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Sample records for genome-wide breeding values

  1. Genome Wide Screening of Candidate Genes for Improving Piglet Birth Weight Using High and Low Estimated Breeding Value Populations

    PubMed Central

    Zhang, Lifan; Zhou, Xiang; Michal, Jennifer J.; Ding, Bo; Li, Rui; Jiang, Zhihua

    2014-01-01

    Birth weight is an economically important trait in pig production because it directly impacts piglet growth and survival rate. In the present study, we performed a genome wide survey of candidate genes and pathways associated with individual birth weight (IBW) using the Illumina PorcineSNP60 BeadChip on 24 high (HEBV) and 24 low estimated breeding value (LEBV) animals. These animals were selected from a reference population of 522 individuals produced by three sires and six dam lines, which were crossbreds with multiple breeds. After quality-control, 43,257 SNPs (single nucleotide polymorphisms), including 42,243 autosomal SNPs and 1,014 SNPs on chromosome X, were used in the data analysis. A total of 27 differentially selected regions (DSRs), including 1 on Sus scrofa chromosome 1 (SSC1), 1 on SSC4, 2 on SSC5, 4 on SSC6, 2 on SSC7, 5 on SSC8, 3 on SSC9, 1 on SSC14, 3 on SSC18, and 5 on SSCX, were identified to show the genome wide separations between the HEBV and LEBV groups for IBW in piglets. A DSR with the most number of significant SNPs (including 7 top 0.1% and 31 top 5% SNPs) was located on SSC6, while another DSR with the largest genetic differences in FST was found on SSC18. These regions harbor known functionally important genes involved in growth and development, such as TNFRSF9 (tumor necrosis factor receptor superfamily member 9), CA6 (carbonic anhydrase VI) and MDFIC (MyoD family inhibitor domain containing). A DSR rich in imprinting genes appeared on SSC9, which included PEG10 (paternally expressed 10), SGCE (sarcoglycan, epsilon), PPP1R9A (protein phosphatase 1, regulatory subunit 9A) and ASB4 (ankyrin repeat and SOCS box containing 4). More importantly, our present study provided evidence to support six quantitative trait loci (QTL) regions for pig birth weight, six QTL regions for average birth weight (ABW) and three QTL regions for litter birth weight (LBW) reported previously by other groups. Furthermore, gene ontology analysis with 183 genes

  2. Genome-wide association and prediction of direct genomic breeding values for composition of fatty acids in Angus beef cattlea

    PubMed Central

    2013-01-01

    Background As consumers continue to request food products that have health advantages, it will be important for the livestock industry to supply a product that meet these demands. One such nutrient is fatty acids, which have been implicated as playing a role in cardiovascular disease. Therefore, the objective of this study was to determine the extent to which molecular markers could account for variation in fatty acid composition of skeletal muscle and identify genomic regions that harbor genetic variation. Results Subsets of markers on the Illumina 54K bovine SNPchip were able to account for up to 57% of the variance observed in fatty acid composition. In addition, these markers could be used to calculate a direct genomic breeding values (DGV) for a given fatty acids with an accuracy (measured as simple correlations between DGV and phenotype) ranging from -0.06 to 0.57. Furthermore, 57 1-Mb regions were identified that were associated with at least one fatty acid with a posterior probability of inclusion greater than 0.90. 1-Mb regions on BTA19, BTA26 and BTA29, which harbored fatty acid synthase, Sterol-CoA desaturase and thyroid hormone responsive candidate genes, respectively, explained a high percentage of genetic variance in more than one fatty acid. It was also observed that the correlation between DGV for different fatty acids at a given 1-Mb window ranged from almost 1 to -1. Conclusions Further investigations are needed to identify the causal variants harbored within the identified 1-Mb windows. For the first time, Angus breeders have a tool whereby they could select for altered fatty acid composition. Furthermore, these reported results could improve our understanding of the biology of fatty acid metabolism and deposition. PMID:24156620

