, genetic drift and selection among populations living in contrasting environments. Using the gastropod Radix balthica as a system, we analyzed 376 AFLP markers and 25 mtDNA COI haplotypes for candidate loci and associations with local adaptation among contrasting thermal environments in Lake Mývatn, a volcanic lake in northern Iceland. We found that 2% of the analysed AFLP markers were under directional selection and 12% of the mitochondrial haplotypes correlated with differing thermal habitats. The genetic networks were concordant for AFLP markers and mitochondrial haplotypes, depicting distinct topologies at neutral and candidate loci. Neutral topologies were characterized by intense gene flow revealed by dense nets with edges connecting contrasting thermal habitats, whereas the connections at candidate loci were mostly restricted to populations within each thermal habitat and the number of edges decreased with temperature. Our results suggest microgeographic adaptation within Lake Mývatn and highlight the utility of genome scans in detecting adaptive divergence. PMID:25007329

Comparison of Computed Condon Loci with Franck-Condon Factors in Deslandres Tables of Molecular Band Systems

NASA Astrophysics Data System (ADS)

Hefferlin, R.; Clark, B.; Tatum, J.

2012-06-01

The literature often shows a Condon parabola not quite tracking the Franck-Condon factors for the strongest bands in the Deslandres table for a diatomic molecular band system; often the parabola appears to have been hand-drawn. We have calculated Condon loci, assuming originally that the lower and upper electronic potentials are simple harmonic potentials, and assuming now that they are Morse potentials. In the harmonic case the Condon loci are parabolas. These calculations are for small vibrational quantum numbers, where the Morse loci also begin as parabolas. We will present these loci for representative molecular band systems and discuss the extent to which the loci track the strongest Franck-Condon factors. In the event that neither does, calculations for arbitrary potentials are available. The importance of this study is that we have previously calculated the latera recta and the symmetry-axis angles of the harmonic oscillator parabolas in Deslandres tables appropriate to molecules in several isoelectronic sequences. We have found that the angle increases along the sequence until the species one proton-shift away from “rare-gas” molecules, such as LiNe, is reached. This phenomenon is a suggestion that diatomic molecules are periodic with respect to each of their two atoms. G. Herzberg, Molecular Spectra and Molecular Structure, 1950, pg. 197 D. J. Flynn, R. J. Spindler; S. Fifer; M. Kelly, J. Quant. Spectr. Radiat. Transfer 4, 271-282, (1964) R. W. Nicholls, J. Quant. Spectr. Radiat. Transfer 28, 481-492, (1982).

Genetic diversity among sea otter isolates of Toxoplasma gondii

USGS Publications Warehouse

Sundar, N.; Cole, Rebecca A.; Thomas, N.J.; Majumdar, D.; Dubey, J.P.; Su, C.

2008-01-01

Sea otters (Enhydra lutris) have been reported to become infected with Toxoplasma gondiiand at times succumb to clinical disease. Here, we determined genotypes of 39 T. gondiiisolates from 37 sea otters in two geographically distant locations (25 from California and 12 from Washington). Six genotypes were identified using 10 PCR-RFLP genetic markers including SAG1, SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1, and Apico, and by DNA sequencing of loci SAG1 and GRA6 in 13 isolates. Of these 39 isolates, 13 (33%) were clonal Type II which can be further divided into two groups at the locus Apico. Two of the 39 isolates had Type II alleles at all loci except a Type I allele at locus L358. One isolate had Type II alleles at all loci except the Type I alleles at loci L358 and Apico. One isolate had Type III alleles at all loci except Type II alleles at SAG2 and Apico. Two sea otter isolates had a mixed infection. Twenty-one (54%) isolates had an unique allele at SAG1 locus. Further genotyping or DNA sequence analysis for 18 of these 21 isolates at loci SAG1 and GRA6 revealed that there were two different genotypes, including the previously identified Type X (four isolates) and a new genotype named Type A (14 isolates). The results from this study suggest that the sea otter isolates are genetically diverse.

Meta-analysis of genome-wide association studies in East Asian-ancestry populations identifies four new loci for body mass index.

PubMed

Wen, Wanqing; Zheng, Wei; Okada, Yukinori; Takeuchi, Fumihiko; Tabara, Yasuharu; Hwang, Joo-Yeon; Dorajoo, Rajkumar; Li, Huaixing; Tsai, Fuu-Jen; Yang, Xiaobo; He, Jiang; Wu, Ying; He, Meian; Zhang, Yi; Liang, Jun; Guo, Xiuqing; Sheu, Wayne Huey-Herng; Delahanty, Ryan; Guo, Xingyi; Kubo, Michiaki; Yamamoto, Ken; Ohkubo, Takayoshi; Go, Min Jin; Liu, Jian Jun; Gan, Wei; Chen, Ching-Chu; Gao, Yong; Li, Shengxu; Lee, Nanette R; Wu, Chen; Zhou, Xueya; Song, Huaidong; Yao, Jie; Lee, I-Te; Long, Jirong; Tsunoda, Tatsuhiko; Akiyama, Koichi; Takashima, Naoyuki; Cho, Yoon Shin; Ong, Rick Th; Lu, Ling; Chen, Chien-Hsiun; Tan, Aihua; Rice, Treva K; Adair, Linda S; Gui, Lixuan; Allison, Matthew; Lee, Wen-Jane; Cai, Qiuyin; Isomura, Minoru; Umemura, Satoshi; Kim, Young Jin; Seielstad, Mark; Hixson, James; Xiang, Yong-Bing; Isono, Masato; Kim, Bong-Jo; Sim, Xueling; Lu, Wei; Nabika, Toru; Lee, Juyoung; Lim, Wei-Yen; Gao, Yu-Tang; Takayanagi, Ryoichi; Kang, Dae-Hee; Wong, Tien Yin; Hsiung, Chao Agnes; Wu, I-Chien; Juang, Jyh-Ming Jimmy; Shi, Jiajun; Choi, Bo Youl; Aung, Tin; Hu, Frank; Kim, Mi Kyung; Lim, Wei Yen; Wang, Tzung-Dao; Shin, Min-Ho; Lee, Jeannette; Ji, Bu-Tian; Lee, Young-Hoon; Young, Terri L; Shin, Dong Hoon; Chun, Byung-Yeol; Cho, Myeong-Chan; Han, Bok-Ghee; Hwu, Chii-Min; Assimes, Themistocles L; Absher, Devin; Yan, Xiaofei; Kim, Eric; Kuo, Jane Z; Kwon, Soonil; Taylor, Kent D; Chen, Yii-Der I; Rotter, Jerome I; Qi, Lu; Zhu, Dingliang; Wu, Tangchun; Mohlke, Karen L; Gu, Dongfeng; Mo, Zengnan; Wu, Jer-Yuarn; Lin, Xu; Miki, Tetsuro; Tai, E Shyong; Lee, Jong-Young; Kato, Norihiro; Shu, Xiao-Ou; Tanaka, Toshihiro

2014-10-15

Recent genetic association studies have identified 55 genetic loci associated with obesity or body mass index (BMI). The vast majority, 51 loci, however, were identified in European-ancestry populations. We conducted a meta-analysis of associations between BMI and ∼2.5 million genotyped or imputed single nucleotide polymorphisms among 86 757 individuals of Asian ancestry, followed by in silico and de novo replication among 7488-47 352 additional Asian-ancestry individuals. We identified four novel BMI-associated loci near the KCNQ1 (rs2237892, P = 9.29 × 10(-13)), ALDH2/MYL2 (rs671, P = 3.40 × 10(-11); rs12229654, P = 4.56 × 10(-9)), ITIH4 (rs2535633, P = 1.77 × 10(-10)) and NT5C2 (rs11191580, P = 3.83 × 10(-8)) genes. The association of BMI with rs2237892, rs671 and rs12229654 was significantly stronger among men than among women. Of the 51 BMI-associated loci initially identified in European-ancestry populations, we confirmed eight loci at the genome-wide significance level (P < 5.0 × 10(-8)) and an additional 14 at P < 1.0 × 10(-3) with the same direction of effect as reported previously. Findings from this analysis expand our knowledge of the genetic basis of obesity. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

PCR-based study of conserved and variable DNA sequences of Tritrichomonas foetus isolates from Saskatchewan, Canada.

PubMed Central

Riley, D E; Wagner, B; Polley, L; Krieger, J N

1995-01-01

The protozoan parasite Tritrichomonas foetus causes infertility and spontaneous abortion in cattle. In Saskatchewan, Canada, the culture prevalence of trichomonads was 65 of 1,048 (6%) among 1,048 bulls tested within a 1-year period ending in April 1994. Saskatchewan was previously thought to be free of the parasite. To confirm the culture results, possible T. foetus DNA presence was determined by the PCR. All of the 16 culture-positive isolates tested were PCR positive by a single-band test, but one PCR product was weak. DNA fingerprinting by both T17 PCR and randomly amplified polymorphic DNA PCR revealed genetic variation or polymorphism among the T. foetus isolates. T17 PCR also revealed conserved loci that distinguished these T. foetus isolates from Trichomonas vaginalis, from a variety of other protozoa, and from prokaryotes. TCO-1 PCR, a PCR test designed to sample DNA sequence homologous to the 5' flank of a highly conserved cell division control gene, detected genetic polymorphism at low stringency and a conserved, single locus at higher stringency. These findings suggested that T. foetus isolates exhibit both conserved genetic loci and polymorphic loci detectable by independent PCR methods. Both conserved and polymorphic genetic loci may prove useful for improved clinical diagnosis of T. foetus. The polymorphic loci detected by PCR suggested either a long history of infection or multiple lines of T. foetus infection in Saskatchewan. Polymorphic loci detected by PCR may provide data for epidemiologic studies of T. foetus. PMID:7615746

Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk.

PubMed

Warren, Helen R; Evangelou, Evangelos; Cabrera, Claudia P; Gao, He; Ren, Meixia; Mifsud, Borbala; Ntalla, Ioanna; Surendran, Praveen; Liu, Chunyu; Cook, James P; Kraja, Aldi T; Drenos, Fotios; Loh, Marie; Verweij, Niek; Marten, Jonathan; Karaman, Ibrahim; Lepe, Marcelo P Segura; O'Reilly, Paul F; Knight, Joanne; Snieder, Harold; Kato, Norihiro; He, Jiang; Tai, E Shyong; Said, M Abdullah; Porteous, David; Alver, Maris; Poulter, Neil; Farrall, Martin; Gansevoort, Ron T; Padmanabhan, Sandosh; Mägi, Reedik; Stanton, Alice; Connell, John; Bakker, Stephan J L; Metspalu, Andres; Shields, Denis C; Thom, Simon; Brown, Morris; Sever, Peter; Esko, Tõnu; Hayward, Caroline; van der Harst, Pim; Saleheen, Danish; Chowdhury, Rajiv; Chambers, John C; Chasman, Daniel I; Chakravarti, Aravinda; Newton-Cheh, Christopher; Lindgren, Cecilia M; Levy, Daniel; Kooner, Jaspal S; Keavney, Bernard; Tomaszewski, Maciej; Samani, Nilesh J; Howson, Joanna M M; Tobin, Martin D; Munroe, Patricia B; Ehret, Georg B; Wain, Louise V

2017-03-01

Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. In combination with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure-raising genetic variants on future cardiovascular disease risk.

Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk

PubMed Central

Ntalla, Ioanna; Surendran, Praveen; Liu, Chunyu; Cook, James P; Kraja, Aldi T; Drenos, Fotios; Loh, Marie; Verweij, Niek; Marten, Jonathan; Karaman, Ibrahim; Segura Lepe, Marcelo P; O’Reilly, Paul F; Knight, Joanne; Snieder, Harold; Kato, Norihiro; He, Jiang; Tai, E Shyong; Said, M Abdullah; Porteous, David; Alver, Maris; Poulter, Neil; Farrall, Martin; Gansevoort, Ron T; Padmanabhan, Sandosh; Mägi, Reedik; Stanton, Alice; Connell, John; Bakker, Stephan J L; Metspalu, Andres; Shields, Denis C; Thom, Simon; Brown, Morris; Sever, Peter; Esko, Tõnu; Hayward, Caroline; van der Harst, Pim; Saleheen, Danish; Chowdhury, Rajiv; Chambers, John C; Chasman, Daniel I; Chakravarti, Aravinda; Newton-Cheh, Christopher; Lindgren, Cecilia M; Levy, Daniel; Kooner, Jaspal S; Keavney, Bernard; Tomaszewski, Maciej; Samani, Nilesh J; Howson, Joanna M M; Tobin, Martin D; Munroe, Patricia B; Ehret, Georg B; Wain, Louise V

2017-01-01

Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of European ancestry with independent replication in other cohorts, and robust validation of 107 independent loci. We also identify new independent variants at 11 previously reported blood pressure loci. Combined with results from a range of in silico functional analyses and wet bench experiments, our findings highlight new biological pathways for blood pressure regulation enriched for genes expressed in vascular tissues and identify potential therapeutic targets for hypertension. Results from genetic risk score models raise the possibility of a precision medicine approach through early lifestyle intervention to offset the impact of blood pressure raising genetic variants on future cardiovascular disease risk. PMID:28135244

Progress in a genome scan for linkage in schizophrenia in a large Swedish kindred

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barr, C.L.; Kennedy, J.L.; Pakstis, A.J.

1994-03-15

Genetic linkage studies of a kindred from Sweden segregating for schizophrenia have been performed using a genetic model (autosomal dominant, f - 0.72, q - 0.02, phenocopies=0.001) as described in Kennedy et al., 1988. Analyses of the restriction fragment length polymorphism (RFLP), allele-specific oligonucleotides (ASO), and short tandem repeat (STR also called microsatellite) data for 180 polymorphisms (individual probe-enzyme, ASO, or STR systems) at 155 loci have been completed using the MLINK and LIPED programs. Linkage to schizophrenia was excluded, under the given model, at 47 loci; indeterminate lod scores occurred at 108 loci. The total exclusion region across 20more » chromosomes is estimated at 330 cM; 211 cM excluded by pairwise analyses and 119 cM previously excluded by multipoint analyses. 37 refs., 2 tabs.« less

Model of chromosomal loci dynamics in bacteria as fractional diffusion with intermittent transport

NASA Astrophysics Data System (ADS)

Gherardi, Marco; Calabrese, Ludovico; Tamm, Mikhail; Cosentino Lagomarsino, Marco

2017-10-01

The short-time dynamics of bacterial chromosomal loci is a mixture of subdiffusive and active motion, in the form of rapid relocations with near-ballistic dynamics. While previous work has shown that such rapid motions are ubiquitous, we still have little grasp on their physical nature, and no positive model is available that describes them. Here, we propose a minimal theoretical model for loci movements as a fractional Brownian motion subject to a constant but intermittent driving force, and compare simulations and analytical calculations to data from high-resolution dynamic tracking in E. coli. This analysis yields the characteristic time scales for intermittency. Finally, we discuss the possible shortcomings of this model, and show that an increase in the effective local noise felt by the chromosome associates to the active relocations.

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants.

PubMed

Dadaev, Tokhir; Saunders, Edward J; Newcombe, Paul J; Anokian, Ezequiel; Leongamornlert, Daniel A; Brook, Mark N; Cieza-Borrella, Clara; Mijuskovic, Martina; Wakerell, Sarah; Olama, Ali Amin Al; Schumacher, Fredrick R; Berndt, Sonja I; Benlloch, Sara; Ahmed, Mahbubl; Goh, Chee; Sheng, Xin; Zhang, Zhuo; Muir, Kenneth; Govindasami, Koveela; Lophatananon, Artitaya; Stevens, Victoria L; Gapstur, Susan M; Carter, Brian D; Tangen, Catherine M; Goodman, Phyllis; Thompson, Ian M; Batra, Jyotsna; Chambers, Suzanne; Moya, Leire; Clements, Judith; Horvath, Lisa; Tilley, Wayne; Risbridger, Gail; Gronberg, Henrik; Aly, Markus; Nordström, Tobias; Pharoah, Paul; Pashayan, Nora; Schleutker, Johanna; Tammela, Teuvo L J; Sipeky, Csilla; Auvinen, Anssi; Albanes, Demetrius; Weinstein, Stephanie; Wolk, Alicja; Hakansson, Niclas; West, Catharine; Dunning, Alison M; Burnet, Neil; Mucci, Lorelei; Giovannucci, Edward; Andriole, Gerald; Cussenot, Olivier; Cancel-Tassin, Géraldine; Koutros, Stella; Freeman, Laura E Beane; Sorensen, Karina Dalsgaard; Orntoft, Torben Falck; Borre, Michael; Maehle, Lovise; Grindedal, Eli Marie; Neal, David E; Donovan, Jenny L; Hamdy, Freddie C; Martin, Richard M; Travis, Ruth C; Key, Tim J; Hamilton, Robert J; Fleshner, Neil E; Finelli, Antonio; Ingles, Sue Ann; Stern, Mariana C; Rosenstein, Barry; Kerns, Sarah; Ostrer, Harry; Lu, Yong-Jie; Zhang, Hong-Wei; Feng, Ninghan; Mao, Xueying; Guo, Xin; Wang, Guomin; Sun, Zan; Giles, Graham G; Southey, Melissa C; MacInnis, Robert J; FitzGerald, Liesel M; Kibel, Adam S; Drake, Bettina F; Vega, Ana; Gómez-Caamaño, Antonio; Fachal, Laura; Szulkin, Robert; Eklund, Martin; Kogevinas, Manolis; Llorca, Javier; Castaño-Vinyals, Gemma; Penney, Kathryn L; Stampfer, Meir; Park, Jong Y; Sellers, Thomas A; Lin, Hui-Yi; Stanford, Janet L; Cybulski, Cezary; Wokolorczyk, Dominika; Lubinski, Jan; Ostrander, Elaine A; Geybels, Milan S; Nordestgaard, Børge G; Nielsen, Sune F; Weisher, Maren; Bisbjerg, Rasmus; Røder, Martin Andreas; Iversen, Peter; Brenner, Hermann; Cuk, Katarina; Holleczek, Bernd; Maier, Christiane; Luedeke, Manuel; Schnoeller, Thomas; Kim, Jeri; Logothetis, Christopher J; John, Esther M; Teixeira, Manuel R; Paulo, Paula; Cardoso, Marta; Neuhausen, Susan L; Steele, Linda; Ding, Yuan Chun; De Ruyck, Kim; De Meerleer, Gert; Ost, Piet; Razack, Azad; Lim, Jasmine; Teo, Soo-Hwang; Lin, Daniel W; Newcomb, Lisa F; Lessel, Davor; Gamulin, Marija; Kulis, Tomislav; Kaneva, Radka; Usmani, Nawaid; Slavov, Chavdar; Mitev, Vanio; Parliament, Matthew; Singhal, Sandeep; Claessens, Frank; Joniau, Steven; Van den Broeck, Thomas; Larkin, Samantha; Townsend, Paul A; Aukim-Hastie, Claire; Gago-Dominguez, Manuela; Castelao, Jose Esteban; Martinez, Maria Elena; Roobol, Monique J; Jenster, Guido; van Schaik, Ron H N; Menegaux, Florence; Truong, Thérèse; Koudou, Yves Akoli; Xu, Jianfeng; Khaw, Kay-Tee; Cannon-Albright, Lisa; Pandha, Hardev; Michael, Agnieszka; Kierzek, Andrzej; Thibodeau, Stephen N; McDonnell, Shannon K; Schaid, Daniel J; Lindstrom, Sara; Turman, Constance; Ma, Jing; Hunter, David J; Riboli, Elio; Siddiq, Afshan; Canzian, Federico; Kolonel, Laurence N; Le Marchand, Loic; Hoover, Robert N; Machiela, Mitchell J; Kraft, Peter; Freedman, Matthew; Wiklund, Fredrik; Chanock, Stephen; Henderson, Brian E; Easton, Douglas F; Haiman, Christopher A; Eeles, Rosalind A; Conti, David V; Kote-Jarai, Zsofia

2018-06-11

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.

Genetic Determinants of Pubertal Timing in the General Population

PubMed Central

Gajdos, Zofia K.Z.; Henderson, Katherine D.; Hirschhorn, Joel N.

2010-01-01

Puberty is an important developmental stage during which reproductive capacity is attained. The timing of puberty varies greatly among healthy individuals in the general population and is influenced by both genetic and environmental factors. Although genetic variation is known to influence the normal spectrum of pubertal timing, the specific genes involved remain largely unknown. Genetic analyses have identified a number of genes responsible for rare disorders of pubertal timing such as hypogonadotropic hypogonadism and Kallmann syndrome. Recently, the first loci with common variation reproducibly associated with population variation in the timing of puberty were identified at 6q21 in or near LIN28B and at 9q31.2. However, these two loci explain only a small fraction of the genetic contribution to population variation in pubertal timing, suggesting the need to continue to consider other loci and other types of variants. Here we provide an update of the genes implicated in disorders of puberty, discuss genes and pathways that may be involved in the timing of normal puberty, and suggest additional avenues of investigation to identify genetic regulators of puberty in the general population. PMID:20144687

Genome re-assignment of Arachis trinitensis (Sect. Arachis, Leguminosae) and its implications for the genetic origin of cultivated peanut

PubMed Central

2010-01-01

The karyotype structure of Arachis trinitensis was studied by conventional Feulgen staining, CMA/DAPI banding and rDNA loci detection by fluorescence in situ hybridization (FISH) in order to establish its genome status and test the hypothesis that this species is a genome donor of cultivated peanut. Conventional staining revealed that the karyotype lacked the small “A chromosomes” characteristic of the A genome. In agreement with this, chromosomal banding showed that none of the chromosomes had the large centromeric bands expected for A chromosomes. FISH revealed one pair each of 5S and 45S rDNA loci, located in different medium-sized metacentric chromosomes. Collectively, these results suggest that A. trinitensis should be removed from the A genome and be considered as a B or non-A genome species. The pattern of heterochromatic bands and rDNA loci of A. trinitensis differ markedly from any of the complements of A. hypogaea, suggesting that the former species is unlikely to be one of the wild diploid progenitors of the latter. PMID:21637581

Genetic fine-mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

PubMed Central

Mahajan, Anubha; Locke, Adam; Rayner, N William; Robertson, Neil; Scott, Robert A; Prokopenko, Inga; Scott, Laura J; Green, Todd; Sparso, Thomas; Thuillier, Dorothee; Yengo, Loic; Grallert, Harald; Wahl, Simone; Frånberg, Mattias; Strawbridge, Rona J; Kestler, Hans; Chheda, Himanshu; Eisele, Lewin; Gustafsson, Stefan; Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Qi, Lu; Karssen, Lennart C; van Leeuwen, Elisabeth M; Willems, Sara M; Li, Man; Chen, Han; Fuchsberger, Christian; Kwan, Phoenix; Ma, Clement; Linderman, Michael; Lu, Yingchang; Thomsen, Soren K; Rundle, Jana K; Beer, Nicola L; van de Bunt, Martijn; Chalisey, Anil; Kang, Hyun Min; Voight, Benjamin F; Abecasis, Goncalo R; Almgren, Peter; Baldassarre, Damiano; Balkau, Beverley; Benediktsson, Rafn; Blüher, Matthias; Boeing, Heiner; Bonnycastle, Lori L; Borringer, Erwin P; Burtt, Noël P; Carey, Jason; Charpentier, Guillaume; Chines, Peter S; Cornelis, Marilyn C; Couper, David J; Crenshaw, Andrew T; van Dam, Rob M; Doney, Alex SF; Dorkhan, Mozhgan; Edkins, Sarah; Eriksson, Johan G; Esko, Tonu; Eury, Elodie; Fadista, João; Flannick, Jason; Fontanillas, Pierre; Fox, Caroline; Franks, Paul W; Gertow, Karl; Gieger, Christian; Gigante, Bruna; Gottesman, Omri; Grant, George B; Grarup, Niels; Groves, Christopher J; Hassinen, Maija; Have, Christian T; Herder, Christian; Holmen, Oddgeir L; Hreidarsson, Astradur B; Humphries, Steve E; Hunter, David J; Jackson, Anne U; Jonsson, Anna; Jørgensen, Marit E; Jørgensen, Torben; Kerrison, Nicola D; Kinnunen, Leena; Klopp, Norman; Kong, Augustine; Kovacs, Peter; Kraft, Peter; Kravic, Jasmina; Langford, Cordelia; Leander, Karin; Liang, Liming; Lichtner, Peter; Lindgren, Cecilia M; Lindholm, Eero; Linneberg, Allan; Liu, Ching-Ti; Lobbens, Stéphane; Luan, Jian’an; Lyssenko, Valeriya; Männistö, Satu; McLeod, Olga; Meyer, Julia; Mihailov, Evelin; Mirza, Ghazala; Mühleisen, Thomas W; Müller-Nurasyid, Martina; Navarro, Carmen; Nöthen, Markus M; Oskolkov, Nikolay N; Owen, Katharine R; Palli, Domenico; Pechlivanis, Sonali; Perry, John RB; Platou, Carl GP; Roden, Michael; Ruderfer, Douglas; Rybin, Denis; van der Schouw, Yvonne T; Sennblad, Bengt; Sigurðsson, Gunnar; Stančáková, Alena; Steinbach, Gerald; Storm, Petter; Strauch, Konstantin; Stringham, Heather M; Sun, Qi; Thorand, Barbara; Tikkanen, Emmi; Tonjes, Anke; Trakalo, Joseph; Tremoli, Elena; Tuomi, Tiinamaija; Wennauer, Roman; Wood, Andrew R; Zeggini, Eleftheria; Dunham, Ian; Birney, Ewan; Pasquali, Lorenzo; Ferrer, Jorge; Loos, Ruth JF; Dupuis, Josée; Florez, Jose C; Boerwinkle, Eric; Pankow, James S; van Duijn, Cornelia; Sijbrands, Eric; Meigs, James B; Hu, Frank B; Thorsteinsdottir, Unnur; Stefansson, Kari; Lakka, Timo A; Rauramaa, Rainer; Stumvoll, Michael; Pedersen, Nancy L; Lind, Lars; Keinanen-Kiukaanniemi, Sirkka M; Korpi-Hyövälti, Eeva; Saaristo, Timo E; Saltevo, Juha; Kuusisto, Johanna; Laakso, Markku; Metspalu, Andres; Erbel, Raimund; Jöckel, Karl-Heinz; Moebus, Susanne; Ripatti, Samuli; Salomaa, Veikko; Ingelsson, Erik; Boehm, Bernhard O; Bergman, Richard N; Collins, Francis S; Mohlke, Karen L; Koistinen, Heikki; Tuomilehto, Jaakko; Hveem, Kristian; Njølstad, Inger; Deloukas, Panagiotis; Donnelly, Peter J; Frayling, Timothy M; Hattersley, Andrew T; de Faire, Ulf; Hamsten, Anders; Illig, Thomas; Peters, Annette; Cauchi, Stephane; Sladek, Rob; Froguel, Philippe; Hansen, Torben; Pedersen, Oluf; Morris, Andrew D; Palmer, Collin NA; Kathiresan, Sekar; Melander, Olle; Nilsson, Peter M; Groop, Leif C; Barroso, Inês; Langenberg, Claudia; Wareham, Nicholas J; O’Callaghan, Christopher A; Gloyn, Anna L; Altshuler, David; Boehnke, Michael; Teslovich, Tanya M; McCarthy, Mark I; Morris, Andrew P

2015-01-01

We performed fine-mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in/near KCNQ1. “Credible sets” of variants most likely to drive each distinct signal mapped predominantly to non-coding sequence, implying that T2D association is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine-mapping implicated rs10830963 as driving T2D association. We confirmed that this T2D-risk allele increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D-risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease. PMID:26551672

Epistasis modifies the dominance of loci causing hybrid male sterility in the Drosophila pseudoobscura species group

PubMed Central

Chang, Audrey S.; Noor, Mohamed A. F.

2009-01-01

Speciation, the evolution of reproductive isolation between populations, serves as the driving force for generating biodiversity. Postzygotic barriers to gene flow, such as F1 hybrid sterility and inviability, play important roles in the establishment and maintenance of biological species. F1 hybrid incompatibilities in taxa that obey Haldane's rule, the observation that the heterogametic sex suffers greater hybrid fitness problems than the homogametic sex, are thought to often result from interactions between recessive-acting X-linked loci and dominant-acting autosomal loci. Because they play such prominent roles in producing hybrid incompatibilities, we examine the dominance and nature of epistasis between alleles derived from Drosophila persimilis that confer hybrid male sterility in the genetic background of its sister species, D. pseudoobscura bogotana. We show that epistasis elevates the apparent dominance of individually recessive-acting QTL such that they can contribute to F1 hybrid sterility. These results have important implications for assumptions underlying theoretical models of hybrid incompatibilities and may offer a possible explanation for why, to date identification of dominant-acting autosomal “speciation genes” has been challenging. PMID:19686263

Epistasis modifies the dominance of loci causing hybrid male sterility in the Drosophila pseudoobscura species group.

PubMed

Chang, Audrey S; Noor, Mohamed A F

2010-01-01

Speciation, the evolution of reproductive isolation between populations, serves as the driving force for generating biodiversity. Postzygotic barriers to gene flow, such as F(1) hybrid sterility and inviability, play important roles in the establishment and maintenance of biological species. F(1) hybrid incompatibilities in taxa that obey Haldane's rule, the observation that the heterogametic sex suffers greater hybrid fitness problems than the homogametic sex, are thought to often result from interactions between recessive-acting X-linked loci and dominant-acting autosomal loci. Because they play such prominent roles in producing hybrid incompatibilities, we examine the dominance and nature of epistasis between alleles derived from Drosophila persimilis that confer hybrid male sterility in the genetic background of its sister species, D. pseudoobscura bogotana. We show that epistasis elevates the apparent dominance of individually recessive-acting QTL such that they can contribute to F(1) hybrid sterility. These results have important implications for assumptions underlying theoretical models of hybrid incompatibilities and may offer a possible explanation for why, to date, identification of dominant-acting autosomal "speciation genes" has been challenging.

VNTR alleles associated with the {alpha}-globin locus are haplotype and population related

DOE Office of Scientific and Technical Information (OSTI.GOV)

Martinson, J.J.; Clegg, J.B.; Boyce, A.J.

1994-09-01

The human {alpha}-globin complex contains several polymorphic restriction-enzyme sites (i.e., RFLPs) linked to form haplotypes and is flanked by two hypervariable VNTR loci, the 5{prime} hypervariable region (HVR) and the more highly polymorphic 3{prime}HVR. Using a combination of RFLP analysis and PCR, the authors have characterized the 5{prime}HVR and 3{prime}HVR alleles associated with the {alpha}-globin haplotypes of 133 chromosomes, and they here show that specific {alpha}-globin haplotypes are each associated with discrete subsets of the alleles observed at these two VNTR loci. This statistically highly significant association is observed over a region spanning {approximately} 100 kb. With the exception ofmore » closely related haplotypes, different haplotypes do not share identically sized 3{prime}HVR alleles. Earlier studies have shown that {alpha}-globin haplotype distributions differ between populations; the current findings also reveal extensive population substructure in the repertoire of {alpha}-globin VNTRs. If similar features are characteristic of other VNTR loci, this will have important implications for forensic and anthropological studies. 42 refs., 5 figs., 5 tabs.« less

Genome-wide association analysis identifies three new risk loci for gout arthritis in Han Chinese

PubMed Central

Li, Changgui; Li, Zhiqiang; Liu, Shiguo; Wang, Can; Han, Lin; Cui, Lingling; Zhou, Jingguo; Zou, Hejian; Liu, Zhen; Chen, Jianhua; Cheng, Xiaoyu; Zhou, Zhaowei; Ding, Chengcheng; Wang, Meng; Chen, Tong; Cui, Ying; He, Hongmei; Zhang, Keke; Yin, Congcong; Wang, Yunlong; Xing, Shichao; Li, Baojie; Ji, Jue; Jia, Zhaotong; Ma, Lidan; Niu, Jiapeng; Xin, Ying; Liu, Tian; Chu, Nan; Yu, Qing; Ren, Wei; Wang, Xuefeng; Zhang, Aiqing; Sun, Yuping; Wang, Haili; Lu, Jie; Li, Yuanyuan; Qing, Yufeng; Chen, Gang; Wang, Yangang; Zhou, Li; Niu, Haitao; Liang, Jun; Dong, Qian; Li, Xinde; Mi, Qing-Sheng; Shi, Yongyong

2015-01-01

Gout is one of the most common types of inflammatory arthritis, caused by the deposition of monosodium urate crystals in and around the joints. Previous genome-wide association studies (GWASs) have identified many genetic loci associated with raised serum urate concentrations. However, hyperuricemia alone is not sufficient for the development of gout arthritis. Here we conduct a multistage GWAS in Han Chinese using 4,275 male gout patients and 6,272 normal male controls (1,255 cases and 1,848 controls were genome-wide genotyped), with an additional 1,644 hyperuricemic controls. We discover three new risk loci, 17q23.2 (rs11653176, P=1.36 × 10−13, BCAS3), 9p24.2 (rs12236871, P=1.48 × 10−10, RFX3) and 11p15.5 (rs179785, P=1.28 × 10−8, KCNQ1), which contain inflammatory candidate genes. Our results suggest that these loci are most likely related to the progression from hyperuricemia to inflammatory gout, which will provide new insights into the pathogenesis of gout arthritis. PMID:25967671

Genome-wide association analysis identifies three new risk loci for gout arthritis in Han Chinese.

PubMed

Li, Changgui; Li, Zhiqiang; Liu, Shiguo; Wang, Can; Han, Lin; Cui, Lingling; Zhou, Jingguo; Zou, Hejian; Liu, Zhen; Chen, Jianhua; Cheng, Xiaoyu; Zhou, Zhaowei; Ding, Chengcheng; Wang, Meng; Chen, Tong; Cui, Ying; He, Hongmei; Zhang, Keke; Yin, Congcong; Wang, Yunlong; Xing, Shichao; Li, Baojie; Ji, Jue; Jia, Zhaotong; Ma, Lidan; Niu, Jiapeng; Xin, Ying; Liu, Tian; Chu, Nan; Yu, Qing; Ren, Wei; Wang, Xuefeng; Zhang, Aiqing; Sun, Yuping; Wang, Haili; Lu, Jie; Li, Yuanyuan; Qing, Yufeng; Chen, Gang; Wang, Yangang; Zhou, Li; Niu, Haitao; Liang, Jun; Dong, Qian; Li, Xinde; Mi, Qing-Sheng; Shi, Yongyong

2015-05-13

Gout is one of the most common types of inflammatory arthritis, caused by the deposition of monosodium urate crystals in and around the joints. Previous genome-wide association studies (GWASs) have identified many genetic loci associated with raised serum urate concentrations. However, hyperuricemia alone is not sufficient for the development of gout arthritis. Here we conduct a multistage GWAS in Han Chinese using 4,275 male gout patients and 6,272 normal male controls (1,255 cases and 1,848 controls were genome-wide genotyped), with an additional 1,644 hyperuricemic controls. We discover three new risk loci, 17q23.2 (rs11653176, P=1.36 × 10(-13), BCAS3), 9p24.2 (rs12236871, P=1.48 × 10(-10), RFX3) and 11p15.5 (rs179785, P=1.28 × 10(-8), KCNQ1), which contain inflammatory candidate genes. Our results suggest that these loci are most likely related to the progression from hyperuricemia to inflammatory gout, which will provide new insights into the pathogenesis of gout arthritis.

Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia.

PubMed

Verhoeven, Virginie J M; Hysi, Pirro G; Wojciechowski, Robert; Fan, Qiao; Guggenheim, Jeremy A; Höhn, René; MacGregor, Stuart; Hewitt, Alex W; Nag, Abhishek; Cheng, Ching-Yu; Yonova-Doing, Ekaterina; Zhou, Xin; Ikram, M Kamran; Buitendijk, Gabriëlle H S; McMahon, George; Kemp, John P; Pourcain, Beate St; Simpson, Claire L; Mäkelä, Kari-Matti; Lehtimäki, Terho; Kähönen, Mika; Paterson, Andrew D; Hosseini, S Mohsen; Wong, Hoi Suen; Xu, Liang; Jonas, Jost B; Pärssinen, Olavi; Wedenoja, Juho; Yip, Shea Ping; Ho, Daniel W H; Pang, Chi Pui; Chen, Li Jia; Burdon, Kathryn P; Craig, Jamie E; Klein, Barbara E K; Klein, Ronald; Haller, Toomas; Metspalu, Andres; Khor, Chiea-Chuen; Tai, E-Shyong; Aung, Tin; Vithana, Eranga; Tay, Wan-Ting; Barathi, Veluchamy A; Chen, Peng; Li, Ruoying; Liao, Jiemin; Zheng, Yingfeng; Ong, Rick T; Döring, Angela; Evans, David M; Timpson, Nicholas J; Verkerk, Annemieke J M H; Meitinger, Thomas; Raitakari, Olli; Hawthorne, Felicia; Spector, Tim D; Karssen, Lennart C; Pirastu, Mario; Murgia, Federico; Ang, Wei; Mishra, Aniket; Montgomery, Grant W; Pennell, Craig E; Cumberland, Phillippa M; Cotlarciuc, Ioana; Mitchell, Paul; Wang, Jie Jin; Schache, Maria; Janmahasatian, Sarayut; Janmahasathian, Sarayut; Igo, Robert P; Lass, Jonathan H; Chew, Emily; Iyengar, Sudha K; Gorgels, Theo G M F; Rudan, Igor; Hayward, Caroline; Wright, Alan F; Polasek, Ozren; Vatavuk, Zoran; Wilson, James F; Fleck, Brian; Zeller, Tanja; Mirshahi, Alireza; Müller, Christian; Uitterlinden, André G; Rivadeneira, Fernando; Vingerling, Johannes R; Hofman, Albert; Oostra, Ben A; Amin, Najaf; Bergen, Arthur A B; Teo, Yik-Ying; Rahi, Jugnoo S; Vitart, Veronique; Williams, Cathy; Baird, Paul N; Wong, Tien-Yin; Oexle, Konrad; Pfeiffer, Norbert; Mackey, David A; Young, Terri L; van Duijn, Cornelia M; Saw, Seang-Mei; Bailey-Wilson, Joan E; Stambolian, Dwight; Klaver, Caroline C; Hammond, Christopher J

2013-03-01

Refractive error is the most common eye disorder worldwide and is a prominent cause of blindness. Myopia affects over 30% of Western populations and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses, including 37,382 individuals from 27 studies of European ancestry and 8,376 from 5 Asian cohorts. We identified 16 new loci for refractive error in individuals of European ancestry, of which 8 were shared with Asians. Combined analysis identified 8 additional associated loci. The new loci include candidate genes with functions in neurotransmission (GRIA4), ion transport (KCNQ5), retinoic acid metabolism (RDH5), extracellular matrix remodeling (LAMA2 and BMP2) and eye development (SIX6 and PRSS56). We also confirmed previously reported associations with GJD2 and RASGRF1. Risk score analysis using associated SNPs showed a tenfold increased risk of myopia for individuals carrying the highest genetic load. Our results, based on a large meta-analysis across independent multiancestry studies, considerably advance understanding of the mechanisms involved in refractive error and myopia.

[Analysis of genetic polymorphisms and mutations of 20 frequently used STR loci among ethnic Hans from Henan].

PubMed

Wang, Hongdan; Kang, Bing; Gao, Yue; Huo, Xiaodong; Li, Tao; Guo, Qiannan; Zhu, Bofeng; Liao, Shixiu

2017-04-10

To study the genetic polymorphisms and mutations of 20 frequently used autosomal microsatellites among ethnic Hans from Henan. Peripheral blood samples of 2604 individuals were collected. DNA was amplified and genotyped using a PowerPlex(TM) 21 system. The frequencies, forensic parameters and mutation rates of the 20 short tandem repeat (STR) loci were analyzed. A total of 323 alleles were found in this population and the allelic frequencies have ranged from 0.0003 to 0.5144. Except for D3S1358, TH01 and TPOX, mutations have been found in all of the remaining 17 STR loci, which totaled 47, with mutation rates ranging from 0 to 3.46 × 10 -3 . The 20 STR loci selected by the PowerPlex(TM) 21 system are highly polymorphic among ethnic Hans from Henan, and may be of great value in forensic and human population studies. As no similar study has been carried out previously, above results may be of great value for individual discrimination and paternal testing.

Preferential Mating in Symmetric Multilocus Systems: Limits for Multiallelism and for Many Loci

PubMed Central

Raper, J.

1982-01-01

Models in which general forms of preferential mating have been superimposed on the framework of the symmetric heterozygosity selection regime have been examined previously with respect to the existence and local stability of a central polymorphic equilibrium. The results are now extended to produce the limiting form of the stability conditions in two cases: First, where the number of alleles per locus is assumed to be very large; second, where the number of loci affecting the character is very large. It is argued that some type of frequency dependence in the mating pattern must be included, and a particular case is examined in detail. It is shown that multiallelism is ambiguous in its effect on stability, while an increasing number of loci, at least under zero linkage, leads to a simple stability condition which is analogous to the one-locus heterosis principle. Assortative mating appears to be more likely to produce a stable central polymorphism under high levels of allelism than is sexual selection, but is relatively very much weaker than sexual or viability selection if the number of loci involved is large. PMID:17246061

Distinct Genetic Architectures for Male and Female Inflorescence Traits of Maize

PubMed Central

Brown, Patrick J.; Upadyayula, Narasimham; Mahone, Gregory S.; Tian, Feng; Bradbury, Peter J.; Myles, Sean; Holland, James B.; Flint-Garcia, Sherry; McMullen, Michael D.; Buckler, Edward S.; Rocheford, Torbert R.

2011-01-01

We compared the genetic architecture of thirteen maize morphological traits in a large population of recombinant inbred lines. Four traits from the male inflorescence (tassel) and three traits from the female inflorescence (ear) were measured and studied using linkage and genome-wide association analyses and compared to three flowering and three leaf traits previously studied in the same population. Inflorescence loci have larger effects than flowering and leaf loci, and ear effects are larger than tassel effects. Ear trait models also have lower predictive ability than tassel, flowering, or leaf trait models. Pleiotropic loci were identified that control elongation of ear and tassel, consistent with their common developmental origin. For these pleiotropic loci, the ear effects are larger than tassel effects even though the same causal polymorphisms are likely involved. This implies that the observed differences in genetic architecture are not due to distinct features of the underlying polymorphisms. Our results support the hypothesis that genetic architecture is a function of trait stability over evolutionary time, since the traits that changed most during the relatively recent domestication of maize have the largest effects. PMID:22125498

Genome-wide association study identifies five new susceptibility loci for primary angle closure glaucoma.

PubMed

Khor, Chiea Chuen; Do, Tan; Jia, Hongyan; Nakano, Masakazu; George, Ronnie; Abu-Amero, Khaled; Duvesh, Roopam; Chen, Li Jia; Li, Zheng; Nongpiur, Monisha E; Perera, Shamira A; Qiao, Chunyan; Wong, Hon-Tym; Sakai, Hiroshi; Barbosa de Melo, Mônica; Lee, Mei-Chin; Chan, Anita S; Azhany, Yaakub; Dao, Thi Lam Huong; Ikeda, Yoko; Perez-Grossmann, Rodolfo A; Zarnowski, Tomasz; Day, Alexander C; Jonas, Jost B; Tam, Pancy O S; Tran, Tuan Anh; Ayub, Humaira; Akhtar, Farah; Micheal, Shazia; Chew, Paul T K; Aljasim, Leyla A; Dada, Tanuj; Luu, Tam Thi; Awadalla, Mona S; Kitnarong, Naris; Wanichwecharungruang, Boonsong; Aung, Yee Yee; Mohamed-Noor, Jelinar; Vijayan, Saravanan; Sarangapani, Sripriya; Husain, Rahat; Jap, Aliza; Baskaran, Mani; Goh, David; Su, Daniel H; Wang, Huaizhou; Yong, Vernon K; Yip, Leonard W; Trinh, Tuyet Bach; Makornwattana, Manchima; Nguyen, Thanh Thu; Leuenberger, Edgar U; Park, Ki-Ho; Wiyogo, Widya Artini; Kumar, Rajesh S; Tello, Celso; Kurimoto, Yasuo; Thapa, Suman S; Pathanapitoon, Kessara; Salmon, John F; Sohn, Yong Ho; Fea, Antonio; Ozaki, Mineo; Lai, Jimmy S M; Tantisevi, Visanee; Khaing, Chaw Chaw; Mizoguchi, Takanori; Nakano, Satoko; Kim, Chan-Yun; Tang, Guangxian; Fan, Sujie; Wu, Renyi; Meng, Hailin; Nguyen, Thi Thuy Giang; Tran, Tien Dat; Ueno, Morio; Martinez, Jose Maria; Ramli, Norlina; Aung, Yin Mon; Reyes, Rigo Daniel; Vernon, Stephen A; Fang, Seng Kheong; Xie, Zhicheng; Chen, Xiao Yin; Foo, Jia Nee; Sim, Kar Seng; Wong, Tina T; Quek, Desmond T; Venkatesh, Rengaraj; Kavitha, Srinivasan; Krishnadas, Subbiah R; Soumittra, Nagaswamy; Shantha, Balekudaru; Lim, Boon-Ang; Ogle, Jeanne; de Vasconcellos, José P C; Costa, Vital P; Abe, Ricardo Y; de Souza, Bruno B; Sng, Chelvin C; Aquino, Maria C; Kosior-Jarecka, Ewa; Fong, Guillermo Barreto; Tamanaja, Vania Castro; Fujita, Ricardo; Jiang, Yuzhen; Waseem, Naushin; Low, Sancy; Pham, Huan Nguyen; Al-Shahwan, Sami; Craven, E Randy; Khan, Muhammad Imran; Dada, Rrima; Mohanty, Kuldeep; Faiq, Muneeb A; Hewitt, Alex W; Burdon, Kathryn P; Gan, Eng Hui; Prutthipongsit, Anuwat; Patthanathamrongkasem, Thipnapa; Catacutan, Mary Ann T; Felarca, Irene R; Liao, Chona S; Rusmayani, Emma; Istiantoro, Vira Wardhana; Consolandi, Giulia; Pignata, Giulia; Lavia, Carlo; Rojanapongpun, Prin; Mangkornkanokpong, Lerprat; Chansangpetch, Sunee; Chan, Jonathan C H; Choy, Bonnie N K; Shum, Jennifer W H; Than, Hlaing May; Oo, Khin Thida; Han, Aye Thi; Yong, Victor H; Ng, Xiao-Yu; Goh, Shuang Ru; Chong, Yaan Fun; Hibberd, Martin L; Seielstad, Mark; Png, Eileen; Dunstan, Sarah J; Chau, Nguyen Van Vinh; Bei, Jinxin; Zeng, Yi Xin; Karkey, Abhilasha; Basnyat, Buddha; Pasutto, Francesca; Paoli, Daniela; Frezzotti, Paolo; Wang, Jie Jin; Mitchell, Paul; Fingert, John H; Allingham, R Rand; Hauser, Michael A; Lim, Soon Thye; Chew, Soo Hong; Ebstein, Richard P; Sakuntabhai, Anavaj; Park, Kyu Hyung; Ahn, Jeeyun; Boland, Greet; Snippe, Harm; Stead, Richard; Quino, Raquel; Zaw, Su Nyunt; Lukasik, Urszula; Shetty, Rohit; Zahari, Mimiwati; Bae, Hyoung Won; Oo, Nay Lin; Kubota, Toshiaki; Manassakorn, Anita; Ho, Wing Lau; Dallorto, Laura; Hwang, Young Hoon; Kiire, Christine A; Kuroda, Masako; Djamal, Zeiras Eka; Peregrino, Jovell Ian M; Ghosh, Arkasubhra; Jeoung, Jin Wook; Hoan, Tung S; Srisamran, Nuttamon; Sandragasu, Thayanithi; Set, Saw Htoo; Doan, Vi Huyen; Bhattacharya, Shomi S; Ho, Ching-Lin; Tan, Donald T; Sihota, Ramanjit; Loon, Seng-Chee; Mori, Kazuhiko; Kinoshita, Shigeru; Hollander, Anneke I den; Qamar, Raheel; Wang, Ya-Xing; Teo, Yik Y; Tai, E-Shyong; Hartleben-Matkin, Curt; Lozano-Giral, David; Saw, Seang Mei; Cheng, Ching-Yu; Zenteno, Juan C; Pang, Chi Pui; Bui, Huong T T; Hee, Owen; Craig, Jamie E; Edward, Deepak P; Yonahara, Michiko; Neto, Jamil Miguel; Guevara-Fujita, Maria L; Xu, Liang; Ritch, Robert; Liza-Sharmini, Ahmad Tajudin; Wong, Tien Y; Al-Obeidan, Saleh; Do, Nhu Hon; Sundaresan, Periasamy; Tham, Clement C; Foster, Paul J; Vijaya, Lingam; Tashiro, Kei; Vithana, Eranga N; Wang, Ningli; Aung, Tin

2016-05-01

Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 × 10(-15)), CHAT rs1258267 (OR = 1.22, P = 2.85 × 10(-16)), GLIS3 rs736893 (OR = 1.18, P = 1.43 × 10(-14)), FERMT2 rs7494379 (OR = 1.14, P = 3.43 × 10(-11)), and DPM2-FAM102A rs3739821 (OR = 1.15, P = 8.32 × 10(-12)). We also confirmed significant association at three previously described loci (P < 5 × 10(-8) for each sentinel SNP at PLEKHA7, COL11A1, and PCMTD1-ST18), providing new insights into the biology of PACG.

Further Evidence of Subphenotype Association with Systemic Lupus Erythematosus Susceptibility Loci: A European Cases Only Study

PubMed Central

Alonso-Perez, Elisa; Suarez-Gestal, Marian; Calaza, Manuel; Ordi-Ros, Josep; Balada, Eva; Bijl, Marc; Papasteriades, Chryssa; Carreira, Patricia; Skopouli, Fotini N.; Witte, Torsten; Endreffy, Emöke; Marchini, Maurizio; Migliaresi, Sergio; Sebastiani, Gian Domenico; Santos, Maria Jose; Suarez, Ana; Blanco, Francisco J.; Barizzone, Nadia; Pullmann, Rudolf; Ruzickova, Sarka; Lauwerys, Bernard R.; Gomez-Reino, Juan J.; Gonzalez, Antonio

2012-01-01

Introduction Systemic Lupus Erythematosus (SLE) shows a spectrum of clinical manifestations that complicate its diagnosis, treatment and research. This variability is likely related with environmental exposures and genetic factors among which known SLE susceptibility loci are prime candidates. The first published analyses seem to indicate that this is the case for some of them, but results are still inconclusive and we aimed to further explore this question. Methods European SLE patients, 1444, recruited at 17 centres from 10 countries were analyzed. Genotypes for 26 SLE associated SNPs were compared between patients with and without each of 11 clinical features: ten of the American College of Rheumatology (ACR) classification criteria (except ANAs) and age of disease onset. These analyses were adjusted for centre of recruitment, top ancestry informative markers, gender and time of follow-up. Overlap of samples with previous studies was excluded for assessing replication. Results There were three new associations: the SNPs in XKR6 and in FAM167A-BLK were associated with lupus nephritis (OR = 0.76 and 1.30, Pcorr = 0.007 and 0.03, respectively) and the SNP of MECP2, which is in chromosome X, with earlier age of disease onset in men. The previously reported association of STAT4 with early age of disease onset was replicated. Some other results were suggestive of the presence of additional associations. Together, the association signals provided support to some previous findings and to the characterization of lupus nephritis, autoantibodies and age of disease onset as the clinical features more associated with SLE loci. Conclusion Some of the SLE loci shape the disease phenotype in addition to increase susceptibility to SLE. This influence is more prominent for some clinical features than for others. However, results are only partially consistent between studies and subphenotype specific GWAS are needed to unravel their genetic component. PMID:23049788

RNA polymerase V-dependent small RNAs in Arabidopsis originate from small, intergenic loci including most SINE repeats.

PubMed

Lee, Tzuu-fen; Gurazada, Sai Guna Ranjan; Zhai, Jixian; Li, Shengben; Simon, Stacey A; Matzke, Marjori A; Chen, Xuemei; Meyers, Blake C

2012-07-01

In plants, heterochromatin is maintained by a small RNA-based gene silencing mechanism known as RNA-directed DNA methylation (RdDM). RdDM requires the non-redundant functions of two plant-specific DNA-dependent RNA polymerases (RNAP), RNAP IV and RNAP V. RNAP IV plays a major role in siRNA biogenesis, while RNAP V may recruit DNA methylation machinery to target endogenous loci for silencing. Although small RNA-generating regions that are dependent on both RNAP IV and RNAP V have been identified previously, the genomic loci targeted by RNAP V for siRNA accumulation and silencing have not been described extensively. To characterize the RNAP V-dependent, heterochromatic siRNA-generating regions in the Arabidopsis genome, we deeply sequenced the small RNA populations of wild-type and RNAP V null mutant (nrpe1) plants. Our results showed that RNAP V-dependent siRNA-generating loci are associated predominately with short repetitive sequences in intergenic regions. Suppression of small RNA production from short repetitive sequences was also prominent in RdDM mutants including dms4, drd1, dms3 and rdm1, reflecting the known association of these RdDM effectors with RNAP V. The genomic regions targeted by RNAP V were small, with an estimated average length of 238 bp. Our results suggest that RNAP V affects siRNA production from genomic loci with features dissimilar to known RNAP IV-dependent loci. RNAP V, along with RNAP IV and DRM1/2, may target and silence a set of small, intergenic transposable elements located in dispersed genomic regions for silencing. Silencing at these loci may be actively reinforced by RdDM.