  3. Genome-wide Association Study (GWAS) and Its Application for Improving the Genomic Estimated Breeding Values (GEBV) of the Berkshire Pork Quality Traits

    PubMed Central

    Lee, Young-Sup; Jeong, Hyeonsoo; Taye, Mengistie; Kim, Hyeon Jeong; Ka, Sojeong; Ryu, Youn-Chul; Cho, Seoae

    2015-01-01

    The missing heritability has been a major problem in the analysis of best linear unbiased prediction (BLUP). We introduced the traditional genome-wide association study (GWAS) into the BLUP to improve the heritability estimation. We analyzed eight pork quality traits of the Berkshire breeds using GWAS and BLUP. GWAS detects the putative quantitative trait loci regions given traits. The single nucleotide polymorphisms (SNPs) were obtained using GWAS results with p value <0.01. BLUP analyzed with significant SNPs was much more accurate than that with total genotyped SNPs in terms of narrow-sense heritability. It implies that genomic estimated breeding values (GEBVs) of pork quality traits can be calculated by BLUP via GWAS. The GWAS model was the linear regression using PLINK and BLUP model was the G-BLUP and SNP-GBLUP. The SNP-GBLUP uses SNP-SNP relationship matrix. The BLUP analysis using preprocessing of GWAS can be one of the possible alternatives of solving the missing heritability problem and it can provide alternative BLUP method which can find more accurate GEBVs. PMID:26580278

  4. Genome-wide genetic changes during modern breeding of maize.

    PubMed

    Jiao, Yinping; Zhao, Hainan; Ren, Longhui; Song, Weibin; Zeng, Biao; Guo, Jinjie; Wang, Baobao; Liu, Zhipeng; Chen, Jing; Li, Wei; Zhang, Mei; Xie, Shaojun; Lai, Jinsheng

    2012-07-01

    The success of modern maize breeding has been demonstrated by remarkable increases in productivity over the last four decades. However, the underlying genetic changes correlated with these gains remain largely unknown. We report here the sequencing of 278 temperate maize inbred lines from different stages of breeding history, including deep resequencing of 4 lines with known pedigree information. The results show that modern breeding has introduced highly dynamic genetic changes into the maize genome. Artificial selection has affected thousands of targets, including genes and non-genic regions, leading to a reduction in nucleotide diversity and an increase in the proportion of rare alleles. Genetic changes during breeding happen rapidly, with extensive variation (SNPs, indels and copy-number variants (CNVs)) occurring, even within identity-by-descent regions. Our genome-wide assessment of genetic changes during modern maize breeding provides new strategies as well as practical targets for future crop breeding and biotechnology. PMID:22660547

  5. Genome-Wide Specific Selection in Three Domestic Sheep Breeds

    PubMed Central

    Cao, Jiaxve; Wu, Mingming; Ma, Xiaomeng; Liu, Zhen; Liu, Ruizao; Zhao, Fuping; Wei, Caihong; Du, Lixin

    2015-01-01

    Background Commercial sheep raised for mutton grow faster than traditional Chinese sheep breeds. Here, we aimed to evaluate genetic selection among three different types of sheep breed: two well-known commercial mutton breeds and one indigenous Chinese breed. Results We first combined locus-specific branch lengths and di statistical methods to detect candidate regions targeted by selection in the three different populations. The results showed that the genetic distances reached at least medium divergence for each pairwise combination. We found these two methods were highly correlated, and identified many growth-related candidate genes undergoing artificial selection. For production traits, APOBR and FTO are associated with body mass index. For meat traits, ALDOA, STK32B and FAM190A are related to marbling. For reproduction traits, CCNB2 and SLC8A3 affect oocyte development. We also found two well-known genes, GHR (which affects meat production and quality) and EDAR (associated with hair thickness) were associated with German mutton merino sheep. Furthermore, four genes (POL, RPL7, MSL1 and SHISA9) were associated with pre-weaning gain in our previous genome-wide association study. Conclusions Our results indicated that combine locus-specific branch lengths and di statistical approaches can reduce the searching ranges for specific selection. And we got many credible candidate genes which not only confirm the results of previous reports, but also provide a suite of novel candidate genes in defined breeds to guide hybridization breeding. PMID:26083354

  6. A Genome Wide Survey of SNP Variation Reveals the Genetic Structure of Sheep Breeds

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The genetic structure of sheep reflects their domestication and subsequent formation into discrete breeds. Understanding genetic structure is essential for achieving genetic improvement through genome-wide association studies, genomic selection and the dissection of quantitative traits. After identi...

  7. A genome-wide scan for signatures of differential artificial selection in ten cattle breeds

    PubMed Central

    2013-01-01

    Background Since the times of domestication, cattle have been continually shaped by the influence of humans. Relatively recent history, including breed formation and the still enduring enormous improvement of economically important traits, is expected to have left distinctive footprints of selection within the genome. The purpose of this study was to map genome-wide selection signatures in ten cattle breeds and thus improve the understanding of the genome response to strong artificial selection and support the identification of the underlying genetic variants of favoured phenotypes. We analysed 47,651 single nucleotide polymorphisms (SNP) using Cross Population Extended Haplotype Homozygosity (XP-EHH). Results We set the significance thresholds using the maximum XP-EHH values of two essentially artificially unselected breeds and found up to 229 selection signatures per breed. Through a confirmation process we verified selection for three distinct phenotypes typical for one breed (polledness in Galloway, double muscling in Blanc-Bleu Belge and red coat colour in Red Holstein cattle). Moreover, we detected six genes strongly associated with known QTL for beef or dairy traits (TG, ABCG2, DGAT1, GH1, GHR and the Casein Cluster) within selection signatures of at least one breed. A literature search for genes lying in outstanding signatures revealed further promising candidate genes. However, in concordance with previous genome-wide studies, we also detected a substantial number of signatures without any yet known gene content. Conclusions These results show the power of XP-EHH analyses in cattle to discover promising candidate genes and raise the hope of identifying phenotypically important variants in the near future. The finding of plausible functional candidates in some short signatures supports this hope. For instance, MAP2K6 is the only annotated gene of two signatures detected in Galloway and Gelbvieh cattle and is already known to be associated with carcass

  8. Genome-wide association analysis for quantitative trait loci influencing Warner–Bratzler shear force in five taurine cattle breeds

    PubMed Central

    McClure, M C; Ramey, H R; Rolf, M M; McKay, S D; Decker, J E; Chapple, R H; Kim, J W; Taxis, T M; Weaber, R L; Schnabel, R D; Taylor, J F

    2012-01-01

    Summary We performed a genome-wide association study for Warner–Bratzler shear force (WBSF), a measure of meat tenderness, by genotyping 3360 animals from five breeds with 54 790 BovineSNP50 and 96 putative single-nucleotide polymorphisms (SNPs) within μ-calpain [HUGO nomenclature calpain 1, (mu/I) large subunit; CAPN1] and calpastatin (CAST). Within- and across-breed analyses estimated SNP allele substitution effects (ASEs) by genomic best linear unbiased prediction (GBLUP) and variance components by restricted maximum likelihood under an animal model incorporating a genomic relationship matrix. GBLUP estimates of ASEs from the across-breed analysis were moderately correlated (0.31–0.66) with those from the individual within-breed analyses, indicating that prediction equations for molecular estimates of breeding value developed from across-breed analyses should be effective for genomic selection within breeds. We identified 79 genomic regions associated with WBSF in at least three breeds, but only eight were detected in all five breeds, suggesting that the within-breed analyses were underpowered, that different quantitative trait loci (QTL) underlie variation between breeds or that the BovineSNP50 SNP density is insufficient to detect common QTL among breeds. In the across-breed analysis, CAPN1 was followed by CAST as the most strongly associated WBSF QTL genome-wide, and associations with both were detected in all five breeds. We show that none of the four commercialized CAST and CAPN1SNP diagnostics are causal for associations with WBSF, and we putatively fine-map the CAPN1 causal mutation to a 4581-bp region. We estimate that variation in CAST and CAPN1 explains 1.02 and 1.85% of the phenotypic variation in WBSF respectively. PMID:22497286