Estimation of loci involved in non-shattering of seeds in early rice domestication.

PubMed

Ishikawa, Ryo; Nishimura, Akinori; Htun, Than Myint; Nishioka, Ryo; Oka, Yumi; Tsujimura, Yuki; Inoue, Chizuru; Ishii, Takashige

2017-04-01

Rice (Oryza sativa L.) is widely cultivated around the world and is known to be domesticated from its wild form, O. rufipogon. A loss of seed shattering is one of the most obvious phenotypic changes selected for during rice domestication. Previously, three seed-shattering loci, qSH1, sh4, and qSH3 were reported to be involved in non-shattering of seeds of Japonica-type cultivated rice, O. sativa cv. Nipponbare. In this study, we focused on non-shattering characteristics of O. sativa Indica cv. IR36 having functional allele at qSH1. We produced backcross recombinant inbred lines having chromosomal segments from IR36 in the genetic background of wild rice, O. rufipogon W630. Histological and quantitative trait loci analyses of abscission layer formation were conducted. In the analysis of quantitative trait loci, a strong peak was observed close to sh4. We, nevertheless, found that some lines showed complete abscission layer formation despite carrying the IR36 allele at sh4, implying that non-shattering of seeds of IR36 could be regulated by the combination of mutations at sh4 and other seed-shattering loci. We also genotyped qSH3, a recently identified seed-shattering locus. Lines that have the IR36 alleles at sh4 and qSH3 showed inhibition of abscission layer formation but the degree of seed shattering was different from that of IR36. On the basis of these results, we estimated that non-shattering of seeds in early rice domestication involved mutations in at least three loci, and these genetic materials produced in this study may help to identify novel seed-shattering loci.

Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts

PubMed Central

Aulchenko, Yurii S; Ripatti, Samuli; Lindqvist, Ida; Boomsma, Dorret; Heid, Iris M; Pramstaller, Peter P; Penninx, Brenda W J H; Janssens, A Cecile J W; Wilson, James F; Spector, Tim; Martin, Nicholas G; Pedersen, Nancy L; Kyvik, Kirsten Ohm; Kaprio, Jaakko; Hofman, Albert; Freimer, Nelson B; Jarvelin, Marjo-Riitta; Gyllensten, Ulf; Campbell, Harry; Rudan, Igor; Johansson, Åsa; Marroni, Fabio; Hayward, Caroline; Vitart, Veronique; Jonasson, Inger; Pattaro, Cristian; Wright, Alan; Hastie, Nick; Pichler, Irene; Hicks, Andrew A; Falchi, Mario; Willemsen, Gonneke; Hottenga, Jouke-Jan; de Geus, Eco J C; Montgomery, Grant W; Whitfield, John; Magnusson, Patrik; Saharinen, Juha; Perola, Markus; Silander, Kaisa; Isaacs, Aaron; Sijbrands, Eric J G; Uitterlinden, Andre G; Witteman, Jacqueline C M; Oostra, Ben A; Elliott, Paul; Ruokonen, Aimo; Sabatti, Chiara; Gieger, Christian; Meitinger, Thomas; Kronenberg, Florian; Döring, Angela; Wichmann, H-Erich; Smit, Johannes H; McCarthy, Mark I; van Duijn, Cornelia M; Peltonen, Leena

2009-01-01

Recent genome-wide association (GWA) studies of lipids have been conducted in samples ascertained for other phenotypes, particularly diabetes. Here we report the first GWA analysis of loci affecting total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides sampled randomly from 16 population-based cohorts and genotyped using mainly the Illumina HumanHap300-Duo platform. Our study included a total of 17,797-22,562 persons, aged 18-104 years and from geographic regions spanning from the Nordic countries to Southern Europe. We established 22 loci associated with serum lipid levels at a genome-wide significance level (P < 5 × 10-8), including 16 loci that were identified by previous GWA studies. The six newly identified loci in our cohort samples are ABCG5 (TC, P = 1.5 × 10-11; LDL, P = 2.6 × 10-10), TMEM57 (TC, P = 5.4 × 10-10), CTCF-PRMT8 region (HDL, P = 8.3 × 10-16), DNAH11 (LDL, P = 6.1 × 10-9), FADS3-FADS2 (TC, P = 1.5 × 10-10; LDL, P = 4.4 × 10-13) and MADD-FOLH1 region (HDL, P = 6 × 10-11). For three loci, effect sizes differed significantly by sex. Genetic risk scores based on lipid loci explain up to 4.8% of variation in lipids and were also associated with increased intima media thickness (P = 0.001) and coronary heart disease incidence (P = 0.04). The genetic risk score improves the screening of high-risk groups of dyslipidemia over classical risk factors. PMID:19060911

The phylogenetic utility of acetyltransferase (ARD1) and glutaminyl tRNA synthetase (QtRNA) for reconstructing Cenozoic relationships as exemplified by the large Australian cicada Pauropsalta generic complex.

PubMed

Owen, Christopher L; Marshall, David C; Hill, Kathy B R; Simon, Chris

2015-02-01

The Pauropsalta generic complex is a large group of cicadas (72 described spp.; >82 undescribed spp.) endemic to Australia. No previous molecular work on deep level relationships within this complex has been conducted, but a recent morphological revision and phylogenetic analysis proposed relationships among the 11 genera. We present here the first comprehensive molecular phylogeny of the complex using five loci (1 mtDNA, 4 nDNA), two of which are from nuclear genes new to cicada systematics. We compare the molecular phylogeny to the morphological phylogeny. We evaluate the phylogenetic informativeness of the new loci to traditional cicada systematics loci to generate a baseline of performance and behavior to aid in gene choice decisions in future systematic and phylogenomic studies. Our maximum likelihood and Bayesian inference phylogenies strongly support the monophyly of most of the newly described genera; however, relationships among genera differ from the morphological phylogeny. A comparison of phylogenetic informativeness among all loci revealed that COI 3rd positions dominate the informativeness profiles relative to all other loci but exhibit some among taxon nucleotide bias. After removing COI 3rd positions, COI 1st positions dominate near the terminals, while the period intron has the most phylogenetic informativeness near the root. Among the nuclear loci, ARD1 and QtRNA have lower phylogenetic informativeness than period intron and elongation factor 1 alpha intron, but the informativeness increases at you move from the tips to the root. The increase in phylogenetic informativeness deeper in the tree suggests these loci may be useful for resolving older relationships. Copyright © 2015. Published by Elsevier Inc.

Detailed Physiologic Characterization Reveals Diverse Mechanisms for Novel Genetic Loci Regulating Glucose and Insulin Metabolism in Humans

PubMed Central

Ingelsson, Erik; Langenberg, Claudia; Hivert, Marie-France; Prokopenko, Inga; Lyssenko, Valeriya; Dupuis, Josée; Mägi, Reedik; Sharp, Stephen; Jackson, Anne U.; Assimes, Themistocles L.; Shrader, Peter; Knowles, Joshua W.; Zethelius, Björn; Abbasi, Fahim A.; Bergman, Richard N.; Bergmann, Antje; Berne, Christian; Boehnke, Michael; Bonnycastle, Lori L.; Bornstein, Stefan R.; Buchanan, Thomas A.; Bumpstead, Suzannah J.; Böttcher, Yvonne; Chines, Peter; Collins, Francis S.; Cooper, Cyrus C.; Dennison, Elaine M.; Erdos, Michael R.; Ferrannini, Ele; Fox, Caroline S.; Graessler, Jürgen; Hao, Ke; Isomaa, Bo; Jameson, Karen A.; Kovacs, Peter; Kuusisto, Johanna; Laakso, Markku; Ladenvall, Claes; Mohlke, Karen L.; Morken, Mario A.; Narisu, Narisu; Nathan, David M.; Pascoe, Laura; Payne, Felicity; Petrie, John R.; Sayer, Avan A.; Schwarz, Peter E. H.; Scott, Laura J.; Stringham, Heather M.; Stumvoll, Michael; Swift, Amy J.; Syvänen, Ann-Christine; Tuomi, Tiinamaija; Tuomilehto, Jaakko; Tönjes, Anke; Valle, Timo T.; Williams, Gordon H.; Lind, Lars; Barroso, Inês; Quertermous, Thomas; Walker, Mark; Wareham, Nicholas J.; Meigs, James B.; McCarthy, Mark I.; Groop, Leif; Watanabe, Richard M.; Florez, Jose C.

2010-01-01

OBJECTIVE Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action. RESEARCH DESIGN AND METHODS We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084). RESULTS The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance (P = 2.1 × 10−71). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction. CONCLUSIONS Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes. PMID:20185807

Meta-Analysis of Genome-Wide Association Studies and Network Analysis-Based Integration with Gene Expression Data Identify New Suggestive Loci and Unravel a Wnt-Centric Network Associated with Dupuytren’s Disease

PubMed Central

Becker, Kerstin; Siegert, Sabine; Toliat, Mohammad Reza; Du, Juanjiangmeng; Casper, Ramona; Dolmans, Guido H.; Werker, Paul M.; Tinschert, Sigrid; Franke, Andre; Gieger, Christian; Strauch, Konstantin; Nothnagel, Michael; Nürnberg, Peter; Hennies, Hans Christian

2016-01-01

Dupuytren´s disease, a fibromatosis of the connective tissue in the palm, is a common complex disease with a strong genetic component. Up to date nine genetic loci have been found to be associated with the disease. Six of these loci contain genes that code for Wnt signalling proteins. In spite of this striking first insight into the genetic factors in Dupuytren´s disease, much of the inherited risk in Dupuytren´s disease still needs to be discovered. The already identified loci jointly explain ~1% of the heritability in this disease. To further elucidate the genetic basis of Dupuytren´s disease, we performed a genome-wide meta-analysis combining three genome-wide association study (GWAS) data sets, comprising 1,580 cases and 4,480 controls. We corroborated all nine previously identified loci, six of these with genome-wide significance (p-value < 5x10-8). In addition, we identified 14 new suggestive loci (p-value < 10−5). Intriguingly, several of these new loci contain genes associated with Wnt signalling and therefore represent excellent candidates for replication. Next, we compared whole-transcriptome data between patient- and control-derived tissue samples and found the Wnt/β-catenin pathway to be the top deregulated pathway in patient samples. We then conducted network and pathway analyses in order to identify protein networks that are enriched for genes highlighted in the GWAS meta-analysis and expression data sets. We found further evidence that the Wnt signalling pathways in conjunction with other pathways may play a critical role in Dupuytren´s disease. PMID:27467239

Linkage analysis excludes the glaucoma locus on 1q from involvement in autosomal dominant glaucoma with iris hypoplasia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Heon, E.; Sheth, B.P.; Kalenak, J.W.

1994-09-01

Genetic factors have been implicated in a variety of types of glaucoma including primary open-angle glaucoma, infantile glaucoma, pigmentary glaucoma, and juvenile open-angle glaucoma. We previously mapped the disease-causing gene for one type of juvenile open angle glaucoma to chromosome 1q21-31. Weatherill and Hart (1969) and Pearce (1983) each noted the association of iris hypoplasia and early-onset autosomal dominant glaucoma. We recently had the opportunity to study a large family (12 affected members) with this phenotype. Affected individuals developed glaucoma at an average age of 30 years. These patients also have a strikingly underdeveloped iris stroma which causes a peculiarmore » eye color. Linkage analysis was able to completely exclude the 1q glaucoma locus from involvement in the disorder that affects this family. A complete clinical description of the family and linkage results at additional candidate loci will be presented.« less

Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus

PubMed Central

Graham, Deborah S Cunninghame; Pinder, Christopher L; Tombleson, Philip; Behrens, Timothy W; Martín, Javier; Fairfax, Benjamin P; Knight, Julian C; Chen, Lingyan; Replogle, Joseph; Syvänen, Ann-Christine; Rönnblom, Lars; Graham, Robert R; Wither, Joan E; Rioux, John D; Alarcón-Riquelme, Marta E; Vyse, Timothy J

2015-01-01

Systemic lupus erythematosus (SLE; OMIM 152700) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry: a new GWAS, meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including 10 novel associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n=16) of transcription factors among SLE susceptibility genes. This supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE. PMID:26502338

Defining the role of common variation in the genomic and biological architecture of adult human height.

PubMed

Wood, Andrew R; Esko, Tonu; Yang, Jian; Vedantam, Sailaja; Pers, Tune H; Gustafsson, Stefan; Chu, Audrey Y; Estrada, Karol; Luan, Jian'an; Kutalik, Zoltán; Amin, Najaf; Buchkovich, Martin L; Croteau-Chonka, Damien C; Day, Felix R; Duan, Yanan; Fall, Tove; Fehrmann, Rudolf; Ferreira, Teresa; Jackson, Anne U; Karjalainen, Juha; Lo, Ken Sin; Locke, Adam E; Mägi, Reedik; Mihailov, Evelin; Porcu, Eleonora; Randall, Joshua C; Scherag, André; Vinkhuyzen, Anna A E; Westra, Harm-Jan; Winkler, Thomas W; Workalemahu, Tsegaselassie; Zhao, Jing Hua; Absher, Devin; Albrecht, Eva; Anderson, Denise; Baron, Jeffrey; Beekman, Marian; Demirkan, Ayse; Ehret, Georg B; Feenstra, Bjarke; Feitosa, Mary F; Fischer, Krista; Fraser, Ross M; Goel, Anuj; Gong, Jian; Justice, Anne E; Kanoni, Stavroula; Kleber, Marcus E; Kristiansson, Kati; Lim, Unhee; Lotay, Vaneet; Lui, Julian C; Mangino, Massimo; Mateo Leach, Irene; Medina-Gomez, Carolina; Nalls, Michael A; Nyholt, Dale R; Palmer, Cameron D; Pasko, Dorota; Pechlivanis, Sonali; Prokopenko, Inga; Ried, Janina S; Ripke, Stephan; Shungin, Dmitry; Stancáková, Alena; Strawbridge, Rona J; Sung, Yun Ju; Tanaka, Toshiko; Teumer, Alexander; Trompet, Stella; van der Laan, Sander W; van Setten, Jessica; Van Vliet-Ostaptchouk, Jana V; Wang, Zhaoming; Yengo, Loïc; Zhang, Weihua; Afzal, Uzma; Arnlöv, Johan; Arscott, Gillian M; Bandinelli, Stefania; Barrett, Amy; Bellis, Claire; Bennett, Amanda J; Berne, Christian; Blüher, Matthias; Bolton, Jennifer L; Böttcher, Yvonne; Boyd, Heather A; Bruinenberg, Marcel; Buckley, Brendan M; Buyske, Steven; Caspersen, Ida H; Chines, Peter S; Clarke, Robert; Claudi-Boehm, Simone; Cooper, Matthew; Daw, E Warwick; De Jong, Pim A; Deelen, Joris; Delgado, Graciela; Denny, Josh C; Dhonukshe-Rutten, Rosalie; Dimitriou, Maria; Doney, Alex S F; Dörr, Marcus; Eklund, Niina; Eury, Elodie; Folkersen, Lasse; Garcia, Melissa E; Geller, Frank; Giedraitis, Vilmantas; Go, Alan S; Grallert, Harald; Grammer, Tanja B; Gräßler, Jürgen; Grönberg, Henrik; de Groot, Lisette C P G M; Groves, Christopher J; Haessler, Jeffrey; Hall, Per; Haller, Toomas; Hallmans, Goran; Hannemann, Anke; Hartman, Catharina A; Hassinen, Maija; Hayward, Caroline; Heard-Costa, Nancy L; Helmer, Quinta; Hemani, Gibran; Henders, Anjali K; Hillege, Hans L; Hlatky, Mark A; Hoffmann, Wolfgang; Hoffmann, Per; Holmen, Oddgeir; Houwing-Duistermaat, Jeanine J; Illig, Thomas; Isaacs, Aaron; James, Alan L; Jeff, Janina; Johansen, Berit; Johansson, Åsa; Jolley, Jennifer; Juliusdottir, Thorhildur; Junttila, Juhani; Kho, Abel N; Kinnunen, Leena; Klopp, Norman; Kocher, Thomas; Kratzer, Wolfgang; Lichtner, Peter; Lind, Lars; Lindström, Jaana; Lobbens, Stéphane; Lorentzon, Mattias; Lu, Yingchang; Lyssenko, Valeriya; Magnusson, Patrik K E; Mahajan, Anubha; Maillard, Marc; McArdle, Wendy L; McKenzie, Colin A; McLachlan, Stela; McLaren, Paul J; Menni, Cristina; Merger, Sigrun; Milani, Lili; Moayyeri, Alireza; Monda, Keri L; Morken, Mario A; Müller, Gabriele; Müller-Nurasyid, Martina; Musk, Arthur W; Narisu, Narisu; Nauck, Matthias; Nolte, Ilja M; Nöthen, Markus M; Oozageer, Laticia; Pilz, Stefan; Rayner, Nigel W; Renstrom, Frida; Robertson, Neil R; Rose, Lynda M; Roussel, Ronan; Sanna, Serena; Scharnagl, Hubert; Scholtens, Salome; Schumacher, Fredrick R; Schunkert, Heribert; Scott, Robert A; Sehmi, Joban; Seufferlein, Thomas; Shi, Jianxin; Silventoinen, Karri; Smit, Johannes H; Smith, Albert Vernon; Smolonska, Joanna; Stanton, Alice V; Stirrups, Kathleen; Stott, David J; Stringham, Heather M; Sundström, Johan; Swertz, Morris A; Syvänen, Ann-Christine; Tayo, Bamidele O; Thorleifsson, Gudmar; Tyrer, Jonathan P; van Dijk, Suzanne; van Schoor, Natasja M; van der Velde, Nathalie; van Heemst, Diana; van Oort, Floor V A; Vermeulen, Sita H; Verweij, Niek; Vonk, Judith M; Waite, Lindsay L; Waldenberger, Melanie; Wennauer, Roman; Wilkens, Lynne R; Willenborg, Christina; Wilsgaard, Tom; Wojczynski, Mary K; Wong, Andrew; Wright, Alan F; Zhang, Qunyuan; Arveiler, Dominique; Bakker, Stephan J L; Beilby, John; Bergman, Richard N; Bergmann, Sven; Biffar, Reiner; Blangero, John; Boomsma, Dorret I; Bornstein, Stefan R; Bovet, Pascal; Brambilla, Paolo; Brown, Morris J; Campbell, Harry; Caulfield, Mark J; Chakravarti, Aravinda; Collins, Rory; Collins, Francis S; Crawford, Dana C; Cupples, L Adrienne; Danesh, John; de Faire, Ulf; den Ruijter, Hester M; Erbel, Raimund; Erdmann, Jeanette; Eriksson, Johan G; Farrall, Martin; Ferrannini, Ele; Ferrières, Jean; Ford, Ian; Forouhi, Nita G; Forrester, Terrence; Gansevoort, Ron T; Gejman, Pablo V; Gieger, Christian; Golay, Alain; Gottesman, Omri; Gudnason, Vilmundur; Gyllensten, Ulf; Haas, David W; Hall, Alistair S; Harris, Tamara B; Hattersley, Andrew T; Heath, Andrew C; Hengstenberg, Christian; Hicks, Andrew A; Hindorff, Lucia A; Hingorani, Aroon D; Hofman, Albert; Hovingh, G Kees; Humphries, Steve E; Hunt, Steven C; Hypponen, Elina; Jacobs, Kevin B; Jarvelin, Marjo-Riitta; Jousilahti, Pekka; Jula, Antti M; Kaprio, Jaakko; Kastelein, John J P; Kayser, Manfred; Kee, Frank; Keinanen-Kiukaanniemi, Sirkka M; Kiemeney, Lambertus A; Kooner, Jaspal S; Kooperberg, Charles; Koskinen, Seppo; Kovacs, Peter; Kraja, Aldi T; Kumari, Meena; Kuusisto, Johanna; Lakka, Timo A; Langenberg, Claudia; Le Marchand, Loic; Lehtimäki, Terho; Lupoli, Sara; Madden, Pamela A F; Männistö, Satu; Manunta, Paolo; Marette, André; Matise, Tara C; McKnight, Barbara; Meitinger, Thomas; Moll, Frans L; Montgomery, Grant W; Morris, Andrew D; Morris, Andrew P; Murray, Jeffrey C; Nelis, Mari; Ohlsson, Claes; Oldehinkel, Albertine J; Ong, Ken K; Ouwehand, Willem H; Pasterkamp, Gerard; Peters, Annette; Pramstaller, Peter P; Price, Jackie F; Qi, Lu; Raitakari, Olli T; Rankinen, Tuomo; Rao, D C; Rice, Treva K; Ritchie, Marylyn; Rudan, Igor; Salomaa, Veikko; Samani, Nilesh J; Saramies, Jouko; Sarzynski, Mark A; Schwarz, Peter E H; Sebert, Sylvain; Sever, Peter; Shuldiner, Alan R; Sinisalo, Juha; Steinthorsdottir, Valgerdur; Stolk, Ronald P; Tardif, Jean-Claude; Tönjes, Anke; Tremblay, Angelo; Tremoli, Elena; Virtamo, Jarmo; Vohl, Marie-Claude; Amouyel, Philippe; Asselbergs, Folkert W; Assimes, Themistocles L; Bochud, Murielle; Boehm, Bernhard O; Boerwinkle, Eric; Bottinger, Erwin P; Bouchard, Claude; Cauchi, Stéphane; Chambers, John C; Chanock, Stephen J; Cooper, Richard S; de Bakker, Paul I W; Dedoussis, George; Ferrucci, Luigi; Franks, Paul W; Froguel, Philippe; Groop, Leif C; Haiman, Christopher A; Hamsten, Anders; Hayes, M Geoffrey; Hui, Jennie; Hunter, David J; Hveem, Kristian; Jukema, J Wouter; Kaplan, Robert C; Kivimaki, Mika; Kuh, Diana; Laakso, Markku; Liu, Yongmei; Martin, Nicholas G; März, Winfried; Melbye, Mads; Moebus, Susanne; Munroe, Patricia B; Njølstad, Inger; Oostra, Ben A; Palmer, Colin N A; Pedersen, Nancy L; Perola, Markus; Pérusse, Louis; Peters, Ulrike; Powell, Joseph E; Power, Chris; Quertermous, Thomas; Rauramaa, Rainer; Reinmaa, Eva; Ridker, Paul M; Rivadeneira, Fernando; Rotter, Jerome I; Saaristo, Timo E; Saleheen, Danish; Schlessinger, David; Slagboom, P Eline; Snieder, Harold; Spector, Tim D; Strauch, Konstantin; Stumvoll, Michael; Tuomilehto, Jaakko; Uusitupa, Matti; van der Harst, Pim; Völzke, Henry; Walker, Mark; Wareham, Nicholas J; Watkins, Hugh; Wichmann, H-Erich; Wilson, James F; Zanen, Pieter; Deloukas, Panos; Heid, Iris M; Lindgren, Cecilia M; Mohlke, Karen L; Speliotes, Elizabeth K; Thorsteinsdottir, Unnur; Barroso, Inês; Fox, Caroline S; North, Kari E; Strachan, David P; Beckmann, Jacques S; Berndt, Sonja I; Boehnke, Michael; Borecki, Ingrid B; McCarthy, Mark I; Metspalu, Andres; Stefansson, Kari; Uitterlinden, André G; van Duijn, Cornelia M; Franke, Lude; Willer, Cristen J; Price, Alkes L; Lettre, Guillaume; Loos, Ruth J F; Weedon, Michael N; Ingelsson, Erik; O'Connell, Jeffrey R; Abecasis, Goncalo R; Chasman, Daniel I; Goddard, Michael E; Visscher, Peter M; Hirschhorn, Joel N; Frayling, Timothy M

2014-11-01

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

Defining the role of common variation in the genomic and biological architecture of adult human height