  9. A genome-wide association study of malting quality across eight U.S. barley breeding programs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study leverages the breeding data of 1,862 breeding lines evaluated in 97 field trials for genome-wide association study of malting quality traits in barley. The breeding lines were six-row and two-row barley advanced breeding lines from eight barley breeding populations established at six pub...

  10. A Genome Wide Survey of SNP Variation Reveals the Genetic Structure of Sheep Breeds

    PubMed Central

    Kijas, James W.; Townley, David; Dalrymple, Brian P.; Heaton, Michael P.; Maddox, Jillian F.; McGrath, Annette; Wilson, Peter; Ingersoll, Roxann G.; McCulloch, Russell; McWilliam, Sean; Tang, Dave; McEwan, John; Cockett, Noelle; Oddy, V. Hutton; Nicholas, Frank W.; Raadsma, Herman

    2009-01-01

    The genetic structure of sheep reflects their domestication and subsequent formation into discrete breeds. Understanding genetic structure is essential for achieving genetic improvement through genome-wide association studies, genomic selection and the dissection of quantitative traits. After identifying the first genome-wide set of SNP for sheep, we report on levels of genetic variability both within and between a diverse sample of ovine populations. Then, using cluster analysis and the partitioning of genetic variation, we demonstrate sheep are characterised by weak phylogeographic structure, overlapping genetic similarity and generally low differentiation which is consistent with their short evolutionary history. The degree of population substructure was, however, sufficient to cluster individuals based on geographic origin and known breed history. Specifically, African and Asian populations clustered separately from breeds of European origin sampled from Australia, New Zealand, Europe and North America. Furthermore, we demonstrate the presence of stratification within some, but not all, ovine breeds. The results emphasize that careful documentation of genetic structure will be an essential prerequisite when mapping the genetic basis of complex traits. Furthermore, the identification of a subset of SNP able to assign individuals into broad groupings demonstrates even a small panel of markers may be suitable for applications such as traceability. PMID:19270757

  11. Opportunities for genome-wide selection for pig breeding in developing countries.

    PubMed

    Akanno, E C; Schenkel, F S; Sargolzaei, M; Friendship, R M; Robinson, J A B

    2013-07-26

    Genetic improvement of exotic and indigenous pigs in tropical developing countries is desired. Implementations of traditional selection methods on tropical pig populations are limited by lack of data recording and analysis infrastructure. Genome-wide selection (GS) provides an approach for achieving faster genetic progress without developing a pedigree recording system. The implications of GS on long term gain and inbreeding should be studied before actual implementation especially where low linkage disequilibrium (LD) is anticipated in the target population. A simulation case-study of this option was carried out based on the available 60 K SNP panel for porcine genome. Computer simulation was used to explore the effects of various selection methods, trait heritability and different breeding programs when applying GS. Genomic predictions were based on the ridge regression method. Genome-wide selection performed better than BLUP and phenotypic selection methods by increasing genetic gain and maintaining genetic variation while lowering inbreeding especially for traits with low heritability. Indigenous pig populations with low LD can be improved by using GS if high density marker panels are available. The combination of GS with repeated backcrossing of crossbreds to exotic pigs in developing countries promises to rapidly improve the genetic merit of the commercial population. Application of this novel method on a real population will need to be carried out to validate these results. PMID:23893977

  12. Opportunities for genome-wide selection for pig breeding in developing countries.

    PubMed

    Akanno, E C; Schenkel, F S; Sargolzaei, M; Friendship, R M; Robinson, J A B

    2013-10-01

    Genetic improvement of exotic and indigenous pigs in tropical developing countries is desired. Implementations of traditional selection methods on tropical pig populations are limited by lack of data recording and analysis infrastructure. Genome-wide selection (GS) provides an approach for achieving faster genetic progress without developing a pedigree recording system. The implications of GS on long-term gain and inbreeding should be studied before actual implementation, especially where low linkage disequilibrium (LD) is anticipated in the target population. A simulation case study of this option was performed on the basis of the available 60,000 SNP panel for porcine genome. Computer simulation was used to explore the effects of various selection methods, trait heritability, and different breeding programs when applying GS. Genomic predictions were based on the ridge regression method. Genome-wide selection performed better than BLUP and phenotypic selection methods by increasing genetic gain and maintaining genetic variation while lowering inbreeding, especially for traits with low heritability. Indigenous pig populations with low LD can be improved by using GS if high-density marker panels are available. The combination of GS with repeated backcrossing of crossbreds to exotic pigs in developing countries promises to rapidly improve the genetic merit of the commercial population. Application of this novel method on a real population will need to be performed to validate these results. PMID:24078617

  13. Genome-wide analysis of DNA methylation in obese, lean, and miniature pig breeds.

    PubMed

    Yang, Yalan; Zhou, Rong; Mu, Yulian; Hou, Xinhua; Tang, Zhonglin; Li, Kui

    2016-01-01

    DNA methylation is a crucial epigenetic modification involved in diverse biological processes. There is significant phenotypic variance between Chinese indigenous and western pig breeds. Here, we surveyed the genome-wide DNA methylation profiles of blood leukocytes from three pig breeds (Tongcheng, Landrace, and Wuzhishan) by methylated DNA immunoprecipitation sequencing. The results showed that DNA methylation was enriched in gene body regions and repetitive sequences. LINE/L1 and SINE/tRNA-Glu were the predominant methylated repeats in pigs. The methylation level in the gene body regions was higher than in the 5' and 3' flanking regions of genes. About 15% of CpG islands were methylated in the pig genomes. Additionally, 2,807, 2,969, and 5,547 differentially methylated genes (DMGs) were identified in the Tongcheng vs. Landrace, Tongcheng vs. Wuzhishan, and Landrace vs. Wuzhishan comparisons, respectively. A total of 868 DMGs were shared by the three contrasts. The DMGs were significantly enriched in development- and metabolism-related biological processes and pathways. Finally, we identified 32 candidate DMGs associated with phenotype variance in pigs. Our research provides a DNA methylome resource for pigs and furthers understanding of epigenetically regulated phenotype variance in mammals. PMID:27444743

  14. Genome-wide analysis of DNA methylation in obese, lean, and miniature pig breeds

    PubMed Central

    Yang, Yalan; Zhou, Rong; Mu, Yulian; Hou, Xinhua; Tang, Zhonglin; Li, Kui

    2016-01-01

    DNA methylation is a crucial epigenetic modification involved in diverse biological processes. There is significant phenotypic variance between Chinese indigenous and western pig breeds. Here, we surveyed the genome-wide DNA methylation profiles of blood leukocytes from three pig breeds (Tongcheng, Landrace, and Wuzhishan) by methylated DNA immunoprecipitation sequencing. The results showed that DNA methylation was enriched in gene body regions and repetitive sequences. LINE/L1 and SINE/tRNA-Glu were the predominant methylated repeats in pigs. The methylation level in the gene body regions was higher than in the 5′ and 3′ flanking regions of genes. About 15% of CpG islands were methylated in the pig genomes. Additionally, 2,807, 2,969, and 5,547 differentially methylated genes (DMGs) were identified in the Tongcheng vs. Landrace, Tongcheng vs. Wuzhishan, and Landrace vs. Wuzhishan comparisons, respectively. A total of 868 DMGs were shared by the three contrasts. The DMGs were significantly enriched in development- and metabolism-related biological processes and pathways. Finally, we identified 32 candidate DMGs associated with phenotype variance in pigs. Our research provides a DNA methylome resource for pigs and furthers understanding of epigenetically regulated phenotype variance in mammals. PMID:27444743