PubMed Central

Chu, Audrey Y; Estrada, Karol; Luan, Jian’an; Kutalik, Zoltán; Amin, Najaf; Buchkovich, Martin L; Croteau-Chonka, Damien C; Day, Felix R; Duan, Yanan; Fall, Tove; Fehrmann, Rudolf; Ferreira, Teresa; Jackson, Anne U; Karjalainen, Juha; Lo, Ken Sin; Locke, Adam E; Mägi, Reedik; Mihailov, Evelin; Porcu, Eleonora; Randall, Joshua C; Scherag, André; Vinkhuyzen, Anna AE; Westra, Harm-Jan; Winkler, Thomas W; Workalemahu, Tsegaselassie; Zhao, Jing Hua; Absher, Devin; Albrecht, Eva; Anderson, Denise; Baron, Jeffrey; Beekman, Marian; Demirkan, Ayse; Ehret, Georg B; Feenstra, Bjarke; Feitosa, Mary F; Fischer, Krista; Fraser, Ross M; Goel, Anuj; Gong, Jian; Justice, Anne E; Kanoni, Stavroula; Kleber, Marcus E; Kristiansson, Kati; Lim, Unhee; Lotay, Vaneet; Lui, Julian C; Mangino, Massimo; Leach, Irene Mateo; Medina-Gomez, Carolina; Nalls, Michael A; Nyholt, Dale R; Palmer, Cameron D; Pasko, Dorota; Pechlivanis, Sonali; Prokopenko, Inga; Ried, Janina S; Ripke, Stephan; Shungin, Dmitry; Stancáková, Alena; Strawbridge, Rona J; Sung, Yun Ju; Tanaka, Toshiko; Teumer, Alexander; Trompet, Stella; van der Laan, Sander W; van Setten, Jessica; Van Vliet-Ostaptchouk, Jana V; Wang, Zhaoming; Yengo, Loïc; Zhang, Weihua; Afzal, Uzma; Ärnlöv, Johan; Arscott, Gillian M; Bandinelli, Stefania; Barrett, Amy; Bellis, Claire; Bennett, Amanda J; Berne, Christian; Blüher, Matthias; Bolton, Jennifer L; Böttcher, Yvonne; Boyd, Heather A; Bruinenberg, Marcel; Buckley, Brendan M; Buyske, Steven; Caspersen, Ida H; Chines, Peter S; Clarke, Robert; Claudi-Boehm, Simone; Cooper, Matthew; Daw, E Warwick; De Jong, Pim A; Deelen, Joris; Delgado, Graciela; Denny, Josh C; Dhonukshe-Rutten, Rosalie; Dimitriou, Maria; Doney, Alex SF; Dörr, Marcus; Eklund, Niina; Eury, Elodie; Folkersen, Lasse; Garcia, Melissa E; Geller, Frank; Giedraitis, Vilmantas; Go, Alan S; Grallert, Harald; Grammer, Tanja B; Gräßler, Jürgen; Grönberg, Henrik; de Groot, Lisette C.P.G.M.; Groves, Christopher J; Haessler, Jeffrey; Hall, Per; Haller, Toomas; Hallmans, Goran; Hannemann, Anke; Hartman, Catharina A; Hassinen, Maija; Hayward, Caroline; Heard-Costa, Nancy L; Helmer, Quinta; Hemani, Gibran; Henders, Anjali K; Hillege, Hans L; Hlatky, Mark A; Hoffmann, Wolfgang; Hoffmann, Per; Holmen, Oddgeir; Houwing-Duistermaat, Jeanine J; Illig, Thomas; Isaacs, Aaron; James, Alan L; Jeff, Janina; Johansen, Berit; Johansson, Åsa; Jolley, Jennifer; Juliusdottir, Thorhildur; Junttila, Juhani; Kho, Abel N; Kinnunen, Leena; Klopp, Norman; Kocher, Thomas; Kratzer, Wolfgang; Lichtner, Peter; Lind, Lars; Lindström, Jaana; Lobbens, Stéphane; Lorentzon, Mattias; Lu, Yingchang; Lyssenko, Valeriya; Magnusson, Patrik KE; Mahajan, Anubha; Maillard, Marc; McArdle, Wendy L; McKenzie, Colin A; McLachlan, Stela; McLaren, Paul J; Menni, Cristina; Merger, Sigrun; Milani, Lili; Moayyeri, Alireza; Monda, Keri L; Morken, Mario A; Müller, Gabriele; Müller-Nurasyid, Martina; Musk, Arthur W; Narisu, Narisu; Nauck, Matthias; Nolte, Ilja M; Nöthen, Markus M; Oozageer, Laticia; Pilz, Stefan; Rayner, Nigel W; Renstrom, Frida; Robertson, Neil R; Rose, Lynda M; Roussel, Ronan; Sanna, Serena; Scharnagl, Hubert; Scholtens, Salome; Schumacher, Fredrick R; Schunkert, Heribert; Scott, Robert A; Sehmi, Joban; Seufferlein, Thomas; Shi, Jianxin; Silventoinen, Karri; Smit, Johannes H; Smith, Albert Vernon; Smolonska, Joanna; Stanton, Alice V; Stirrups, Kathleen; Stott, David J; Stringham, Heather M; Sundström, Johan; Swertz, Morris A; Syvänen, Ann-Christine; Tayo, Bamidele O; Thorleifsson, Gudmar; Tyrer, Jonathan P; van Dijk, Suzanne; van Schoor, Natasja M; van der Velde, Nathalie; van Heemst, Diana; van Oort, Floor VA; Vermeulen, Sita H; Verweij, Niek; Vonk, Judith M; Waite, Lindsay L; Waldenberger, Melanie; Wennauer, Roman; Wilkens, Lynne R; Willenborg, Christina; Wilsgaard, Tom; Wojczynski, Mary K; Wong, Andrew; Wright, Alan F; Zhang, Qunyuan; Arveiler, Dominique; Bakker, Stephan JL; Beilby, John; Bergman, Richard N; Bergmann, Sven; Biffar, Reiner; Blangero, John; Boomsma, Dorret I; Bornstein, Stefan R; Bovet, Pascal; Brambilla, Paolo; Brown, Morris J; Campbell, Harry; Caulfield, Mark J; Chakravarti, Aravinda; Collins, Rory; Collins, Francis S; Crawford, Dana C; Cupples, L Adrienne; Danesh, John; de Faire, Ulf; den Ruijter, Hester M; Erbel, Raimund; Erdmann, Jeanette; Eriksson, Johan G; Farrall, Martin; Ferrannini, Ele; Ferrières, Jean; Ford, Ian; Forouhi, Nita G; Forrester, Terrence; Gansevoort, Ron T; Gejman, Pablo V; Gieger, Christian; Golay, Alain; Gottesman, Omri; Gudnason, Vilmundur; Gyllensten, Ulf; Haas, David W; Hall, Alistair S; Harris, Tamara B; Hattersley, Andrew T; Heath, Andrew C; Hengstenberg, Christian; Hicks, Andrew A; Hindorff, Lucia A; Hingorani, Aroon D; Hofman, Albert; Hovingh, G Kees; Humphries, Steve E; Hunt, Steven C; Hypponen, Elina; Jacobs, Kevin B; Jarvelin, Marjo-Riitta; Jousilahti, Pekka; Jula, Antti M; Kaprio, Jaakko; Kastelein, John JP; Kayser, Manfred; Kee, Frank; Keinanen-Kiukaanniemi, Sirkka M; Kiemeney, Lambertus A; Kooner, Jaspal S; Kooperberg, Charles; Koskinen, Seppo; Kovacs, Peter; Kraja, Aldi T; Kumari, Meena; Kuusisto, Johanna; Lakka, Timo A; Langenberg, Claudia; Le Marchand, Loic; Lehtimäki, Terho; Lupoli, Sara; Madden, Pamela AF; Männistö, Satu; Manunta, Paolo; Marette, André; Matise, Tara C; McKnight, Barbara; Meitinger, Thomas; Moll, Frans L; Montgomery, Grant W; Morris, Andrew D; Morris, Andrew P; Murray, Jeffrey C; Nelis, Mari; Ohlsson, Claes; Oldehinkel, Albertine J; Ong, Ken K; Ouwehand, Willem H; Pasterkamp, Gerard; Peters, Annette; Pramstaller, Peter P; Price, Jackie F; Qi, Lu; Raitakari, Olli T; Rankinen, Tuomo; Rao, DC; Rice, Treva K; Ritchie, Marylyn; Rudan, Igor; Salomaa, Veikko; Samani, Nilesh J; Saramies, Jouko; Sarzynski, Mark A; Schwarz, Peter EH; Sebert, Sylvain; Sever, Peter; Shuldiner, Alan R; Sinisalo, Juha; Steinthorsdottir, Valgerdur; Stolk, Ronald P; Tardif, Jean-Claude; Tönjes, Anke; Tremblay, Angelo; Tremoli, Elena; Virtamo, Jarmo; Vohl, Marie-Claude; Amouyel, Philippe; Asselbergs, Folkert W; Assimes, Themistocles L; Bochud, Murielle; Boehm, Bernhard O; Boerwinkle, Eric; Bottinger, Erwin P; Bouchard, Claude; Cauchi, Stéphane; Chambers, John C; Chanock, Stephen J; Cooper, Richard S; de Bakker, Paul IW; Dedoussis, George; Ferrucci, Luigi; Franks, Paul W; Froguel, Philippe; Groop, Leif C; Haiman, Christopher A; Hamsten, Anders; Hayes, M Geoffrey; Hui, Jennie; Hunter, David J.; Hveem, Kristian; Jukema, J Wouter; Kaplan, Robert C; Kivimaki, Mika; Kuh, Diana; Laakso, Markku; Liu, Yongmei; Martin, Nicholas G; März, Winfried; Melbye, Mads; Moebus, Susanne; Munroe, Patricia B; Njølstad, Inger; Oostra, Ben A; Palmer, Colin NA; Pedersen, Nancy L; Perola, Markus; Pérusse, Louis; Peters, Ulrike; Powell, Joseph E; Power, Chris; Quertermous, Thomas; Rauramaa, Rainer; Reinmaa, Eva; Ridker, Paul M; Rivadeneira, Fernando; Rotter, Jerome I; Saaristo, Timo E; Saleheen, Danish; Schlessinger, David; Slagboom, P Eline; Snieder, Harold; Spector, Tim D; Strauch, Konstantin; Stumvoll, Michael; Tuomilehto, Jaakko; Uusitupa, Matti; van der Harst, Pim; Völzke, Henry; Walker, Mark; Wareham, Nicholas J; Watkins, Hugh; Wichmann, H-Erich; Wilson, James F; Zanen, Pieter; Deloukas, Panos; Heid, Iris M; Lindgren, Cecilia M; Mohlke, Karen L; Speliotes, Elizabeth K; Thorsteinsdottir, Unnur; Barroso, Inês; Fox, Caroline S; North, Kari E; Strachan, David P; Beckmann, Jacques S.; Berndt, Sonja I; Boehnke, Michael; Borecki, Ingrid B; McCarthy, Mark I; Metspalu, Andres; Stefansson, Kari; Uitterlinden, André G; van Duijn, Cornelia M; Franke, Lude; Willer, Cristen J; Price, Alkes L.; Lettre, Guillaume; Loos, Ruth JF; Weedon, Michael N; Ingelsson, Erik; O’Connell, Jeffrey R; Abecasis, Goncalo R; Chasman, Daniel I; Goddard, Michael E

2014-01-01

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explain one-fifth of heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ~2,000, ~3,700 and ~9,500 SNPs explained ~21%, ~24% and ~29% of phenotypic variance. Furthermore, all common variants together captured the majority (60%) of heritability. The 697 variants clustered in 423 loci enriched for genes, pathways, and tissue-types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin, and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants. PMID:25282103

Insights into DDT Resistance from the Drosophila melanogaster Genetic Reference Panel.

PubMed

Schmidt, Joshua M; Battlay, Paul; Gledhill-Smith, Rebecca S; Good, Robert T; Lumb, Chris; Fournier-Level, Alexandre; Robin, Charles

2017-11-01

Insecticide resistance is considered a classic model of microevolution, where a strong selective agent is applied to a large natural population, resulting in a change in frequency of alleles that confer resistance. While many insecticide resistance variants have been characterized at the gene level, they are typically single genes of large effect identified in highly resistant pest species. In contrast, multiple variants have been implicated in DDT resistance in Drosophila melanogaster ; however, only the Cyp6g1 locus has previously been shown to be relevant to field populations. Here we use genome-wide association studies (GWAS) to identify DDT-associated polygenes and use selective sweep analyses to assess their adaptive significance. We identify and verify two candidate DDT resistance loci. A largely uncharacterized gene, CG10737 , has a function in muscles that ameliorates the effects of DDT, while a putative detoxifying P450, Cyp6w1 , shows compelling evidence of positive selection. Copyright © 2017 by the Genetics Society of America.

Identification of seven new prostate cancer susceptibility loci through a genome-wide association study.

PubMed

Eeles, Rosalind A; Kote-Jarai, Zsofia; Al Olama, Ali Amin; Giles, Graham G; Guy, Michelle; Severi, Gianluca; Muir, Kenneth; Hopper, John L; Henderson, Brian E; Haiman, Christopher A; Schleutker, Johanna; Hamdy, Freddie C; Neal, David E; Donovan, Jenny L; Stanford, Janet L; Ostrander, Elaine A; Ingles, Sue A; John, Esther M; Thibodeau, Stephen N; Schaid, Daniel; Park, Jong Y; Spurdle, Amanda; Clements, Judith; Dickinson, Joanne L; Maier, Christiane; Vogel, Walther; Dörk, Thilo; Rebbeck, Timothy R; Cooney, Kathleen A; Cannon-Albright, Lisa; Chappuis, Pierre O; Hutter, Pierre; Zeegers, Maurice; Kaneva, Radka; Zhang, Hong-Wei; Lu, Yong-Jie; Foulkes, William D; English, Dallas R; Leongamornlert, Daniel A; Tymrakiewicz, Malgorzata; Morrison, Jonathan; Ardern-Jones, Audrey T; Hall, Amanda L; O'Brien, Lynne T; Wilkinson, Rosemary A; Saunders, Edward J; Page, Elizabeth C; Sawyer, Emma J; Edwards, Stephen M; Dearnaley, David P; Horwich, Alan; Huddart, Robert A; Khoo, Vincent S; Parker, Christopher C; Van As, Nicholas; Woodhouse, Christopher J; Thompson, Alan; Christmas, Tim; Ogden, Chris; Cooper, Colin S; Southey, Melissa C; Lophatananon, Artitaya; Liu, Jo-Fen; Kolonel, Laurence N; Le Marchand, Loic; Wahlfors, Tiina; Tammela, Teuvo L; Auvinen, Anssi; Lewis, Sarah J; Cox, Angela; FitzGerald, Liesel M; Koopmeiners, Joseph S; Karyadi, Danielle M; Kwon, Erika M; Stern, Mariana C; Corral, Roman; Joshi, Amit D; Shahabi, Ahva; McDonnell, Shannon K; Sellers, Thomas A; Pow-Sang, Julio; Chambers, Suzanne; Aitken, Joanne; Gardiner, R A Frank; Batra, Jyotsna; Kedda, Mary Anne; Lose, Felicity; Polanowski, Andrea; Patterson, Briony; Serth, Jürgen; Meyer, Andreas; Luedeke, Manuel; Stefflova, Klara; Ray, Anna M; Lange, Ethan M; Farnham, Jim; Khan, Humera; Slavov, Chavdar; Mitkova, Atanaska; Cao, Guangwen; Easton, Douglas F

2009-10-01

Prostate cancer (PrCa) is the most frequently diagnosed cancer in males in developed countries. To identify common PrCa susceptibility alleles, we previously conducted a genome-wide association study in which 541,129 SNPs were genotyped in 1,854 PrCa cases with clinically detected disease and in 1,894 controls. We have now extended the study to evaluate promising associations in a second stage in which we genotyped 43,671 SNPs in 3,650 PrCa cases and 3,940 controls and in a third stage involving an additional 16,229 cases and 14,821 controls from 21 studies. In addition to replicating previous associations, we identified seven new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11 and 22 (with P = 1.6 x 10(-8) to P = 2.7 x 10(-33)).

Rapid adaptation to climate change.

PubMed

Hancock, Angela M

2016-08-01

In recent years, amid growing concerns that changing climate is affecting species distributions and ecosystems, predicting responses to rapid environmental change has become a major goal. In this issue, Franks and colleagues take a first step towards this objective (Franks et al. 2016). They examine genomewide signatures of selection in populations of Brassica rapa after a severe multiyear drought. Together with other authors, Franks had previously shown that flowering time was reduced after this particular drought and that the reduction was genetically encoded. Now, the authors have sequenced previously stored samples to compare allele frequencies before and after the drought and identify the loci with the most extreme shifts in frequencies. The loci they identify largely differ between populations, suggesting that different genetic variants may be responsible for reduction in flowering time in the two populations. © 2016 John Wiley & Sons Ltd.

Epistasis between QTLs for bone density variation in Copenhagen × dark agouti F2 rats

PubMed Central

Liu, Lixiang; Alam, Imranul; Sun, Qiwei; Econs, Michael J.; Foroud, Tatiana; Turner, Charles H.

2010-01-01

The variation in several of the risk factors for osteoporotic fracture, including bone mineral density (BMD), has been shown to be strongly influenced by genetic differences. However, the genetic architecture of BMD is complex in both humans and in model organisms. We previously reported quantitative trait locus (QTL) results for BMD from a genome screen of 828 F2 progeny of Copenhagen and dark agouti rats. These progeny also provide an excellent opportunity to search for epistatic effects, or interaction between genetic loci, that contribute to fracture risk. Microsatellite marker data from a 20-cM genome screen was analyzed along with weight-adjusted bone density (DXA and pQCT) phenotypic data using the R/qtl software package. Genotype and phenotype data were permuted to determine genome-wide significance thresholds for the full model and epistasis (interaction) LOD scores corresponding to an alpha level of 0.01. A novel locus on chromosome 15 and a previously reported chromosome 14 QTL demonstrated a strong epistatic effect on BMD at the femur by DXA (LOD = 5.4). Two novel QTLs on chromosomes 2 and 12 were found to interact to affect total BMD at the femur midshaft by pQCT (LOD = 5.0). These results provide new information regarding the mode of action of previously identified QTL in the rat, as well as identifying novel loci that act in combination with known QTL or with other novel loci to contribute to BMD variation. PMID:19153792

Epistasis between QTLs for bone density variation in Copenhagen x dark agouti F2 rats.

PubMed

Koller, Daniel L; Liu, Lixiang; Alam, Imranul; Sun, Qiwei; Econs, Michael J; Foroud, Tatiana; Turner, Charles H

2009-03-01

The variation in several of the risk factors for osteoporotic fracture, including bone mineral density (BMD), has been shown to be strongly influenced by genetic differences. However, the genetic architecture of BMD is complex in both humans and in model organisms. We previously reported quantitative trait locus (QTL) results for BMD from a genome screen of 828 F2 progeny of Copenhagen and dark agouti rats. These progeny also provide an excellent opportunity to search for epistatic effects, or interaction between genetic loci, that contribute to fracture risk. Microsatellite marker data from a 20-cM genome screen was analyzed along with weight-adjusted bone density (DXA and pQCT) phenotypic data using the R/qtl software package. Genotype and phenotype data were permuted to determine genome-wide significance thresholds for the full model and epistasis (interaction) LOD scores corresponding to an alpha level of 0.01. A novel locus on chromosome 15 and a previously reported chromosome 14 QTL demonstrated a strong epistatic effect on BMD at the femur by DXA (LOD = 5.4). Two novel QTLs on chromosomes 2 and 12 were found to interact to affect total BMD at the femur midshaft by pQCT (LOD = 5.0). These results provide new information regarding the mode of action of previously identified QTL in the rat, as well as identifying novel loci that act in combination with known QTL or with other novel loci to contribute to BMD variation.

Characterization of Novel Sorghum brown midrib Mutants from an EMS-Mutagenized Population

PubMed Central

Sattler, Scott E.; Saballos, Ana; Xin, Zhanguo; Funnell-Harris, Deanna L.; Vermerris, Wilfred; Pedersen, Jeffrey F.

2014-01-01

Reducing lignin concentration in lignocellulosic biomass can increase forage digestibility for ruminant livestock and saccharification yields of biomass for bioenergy. In sorghum (Sorghum bicolor (L.) Moench) and several other C4 grasses, brown midrib (bmr) mutants have been shown to reduce lignin concentration. Putative bmr mutants isolated from an EMS-mutagenized population were characterized and classified based on their leaf midrib phenotype and allelism tests with the previously described sorghum bmr mutants bmr2, bmr6, and bmr12. These tests resulted in the identification of additional alleles of bmr2, bmr6, and bmr12, and, in addition, six bmr mutants were identified that were not allelic to these previously described loci. Further allelism testing among these six bmr mutants showed that they represented four novel bmr loci. Based on this study, the number of bmr loci uncovered in sorghum has doubled. The impact of these lines on agronomic traits and lignocellulosic composition was assessed in a 2-yr field study. Overall, most of the identified bmr lines showed reduced lignin concentration of their biomass relative to wild-type (WT). Effects of the six new bmr mutants on enzymatic saccharification of lignocellulosic materials were determined, but the amount of glucose released from the stover was similar to WT in all cases. Like bmr2, bmr6, and bmr12, these mutants may affect monolignol biosynthesis and may be useful for bioenergy and forage improvement when stacked together or in combination with the three previously described bmr alleles. PMID:25187038

Genome-wide association studies identify genetic loci for low von Willebrand factor levels

PubMed Central

van Loon, Janine; Dehghan, Abbas; Weihong, Tang; Trompet, Stella; McArdle, Wendy L; Asselbergs, Folkert F W; Chen, Ming-Huei; Lopez, Lorna M; Huffman, Jennifer E; Leebeek, Frank W G; Basu, Saonli; Stott, David J; Rumley, Ann; Gansevoort, Ron T; Davies, Gail; Wilson, James J F; Witteman, Jacqueline C M; Cao, Xiting; de Craen, Anton J M; Bakker, Stephan J L; Psaty, Bruce M; Starr, John M; Hofman, Albert; Wouter Jukema, J; Deary, Ian J; Hayward, Caroline; van der Harst, Pim; Lowe, Gordon D O; Folsom, Aaron R; Strachan, David P; Smith, Nicolas; de Maat, Moniek P M; O'Donnell, Christopher

2016-01-01

Low von Willebrand factor (VWF) levels are associated with bleeding symptoms and are a diagnostic criterion for von Willebrand disease, the most common inherited bleeding disorder. To date, it is unclear which genetic loci are associated with reduced VWF levels. Therefore, we conducted a meta-analysis of genome-wide association studies to identify genetic loci associated with low VWF levels. For this meta-analysis, we included 31 149 participants of European ancestry from 11 community-based studies. From all participants, VWF antigen (VWF:Ag) measurements and genome-wide single-nucleotide polymorphism (SNP) scans were available. Each study conducted analyses using logistic regression of SNPs on dichotomized VWF:Ag measures (lowest 5% for blood group O and non-O) with an additive genetic model adjusted for age and sex. An inverse-variance weighted meta-analysis was performed for VWF:Ag levels. A total of 97 SNPs exceeded the genome-wide significance threshold of 5 × 10−8 and comprised five loci on four different chromosomes: 6q24 (smallest P-value 5.8 × 10−10), 9q34 (2.4 × 10−64), 12p13 (5.3 × 10−22), 12q23 (1.2 × 10−8) and 13q13 (2.6 × 10−8). All loci were within or close to genes, including STXBP5 (Syntaxin Binding Protein 5) (6q24), STAB5 (stabilin-5) (12q23), ABO (9q34), VWF (12p13) and UFM1 (ubiquitin-fold modifier 1) (13q13). Of these, UFM1 has not been previously associated with VWF:Ag levels. Four genes that were previously associated with VWF levels (VWF, ABO, STXBP5 and STAB2) were also associated with low VWF levels, and, in addition, we identified a new gene, UFM1, that is associated with low VWF levels. These findings point to novel mechanisms for the occurrence of low VWF levels. PMID:26486471

iLOCi: a SNP interaction prioritization technique for detecting epistasis in genome-wide association studies

PubMed Central

2012-01-01

Background Genome-wide association studies (GWAS) do not provide a full account of the heritability of genetic diseases since gene-gene interactions, also known as epistasis are not considered in single locus GWAS. To address this problem, a considerable number of methods have been developed for identifying disease-associated gene-gene interactions. However, these methods typically fail to identify interacting markers explaining more of the disease heritability over single locus GWAS, since many of the interactions significant for disease are obscured by uninformative marker interactions e.g., linkage disequilibrium (LD). Results In this study, we present a novel SNP interaction prioritization algorithm, named iLOCi (Interacting Loci). This algorithm accounts for marker dependencies separately in case and control groups. Disease-associated interactions are then prioritized according to a novel ranking score calculated from the difference in marker dependencies for every possible pair between case and control groups. The analysis of a typical GWAS dataset can be completed in less than a day on a standard workstation with parallel processing capability. The proposed framework was validated using simulated data and applied to real GWAS datasets using the Wellcome Trust Case Control Consortium (WTCCC) data. The results from simulated data showed the ability of iLOCi to identify various types of gene-gene interactions, especially for high-order interaction. From the WTCCC data, we found that among the top ranked interacting SNP pairs, several mapped to genes previously known to be associated with disease, and interestingly, other previously unreported genes with biologically related roles. Conclusion iLOCi is a powerful tool for uncovering true disease interacting markers and thus can provide a more complete understanding of the genetic basis underlying complex disease. The program is available for download at http://www4a.biotec.or.th/GI/tools/iloci. PMID:23281813

Genome-wide association analysis in primary sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4.

PubMed

Ellinghaus, David; Folseraas, Trine; Holm, Kristian; Ellinghaus, Eva; Melum, Espen; Balschun, Tobias; Laerdahl, Jon K; Shiryaev, Alexey; Gotthardt, Daniel N; Weismüller, Tobias J; Schramm, Christoph; Wittig, Michael; Bergquist, Annika; Björnsson, Einar; Marschall, Hanns-Ulrich; Vatn, Morten; Teufel, Andreas; Rust, Christian; Gieger, Christian; Wichmann, H-Erich; Runz, Heiko; Sterneck, Martina; Rupp, Christian; Braun, Felix; Weersma, Rinse K; Wijmenga, Cisca; Ponsioen, Cyriel Y; Mathew, Christopher G; Rutgeerts, Paul; Vermeire, Séverine; Schrumpf, Erik; Hov, Johannes R; Manns, Michael P; Boberg, Kirsten M; Schreiber, Stefan; Franke, Andre; Karlsen, Tom H

2013-09-01

Approximately 60%-80% of patients with primary sclerosing cholangitis (PSC) have concurrent ulcerative colitis (UC). Previous genome-wide association studies (GWAS) in PSC have detected a number of susceptibility loci that also show associations in UC and other immune-mediated diseases. We aimed to systematically compare genetic associations in PSC with genotype data in UC patients with the aim of detecting new susceptibility loci for PSC. We performed combined analyses of GWAS for PSC and UC comprising 392 PSC cases, 987 UC cases, and 2,977 controls and followed up top association signals in an additional 1,012 PSC cases, 4,444 UC cases, and 11,659 controls. We discovered novel genome-wide significant associations with PSC at 2q37 [rs3749171 at G-protein-coupled receptor 35 (GPR35); P = 3.0 × 10(-9) in the overall study population, combined odds ratio [OR] and 95% confidence interval [CI] of 1.39 (1.24-1.55)] and at 18q21 [rs1452787 at transcription factor 4 (TCF4); P = 2.61 × 10(-8) , OR (95% CI) = 0.75 (0.68-0.83)]. In addition, several suggestive PSC associations were detected. The GPR35 rs3749171 is a missense single nucleotide polymorphism resulting in a shift from threonine to methionine. Structural modeling showed that rs3749171 is located in the third transmembrane helix of GPR35 and could possibly alter efficiency of signaling through the GPR35 receptor. By refining the analysis of a PSC GWAS by parallel assessments in a UC GWAS, we were able to detect two novel risk loci at genome-wide significance levels. GPR35 shows associations in both UC and PSC, whereas TCF4 represents a PSC risk locus not associated with UC. Both loci may represent previously unexplored aspects of PSC pathogenesis. Copyright © 2012 American Association for the Study of Liver Diseases.