  15. Genome wide association study of seedling and adult plant leaf rust resistance in elite spring wheat breeding lines

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Leaf rust is an important disease, threatening wheat production annually. Identification of resistance genes or QTLs for effective field resistance could greatly enhance our ability to breed durably resistant varieties. We applied a genome wide association study (GWAS) approach to identify resista...

  16. Genome wide analysis reveals single nucleotide polymorphisms associated with fatness and putative novel copy number variants in three pig breeds

    PubMed Central

    2013-01-01

    Background Obesity, excess fat tissue in the body, can underlie a variety of medical complaints including heart disease, stroke and cancer. The pig is an excellent model organism for the study of various human disorders, including obesity, as well as being the foremost agricultural species. In order to identify genetic variants associated with fatness, we used a selective genomic approach sampling DNA from animals at the extreme ends of the fat and lean spectrum using estimated breeding values derived from a total population size of over 70,000 animals. DNA from 3 breeds (Sire Line Large White, Duroc and a white Pietrain composite line (Titan)) was used to interrogate the Illumina Porcine SNP60 Genotyping Beadchip in order to identify significant associations in terms of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs). Results By sampling animals at each end of the fat/lean EBV (estimate breeding value) spectrum the whole population could be assessed using less than 300 animals, without losing statistical power. Indeed, several significant SNPs (at the 5% genome wide significance level) were discovered, 4 of these linked to genes with ontologies that had previously been correlated with fatness (NTS, FABP6, SST and NR3C2). Quantitative analysis of the data identified putative CNV regions containing genes whose ontology suggested fatness related functions (MCHR1, PPARα, SLC5A1 and SLC5A4). Conclusions Selective genotyping of EBVs at either end of the phenotypic spectrum proved to be a cost effective means of identifying SNPs and CNVs associated with fatness and with estimated major effects in a large population of animals. PMID:24225222

  17. Genome Wide Scan for Loci influencing Warner Bratzler Shear Force in Five Bos taurus Breeds

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genetic tests for beef tenderness are currently limited to single nucleotide polymorphisms (SNPs) within µ-calpain (CAPN1) and calpastatin (CAST) and explain little of the phenotypic variation in Warner-Bratzler shear force (WBSF). We performed a genome-wide association study for WBSF by genotyping...

  18. A genome-wide SNP panel for genetic diversity, mapping and breeding studies in rice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A genome-wide SNP resource was developed for rice using the GoldenGate assay and used to genotype 400 landrace accessions of O. sativa. SNPs were originally discovered using Perlegen re-sequencing technology in 20 diverse landraces of O. sativa as part of OryzaSNP project (http://irfgc.irri.org). An...

  19. Singular value decomposition for genome-wide expression data processing and modeling

    PubMed Central

    Alter, Orly; Brown, Patrick O.; Botstein, David

    2000-01-01

    We describe the use of singular value decomposition in transforming genome-wide expression data from genes × arrays space to reduced diagonalized “eigengenes” × “eigenarrays” space, where the eigengenes (or eigenarrays) are unique orthonormal superpositions of the genes (or arrays). Normalizing the data by filtering out the eigengenes (and eigenarrays) that are inferred to represent noise or experimental artifacts enables meaningful comparison of the expression of different genes across different arrays in different experiments. Sorting the data according to the eigengenes and eigenarrays gives a global picture of the dynamics of gene expression, in which individual genes and arrays appear to be classified into groups of similar regulation and function, or similar cellular state and biological phenotype, respectively. After normalization and sorting, the significant eigengenes and eigenarrays can be associated with observed genome-wide effects of regulators, or with measured samples, in which these regulators are overactive or underactive, respectively. PMID:10963673

  20. Quantitative trait loci for rice blast resistance detected in a local rice breeding population by genome-wide association mapping

    PubMed Central

    Shinada, Hiroshi; Yamamoto, Toshio; Sato, Hirokazu; Yamamoto, Eiji; Hori, Kiyosumi; Yonemaru, Junichi; Sato, Takashi; Fujino, Kenji

    2015-01-01

    Plant breeding programs aim to develop cultivars with high adaptability to the specific conditions in a local region. As a result, unique genes and gene combinations have been accumulated in local elite breeding populations during the long history of plant breeding. Genetic analyses on such genes and combinations may be useful for developing new cultivars with more-desirable agronomic traits. Here, we attempted to detect quantitative trait loci (QTL) for rice blast resistance (BR) using a local breeding rice population from Hokkaido, Japan. Using genotyping data on single nucleotide polymorphisms and simple sequence repeat markers distributed throughout the whole genomic region, we detected genetic regions associated with phenotypic variation in BR by a genome-wide association mapping study (GWAS). An additional association analysis using other breeding cultivars verified the effect and inheritance of the associated region. Furthermore, the existence of a gene for BR in the associated region was confirmed by QTL mapping. The results from these studies enabled us to estimate potential of the Hokkaido rice population as a gene pool for improving BR. The results of this study could be useful for developing novel cultivars with vigorous BR in rice breeding programs. PMID:26719741

  1. Genome-Wide Survey of SNP Variation Uncovers the Genetic Structure of Cattle Breeds.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A deep draft sequence assembly derived from shotgun reads from a single Hereford female and comparative sampling sequences from cows representing six additional bovine breeds has enabled the development of genetic probes to interrogate single nucleotide polymorphisms for population and breed analyse...

  2. Enhancing Genome-Wide Copy Number Variation Identification by High Density Array CGH Using Diverse Resources of Pig Breeds

    PubMed Central

    Wang, Jiying; Jiang, Jicai; Wang, Haifei; Kang, Huimin; Zhang, Qin; Liu, Jian-Feng

    2014-01-01

    Copy number variations (CNVs) are important forms of genomic variation, and have attracted extensive attentions in humans as well as domestic animals. In the study, using a custom-designed 2.1 M array comparative genomic hybridization (aCGH), genome-wide CNVs were identified among 12 individuals from diverse pig breeds, including one Asian wild population, six Chinese indigenous breeds and two modern commercial breeds (Yorkshire and Landrace), with one individual of the other modern commercial breed, Duroc, as the reference. A total of 1,344 CNV regions (CNVRs) were identified, covering 47.79 Mb (∼1.70%) of the pig genome. The length of these CNVRs ranged from 3.37 Kb to 1,319.0 Kb with a mean of 35.56 Kb and a median of 11.11 Kb. Compared with similar studies reported, most of the CNVRs (74.18%) were firstly identified in present study. In order to confirm these CNVRs, 21 CNVRs were randomly chosen to be validated by quantitative real time PCR (qPCR) and a high rate (85.71%) of confirmation was obtained. Functional annotation of CNVRs suggested that the identified CNVRs have important function, and may play an important role in phenotypic and production traits difference among various breeds. Our results are essential complementary to the CNV map in the pig genome, which will provide abundant genetic markers to investigate association studies between various phenotypes and CNVs in pigs. PMID:24475311

  3. Genome-Wide Analysis of Positively Selected Genes in Seasonal and Non-Seasonal Breeding Species

    PubMed Central

    Liu, Mingyu; Chen, Junhui; Tian, Shuai; Zhuo, Min; Zhang, Yu; Zhong, Yang; Du, Hongli; Wang, Xiaoning