Convergence of GWA and candidate gene studies for alcoholism

PubMed Central

Olfson, Emily; Bierut, Laura Jean

2012-01-01

Background Genome-wide association (GWA) studies have led to a paradigm shift in how researchers study the genetics underlying disease. Many GWA studies are now publicly available and can be used to examine whether or not previously proposed candidate genes are supported by GWA data. This approach is particularly important for the field of alcoholism because the contribution of many candidate genes remains controversial. Methods Using the Human Genome Epidemiology (HuGE) Navigator, we selected candidate genes for alcoholism that have been frequently examined in scientific articles in the past decade. Specific candidate loci as well as all the reported SNPs in candidate genes were examined in the Study of Alcohol Addiction: Genetics and Addiction (SAGE), a GWA study comparing alcohol dependent and non-dependent subjects. Results Several commonly reported candidate loci, including rs1800497 in DRD2, rs698 in ADH1C, rs1799971 in OPRM1 and rs4680 in COMT, are not replicated in SAGE (p> .05). Among candidate loci available for analysis, only rs279858 in GABRA2 (p=0.0052, OR=1.16) demonstrated a modest association. Examination of all SNPs reported in SAGE in over 50 candidate genes revealed no SNPs with large frequency differences between cases and controls and the lowest p value of any SNP was .0006. Discussion We provide evidence that several extensively studied candidate loci do not have a strong contribution to risk of developing alcohol dependence in European and African Ancestry populations. Due to lack of coverage, we were unable to rule out the contribution of other variants and these genes and particular loci warrant further investigation. Our analysis demonstrates that publicly available GWA results can be used to better understand which if any of previously proposed candidate genes contribute to disease. Furthermore, we illustrate how examining the convergence of candidate gene and GWA studies can help elucidate the genetic architecture of alcoholism and more generally complex diseases. PMID:22978509

The MC1R and ASIP Coat Color Loci May Impact Behavior in the Horse

PubMed Central

Jacobs, Lauren N.; Staiger, Elizabeth A.; Albright, Julia D.

2016-01-01

Shared signaling pathways utilized by melanocytes and neurons result in pleiotropic traits of coat color and behavior in many mammalian species. For example, in humans polymorphisms at MC1R cause red hair, increased heat sensitivity, and lower pain tolerance. In deer mice, rats, and foxes, ASIP polymorphisms causing black coat color lead to more docile demeanors and reduced activity. Horse (Equus caballus) base coat color is primarily determined by polymorphisms at the Melanocortin-1 Receptor (MC1R) and Agouti Signaling Protein (ASIP) loci, creating a black, bay, or chestnut coat. Our goal was to investigate correlations between genetic loci for coat color and temperament traits in the horse. We genotyped a total of 215 North American Tennessee Walking Horses for the 2 most common alleles at the MC1R (E/e) and ASIP (A/a) loci using previously published PCR and RFLP methods. The horses had a mean age of 10.5 years and comprised 83 geldings, 25 stallions, and 107 mares. To assess behavior, we adapted a previously published survey for handlers to score horses from 1 to 9 on 20 questions related to specific aspects of temperament. We utilized principle component analysis to combine the individual survey scores into 4 factors of variation in temperament phenotype. A factor component detailing self-reliance correlated with genotypes at the ASIP locus; black mares (aa) were more independent than bay mares (A_) (P = 0.0063). These findings illuminate a promising and novel animal model for future study of neuroendocrine mechanisms in complex behavioral phenotypes. PMID:26884605

Trans-ethnic meta-analysis of white blood cell phenotypes

PubMed Central

Keller, Margaux F.; Reiner, Alexander P.; Okada, Yukinori; van Rooij, Frank J.A.; Johnson, Andrew D.; Chen, Ming-Huei; Smith, Albert V.; Morris, Andrew P.; Tanaka, Toshiko; Ferrucci, Luigi; Zonderman, Alan B.; Lettre, Guillaume; Harris, Tamara; Garcia, Melissa; Bandinelli, Stefania; Qayyum, Rehan; Yanek, Lisa R.; Becker, Diane M.; Becker, Lewis C.; Kooperberg, Charles; Keating, Brendan; Reis, Jared; Tang, Hua; Boerwinkle, Eric; Kamatani, Yoichiro; Matsuda, Koichi; Kamatani, Naoyuki; Nakamura, Yusuke; Kubo, Michiaki; Liu, Simin; Dehghan, Abbas; Felix, Janine F.; Hofman, Albert; Uitterlinden, André G.; van Duijn, Cornelia M.; Franco, Oscar H.; Longo, Dan L.; Singleton, Andrew B.; Psaty, Bruce M.; Evans, Michelle K.; Cupples, L. Adrienne; Rotter, Jerome I.; O'Donnell, Christopher J.; Takahashi, Atsushi; Wilson, James G.; Ganesh, Santhi K.; Nalls, Mike A.

2014-01-01

White blood cell (WBC) count is a common clinical measure used as a predictor of certain aspects of human health, including immunity and infection status. WBC count is also a complex trait that varies among individuals and ancestry groups. Differences in linkage disequilibrium structure and heterogeneity in allelic effects are expected to play a role in the associations observed between populations. Prior genome-wide association study (GWAS) meta-analyses have identified genomic loci associated with WBC and its subtypes, but much of the heritability of these phenotypes remains unexplained. Using GWAS summary statistics for over 50 000 individuals from three diverse populations (Japanese, African-American and European ancestry), a Bayesian model methodology was employed to account for heterogeneity between ancestry groups. This approach was used to perform a trans-ethnic meta-analysis of total WBC, neutrophil and monocyte counts. Ten previously known associations were replicated and six new loci were identified, including several regions harboring genes related to inflammation and immune cell function. Ninety-five percent credible interval regions were calculated to narrow the association signals and fine-map the putatively causal variants within loci. Finally, a conditional analysis was performed on the most significant SNPs identified by the trans-ethnic meta-analysis (MA), and nine secondary signals within loci previously associated with WBC or its subtypes were identified. This work illustrates the potential of trans-ethnic analysis and ascribes a critical role to multi-ethnic cohorts and consortia in exploring complex phenotypes with respect to variants that lie outside the European-biased GWAS pool. PMID:25096241

A comprehensive examination of breast cancer risk loci in African American women

PubMed Central

Feng, Ye; Stram, Daniel O.; Rhie, Suhn Kyong; Millikan, Robert C.; Ambrosone, Christine B.; John, Esther M.; Bernstein, Leslie; Zheng, Wei; Olshan, Andrew F.; Hu, Jennifer J.; Ziegler, Regina G.; Nyante, Sarah; Bandera, Elisa V.; Ingles, Sue A.; Press, Michael F.; Deming, Sandra L.; Rodriguez-Gil, Jorge L.; Palmer, Julie R.; Olopade, Olufunmilayo I.; Huo, Dezheng; Adebamowo, Clement A.; Ogundiran, Temidayo; Chen, Gary K.; Stram, Alex; Park, Karen; Rand, Kristin A.; Chanock, Stephen J.; Le Marchand, Loic; Kolonel, Laurence N.; Conti, David V.; Easton, Douglas; Henderson, Brian E.; Haiman, Christopher A.

2014-01-01

Genome-wide association studies have identified 73 breast cancer risk variants mainly in European populations. Given considerable differences in linkage disequilibrium structure between populations of European and African ancestry, the known risk variants may not be informative for risk in African ancestry populations. In a previous fine-mapping investigation of 19 breast cancer loci, we were able to identify SNPs in four regions that better captured risk associations in African American women. In this study of breast cancer in African American women (3016 cases, 2745 controls), we tested an additional 54 novel breast cancer risk variants. Thirty-eight variants (70%) were found to have an association with breast cancer in the same direction as previously reported, with eight (15%) replicating at P < 0.05. Through fine-mapping, in three regions (1q32, 3p24, 10q25), we identified variants that better captured associations with overall breast cancer or estrogen receptor positive disease. We also observed suggestive associations with variants (at P < 5 × 10−6) in three separate regions (6q25, 14q13, 22q12) that may represent novel risk variants. Directional consistency of association observed for ∼65–70% of currently known genetic variants for breast cancer in women of African ancestry implies a shared functional common variant at most loci. To validate and enhance the spectrum of alleles that define associations at the known breast cancer risk loci, as well as genome-wide, will require even larger collaborative efforts in women of African ancestry. PMID:24852375

The complexity of selection at the major primate beta-defensin locus.

PubMed

Semple, Colin A M; Maxwell, Alison; Gautier, Philippe; Kilanowski, Fiona M; Eastwood, Hayden; Barran, Perdita E; Dorin, Julia R

2005-05-18

We have examined the evolution of the genes at the major human beta-defensin locus and the orthologous loci in a range of other primates and mouse. For the first time these data allow us to examine selective episodes in the more recent evolutionary history of this locus as well as the ancient past. We have used a combination of maximum likelihood based tests and a maximum parsimony based sliding window approach to give a detailed view of the varying modes of selection operating at this locus. We provide evidence for strong positive selection soon after the duplication of these genes within an ancestral mammalian genome. Consequently variable selective pressures have acted on beta-defensin genes in different evolutionary lineages, with episodes both of negative, and more rarely positive selection, during the divergence of primates. Positive selection appears to have been more common in the rodent lineage, accompanying the birth of novel, rodent-specific beta-defensin genes. These observations allow a fuller understanding of the evolution of mammalian innate immunity. In both the rodent and primate lineages, sites in the second exon have been subject to positive selection and by implication are important in functional diversity. A small number of sites in the mature human peptides were found to have undergone repeated episodes of selection in different primate lineages. Particular sites were consistently implicated by multiple methods at positions throughout the mature peptides. These sites are clustered at positions predicted to be important for the specificity of the antimicrobial or chemoattractant properties of beta-defensins. Surprisingly, sites within the prepropeptide region were also implicated as being subject to significant positive selection, suggesting previously unappreciated functional significance for this region. Identification of these putatively functional sites has important implications for our understanding of beta-defensin function and for novel antibiotic design.

Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types.

PubMed

Kar, Siddhartha P; Beesley, Jonathan; Amin Al Olama, Ali; Michailidou, Kyriaki; Tyrer, Jonathan; Kote-Jarai, ZSofia; Lawrenson, Kate; Lindstrom, Sara; Ramus, Susan J; Thompson, Deborah J; Kibel, Adam S; Dansonka-Mieszkowska, Agnieszka; Michael, Agnieszka; Dieffenbach, Aida K; Gentry-Maharaj, Aleksandra; Whittemore, Alice S; Wolk, Alicja; Monteiro, Alvaro; Peixoto, Ana; Kierzek, Andrzej; Cox, Angela; Rudolph, Anja; Gonzalez-Neira, Anna; Wu, Anna H; Lindblom, Annika; Swerdlow, Anthony; Ziogas, Argyrios; Ekici, Arif B; Burwinkel, Barbara; Karlan, Beth Y; Nordestgaard, Børge G; Blomqvist, Carl; Phelan, Catherine; McLean, Catriona; Pearce, Celeste Leigh; Vachon, Celine; Cybulski, Cezary; Slavov, Chavdar; Stegmaier, Christa; Maier, Christiane; Ambrosone, Christine B; Høgdall, Claus K; Teerlink, Craig C; Kang, Daehee; Tessier, Daniel C; Schaid, Daniel J; Stram, Daniel O; Cramer, Daniel W; Neal, David E; Eccles, Diana; Flesch-Janys, Dieter; Edwards, Digna R Velez; Wokozorczyk, Dominika; Levine, Douglas A; Yannoukakos, Drakoulis; Sawyer, Elinor J; Bandera, Elisa V; Poole, Elizabeth M; Goode, Ellen L; Khusnutdinova, Elza; Høgdall, Estrid; Song, Fengju; Bruinsma, Fiona; Heitz, Florian; Modugno, Francesmary; Hamdy, Freddie C; Wiklund, Fredrik; Giles, Graham G; Olsson, Håkan; Wildiers, Hans; Ulmer, Hans-Ulrich; Pandha, Hardev; Risch, Harvey A; Darabi, Hatef; Salvesen, Helga B; Nevanlinna, Heli; Gronberg, Henrik; Brenner, Hermann; Brauch, Hiltrud; Anton-Culver, Hoda; Song, Honglin; Lim, Hui-Yi; McNeish, Iain; Campbell, Ian; Vergote, Ignace; Gronwald, Jacek; Lubiński, Jan; Stanford, Janet L; Benítez, Javier; Doherty, Jennifer A; Permuth, Jennifer B; Chang-Claude, Jenny; Donovan, Jenny L; Dennis, Joe; Schildkraut, Joellen M; Schleutker, Johanna; Hopper, John L; Kupryjanczyk, Jolanta; Park, Jong Y; Figueroa, Jonine; Clements, Judith A; Knight, Julia A; Peto, Julian; Cunningham, Julie M; Pow-Sang, Julio; Batra, Jyotsna; Czene, Kamila; Lu, Karen H; Herkommer, Kathleen; Khaw, Kay-Tee; Matsuo, Keitaro; Muir, Kenneth; Offitt, Kenneth; Chen, Kexin; Moysich, Kirsten B; Aittomäki, Kristiina; Odunsi, Kunle; Kiemeney, Lambertus A; Massuger, Leon F A G; Fitzgerald, Liesel M; Cook, Linda S; Cannon-Albright, Lisa; Hooning, Maartje J; Pike, Malcolm C; Bolla, Manjeet K; Luedeke, Manuel; Teixeira, Manuel R; Goodman, Marc T; Schmidt, Marjanka K; Riggan, Marjorie; Aly, Markus; Rossing, Mary Anne; Beckmann, Matthias W; Moisse, Matthieu; Sanderson, Maureen; Southey, Melissa C; Jones, Michael; Lush, Michael; Hildebrandt, Michelle A T; Hou, Ming-Feng; Schoemaker, Minouk J; Garcia-Closas, Montserrat; Bogdanova, Natalia; Rahman, Nazneen; Le, Nhu D; Orr, Nick; Wentzensen, Nicolas; Pashayan, Nora; Peterlongo, Paolo; Guénel, Pascal; Brennan, Paul; Paulo, Paula; Webb, Penelope M; Broberg, Per; Fasching, Peter A; Devilee, Peter; Wang, Qin; Cai, Qiuyin; Li, Qiyuan; Kaneva, Radka; Butzow, Ralf; Kopperud, Reidun Kristin; Schmutzler, Rita K; Stephenson, Robert A; MacInnis, Robert J; Hoover, Robert N; Winqvist, Robert; Ness, Roberta; Milne, Roger L; Travis, Ruth C; Benlloch, Sara; Olson, Sara H; McDonnell, Shannon K; Tworoger, Shelley S; Maia, Sofia; Berndt, Sonja; Lee, Soo Chin; Teo, Soo-Hwang; Thibodeau, Stephen N; Bojesen, Stig E; Gapstur, Susan M; Kjær, Susanne Krüger; Pejovic, Tanja; Tammela, Teuvo L J; Dörk, Thilo; Brüning, Thomas; Wahlfors, Tiina; Key, Tim J; Edwards, Todd L; Menon, Usha; Hamann, Ute; Mitev, Vanio; Kosma, Veli-Matti; Setiawan, Veronica Wendy; Kristensen, Vessela; Arndt, Volker; Vogel, Walther; Zheng, Wei; Sieh, Weiva; Blot, William J; Kluzniak, Wojciech; Shu, Xiao-Ou; Gao, Yu-Tang; Schumacher, Fredrick; Freedman, Matthew L; Berchuck, Andrew; Dunning, Alison M; Simard, Jacques; Haiman, Christopher A; Spurdle, Amanda; Sellers, Thomas A; Hunter, David J; Henderson, Brian E; Kraft, Peter; Chanock, Stephen J; Couch, Fergus J; Hall, Per; Gayther, Simon A; Easton, Douglas F; Chenevix-Trench, Georgia; Eeles, Rosalind; Pharoah, Paul D P; Lambrechts, Diether

2016-09-01

Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis. We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932. ©2016 American Association for Cancer Research.

Mosaic microecological differential stress causes adaptive microsatellite divergence in wild barley, Hordeum spontaneum, at Neve Yaar, Israel.

PubMed

Huang, Qingyang; Beharav, Alex; Li, Youchun; Kirzhner, Valery; Nevo, Eviatar

2002-12-01

Genetic diversity at 38 microsatellite (short sequence repeats (SSRs)) loci was studied in a sample of 54 plants representing a natural population of wild barley, Hordeum spontaneum, at the Neve Yaar microsite in Israel. Wild barley at the microsite was organized in a mosaic pattern over an area of 3180 m2 in the open Tabor oak forest, which was subdivided into four microniches: (i) sun-rock (11 genotypes), (ii) sun-soil (18 genotypes), (iii) shade-soil (11 genotypes), and (iv) shade-rock (14 genotypes). Fifty-four genotypes were tested for ecological-genetic microniche correlates. Analysis of 36 loci showed that allele distributions at SSR loci were nonrandom but structured by ecological stresses (climatic and edaphic). Sixteen (45.7%) of 35 polymorphic loci varied significantly (p < 0.05) in allele frequencies among the microniches. Significant genetic divergence and diversity were found among the four subpopulations. The soil and shade subpopulations showed higher genetic diversities at SSR loci than the rock and sun subpopulations, and the lowest genetic diversity was observed in the sun-rock subpopulation, in contrast with the previous allozyme and RAPD studies. On average, of 36 loci, 88.75% of the total genetic diversity exists within the four microniches, while 11.25% exists between the microniches. In a permutation test, G(ST) was lower for 4999 out of 5000 randomized data sets (p < 0.001) when compared with real data (0.1125). The highest genetic distance was between shade-soil and sun-rock (D = 0.222). Our results suggest that diversifying natural selection may act upon some regulatory regions, resulting in adaptive SSR divergence. Fixation of some loci (GMS61, GMS1, and EBMAC824) at a specific microniche seems to suggest directional selection. The pattern of other SSR loci suggests the operation of balancing selection. SSRs may be either direct targets of selection or markers of selected haplotypes (selective sweep).

Functional relevance for type 1 diabetes mellitus-associated genetic variants by using integrative analyses.

PubMed

Qiu, Ying-Hua; Deng, Fei-Yan; Tang, Zai-Xiang; Jiang, Zhen-Huan; Lei, Shu-Feng

2015-10-01

Type 1 diabetes mellitus (type 1 DM) is an autoimmune disease. Although genome-wide association studies (GWAS) and meta-analyses have successfully identified numerous type 1 DM-associated susceptibility loci, the underlying mechanisms for these susceptibility loci are currently largely unclear. Based on publicly available datasets, we performed integrative analyses (i.e., integrated gene relationships among implicated loci, differential gene expression analysis, functional prediction and functional annotation clustering analysis) and combined with expression quantitative trait loci (eQTL) results to further explore function mechanisms underlying the associations between genetic variants and type 1 DM. Among a total of 183 type 1 DM-associated SNPs, eQTL analysis showed that 17 SNPs with cis-regulated eQTL effects on 9 genes. All the 9 eQTL genes enrich in immune-related pathways or Gene Ontology (GO) terms. Functional prediction analysis identified 5 SNPs located in transcription factor (TF) binding sites. Of the 9 eQTL genes, 6 (TAP2, HLA-DOB, HLA-DQB1, HLA-DQA1, HLA-DRB5 and CTSH) were differentially expressed in type 1 DM-associated related cells. Especially, rs3825932 in CTSH has integrative functional evidence supporting the association with type 1 DM. These findings indicated that integrative analyses can yield important functional information to link genetic variants and type 1 DM. Copyright © 2015 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

Parasite genetics and the immune host: recombination between antigenic types of Eimeria maxima as an entrée to the identification of protective antigens.

PubMed

Blake, Damer P; Hesketh, Patricia; Archer, Andrew; Carroll, Fionnadh; Smith, Adrian L; Shirley, Martin W

2004-11-01

The genomes of protozoan parasites encode thousands of gene products and identification of the subset that stimulates a protective immune response is a daunting task. Most screens for vaccine candidates identify molecules by capacity to induce immune responses rather than protection. This paper describes the core findings of a strategy developed with the coccidial parasite Eimeria maxima to rationally identify loci within its genome that encode immunoprotective antigens. Our strategy uses a novel combination of parasite genetics, DNA fingerprinting, drug-resistance and strain-specific immunity and centres on two strains of E. maxima that each induce a lethal strain-specific protective immune response in the host and show a differential response to anti-Eimeria chemotherapy. Through classical mating studies with these strains we have demonstrated that loci encoding molecules stimulating strain-specific protective immunity or resistance to the anti-coccidial drug robenidine segregate independently. Furthermore, passage of populations of recombinant parasites in the face of killing in the immune host was accompanied by the elimination of some polymorphic DNA markers defining the parent strain used to immunise the host. Consideration of the numbers of parasites recombinant for the two traits implicates very few antigen-encoding loci. Our data provide a potential strategy to identify putative antigen-encoding loci in other parasites.

Cheetah paradigm revisited: MHC diversity in the world's largest free-ranging population.

PubMed

Castro-Prieto, Aines; Wachter, Bettina; Sommer, Simone

2011-04-01

For more than two decades, the cheetah (Acinonyx jubatus) has been considered a paradigm of disease vulnerability associated with low genetic diversity, particularly at the immune genes of the major histocompatibility complex (MHC). Cheetahs have been used as a classic example in numerous conservation genetics textbooks as well as in many related scientific publications. However, earlier studies used methods with low resolution to quantify MHC diversity and/or small sample sizes. Furthermore, high disease susceptibility was reported only for captive cheetahs, whereas free-ranging cheetahs show no signs of infectious diseases and a good general health status. We examined whether the diversity at MHC class I and class II-DRB loci in 149 Namibian cheetahs was higher than previously reported using single-strand conformation polymorphism analysis, cloning, and sequencing. MHC genes were examined at the genomic and transcriptomic levels. We detected ten MHC class I and four class II-DRB alleles, of which nine MHC class I and all class II-DRB alleles were expressed. Phylogenetic analyses and individual genotypes suggested that the alleles belong to four MHC class I and three class II-DRB putative loci. Evidence of positive selection was detected in both MHC loci. Our study indicated that the low number of MHC class I alleles previously observed in cheetahs was due to a smaller sample size examined. On the other hand, the low number of MHC class II-DRB alleles previously observed in cheetahs was further confirmed. Compared with other mammalian species including felids, cheetahs showed low levels of MHC diversity, but this does not seem to influence the immunocompetence of free-ranging cheetahs in Namibia and contradicts the previous conclusion that the cheetah is a paradigm species of disease vulnerability.

A new three-locus model for rootstock-induced dwarfing in apple revealed by genetic mapping of root bark percentage

PubMed Central

Harrison, Nicola; Harrison, Richard J.; Barber-Perez, Nuria; Cascant-Lopez, Emma; Cobo-Medina, Magdalena; Lipska, Marzena; Conde-Ruíz, Rebeca; Brain, Philip; Gregory, Peter J.; Fernández-Fernández, Felicidad

2016-01-01

Rootstock-induced dwarfing of apple scions revolutionized global apple production during the twentieth century, leading to the development of modern intensive orchards. A high root bark percentage (the percentage of the whole root area constituted by root cortex) has previously been associated with rootstock-induced dwarfing in apple. In this study, the root bark percentage was measured in a full-sib family of ungrafted apple rootstocks and found to be under the control of three loci. Two quantitative trait loci (QTLs) for root bark percentage were found to co-localize to the same genomic regions on chromosome 5 and chromosome 11 previously identified as controlling dwarfing, Dw1 and Dw2, respectively. A third QTL was identified on chromosome 13 in a region that has not been previously associated with dwarfing. The development of closely linked sequence-tagged site markers improved the resolution of allelic classes, thereby allowing the detection of dominance and epistatic interactions between loci, with high root bark percentage only occurring in specific allelic combinations. In addition, we report a significant negative correlation between root bark percentage and stem diameter (an indicator of tree vigour), measured on a clonally propagated grafted subset of the mapping population. The demonstrated link between root bark percentage and rootstock-induced dwarfing of the scion leads us to propose a three-locus model that is able to explain levels of dwarfing from the dwarf ‘M.27’ to the semi-invigorating rootstock ‘M.116’. Moreover, we suggest that the QTL on chromosome 13 (Rb3) might be analogous to a third dwarfing QTL, Dw3, which has not previously been identified. PMID:26826217

Replication of Epigenetic Postpartum Depression Biomarkers and Variation with Hormone Levels

PubMed Central

Osborne, Lauren; Clive, Makena; Kimmel, Mary; Gispen, Fiona; Guintivano, Jerry; Brown, Tori; Cox, Olivia; Judy, Jennifer; Meilman, Samantha; Braier, Aviva; Beckmann, Matthias W; Kornhuber, Johannes; Fasching, Peter A; Goes, Fernando; Payne, Jennifer L; Binder, Elisabeth B; Kaminsky, Zachary

2016-01-01

DNA methylation variation at HP1BP3 and TTC9B is modified by estrogen exposure in the rodent hippocampus and was previously shown to be prospectively predictive of postpartum depression (PPD) when modeled in antenatal blood. The objective of this study was to replicate the predictive efficacy of the previously established model in women with and without a previous psychiatric diagnosis and to understand the effects of changing hormone levels on PPD biomarker loci. Using a statistical model trained on DNA methylation data from N=51 high-risk women, we prospectively predicted PPD status in an independent N=51 women using first trimester antenatal gene expression levels of HP1BP3 and TTC9B, with an area under the receiver operator characteristic curve (AUC) of 0.81 (95% CI: 0.69–0.92, p<5 × 10−4). Modeling DNA methylation of these genes in N=240 women without a previous psychiatric diagnosis resulted in a cross-sectional prediction of PPD status with an AUC of 0.81 (95% CI: 0.68–0.93, p=0.01). TTC9B and HP1BP3 DNA methylation at early antenatal time points showed moderate evidence for association to the change in estradiol and allopregnanolone over the course of pregnancy, suggesting that epigenetic variation at these loci may be important for mediating hormonal sensitivity. In addition both loci showed PPD-specific trajectories with age, possibly mediated by age-associated hormonal changes. The data add to the growing body of evidence suggesting that PPD is mediated by differential gene expression and epigenetic sensitivity to pregnancy hormones and that modeling proxies of this sensitivity enable accurate prediction of PPD. PMID:26503311

A novel iterative mixed model to remap three complex orthopedic traits in dogs

PubMed Central

Huang, Meng; Hayward, Jessica J.; Corey, Elizabeth; Garrison, Susan J.; Wagner, Gabriela R.; Krotscheck, Ursula; Hayashi, Kei; Schweitzer, Peter A.; Lust, George; Boyko, Adam R.; Todhunter, Rory J.

2017-01-01

Hip dysplasia (HD), elbow dysplasia (ED), and rupture of the cranial (anterior) cruciate ligament (RCCL) are the most common complex orthopedic traits of dogs and all result in debilitating osteoarthritis. We reanalyzed previously reported data: the Norberg angle (a quantitative measure of HD) in 921 dogs, ED in 113 cases and 633 controls, and RCCL in 271 cases and 399 controls and their genotypes at ~185,000 single nucleotide polymorphisms. A novel fixed and random model with a circulating probability unification (FarmCPU) function, with marker-based principal components and a kinship matrix to correct for population stratification, was used. A Bonferroni correction at p<0.01 resulted in a P< 6.96 ×10−8. Six loci were identified; three for HD and three for RCCL. An associated locus at CFA28:34,369,342 for HD was described previously in the same dogs using a conventional mixed model. No loci were identified for RCCL in the previous report but the two loci for ED in the previous report did not reach genome-wide significance using the FarmCPU model. These results were supported by simulation which demonstrated that the FarmCPU held no power advantage over the linear mixed model for the ED sample but provided additional power for the HD and RCCL samples. Candidate genes for HD and RCCL are discussed. When using FarmCPU software, we recommend a resampling test, that a positive control be used to determine the optimum pseudo quantitative trait nucleotide-based covariate structure of the model, and a negative control be used consisting of permutation testing and the identical resampling test as for the non-permuted phenotypes. PMID:28614352

Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women.

PubMed

Fox, Caroline S; Liu, Yongmei; White, Charles C; Feitosa, Mary; Smith, Albert V; Heard-Costa, Nancy; Lohman, Kurt; Johnson, Andrew D; Foster, Meredith C; Greenawalt, Danielle M; Griffin, Paula; Ding, Jinghong; Newman, Anne B; Tylavsky, Fran; Miljkovic, Iva; Kritchevsky, Stephen B; Launer, Lenore; Garcia, Melissa; Eiriksdottir, Gudny; Carr, J Jeffrey; Gudnason, Vilmunder; Harris, Tamara B; Cupples, L Adrienne; Borecki, Ingrid B

2012-01-01

Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to ~2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), VAT adjusted for body mass index, and VAT/SAT ratio (a metric of the propensity to store fat viscerally as compared to subcutaneously) in the overall sample and in women and men separately. A weighted z-score meta-analysis was conducted. For the VAT/SAT ratio, our most significant p-value was rs11118316 at LYPLAL1 gene (p = 3.1 × 10E-09), previously identified in association with waist-hip ratio. For SAT, the most significant SNP was in the FTO gene (p = 5.9 × 10E-08). Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, rs1659258 near THNSL2 (p = 1.6 × 10-08), but not men (p = 0.75). Validation of this SNP in the GIANT consortium data demonstrated a similar sex-specific pattern, with observed significance in women (p = 0.006) but not men (p = 0.24) for BMI and waist circumference (p = 0.04 [women], p = 0.49 [men]). Finally, we interrogated our data for the 14 recently published loci for body fat distribution (measured by waist-hip ratio adjusted for BMI); associations were observed at 7 of these loci. In contrast, we observed associations at only 7/32 loci previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not previously uncovered in large-scale GWAS of anthropometric traits.

Characterization of Genetic Loci That Affect Susceptibility to Inflammatory Bowel Diseases in African Americans

PubMed Central

Cutler, David J.; Zwick, Michael E.; Taylor, Kent D.; Datta, Lisa W.; Maranville, Joseph C.; Liu, Zhenqiu; Ellis, Shannon; Chopra, Pankaj; Alexander, Jonathan S.; Baldassano, Robert N.; Cross, Raymond K.; Dassopoulos, Themistocles; Dhere, Tanvi A.; Duerr, Richard H.; Hanson, John S.; Hou, Jason K.; Hussain, Sunny Z.; Isaacs, Kim L.; Kachelries, Kelly E; Kader, Howard; Kappelman, Michael D.; Katz, Jeffrey; Kellermayer, Richard; Kirschner, Barbara S.; Kuemmerle, John F.; Kumar, Archana; Kwon, John H.; Lazarev, Mark; Mannon, Peter; Moulton, Dedrick E.; Osuntokun, Bankole O.; Patel, Ashish; Rioux, John D.; Rotter, Jerome I.; Saeed, Shehzad; Scherl, Ellen J.; Silverberg, Mark S.; Silverman, Ann; Targan, Stephan R.; Valentine, John F.; Wang, Ming-Hsi; Simpson, Claire L.; Bridges, S. Louis; Kimberly, Robert P.; Rich, Stephen S.; Cho, Judy H.; Rienzo, Anna Di; Kao, Linda W.H.

2015-01-01

Background & Aims Inflammatory bowel disease (IBD) has familial aggregation in African Americans (AAs), but little is known about the molecular genetic susceptibility. Mapping studies using the Immunochip genotyping array expand the number of susceptibility loci for IBD in Caucasians to 163, but the contribution of the 163 loci and European admixture to IBD risk in AAs is unclear. We performed a genetic mapping study using the Immunochip to determine whether IBD susceptibility loci in Caucasians also affect risk in AAs and identify new associated loci. Methods We recruited AAs with IBD and without IBD (controls) from 34 IBD centers in the US; additional controls were collected from 4 other immunochip studies. Association and admixture loci were mapped for 1088 patients with Crohn's disease (CD), 361 with ulcerative colitis (UC), 62 with IBD type-unknown (IBDU), and 1797 controls; 130,241 autosomal single-nucleotide polymorphisms (SNPs) were analyzed. Results The strongest associations were observed between UC and HLA rs9271366 (P=7.5e–6), CD and 5p13.1 rs4286721 (P=3.0e–6), and IBD and KAT2A rs730086 (P=2.3e–6). Additional suggestive associations (P<4.2e-5) were observed between CD and IBD and African-specific SNPs in STAT5A and STAT3; between IBD and SNPs in IL23R, IL12B, and C2 open reading frame 43; and between UC and SNPs near HDAC11 and near LINC00994. The latter 3 loci have not been previously associated with IBD, but require replication. Established Caucasian associations were replicated in AAs (P<3.1e-4) at NOD2, IL23R, 5p15.3, and IKZF3. Significant admixture (P<3.9e–4) was observed for 17q12-17q21.31 (IZKF3 through STAT3), 10q11.23-10q21.2, 15q22.2–15q23, and 16p12.2–16p12.1. Network analyses showed significant enrichment (false discovery rate <1e–5) in genes that encode members of the JAK–STAT, cytokine, and chemokine signaling pathways, as well those involved in pathogenesis of measles. Conclusions In a genetic analysis of 3308 AA IBD cases and controls, we found that many variants associated with IBD in Caucasians also showed association evidence with these diseases in AAs; we found evidence for loci and variants not previously associated with IBD. The complex genetic factors that determine risk for or protection from IBD in different populations require further study. PMID:26278503

Putative Digenic Inheritance of Heterozygous RP1L1 and C2orf71 Null Mutations in Syndromic Retinal Dystrophy

PubMed Central

Liu, Yangfan P.; Bosch, Daniëlle G.M.; Siemiatkowska, Anna M.; Rendtorff, Nanna Dahl; Boonstra, F. Nienke; Möller, Claes; Tranebjærg, Lisbeth; Katsanis, Nicholas; Cremers, Frans P.M.

2018-01-01

Background Retinitis pigmentosa (RP) is the most common cause of inherited retinal degeneration and can occur in non-syndromic and syndromic forms. Syndromic RP is accompanied by other symptoms such as intellectual disability, hearing loss, or congenital abnormalities. Both forms are known to exhibit complex genetic interactions that can modulate the penetrance and expressivity of the phenotype. Materials and methods In an individual with atypical RP, hearing loss, ataxia and cerebellar atrophy whole exome sequencing was performed. The candidate pathogenic variants were tested by developing an in vivo zebrafish model and assaying for retinal and cerebellar integrity. Results Exome sequencing revealed a complex heterozygous protein-truncating mutation in RP1L1, p.[(Lys111Glnfs*27; Q2373*)], and a heterozygous nonsense mutation in C2orf71, p.(Ser512*). Mutations in both genes have previously been implicated in autosomal recessive non-syndromic RP, raising the possibility of a digenic model in this family. Functional testing in a zebrafish model for two key phenotypes of the affected person showed that the combinatorial suppression of rp1l1 and c2orf71l induced discrete pathology in terms of reduction of eye size with concomitant loss of rhodopsin in the photoreceptors, and disorganization of the cerebellum. Conclusions We propose that the combination of heterozygous loss-of-function mutations in these genes drives syndromic retinal dystrophy, likely through the genetic interaction of at least two loci. Haploinsufficiency at each of these loci is insufficient to induce overt pathology. PMID:27029556

Incipient Balancing Selection through Adaptive Loss of Aquaporins in Natural Saccharomyces cerevisiae Populations

PubMed Central

Will, Jessica L.; Kim, Hyun Seok; Clarke, Jessica; Painter, John C.; Fay, Justin C.; Gasch, Audrey P.

2010-01-01

A major goal in evolutionary biology is to understand how adaptive evolution has influenced natural variation, but identifying loci subject to positive selection has been a challenge. Here we present the adaptive loss of a pair of paralogous genes in specific Saccharomyces cerevisiae subpopulations. We mapped natural variation in freeze-thaw tolerance to two water transporters, AQY1 and AQY2, previously implicated in freeze-thaw survival. However, whereas freeze-thaw–tolerant strains harbor functional aquaporin genes, the set of sensitive strains lost aquaporin function at least 6 independent times. Several genomic signatures at AQY1 and/or AQY2 reveal low variation surrounding these loci within strains of the same haplotype, but high variation between strain groups. This is consistent with recent adaptive loss of aquaporins in subgroups of strains, leading to incipient balancing selection. We show that, although aquaporins are critical for surviving freeze-thaw stress, loss of both genes provides a major fitness advantage on high-sugar substrates common to many strains' natural niche. Strikingly, strains with non-functional alleles have also lost the ancestral requirement for aquaporins during spore formation. Thus, the antagonistic effect of aquaporin function—providing an advantage in freeze-thaw tolerance but a fitness defect for growth in high-sugar environments—contributes to the maintenance of both functional and nonfunctional alleles in S. cerevisiae. This work also shows that gene loss through multiple missense and nonsense mutations, hallmarks of pseudogenization presumed to emerge after loss of constraint, can arise through positive selection. PMID:20369021

Genome-wide association study of esophageal squamous cell carcinoma in Chinese subjects identifies susceptibility loci at PLCE1 and C20orf54.

PubMed

Wang, Li-Dong; Zhou, Fu-You; Li, Xue-Min; Sun, Liang-Dan; Song, Xin; Jin, Yan; Li, Jiang-Man; Kong, Guo-Qiang; Qi, Hong; Cui, Juan; Zhang, Lian-Qun; Yang, Jie-Zhi; Li, Ji-Lin; Li, Xing-Chuan; Ren, Jing-Li; Liu, Zhi-Cai; Gao, Wen-Jun; Yuan, Ling; Wei, Wu; Zhang, Yan-Rui; Wang, Wei-Peng; Sheyhidin, Ilyar; Li, Feng; Chen, Bao-Ping; Ren, Shu-Wei; Liu, Bin; Li, Dan; Ku, Jian-Wei; Fan, Zong-Min; Zhou, Sheng-Li; Guo, Zhi-Gang; Zhao, Xue-Ke; Liu, Na; Ai, Yong-Hong; Shen, Fang-Fang; Cui, Wen-Yan; Song, Shuang; Guo, Tao; Huang, Jing; Yuan, Chao; Huang, Jia; Wu, Yue; Yue, Wen-Bin; Feng, Chang-Wei; Li, Hong-Lei; Wang, Yan; Tian, Jin-Ya; Lu, Yue; Yuan, Yi; Zhu, Wen-Liang; Liu, Min; Fu, Wen-Jing; Yang, Xia; Wang, Han-Jing; Han, Suo-Li; Chen, Jie; Han, Min; Wang, Hai-Yan; Zhang, Peng; Li, Xiu-Min; Dong, Jin-Cheng; Xing, Guo-Lan; Wang, Ran; Guo, Ming; Chang, Zhi-Wei; Liu, Hai-Lin; Guo, Li; Yuan, Zhi-Qing; Liu, Hai; Lu, Qin; Yang, Liu-Qin; Zhu, Fu-Guo; Yang, Xiu-Feng; Feng, Xiao-Shan; Wang, Zhou; Li, Yin; Gao, She-Gan; Qige, Qirenwang; Bai, Long-Tang; Yang, Wen-Jun; Lei, Guang-Yan; Shen, Zhong-Ying; Chen, Long-Qi; Li, En-Min; Xu, Li-Yan; Wu, Zhi-Yong; Cao, Wei-Ke; Wang, Jian-Po; Bao, Zhi-Qin; Chen, Ji-Li; Ding, Guang-Cheng; Zhuang, Xiang; Zhou, Ying-Fa; Zheng, Hou-Feng; Zhang, Zheng; Zuo, Xian-Bo; Dong, Zi-Ming; Fan, Dong-Mei; He, Xin; Wang, Jin; Zhou, Qi; Zhang, Qin-Xian; Jiao, Xin-Ying; Lian, Shi-Yong; Ji, Ai-Fang; Lu, Xiao-Mei; Wang, Jin-Sheng; Chang, Fu-Bao; Lu, Chang-Dong; Chen, Zhi-Guo; Miao, Jian-Jun; Fan, Zeng-Lin; Lin, Ruo-Bai; Liu, Tai-Jiang; Wei, Jin-Chang; Kong, Qing-Peng; Lan, Yu; Fan, Yu-Jing; Gao, Fu-Sheng; Wang, Tian-Yun; Xie, Dong; Chen, Shu-Qing; Yang, Wan-Cai; Hong, Jun-Yan; Wang, Liang; Qiu, Song-Liang; Cai, Zhi-Ming; Zhang, Xue-Jun

2010-09-01

We performed a genome-wide association study of esophageal squamous cell carcinoma (ESCC) by genotyping 1,077 individuals with ESCC and 1,733 control subjects of Chinese Han descent. We selected 18 promising SNPs for replication in an additional 7,673 cases of ESCC and 11,013 control subjects of Chinese Han descent and 303 cases of ESCC and 537 control subjects of Chinese Uygur-Kazakh descent. We identified two previously unknown susceptibility loci for ESCC: PLCE1 at 10q23 (P(Han combined for ESCC) = 7.46 x 10(-56), odds ratio (OR) = 1.43; P(Uygur-Kazakh for ESCC) = 5.70 x 10(-4), OR = 1.53) and C20orf54 at 20p13 (P(Han combined for ESCC) = 1.21 x 10(-11), OR = 0.86; P(Uygur-Kazakh for ESCC) = 7.88 x 10(-3), OR = 0.66). We also confirmed association in 2,766 cases of gastric cardia adenocarcinoma cases and the same 11,013 control subjects (PLCE1, P(Han for GCA) = 1.74 x 10(-39), OR = 1.55 and C20orf54, P(Han for GCA) = 3.02 x 10(-3), OR = 0.91). PLCE1 and C20orf54 have important biological implications for both ESCC and GCA. PLCE1 might regulate cell growth, differentiation, apoptosis and angiogenesis. C20orf54 is responsible for transporting riboflavin, and deficiency of riboflavin has been documented as a risk factor for ESCC and GCA.

Genomewide screen for negative regulators of sirtuin activity in Saccharomyces cerevisiae reveals 40 loci and links to metabolism.

PubMed

Raisner, Ryan M; Madhani, Hiten D

2008-08-01

Sirtuins are conserved proteins implicated in myriad key processes including gene control, aging, cell survival, metabolism, and DNA repair. In Saccharomyces cerevisiae, the sirtuin Silent information regulator 2 (Sir2) promotes silent chromatin formation, suppresses recombination between repeats, and inhibits senescence. We performed a genomewide screen for factors that negatively regulate Sir activity at a reporter gene placed immediately outside a silenced region. After linkage analysis, assessment of Sir dependency, and knockout tag verification, 40 loci were identified, including 20 that have not been previously described to regulate Sir. In addition to chromatin-associated factors known to prevent ectopic silencing (Bdf1, SAS-I complex, Rpd3L complex, Ku), we identified the Rtt109 DNA repair-associated histone H3 lysine 56 acetyltransferase as an anti-silencing factor. Our findings indicate that Rtt109 functions independently of its proposed effectors, the Rtt101 cullin, Mms1, and Mms22, and demonstrate unexpected interplay between H3K56 and H4K16 acetylation. The screen also identified subunits of mediator (Soh1, Srb2, and Srb5) and mRNA metabolism factors (Kem1, Ssd1), thus raising the possibility that weak silencing affects some aspect of mRNA structure. Finally, several factors connected to metabolism were identified. These include the PAS-domain metabolic sensor kinase Psk2, the mitochondrial homocysteine detoxification enzyme Lap3, and the Fe-S cluster protein maturase Isa2. We speculate that PAS kinase may integrate metabolic signals to control sirtuin activity.

Epigenome-wide analysis of DNA methylation in lung tissue shows concordance with blood studies and identifies tobacco smoke-inducible enhancers.

PubMed

Stueve, Theresa Ryan; Li, Wen-Qing; Shi, Jianxin; Marconett, Crystal N; Zhang, Tongwu; Yang, Chenchen; Mullen, Daniel; Yan, Chunli; Wheeler, William; Hua, Xing; Zhou, Beiyun; Borok, Zea; Caporaso, Neil E; Pesatori, Angela C; Duan, Jubao; Laird-Offringa, Ite A; Landi, Maria Teresa

2017-08-01

Smoking-associated DNA hypomethylation has been observed in blood cells and linked to lung cancer risk. However, its cause and mechanistic relationship to lung cancer remain unclear. We studied the association between tobacco smoking and epigenome-wide methylation in non-tumor lung (NTL) tissue from 237 lung cancer cases in the Environment And Genetics in Lung cancer Etiology study, using the Infinium HumanMethylation450 BeadChip. We identified seven smoking-associated hypomethylated CpGs (P < 1.0 × 10-7), which were replicated in NTL data from The Cancer Genome Atlas. Five of these loci were previously reported as hypomethylated in smokers' blood, suggesting that blood-based biomarkers can reflect changes in the target tissue for these loci. Four CpGs border sequences carrying aryl hydrocarbon receptor binding sites and enhancer-specific histone modifications in primary alveolar epithelium and A549 lung adenocarcinoma cells. A549 cell exposure to cigarette smoke condensate increased these enhancer marks significantly and stimulated expression of predicted target xenobiotic response-related genes AHRR (P = 1.13 × 10-62) and CYP1B1 (P < 2.49 × 10-61). Expression of both genes was linked to smoking-related transversion mutations in lung tumors. Thus, smoking-associated hypomethylation may be a consequence of enhancer activation, revealing environmentally-induced regulatory elements implicated in lung carcinogenesis. Published by Oxford University Press 2017. This work is written by US Government employees and is in the public domain in the US.

Genome-Wide Association Studies of Drug-Resistance Determinants.

PubMed

Volkman, Sarah K; Herman, Jonathan; Lukens, Amanda K; Hartl, Daniel L

2017-03-01

Population genetic strategies that leverage association, selection, and linkage have identified drug-resistant loci. However, challenges and limitations persist in identifying drug-resistance loci in malaria. In this review we discuss the genetic basis of drug resistance and the use of genome-wide association studies, complemented by selection and linkage studies, to identify and understand mechanisms of drug resistance and response. We also discuss the implications of nongenetic mechanisms of drug resistance recently reported in the literature, and present models of the interplay between nongenetic and genetic processes that contribute to the emergence of drug resistance. Throughout, we examine artemisinin resistance as an example to emphasize challenges in identifying phenotypes suitable for population genetic studies as well as complications due to multiple-factor drug resistance. Copyright © 2016. Published by Elsevier Ltd.

Toward a theory of topopatric speciation: The role of genetic assortative mating

NASA Astrophysics Data System (ADS)

Schneider, David M.; do Carmo, Eduardo; Martins, Ayana B.; de Aguiar, Marcus A. M.

2014-09-01

We discuss a minimalist model of assortative mating for sexually reproducing haploid individuals with two biallelic loci. Assortativeness is introduced in the model by preventing mating between individuals whose alleles differ at both loci. Using methods of dynamical systems and population genetics we provide a full description of the evolution of the system for the case of very large populations. We derive the equations governing the evolution of haplotype frequencies and study the equilibrium solutions, stability, and speed of convergence to equilibrium. We find a constant of motion which allows us to introduce a geometrical construction that makes it straightforward to predict the fate of initial conditions. Finally, we discuss the consequences of this class of assortative mating models, including their possible extensions and implications for sympatric and topopatric speciation.

Genome-wide Analysis of Body Proportion Classifies Height-Associated Variants by Mechanism of Action and Implicates Genes Important for Skeletal Development.

PubMed

Chan, Yingleong; Salem, Rany M; Hsu, Yu-Han H; McMahon, George; Pers, Tune H; Vedantam, Sailaja; Esko, Tonu; Guo, Michael H; Lim, Elaine T; Franke, Lude; Smith, George Davey; Strachan, David P; Hirschhorn, Joel N

2015-05-07

Human height is a composite measurement, reflecting the sum of leg, spine, and head lengths. Many common variants influence total height, but the effects of these or other variants on the components of height (body proportion) remain largely unknown. We studied sitting height ratio (SHR), the ratio of sitting height to total height, to identify such effects in 3,545 African Americans and 21,590 individuals of European ancestry. We found that SHR is heritable: 26% and 39% of the total variance of SHR can be explained by common variants in European and African Americans, respectively, and global European admixture is negatively correlated with SHR in African Americans (r(2) ≈ 0.03). Six regions reached genome-wide significance (p < 5 × 10(-8)) for association with SHR and overlapped biological candidate genes, including TBX2 and IGFBP3. We found that 130 of 670 height-associated variants are nominally associated (p < 0.05) with SHR, more than expected by chance (p = 5 × 10(-40)). At these 130 loci, the height-increasing alleles are associated with either a decrease (71 loci) or increase (59 loci) in SHR, suggesting that different height loci disproportionally affect either leg length or spine/head length. Pathway analyses via DEPICT revealed that height loci affecting SHR, and especially those affecting leg length, show enrichment of different biological pathways (e.g., bone/cartilage/growth plate pathways) than do loci with no effect on SHR (e.g., embryonic development). These results highlight the value of using a pair of related but orthogonal phenotypes, in this case SHR with height, as a prism to dissect the biology underlying genetic associations in polygenic traits and diseases. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Three ulcerative colitis susceptibility loci are associated with primary sclerosing cholangitis and indicate a role for IL2, REL, and CARD9.

PubMed

Janse, Marcel; Lamberts, Laetitia E; Franke, Lude; Raychaudhuri, Soumya; Ellinghaus, Eva; Muri Boberg, Kirsten; Melum, Espen; Folseraas, Trine; Schrumpf, Erik; Bergquist, Annika; Björnsson, Einar; Fu, Jingyuan; Jan Westra, Harm; Groen, Harry J M; Fehrmann, Rudolf S N; Smolonska, Joanna; van den Berg, Leonard H; Ophoff, Roel A; Porte, Robert J; Weismüller, Tobias J; Wedemeyer, Jochen; Schramm, Christoph; Sterneck, Martina; Günther, Rainer; Braun, Felix; Vermeire, Severine; Henckaerts, Liesbet; Wijmenga, Cisca; Ponsioen, Cyriel Y; Schreiber, Stefan; Karlsen, Tom H; Franke, Andre; Weersma, Rinse K

2011-06-01

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts. Both environmental and genetic factors contribute to its pathogenesis. To further clarify its genetic background, we investigated susceptibility loci recently identified for ulcerative colitis (UC) in a large cohort of 1,186 PSC patients and 1,748 controls. Single nucleotide polymorphisms (SNPs) tagging 13 UC susceptibility loci were initially genotyped in 854 PSC patients and 1,491 controls from Benelux (331 cases, 735 controls), Germany (265 cases, 368 controls), and Scandinavia (258 cases, 388 controls). Subsequently, a joint analysis was performed with an independent second Scandinavian cohort (332 cases, 257 controls). SNPs at chromosomes 2p16 (P-value 4.12 × 10(-4) ), 4q27 (P-value 4.10 × 10(-5) ), and 9q34 (P-value 8.41 × 10(-4) ) were associated with PSC in the joint analysis after correcting for multiple testing. In PSC patients without inflammatory bowel disease (IBD), SNPs at 4q27 and 9q34 were nominally associated (P < 0.05). We applied additional in silico analyses to identify likely candidate genes at PSC susceptibility loci. To identify nonrandom, evidence-based links we used GRAIL (Gene Relationships Across Implicated Loci) analysis showing interconnectivity between genes in six out of in total nine PSC-associated regions. Expression quantitative trait analysis from 1,469 Dutch and UK individuals demonstrated that five out of nine SNPs had an effect on cis-gene expression. These analyses prioritized IL2, CARD9, and REL as novel candidates. We have identified three UC susceptibility loci to be associated with PSC, harboring the putative candidate genes REL, IL2, and CARD9. These results add to the scarce knowledge on the genetic background of PSC and imply an important role for both innate and adaptive immunological factors. Copyright © 2011 American Association for the Study of Liver Diseases.

DNA barcodes from four loci provide poor resolution of taxonomic groups in the genus Crataegus.

PubMed

Zarrei, Mehdi; Talent, Nadia; Kuzmina, Maria; Lee, Jeanette; Lund, Jensen; Shipley, Paul R; Stefanović, Saša; Dickinson, Timothy A

2015-04-28

DNA barcodes can facilitate identification of organisms especially when morphological characters are limited or unobservable. To what extent this potential is realized in specific groups of plants remains to be determined. Libraries of barcode sequences from well-studied authoritatively identified plants represented by herbarium voucher specimens are needed in order for DNA barcodes to serve their intended purpose, where this is possible, and to understand the reasons behind their failure to do so, when this occurs. We evaluated four loci, widely regarded as universal DNA barcodes for plants, for their utility in hawthorn species identification. Three plastid regions, matK, rbcLa and psbA-trnH, and the internal transcribed spacer 2 (ITS2) of nuclear ribosomal DNA discriminate only some of the species of Crataegus that can be recognized on the basis of their morphology etc. This is, in part, because in Rosaceae tribe Maleae most individual plastid loci yield relatively little taxonomic resolution and, in part, because the effects of allopolyploidization have not been eliminated by concerted evolution of the ITS regions. Although individual plastid markers provided generally poor resolution of taxonomic groups in Crataegus, a few species were notable exceptions. In contrast, analyses of concatenated sequences of the 3 plastid barcode loci plus 11 additional plastid loci gave a well-resolved maternal phylogeny. In the ITS2 tree, different individuals of some species formed groups with taxonomically unrelated species. This is a sign of lineage sorting due to incomplete concerted evolution in ITS2. Incongruence between the ITS2 and plastid trees is best explained by hybridization between different lineages within the genus. In aggregate, limited between-species variation in plastid loci, hybridization and a lack of concerted evolution in ITS2 all combine to limit the utility of standard barcoding markers in Crataegus. These results have implications for authentication of hawthorn materials in natural health products. Published by Oxford University Press on behalf of the Annals of Botany Company.

DNA barcodes from four loci provide poor resolution of taxonomic groups in the genus Crataegus

PubMed Central

Zarrei, Mehdi; Talent, Nadia; Kuzmina, Maria; Lee, Jeanette; Lund, Jensen; Shipley, Paul R.; Stefanović, Saša; Dickinson, Timothy A.

2015-01-01

DNA barcodes can facilitate identification of organisms especially when morphological characters are limited or unobservable. To what extent this potential is realized in specific groups of plants remains to be determined. Libraries of barcode sequences from well-studied authoritatively identified plants represented by herbarium voucher specimens are needed in order for DNA barcodes to serve their intended purpose, where this is possible, and to understand the reasons behind their failure to do so, when this occurs. We evaluated four loci, widely regarded as universal DNA barcodes for plants, for their utility in hawthorn species identification. Three plastid regions, matK, rbcLa and psbA-trnH, and the internal transcribed spacer 2 (ITS2) of nuclear ribosomal DNA discriminate only some of the species of Crataegus that can be recognized on the basis of their morphology etc. This is, in part, because in Rosaceae tribe Maleae most individual plastid loci yield relatively little taxonomic resolution and, in part, because the effects of allopolyploidization have not been eliminated by concerted evolution of the ITS regions. Although individual plastid markers provided generally poor resolution of taxonomic groups in Crataegus, a few species were notable exceptions. In contrast, analyses of concatenated sequences of the 3 plastid barcode loci plus 11 additional plastid loci gave a well-resolved maternal phylogeny. In the ITS2 tree, different individuals of some species formed groups with taxonomically unrelated species. This is a sign of lineage sorting due to incomplete concerted evolution in ITS2. Incongruence between the ITS2 and plastid trees is best explained by hybridization between different lineages within the genus. In aggregate, limited between-species variation in plastid loci, hybridization and a lack of concerted evolution in ITS2 all combine to limit the utility of standard barcoding markers in Crataegus. These results have implications for authentication of hawthorn materials in natural health products. PMID:25926325

Genome-wide association study identifies multiple loci influencing human serum metabolite levels

PubMed Central

Kettunen, Johannes; Tukiainen, Taru; Sarin, Antti-Pekka; Ortega-Alonso, Alfredo; Tikkanen, Emmi; Lyytikäinen, Leo-Pekka; Kangas, Antti J; Soininen, Pasi; Würtz, Peter; Silander, Kaisa; Dick, Danielle M; Rose, Richard J; Savolainen, Markku J; Viikari, Jorma; Kähönen, Mika; Lehtimäki, Terho; Pietiläinen, Kirsi H; Inouye, Michael; McCarthy, Mark I; Jula, Antti; Eriksson, Johan; Raitakari, Olli T; Salomaa, Veikko; Kaprio, Jaakko; Järvelin, Marjo-Riitta; Peltonen, Leena; Perola, Markus; Freimer, Nelson B; Ala-Korpela, Mika; Palotie, Aarno; Ripatti, Samuli

2013-01-01

Nuclear magnetic resonance assays allow for measurement of a wide range of metabolic phenotypes. We report here the results of a GWAS on 8,330 Finnish individuals genotyped and imputed at 7.7 million SNPs for a range of 216 serum metabolic phenotypes assessed by NMR of serum samples. We identified significant associations (P < 2.31 × 10−10) at 31 loci, including 11 for which there have not been previous reports of associations to a metabolic trait or disorder. Analyses of Finnish twin pairs suggested that the metabolic measures reported here show higher heritability than comparable conventional metabolic phenotypes. In accordance with our expectations, SNPs at the 31 loci associated with individual metabolites account for a greater proportion of the genetic component of trait variance (up to 40%) than is typically observed for conventional serum metabolic phenotypes. The identification of such associations may provide substantial insight into cardiometabolic disorders. PMID:22286219

Isolation and characterization of microsatellite markers for red elm (Ulmus rubra Muhl.) and cross-species amplification with Siberian elm (Ulmus pumila L.).

PubMed

Zalapa, J E; Brunet, J; Guries, R P

2008-01-01

Ulmus pumila is an elm species, non-native to the USA that hybridizes with Ulmus rubra. In order to study the genetic structure and hybridization patterns between these two elm species, we developed 15 primer pairs for microsatellite loci in U. rubra and tested their cross-amplification in U. pumila. All 15 primers amplified in both species, 11 of which possessed species-specific alleles. Eight loci were polymorphic in U. pumila and eight in U. rubra, each with two to eight alleles per locus. In addition, five primer pairs previously developed in U. laevis and U. carpinifolia (syn. U. minor) cross-amplified and showed polymorphic loci in U. pumila and/or U. rubra. These markers will facilitate the study of genetic structure and gene flow between U. rubra and exotic, invasive U. pumila. © 2007 Blackwell Publishing Ltd No claim to original US government works.

Expansion of 50 CAG/CTG repeats excluded in schizophrenia by application of a highly efficient approach using repeat expansion detection and a PCR screening set

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bowen, T.; Guy, C.; Speight, G.

Studies of the transmission of schizophrenia in families with affected members in several generations have suggested that an expanded trinucleotide repeat mechanism may contribute to the genetic inheritance of this disorder. Using repeat expansion detection (RED), we and others have previously found that the distribution of CAG/CTG repeat size is larger in patients with schizophrenia than in controls. In an attempt to identify the specific expanded CAG/CTG locus or loci associated with schizophrenia, we have now used an approach based on a CAG/CTG PCR screening set combined with RED data. This has allowed us to minimize genotyping while excluding 43more » polymorphic autosomal loci and 7 X-chromosomal loci from the screening set as candidates for expansion in schizophrenia with a very high degree of confidence. 18 refs., 1 tab.« less

The Aymara of Western Bolivia. IV. Gene frequencies for eight blood groups and 19 protein and erythrocyte enzyme systems.

PubMed Central

Ferrell, R E; Bertin, T; Young, R; Barton, S A; Murillo, F; Schull, W J

1978-01-01

A total of 315 individuals, mainly of Aymara origin, from western Bolivia were examined for genetic variation at eight red cell antigen and 19 serum protein and red cell enzyme loci. The gene frequencies for polymorphic loci and the discovery of several rare variants are discussed in terms of previous work among the Aymara and the closely related Quechua. The effect of inclusion of related individuals in the sample on gene frequency, variance of gene frequency and genetic distance, is discussed. Images Fig. 1 PMID:736042

Characterization of Deletions of the HBA and HBB Loci by Array Comparative Genomic Hybridization

PubMed Central

Sabath, Daniel E.; Bender, Michael A.; Sankaran, Vijay G.; Vamos, Esther; Kentsis, Alex; Yi, Hye-Son; Greisman, Harvey A.

2017-01-01

Thalassemia is among the most common genetic diseases worldwide. α-Thalassemia is usually caused by deletion of one or more of the duplicated HBA genes on chromosome 16. In contrast, most β-thalassemia results from point mutations that decrease or eliminate expression of the HBB gene on chromosome 11. Deletions within the HBB locus result in thalassemia or hereditary persistence of fetal Hb. Although routine diagnostic testing cannot distinguish thalassemia deletions from point mutations, deletional hereditary persistence of fetal Hb is notable for having an elevated HbF level with a normal mean corpuscular volume. A small number of deletions accounts for most α-thalassemias; in contrast, there are no predominant HBB deletions causing β-thalassemia. To facilitate the identification and characterization of deletions of the HBA and HBB globin loci, we performed array-based comparative genomic hybridization using a custom oligonucleotide microarray. We accurately mapped the breakpoints of known and previously uncharacterized HBB deletions defining previously uncharacterized deletion breakpoints by PCR amplification and sequencing. The array also successfully identified the common HBA deletions --SEA and --FIL. In summary, comparative genomic hybridization can be used to characterize deletions of the HBA and HBB loci, allowing high-resolution characterization of novel deletions that are not readily detected by PCR-based methods. PMID:26612711

Genome-wide association links candidate genes to resistance to Plum Pox Virus in apricot (Prunus armeniaca).

PubMed

Mariette, Stéphanie; Wong Jun Tai, Fabienne; Roch, Guillaume; Barre, Aurélien; Chague, Aurélie; Decroocq, Stéphane; Groppi, Alexis; Laizet, Yec'han; Lambert, Patrick; Tricon, David; Nikolski, Macha; Audergon, Jean-Marc; Abbott, Albert G; Decroocq, Véronique

2016-01-01

In fruit tree species, many important traits have been characterized genetically by using single-family descent mapping in progenies segregating for the traits. However, most mapped loci have not been sufficiently resolved to the individual genes due to insufficient progeny sizes for high resolution mapping and the previous lack of whole-genome sequence resources of the study species. To address this problem for Plum Pox Virus (PPV) candidate resistance gene identification in Prunus species, we implemented a genome-wide association (GWA) approach in apricot. This study exploited the broad genetic diversity of the apricot (Prunus armeniaca) germplasm containing resistance to PPV, next-generation sequence-based genotyping, and the high-quality peach (Prunus persica) genome reference sequence for single nucleotide polymorphism (SNP) identification. The results of this GWA study validated previously reported PPV resistance quantitative trait loci (QTL) intervals, highlighted other potential resistance loci, and resolved each to a limited set of candidate genes for further study. This work substantiates the association genetics approach for resolution of QTL to candidate genes in apricot and suggests that this approach could simplify identification of other candidate genes for other marked trait intervals in this germplasm. © 2015 INRA, UMR 1332 BFP New Phytologist © 2015 New Phytologist Trust.

Partial isodisomy for maternal chromosome 7 and short stature in an individual with a mutation at the COL1A2 locus.

PubMed

Spotila, L D; Sereda, L; Prockop, D J

1992-12-01

Uniparental disomy for chromosome 7 has been described previously in two individuals with cystic fibrosis. Here, we describe a third case that was discovered because the proband was homozygous for a mutation in the COL1A2 gene for type I procollagen, although his mother was heterozygous and his father did not have the mutation. Phenotypically, the proband was similar to the two previously reported cases with uniparental disomy for chromosome 7, in that he was short in stature and growth retarded. Paternity was assessed with five polymorphic markers. Chromosome 7 inheritance in the proband was analyzed using 12 polymorphic markers distributed along the entire chromosome. Similar analysis of the proband's two brothers established the phase of the alleles at the various loci, assuming minimal recombination. The proband inherited only maternal alleles at five loci and was homozygous at all loci examined, except one. He was heterozygous for an RFLP at the IGBP-1 locus at 7p13-p12. The results suggest that the isodisomy was not complete because of a recombination event involving the proximal short arms of two maternal chromosomes. In addition, the phenotype of proportional dwarfism in the proband suggests imprinting of one or more growth-related genes on chromosome 7.

Global survey of genomic imprinting by transcriptome sequencing.

PubMed

Babak, Tomas; Deveale, Brian; Armour, Christopher; Raymond, Christopher; Cleary, Michele A; van der Kooy, Derek; Johnson, Jason M; Lim, Lee P

2008-11-25

Genomic imprinting restricts gene expression to a paternal or maternal allele. To date, approximately 90 imprinted transcripts have been identified in mouse, of which the majority were detected after intense interrogation of clusters of imprinted genes identified by phenotype-driven assays in mice with uniparental disomies [1]. Here we use selective priming and parallel sequencing to measure allelic bias in whole transcriptomes. By distinguishing parent-of-origin bias from strain-specific bias in embryos derived from a reciprocal cross of mice, we constructed a genome-wide map of imprinted transcription. This map was able to objectively locate over 80% of known imprinted loci and allowed the detection and confirmation of six novel imprinted genes. Even in the intensely studied embryonic day 9.5 developmental stage that we analyzed, more than half of all imprinted single-nucleotide polymorphisms did not overlap previously discovered imprinted transcripts; a large fraction of these represent novel noncoding RNAs within known imprinted loci. For example, a previously unnoticed, maternally expressed antisense transcript was mapped within the Grb10 locus. This study demonstrates the feasibility of using transcriptome sequencing for mapping of imprinted gene expression in physiologically normal animals. Such an approach will allow researchers to study imprinting without restricting themselves to individual loci or specific transcripts.

A Meta-Analysis of Genome-Wide Association Scans Identifies IL18RAP, PTPN2, TAGAP, and PUS10 As Shared Risk Loci for Crohn's Disease and Celiac Disease

PubMed Central

Boucher, Gabrielle; Beauchamp, Claudine; Trynka, Gosia; Dubois, Patrick C.; Lagacé, Caroline; Stokkers, Pieter C. F.; Hommes, Daan W.; Barisani, Donatella; Palmieri, Orazio; Annese, Vito; van Heel, David A.; Weersma, Rinse K.; Daly, Mark J.; Wijmenga, Cisca; Rioux, John D.

2011-01-01

Crohn's disease (CD) and celiac disease (CelD) are chronic intestinal inflammatory diseases, involving genetic and environmental factors in their pathogenesis. The two diseases can co-occur within families, and studies suggest that CelD patients have a higher risk to develop CD than the general population. These observations suggest that CD and CelD may share common genetic risk loci. Two such shared loci, IL18RAP and PTPN2, have already been identified independently in these two diseases. The aim of our study was to explicitly identify shared risk loci for these diseases by combining results from genome-wide association study (GWAS) datasets of CD and CelD. Specifically, GWAS results from CelD (768 cases, 1,422 controls) and CD (3,230 cases, 4,829 controls) were combined in a meta-analysis. Nine independent regions had nominal association p-value <1.0×10−5 in this meta-analysis and showed evidence of association to the individual diseases in the original scans (p-value <1×10−2 in CelD and <1×10−3 in CD). These include the two previously reported shared loci, IL18RAP and PTPN2, with p-values of 3.37×10−8 and 6.39×10−9, respectively, in the meta-analysis. The other seven had not been reported as shared loci and thus were tested in additional CelD (3,149 cases and 4,714 controls) and CD (1,835 cases and 1,669 controls) cohorts. Two of these loci, TAGAP and PUS10, showed significant evidence of replication (Bonferroni corrected p-values <0.0071) in the combined CelD and CD replication cohorts and were firmly established as shared risk loci of genome-wide significance, with overall combined p-values of 1.55×10−10 and 1.38×10−11 respectively. Through a meta-analysis of GWAS data from CD and CelD, we have identified four shared risk loci: PTPN2, IL18RAP, TAGAP, and PUS10. The combined analysis of the two datasets provided the power, lacking in the individual GWAS for single diseases, to detect shared loci with a relatively small effect. PMID:21298027

Molecular Evolution Perspectives on Intraspecific Lateral DNA Transfer of Topoisomerase and Gyrase Loci in Streptococcus pneumoniae, with Implications for Fluoroquinolone Resistance Development and Spread

PubMed Central

Stanhope, Michael J.; Walsh, Stacey L.; Becker, Julie A.; Italia, Michael J.; Ingraham, Karen A.; Gwynn, Michael N.; Mathie, Tom; Poupard, James A.; Miller, Linda A.; Brown, James R.; Amrine-Madsen, Heather

2005-01-01

Fluoroquinolones are an important class of antibiotics for the treatment of infections arising from the gram-positive respiratory pathogen Streptococcus pneumoniae. Although there is evidence supporting interspecific lateral DNA transfer of fluoroquinolone target loci, no studies have specifically been designed to assess the role of intraspecific lateral transfer of these genes in the spread of fluoroquinolone resistance. This study involves a comparative evolutionary perspective, in which the evolutionary history of a diverse set of S. pneumoniae clinical isolates is reconstructed from an expanded multilocus sequence typing data set, with putative recombinants excluded. This control history is then assessed against networks of each of the four fluoroquinolone target loci from the same isolates. The results indicate that although the majority of fluoroquinolone target loci from this set of 60 isolates are consistent with a clonal dissemination hypothesis, 3 to 10% of the sequences are consistent with an intraspecific lateral transfer hypothesis. Also evident were examples of interspecific transfer, with two isolates possessing a parE-parC gene region arising from viridans group streptococci. The Spain 23F-1 clone is the most dominant fluoroquinolone-nonsusceptible clone in this set of isolates, and the analysis suggests that its members act as frequent donors of fluoroquinolone-nonsusceptible loci. Although the majority of fluoroquinolone target gene sequences in this set of isolates can be explained on the basis of clonal dissemination, a significant number are more parsimoniously explained by intraspecific lateral DNA transfer, and in situations of high S. pneumoniae population density, such events could be an important means of resistance spread. PMID:16189113

Locus category based analysis of a large genome-wide association study of rheumatoid arthritis

PubMed Central

Freudenberg, Jan; Lee, Annette T.; Siminovitch, Katherine A.; Amos, Christopher I.; Ballard, David; Li, Wentian; Gregersen, Peter K.

2010-01-01

To pinpoint true positive single-nucleotide polymorphism (SNP) associations in a genome-wide association study (GWAS) of rheumatoid arthritis (RA), we categorize genetic loci by external knowledge. We test both the ‘enrichment of associated loci’ in a locus category and the ‘combined association’ of a locus category. The former is quantified by the odds ratio for the presence of SNP associations at the loci of a category, whereas the latter is quantified by the number of loci in a category that have SNP associations. These measures are compared with their expected values as obtained from the permutation of the affection status. To account for linkage disequilibrium (LD) among SNPs, we view each LD block as a genetic locus. Positional candidates were defined as loci implicated by earlier GWAS results, whereas functional candidates were defined by annotations regarding the molecular roles of genes, such as gene ontology categories. As expected, immune-related categories show the largest enrichment signal, although it is not very strong. The intersection of positional and functional candidate information predicts novel RA loci near the genes TEC/TXK, MBL2 and PIK3R1/CD180. Notably, a combined association signal is not only produced by immune-related categories, but also by most other categories and even randomly defined categories. The unspecific quality of these signals limits the possible conclusions from combined association tests. It also reduces the magnitude of enrichment test results. These unspecific signals might result from common variants of small effect and hardly concentrated in candidate categories, or an inflated size of associated regions from weak LD with infrequent mutations. PMID:20639398

Association Studies of Sporadic Parkinson’s Disease in the Genomic Era

PubMed Central

Labbé, Catherine; Ross, Owen A

2014-01-01

Parkinson’s disease is a common age-related progressive neurodegenerative disorder. Over the last 10 years, advances have been made in our understanding of the etiology of the disease with the greatest insights perhaps coming from genetic studies, including genome-wide association approaches. These large scale studies allow the identification of genomic regions harboring common variants associated to disease risk. Since the first genome-wide association study on sporadic Parkinson’s disease performed in 2005, improvements in study design, including the advent of meta-analyses, have allowed the identification of ~21 susceptibility loci. The first loci to be nominated were previously associated to familial PD (SNCA, MAPT, LRRK2) and these have been extensively replicated. For other more recently identified loci (SREBF1, SCARB2, RIT2) independent replication is still warranted. Cumulative risk estimates of associated variants suggest that more loci are still to be discovered. Additional association studies combined with deep re-sequencing of known genome-wide association study loci are necessary to identify the functional variants that drive disease risk. As each of these associated genes and variants are identified they will give insight into the biological pathways involved the etiology of Parkinson’s disease. This will ultimately lead to the identification of molecules that can be used as biomarkers for diagnosis and as targets for the development of better, personalized treatment. PMID:24653658

Analysis of RDR1/RDR2/RDR6-independent small RNAs in Arabidopsis thaliana improves MIRNA annotations and reveals unexplained types of short interfering RNA loci.

PubMed

Polydore, Seth; Axtell, Michael J

2018-06-01

Plant small RNAs (sRNAs) modulate key physiological mechanisms through post-transcriptional and transcriptional silencing of gene expression. Small RNAs fall into two major categories: those are reliant on RNA-dependent RNA polymerases (RDRs) for biogenesis and those that are not. Known RDR1/2/6-dependent sRNAs include phased and repeat-associated short interfering RNAs, while known RDR1/2/6-independent sRNAs are primarily microRNAs (miRNA) and other hairpin-derived sRNAs. In this study we produced and analyzed sRNA-seq libraries from rdr1/rdr2/rdr6 triple mutant plants. We found 58 previously annotated miRNA loci that were reliant on RDR1, -2, or -6 function, casting doubt on their classification. We also found 38 RDR1/2/6-independent sRNA loci that are not MIRNAs or otherwise hairpin-derived, and did not fit into other known paradigms for sRNA biogenesis. These 38 sRNA-producing loci have as-yet-undescribed biogenesis mechanisms, and are frequently located in the vicinity of protein-coding genes. Altogether, our analysis suggests that these 38 loci represent one or more undescribed types of sRNA in Arabidopsis thaliana. © 2018 The Authors The Plant Journal © 2018 John Wiley & Sons Ltd.

Identification of multi-loci hubs from 4C-seq demonstrates the functional importance of simultaneous interactions.

PubMed

Jiang, Tingting; Raviram, Ramya; Snetkova, Valentina; Rocha, Pedro P; Proudhon, Charlotte; Badri, Sana; Bonneau, Richard; Skok, Jane A; Kluger, Yuval

2016-10-14

Use of low resolution single cell DNA FISH and population based high resolution chromosome conformation capture techniques have highlighted the importance of pairwise chromatin interactions in gene regulation. However, it is unlikely that associations involving regulatory elements act in isolation of other interacting partners that also influence their impact. Indeed, the influence of multi-loci interactions remains something of an enigma as beyond low-resolution DNA FISH we do not have the appropriate tools to analyze these. Here we present a method that uses standard 4C-seq data to identify multi-loci interactions from the same cell. We demonstrate the feasibility of our method using 4C-seq data sets that identify known pairwise and novel tri-loci interactions involving the Tcrb and Igk antigen receptor enhancers. We further show that the three Igk enhancers, MiEκ, 3'Eκ and Edκ, interact simultaneously in this super-enhancer cluster, which add to our previous findings showing that loss of one element decreases interactions between all three elements as well as reducing their transcriptional output. These findings underscore the functional importance of simultaneous interactions and provide new insight into the relationship between enhancer elements. Our method opens the door for studying multi-loci interactions and their impact on gene regulation in other biological settings. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Identification of multi-loci hubs from 4C-seq demonstrates the functional importance of simultaneous interactions

PubMed Central

Jiang, Tingting; Raviram, Ramya; Snetkova, Valentina; Rocha, Pedro P.; Proudhon, Charlotte; Badri, Sana; Bonneau, Richard; Skok, Jane A.; Kluger, Yuval

2016-01-01

Use of low resolution single cell DNA FISH and population based high resolution chromosome conformation capture techniques have highlighted the importance of pairwise chromatin interactions in gene regulation. However, it is unlikely that associations involving regulatory elements act in isolation of other interacting partners that also influence their impact. Indeed, the influence of multi-loci interactions remains something of an enigma as beyond low-resolution DNA FISH we do not have the appropriate tools to analyze these. Here we present a method that uses standard 4C-seq data to identify multi-loci interactions from the same cell. We demonstrate the feasibility of our method using 4C-seq data sets that identify known pairwise and novel tri-loci interactions involving the Tcrb and Igk antigen receptor enhancers. We further show that the three Igk enhancers, MiEκ, 3′Eκ and Edκ, interact simultaneously in this super-enhancer cluster, which add to our previous findings showing that loss of one element decreases interactions between all three elements as well as reducing their transcriptional output. These findings underscore the functional importance of simultaneous interactions and provide new insight into the relationship between enhancer elements. Our method opens the door for studying multi-loci interactions and their impact on gene regulation in other biological settings. PMID:27439714

A radiation hybrid map of the distal short arm of human chromosome II, containing the Beckwith-Weidemann and associated embroyonal tumor disease loci

DOE Office of Scientific and Technical Information (OSTI.GOV)

Richard, C.W. III; Berg, D.J.; Meeker, T.C.

1993-05-01

The authors describe a high-resolution radiation hybrid (RH) map of the distal short arm of human chromosome 11 containing the Beckwith-Weidemann gene and the associated embryonal tumor disease loci. Thirteen human 11p15 genes and 17 new anonymous probes were mapped by a statistical analysis of the cosegregation of markers in 102 rodent-human radiation hybrids retaining fragments of human chromosome 11. The 17 anonymous probes were generated from lambda phage containing human 11p15.5 inserts, by using ALU-PCR. A comprehensive map of all 30 loci and a framework map of nine clusters of loci ordered at odds of 1,000:1 were constructed bymore » a multipoint maximum-likelihood approach by using the computer program RHMAP. This RH map localizes one new gene to chromosome 11p15 (WEE1), provides more precise order information for several 11p15 genes (CTSD, H19, HPX,.ST5, RNH, and SMPD1), confirms previous map orders for other 11p15 genes (CALCA, PTH, HBBC, TH, HRAS, and DRD4), and maps 17 new anonymous probes within the 11p15.5 region. This RH map should prove useful in better defining the positions of the Beckwith-Weidemann and associated embryonal tumor disease-gene loci. 41 refs., 1 fig., 2 tabs.« less

Activation of int-1 and int-2 loci in GRf mammary tumors.

PubMed

Gray, D A; Jackson, D P; Percy, D H; Morris, V L

1986-10-30

The Mtv-2 locus is known to be associated with a high mammary tumor incidence (97%) and early development of mammary tumors (3-13 months) in GR mice. However, it was not previously known whether the provirus which resides at the Mtv-2 locus is tumorigenic in and of itself or whether reintegration of proviruses generated from Mtv-2 is required for tumorigenesis. Foster-nursing GR mice on C57/BL mice eliminates the milk-borne source of GR virus, and allows the study of Mtv-2 derived proviruses alone. Using this approach, we have tested predictions which follow from the "positional" versus "reintegrational" models of tumorigenesis. Specifically, we have examined tumors from primary foster-nursed (GRf) mice to determine if MMTV proviruses derived from Mtv-2 were scattered randomly throughout the genome or were clustered in the vicinity of the int-1 and int-2 loci, which are thought to be associated with mammary tumorigenesis. It was found that the majority of spontaneous GRf mammary tumors that were tested have MMTV proviral integrations in either or both of the int-1 and int-2 loci and have transcription of either or both of the int loci. Tumors induced by Mtv-2, therefore, appear to have arisen via a mechanism similar to the activation of the int loci by exogenous (milk-borne) MMTV proviruses.

A genome-wide association study reveals novel elite allelic variations in seed oil content of Brassica napus.

PubMed

Liu, Sheng; Fan, Chuchuan; Li, Jiana; Cai, Guangqin; Yang, Qingyong; Wu, Jian; Yi, Xinqi; Zhang, Chunyu; Zhou, Yongming

2016-06-01

A set of additive loci for seed oil content were identified using association mapping and one of the novel loci on the chromosome A5 was validated by linkage mapping. Increasing seed oil content is one of the most important goals in the breeding of oilseed crops including Brassica napus, yet the genetic basis for variations in this important trait remains unclear. By genome-wide association study of seed oil content using 521 B. napus accessions genotyped with the Brassica 60K SNP array, we identified 50 loci significantly associated with seed oil content using three statistical models, the general linear model, the mixed linear model and the Anderson-Darling test. Together, the identified loci could explain approximately 80 % of the total phenotypic variance, and 29 of these loci have not been reported previously. Furthermore, a novel locus on the chromosome A5 that could increase 1.5-1.7 % of seed oil content was validated in an independent bi-parental linkage population. Haplotype analysis showed that the favorable alleles for seed oil content exhibit cumulative effects. Our results thus provide valuable information for understanding the genetic control of seed oil content in B. napus and may facilitate marker-based breeding for a higher seed oil content in this important oil crop.

Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol-response Behaviors in Model Organisms

PubMed Central

Adkins, Amy E.; Hack, Laura M.; Bigdeli, Tim B.; Williamson, Vernell S.; McMichael, G. Omari; Mamdani, Mohammed; Edwards, Alexis; Aliev, Fazil; Chan, Robin F.; Bhandari, Poonam; Raabe, Richard C.; Alaimo, Joseph T.; Blackwell, GinaMari G.; Moscati, Arden A.; Poland, Ryan S.; Rood, Benjamin; Patterson, Diana G.; Walsh, Dermot; Whitfield, John B.; Zhu, Gu; Montgomery, Grant W.; Henders, Anjali K.; Martin, Nicholas G.; Heath, Andrew C.; Madden, Pamela A.F.; Frank, Josef; Ridinger, Monika; Wodarz, Norbert; Soyka, Michael; Zill, Peter; Ising, Marcus; Nöthen, Markus M; Kiefer, Falk; Rietschel, Marcella; Gelernter, Joel; Sherva, Richard; Koesterer, Ryan; Almasy, Laura; Zhao, Hongyu; Kranzler, Henry R.; Farrer, Lindsay A.; Maher, Brion S.; Prescott, Carol A.; Dick, Danielle M.; Bacanu, Silviu A.; Mathies, Laura D.; Davies, Andrew G.; Vladimirov, Vladimir I.; Grotewiel, Mike; Bowers, M. Scott; Bettinger, Jill C.; Webb, Bradley T.; Miles, Michael F.; Kendler, Kenneth S.; Riley, Brien P.

2017-01-01

Background Alcohol Dependence (AD) shows evidence for genetic liability, but genes influencing risk remain largely unidentified. Methods We conducted a genomewide association study in 706 related AD cases and 1748 unscreened population controls from Ireland. We sought replication in 15,496 samples of European descent. We used model organisms to assess the role of orthologous genes in ethanol response behaviors. We tested one primate-specific gene for expression differences in case/control post-mortem brain tissue. Results We detected significant association in COL6A3 and suggestive association in two previously implicated loci, KLF12 and RYR3. None of these signals are significant in replication. A suggestive signal in the long noncoding RNA LOC339975 is significant in case:control meta-analysis, but not in a population sample. Knockdown of a COL6A3 ortholog in C. elegans reduced ethanol sensitivity. Col6a3 expression correlated with handling-induced convulsions in mice. Loss of function of the KLF12 ortholog in C. elegans impaired development of acute functional tolerance. Klf12 expression correlated with locomotor activation following ethanol injection in mice. Loss of function of the RYR3 ortholog reduced ethanol sensitivity in C. elegans and rapid tolerance in Drosophila. The ryanodine receptor antagonist dantrolene reduced motivation to self-administer ethanol in rats. Expression of LOC339975 does not differ between cases and controls but is reduced in carriers of the associated rs11726136 allele in nucleus accumbens. Conclusions We detect association between AD and COL6A3, KLF12, RYR3 and LOC339975. Despite non-replication of COL6A3, KLF12 and RYR3 signals, orthologs of these genes influence behavioral response to ethanol in model organisms, suggesting potential involvement in human ethanol response and AD liability. The associated LOC339975 allele may influence gene expression in human nucleus accumbens. Although the functions of long noncoding RNAs are poorly understood, there is mounting evidence implicating these genes in multiple brain functions and disorders. PMID:28226201

Function of YY1 in Long-Distance DNA Interactions

PubMed Central

Atchison, Michael L.

2014-01-01

During B cell development, long-distance DNA interactions are needed for V(D)J somatic rearrangement of the immunoglobulin (Ig) loci to produce functional Ig genes, and for class switch recombination (CSR) needed for antibody maturation. The tissue-specificity and developmental timing of these mechanisms is a subject of active investigation. A small number of factors are implicated in controlling Ig locus long-distance interactions including Pax5, Yin Yang 1 (YY1), EZH2, IKAROS, CTCF, cohesin, and condensin proteins. Here we will focus on the role of YY1 in controlling these mechanisms. YY1 is a multifunctional transcription factor involved in transcriptional activation and repression, X chromosome inactivation, Polycomb Group (PcG) protein DNA recruitment, and recruitment of proteins required for epigenetic modifications (acetylation, deacetylation, methylation, ubiquitination, sumoylation, etc.). YY1 conditional knock-out indicated that YY1 is required for B cell development, at least in part, by controlling long-distance DNA interactions at the immunoglobulin heavy chain and Igκ loci. Our recent data show that YY1 is also required for CSR. The mechanisms implicated in YY1 control of long-distance DNA interactions include controlling non-coding antisense RNA transcripts, recruitment of PcG proteins to DNA, and interaction with complexes involved in long-distance DNA interactions including the cohesin and condensin complexes. Though common rearrangement mechanisms operate at all Ig loci, their distinct temporal activation along with the ubiquitous nature of YY1 poses challenges for determining the specific mechanisms of YY1 function in these processes, and their regulation at the tissue-specific and B cell stage-specific level. The large numbers of post-translational modifications that control YY1 functions are possible candidates for regulation. PMID:24575094

Genome-Wide Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of Type 2 Diabetes

PubMed Central

Strawbridge, Rona J.; Dupuis, Josée; Prokopenko, Inga; Barker, Adam; Ahlqvist, Emma; Rybin, Denis; Petrie, John R.; Travers, Mary E.; Bouatia-Naji, Nabila; Dimas, Antigone S.; Nica, Alexandra; Wheeler, Eleanor; Chen, Han; Voight, Benjamin F.; Taneera, Jalal; Kanoni, Stavroula; Peden, John F.; Turrini, Fabiola; Gustafsson, Stefan; Zabena, Carina; Almgren, Peter; Barker, David J.P.; Barnes, Daniel; Dennison, Elaine M.; Eriksson, Johan G.; Eriksson, Per; Eury, Elodie; Folkersen, Lasse; Fox, Caroline S.; Frayling, Timothy M.; Goel, Anuj; Gu, Harvest F.; Horikoshi, Momoko; Isomaa, Bo; Jackson, Anne U.; Jameson, Karen A.; Kajantie, Eero; Kerr-Conte, Julie; Kuulasmaa, Teemu; Kuusisto, Johanna; Loos, Ruth J.F.; Luan, Jian'an; Makrilakis, Konstantinos; Manning, Alisa K.; Martínez-Larrad, María Teresa; Narisu, Narisu; Nastase Mannila, Maria; Öhrvik, John; Osmond, Clive; Pascoe, Laura; Payne, Felicity; Sayer, Avan A.; Sennblad, Bengt; Silveira, Angela; Stančáková, Alena; Stirrups, Kathy; Swift, Amy J.; Syvänen, Ann-Christine; Tuomi, Tiinamaija; van 't Hooft, Ferdinand M.; Walker, Mark; Weedon, Michael N.; Xie, Weijia; Zethelius, Björn; Ongen, Halit; Mälarstig, Anders; Hopewell, Jemma C.; Saleheen, Danish; Chambers, John; Parish, Sarah; Danesh, John; Kooner, Jaspal; Östenson, Claes-Göran; Lind, Lars; Cooper, Cyrus C.; Serrano-Ríos, Manuel; Ferrannini, Ele; Forsen, Tom J.; Clarke, Robert; Franzosi, Maria Grazia; Seedorf, Udo; Watkins, Hugh; Froguel, Philippe; Johnson, Paul; Deloukas, Panos; Collins, Francis S.; Laakso, Markku; Dermitzakis, Emmanouil T.; Boehnke, Michael; McCarthy, Mark I.; Wareham, Nicholas J.; Groop, Leif; Pattou, François; Gloyn, Anna L.; Dedoussis, George V.; Lyssenko, Valeriya; Meigs, James B.; Barroso, Inês; Watanabe, Richard M.; Ingelsson, Erik; Langenberg, Claudia; Hamsten, Anders; Florez, Jose C.

2011-01-01

OBJECTIVE Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10−8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10−4), improved β-cell function (P = 1.1 × 10−5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10−6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis. PMID:21873549

Genetic variants underlying risk of endometriosis: insights from meta-analysis of eight genome-wide association and replication datasets

PubMed Central

Rahmioglu, Nilufer; Nyholt, Dale R.; Morris, Andrew P.; Missmer, Stacey A.; Montgomery, Grant W.; Zondervan, Krina T.

2014-01-01

BACKGROUND Endometriosis is a heritable common gynaecological condition influenced by multiple genetic and environmental factors. Genome-wide association studies (GWASs) have proved successful in identifying common genetic variants of moderate effects for various complex diseases. To date, eight GWAS and replication studies from multiple populations have been published on endometriosis. In this review, we investigate the consistency and heterogeneity of the results across all the studies and their implications for an improved understanding of the aetiology of the condition. METHODS Meta-analyses were conducted on four GWASs and four replication studies including a total of 11 506 cases and 32 678 controls, and on the subset of studies that investigated associations for revised American Fertility Society (rAFS) Stage III/IV including 2859 cases. The datasets included 9039 cases and 27 343 controls of European (Australia, Belgium, Italy, UK, USA) and 2467 cases and 5335 controls of Japanese ancestry. Fixed and Han and Elkin random-effects models, and heterogeneity statistics (Cochran's Q test), were used to investigate the evidence of the nine reported genome-wide significant loci across datasets and populations. RESULTS Meta-analysis showed that seven out of nine loci had consistent directions of effect across studies and populations, and six out of nine remained genome-wide significant (P < 5 × 10−8), including rs12700667 on 7p15.2 (P = 1.6 × 10−9), rs7521902 near WNT4 (P = 1.8 × 10−15), rs10859871 near VEZT (P = 4.7 × 10−15), rs1537377 near CDKN2B-AS1 (P = 1.5 × 10−8), rs7739264 near ID4 (P = 6.2 × 10−10) and rs13394619 in GREB1 (P = 4.5 × 10−8). In addition to the six loci, two showed borderline genome-wide significant associations with Stage III/IV endometriosis, including rs1250248 in FN1 (P = 8 × 10−8) and rs4141819 on 2p14 (P = 9.2 × 10−8). Two independent inter-genic loci, rs4141819 and rs6734792 on chromosome 2, showed significant evidence of heterogeneity across datasets (P < 0.005). Eight of the nine loci had stronger effect sizes among Stage III/IV cases, implying that they are likely to be implicated in the development of moderate to severe, or ovarian, disease. While three out of nine loci were inter-genic, the remaining were in or near genes with known functions of biological relevance to endometriosis, varying from roles in developmental pathways to cellular growth/carcinogenesis. CONCLUSIONS Our meta-analysis shows remarkable consistency in endometriosis GWAS results across studies, with little evidence of population-based heterogeneity. They also show that the phenotypic classifications used in GWAS to date have been limited. Stronger associations with Stage III/IV disease observed for most loci emphasize the importance for future studies to include detailed sub-phenotype information. Functional studies in relevant tissues are needed to understand the effect of the variants on downstream biological pathways. PMID:24676469

Eleven loci with new reproducible genetic associations with allergic disease risk.

PubMed

Ferreira, Manuel A R; Vonk, Judith M; Baurecht, Hansjörg; Marenholz, Ingo; Tian, Chao; Hoffman, Joshua D; Helmer, Quinta; Tillander, Annika; Ullemar, Vilhelmina; Lu, Yi; Rüschendorf, Franz; Hinds, David A; Hübner, Norbert; Weidinger, Stephan; Magnusson, Patrik K E; Jorgenson, Eric; Lee, Young-Ae; Boomsma, Dorret I; Karlsson, Robert; Almqvist, Catarina; Koppelman, Gerard H; Paternoster, Lavinia

2018-04-19

A recent genome-wide association study (GWAS) identified 99 loci that contain genetic risk variants shared between asthma, hay fever, and eczema. Many more risk loci shared between these common allergic diseases remain to be discovered, which could point to new therapeutic opportunities. We sought to identify novel risk loci shared between asthma, hay fever, and eczema by applying a gene-based test of association to results from a published GWAS that included data from 360,838 subjects. We used approximate conditional analysis to adjust the results from the published GWAS for the effects of the top risk variants identified in that study. We then analyzed the adjusted GWAS results with the EUGENE gene-based approach, which combines evidence for association with disease risk across regulatory variants identified in different tissues. Novel gene-based associations were followed up in an independent sample of 233,898 subjects from the UK Biobank study. Of the 19,432 genes tested, 30 had a significant gene-based association at a Bonferroni-corrected P value of 2.5 × 10 -6 . Of these, 20 were also significantly associated (P < .05/30 = .0016) with disease risk in the replication sample, including 19 that were located in 11 loci not reported to contain allergy risk variants in previous GWASs. Among these were 9 genes with a known function that is directly relevant to allergic disease: FOSL2, VPRBP, IPCEF1, PRR5L, NCF4, APOBR, IL27, ATXN2L, and LAT. For 4 genes (eg, ATXN2L), a genetically determined decrease in gene expression was associated with decreased allergy risk, and therefore drugs that inhibit gene expression or function are predicted to ameliorate disease symptoms. The opposite directional effect was observed for 14 genes, including IL27, a cytokine known to suppress T H 2 responses. Using a gene-based approach, we identified 11 risk loci for allergic disease that were not reported in previous GWASs. Functional studies that investigate the contribution of the 19 associated genes to the pathophysiology of allergic disease and assess their therapeutic potential are warranted. Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Mapping eQTLs in the Norfolk Island Genetic Isolate Identifies Candidate Genes for CVD Risk Traits

PubMed Central

Benton, Miles C.; Lea, Rod A.; Macartney-Coxson, Donia; Carless, Melanie A.; Göring, Harald H.; Bellis, Claire; Hanna, Michelle; Eccles, David; Chambers, Geoffrey K.; Curran, Joanne E.; Harper, Jacquie L.; Blangero, John; Griffiths, Lyn R.

2013-01-01

Cardiovascular disease (CVD) affects millions of people worldwide and is influenced by numerous factors, including lifestyle and genetics. Expression quantitative trait loci (eQTLs) influence gene expression and are good candidates for CVD risk. Founder-effect pedigrees can provide additional power to map genes associated with disease risk. Therefore, we identified eQTLs in the genetic isolate of Norfolk Island (NI) and tested for associations between these and CVD risk factors. We measured genome-wide transcript levels of blood lymphocytes in 330 individuals and used pedigree-based heritability analysis to identify heritable transcripts. eQTLs were identified by genome-wide association testing of these transcripts. Testing for association between CVD risk factors (i.e., blood lipids, blood pressure, and body fat indices) and eQTLs revealed 1,712 heritable transcripts (p < 0.05) with heritability values ranging from 0.18 to 0.84. From these, we identified 200 cis-acting and 70 trans-acting eQTLs (p < 1.84 × 10−7) An eQTL-centric analysis of CVD risk traits revealed multiple associations, including 12 previously associated with CVD-related traits. Trait versus eQTL regression modeling identified four CVD risk candidates (NAAA, PAPSS1, NME1, and PRDX1), all of which have known biological roles in disease. In addition, we implicated several genes previously associated with CVD risk traits, including MTHFR and FN3KRP. We have successfully identified a panel of eQTLs in the NI pedigree and used this to implicate several genes in CVD risk. Future studies are required for further assessing the functional importance of these eQTLs and whether the findings here also relate to outbred populations. PMID:24314549

The genetic basis of music ability

PubMed Central

Tan, Yi Ting; McPherson, Gary E.; Peretz, Isabelle; Berkovic, Samuel F.; Wilson, Sarah J.

2014-01-01

Music is an integral part of the cultural heritage of all known human societies, with the capacity for music perception and production present in most people. Researchers generally agree that both genetic and environmental factors contribute to the broader realization of music ability, with the degree of music aptitude varying, not only from individual to individual, but across various components of music ability within the same individual. While environmental factors influencing music development and expertise have been well investigated in the psychological and music literature, the interrogation of possible genetic influences has not progressed at the same rate. Recent advances in genetic research offer fertile ground for exploring the genetic basis of music ability. This paper begins with a brief overview of behavioral and molecular genetic approaches commonly used in human genetic analyses, and then critically reviews the key findings of genetic investigations of the components of music ability. Some promising and converging findings have emerged, with several loci on chromosome 4 implicated in singing and music perception, and certain loci on chromosome 8q implicated in absolute pitch and music perception. The gene AVPR1A on chromosome 12q has also been implicated in music perception, music memory, and music listening, whereas SLC6A4 on chromosome 17q has been associated with music memory and choir participation. Replication of these results in alternate populations and with larger samples is warranted to confirm the findings. Through increased research efforts, a clearer picture of the genetic mechanisms underpinning music ability will hopefully emerge. PMID:25018744

Pantoea ananatis Genetic Diversity Analysis Reveals Limited Genomic Diversity as Well as Accessory Genes Correlated with Onion Pathogenicity.

PubMed

Stice, Shaun P; Stumpf, Spencer D; Gitaitis, Ron D; Kvitko, Brian H; Dutta, Bhabesh

2018-01-01

Pantoea ananatis is a member of the family Enterobacteriaceae and an enigmatic plant pathogen with a broad host range. Although P. ananatis strains can be aggressive on onion causing foliar necrosis and onion center rot, previous genomic analysis has shown that P. ananatis lacks the primary virulence secretion systems associated with other plant pathogens. We assessed a collection of fifty P. ananatis strains collected from Georgia over three decades to determine genetic factors that correlated with onion pathogenic potential. Previous genetic analysis studies have compared strains isolated from different hosts with varying diseases potential and isolation sources. Strains varied greatly in their pathogenic potential and aggressiveness on different cultivated Allium species like onion, leek, shallot, and chive. Using multi-locus sequence analysis (MLSA) and repetitive extragenic palindrome repeat (rep)-PCR techniques, we did not observe any correlation between onion pathogenic potential and genetic diversity among strains. Whole genome sequencing and pan-genomic analysis of a sub-set of 10 strains aided in the identification of a novel series of genetic regions, likely plasmid borne, and correlating with onion pathogenicity observed on single contigs of the genetic assemblies. We named these loci Onion Virulence Regions (OVR) A-D. The OVR loci contain genes involved in redox regulation as well as pectate lyase and rhamnogalacturonase genes. Previous studies have not identified distinct genetic loci or plasmids correlating with onion foliar pathogenicity or pathogenicity on a single host pathosystem. The lack of focus on a single host system for this phytopathgenic disease necessitates the pan-genomic analysis performed in this study.

Characterization of novel sorghum brown midrib mutants from an EMS-mutagenized population

DOE PAGES

Sattler, Scott E.; Saballos, Ana; Xin, Zhanguo; ...

2014-09-02

Reducing lignin concentration in lignocellulosic biomass can increase forage digestibility for ruminant livestock and saccharification yields of biomass for bioenergy. In sorghum ( Sorghum bicolor (L.) Moench) and several other C4 grasses, brown midrib ( bmr) mutants have been shown to reduce lignin concentration. Putative bmr mutants isolated from an EMS-mutagenized population were characterized and classified based on their leaf midrib phenotype and allelism tests with the previously described sorghum bmr mutants bmr2, bmr6, and bmr12. These tests resulted in the identification of additional alleles of bmr2, bmr6,and bmr12, and, in addition, six bmr mutants were identified that were notmore » allelic to these previously described loci. Further allelism testing among these six bmr mutants showed that they represented four novel bmr loci. Based on this study, the number of bmr loci uncovered in sorghum has doubled. The impact of these lines on agronomic traits and lignocellulosic composition was assessed in a 2-yr field study. Most of the identified bmr lines showed reduced lignin concentration of their biomass relative to wild-type (WT). Effects of the six new bmr mutants on enzymatic saccharification of lignocellulosic materials were determined, but the amount of glucose released from the stover was similar to WT in all cases. Like bmr2, bmr6, and bmr12, these mutants may affect monolignol biosynthesis and may be useful for bioenergy and forage improvement when stacked together or in combination with the three previously described bmr alleles.« less

Pantoea ananatis Genetic Diversity Analysis Reveals Limited Genomic Diversity as Well as Accessory Genes Correlated with Onion Pathogenicity

PubMed Central

Stice, Shaun P.; Stumpf, Spencer D.; Gitaitis, Ron D.; Kvitko, Brian H.; Dutta, Bhabesh

2018-01-01

Pantoea ananatis is a member of the family Enterobacteriaceae and an enigmatic plant pathogen with a broad host range. Although P. ananatis strains can be aggressive on onion causing foliar necrosis and onion center rot, previous genomic analysis has shown that P. ananatis lacks the primary virulence secretion systems associated with other plant pathogens. We assessed a collection of fifty P. ananatis strains collected from Georgia over three decades to determine genetic factors that correlated with onion pathogenic potential. Previous genetic analysis studies have compared strains isolated from different hosts with varying diseases potential and isolation sources. Strains varied greatly in their pathogenic potential and aggressiveness on different cultivated Allium species like onion, leek, shallot, and chive. Using multi-locus sequence analysis (MLSA) and repetitive extragenic palindrome repeat (rep)-PCR techniques, we did not observe any correlation between onion pathogenic potential and genetic diversity among strains. Whole genome sequencing and pan-genomic analysis of a sub-set of 10 strains aided in the identification of a novel series of genetic regions, likely plasmid borne, and correlating with onion pathogenicity observed on single contigs of the genetic assemblies. We named these loci Onion Virulence Regions (OVR) A-D. The OVR loci contain genes involved in redox regulation as well as pectate lyase and rhamnogalacturonase genes. Previous studies have not identified distinct genetic loci or plasmids correlating with onion foliar pathogenicity or pathogenicity on a single host pathosystem. The lack of focus on a single host system for this phytopathgenic disease necessitates the pan-genomic analysis performed in this study. PMID:29491851

Identification of susceptibility loci for colorectal cancer in a genome-wide meta-analysis

PubMed Central

Whiffin, Nicola; Hosking, Fay J.; Farrington, Susan M.; Palles, Claire; Dobbins, Sara E.; Zgaga, Lina; Lloyd, Amy; Kinnersley, Ben; Gorman, Maggie; Tenesa, Albert; Broderick, Peter; Wang, Yufei; Barclay, Ella; Hayward, Caroline; Martin, Lynn; Buchanan, Daniel D.; Win, Aung Ko; Hopper, John; Jenkins, Mark; Lindor, Noralane M.; Newcomb, Polly A.; Gallinger, Steve; Conti, David; Schumacher, Fred; Casey, Graham; Liu, Tao; Campbell, Harry; Lindblom, Annika; Houlston, Richard S.; Tomlinson, Ian P.; Dunlop, Malcolm G.

2014-01-01

To identify common variants influencing colorectal cancer (CRC) risk, we performed a meta-analysis of five genome-wide association studies, comprising 5626 cases and 7817 controls of European descent. We conducted replication of top ranked single nucleotide polymorphisms (SNPs) in additional series totalling 14 037 cases and 15 937 controls, identifying a new CRC risk locus at 10q24.2 [rs1035209; odds ratio (OR) = 1.13, P = 4.54 × 10−11]. We also performed meta-analysis of our studies, with previously published data, of several recently purported CRC risk loci. We failed to find convincing evidence for a previously reported genome-wide association at rs11903757 (2q32.3). Of the three additional loci for which evidence of an association in Europeans has been previously described we failed to show an association between rs59336 (12q24.21) and CRC risk. However, for the other two SNPs, our analyses demonstrated new, formally significant associations with CRC. These are rs3217810 intronic in CCND2 (12p13.32; OR = 1.19, P = 2.16 × 10−10) and rs10911251 near LAMC1 (1q25.3; OR = 1.09, P = 1.75 × 10−8). Additionally, we found some evidence to support a relationship between, rs647161, rs2423297 and rs10774214 and CRC risk originally identified in East Asians in our European datasets. Our findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CRC. PMID:24737748

STS map of genes and anonymous DNA fragments on human chromosome 18 using a panel of somatic cell hybrids

DOE Office of Scientific and Technical Information (OSTI.GOV)

Overhauser, J.; Mewar, R.; Rojas, K.

1993-02-01

Somatic cell hybrids containing different deleted regions of chromosome 18 derived form patients with balanced translocations or terminal deletions were used to create a deletion mapping panel. Twenty-four sequence-tagged sites (STSs) for 17 genes and 7 anonymous polymorphic DNA fragments were identified. These STSs were used to map the 24 loci to 18 defined regions of chromosome 18. Both ERV1, previously mapped to 18q22-q23, and YES1, previously mapped to 18q21.3, were found to map to 18p11.21-pter. Several genes previously mapped to 18q21 were found to be in the order cen-SSAV1-DCC-FECH-GRP-BCL2-PLANH2-tel. The precise mapping of genes to chromosome 18 should helpmore » in determining whether these genes may be involved in the etiology of specific chromosomal syndromes associated with chromosome 18. The mapping of the poloymorphic loci will assist in the integration of the physical map with the recombination map of chromosome 18. 43 refs., 2 figs., 1 tab.« less

Genetic analysis of autoimmune sialadenitis in nonobese diabetic mice: a major susceptibility region on chromosome 1.

PubMed

Boulard, Olivier; Fluteau, Guy; Eloy, Laure; Damotte, Diane; Bedossa, Pierre; Garchon, Henri-Jean

2002-04-15

The nonobese diabetic (NOD) mouse strain provides a good study model for Sjögren's syndrome (SS). The genetic control of SS was investigated in this model using different matings, including a (NOD x C57BL/6 (B6))F(2) cross, a (NOD x NZW)F(2) cross, and ((NOD x B6) x NOD) backcross. Multiple and different loci were detected depending on parent strain combination and sex. Despite significant complexity, two main features were prominent. First, the middle region of chromosome 1 (chr.1) was detected in all crosses. Its effect was most visible in the (NOD x B6)F(2) cross and dominated over that of other loci, including those mapping on chr.8, 9, 10, and 16; the effect of these minor loci was observed only in the absence of the NOD haplotype on chr.1. Most critically, the chr.1 region was sufficient to trigger an SS-like inflammatory infiltrate of salivary glands as shown by the study of a new C57BL/6 congenic strain carrying a restricted segment derived from NOD chr.1. Second, several chromosomal regions were previously associated with NOD autoimmune phenotypes, including Iddm (chr.1, 2, 3, 9, and 17, corresponding to Idd5, Idd13, Idd3, Idd2, and Idd1, respectively), accounting for the strong linkage previously reported between insulitis and sialitis, and autoantibody production (chr.10 and 16, corresponding to Bana2 and Bah2, respectively). Interestingly, only two loci were detected in the (NOD x NZW)F(2) cross, on chr.1 in females and on chr.7 in males, probably because of the latent autoimmune predisposition of the NZW strain. Altogether these findings reflect the complexity and heterogeneity of human SS.