    2015-01-01

    Some mammals breed throughout the year, while others breed only at certain times of year. These differences in reproductive behavior can be explained by evolution. We identified positively-selected genes in two sets of species with different degrees of relatedness including seasonal and non-seasonal breeding species, using branch-site models. After stringent filtering by sum of pairs scoring, we revealed that more genes underwent positive selection in seasonal compared with non-seasonal breeding species. Positively-selected genes were verified by cDNA mapping of the positive sites with the corresponding cDNA sequences. The design of the evolutionary analysis can effectively lower the false-positive rate and thus identify valid positive genes. Validated, positively-selected genes, including CGA, DNAH1, INVS, and CD151, were related to reproductive behaviors such as spermatogenesis and cell proliferation in non-seasonal breeding species. Genes in seasonal breeding species, including THRAP3, TH1L, and CMTM6, may be related to the evolution of sperm and the circadian rhythm system. Identification of these positively-selected genes might help to identify the molecular mechanisms underlying seasonal and non-seasonal reproductive behaviors. PMID:26000771

  4. Genome-wide association studies based on sequence-derived genotypes reveal new QTL associated with conformation and performance traits in the Franches-Montagnes horse breed.

    PubMed

    Frischknecht, M; Signer-Hasler, H; Leeb, T; Rieder, S; Neuditschko, M

    2016-04-01

    To identify novel quantitative trait loci (QTL) within horses, we performed genome-wide association studies (GWAS) based on sequence-level genotypes for conformation and performance traits in the Franches-Montagnes (FM) horse breed. Sequence-level genotypes of FM horses were derived by re-sequencing 30 key founders and imputing 50K data of genotyped horses. In total, we included 1077 FM horses genotyped for ~4 million SNPs and their respective de-regressed breeding values of the traits in the analysis. Based on this dataset, we identified a total of 14 QTL associated with 18 conformation traits and one performance trait. Therefore, our results suggest that the application of sequence-derived genotypes increases the power to identify novel QTL which were not identified previously based on 50K SNP chip data. PMID:26767322

  5. Genome Wide Association Study of Seedling and Adult Plant Leaf Rust Resistance in Elite Spring Wheat Breeding Lines

    PubMed Central

    Gao, Liangliang; Turner, M. Kathryn; Chao, Shiaoman; Kolmer, James; Anderson, James A.

    2016-01-01

    Leaf rust is an important disease, threatening wheat production annually. Identification of resistance genes or QTLs for effective field resistance could greatly enhance our ability to breed durably resistant varieties. We applied a genome wide association study (GWAS) approach to identify resistance genes or QTLs in 338 spring wheat breeding lines from public and private sectors that were predominately developed in the Americas. A total of 46 QTLs were identified for field and seedling traits and approximately 20–30 confer field resistance in varying degrees. The 10 QTLs accounting for the most variation in field resistance explained 26–30% of the total variation (depending on traits: percent severity, coefficient of infection or response type). Similarly, the 10 QTLs accounting for most of the variation in seedling resistance to different races explained 24–34% of the variation, after correcting for population structure. Two potentially novel QTLs (QLr.umn-1AL, QLr.umn-4AS) were identified. Identification of novel genes or QTLs and validation of previously identified genes or QTLs for seedling and especially adult plant resistance will enhance understanding of leaf rust resistance and assist breeding for resistant wheat varieties. We also developed computer programs to automate field and seedling rust phenotype data conversions. This is the first GWAS study of leaf rust resistance in elite wheat breeding lines genotyped with high density 90K SNP arrays. PMID:26849364

  6. Genome-wide analysis reveals selection for important traits in domestic horse breeds.

    PubMed

    Petersen, Jessica L; Mickelson, James R; Rendahl, Aaron K; Valberg, Stephanie J; Andersson, Lisa S; Axelsson, Jeanette; Bailey, Ernie; Bannasch, Danika; Binns, Matthew M; Borges, Alexandre S; Brama, Pieter; da Câmara Machado, Artur; Capomaccio, Stefano; Cappelli, Katia; Cothran, E Gus; Distl, Ottmar; Fox-Clipsham, Laura; Graves, Kathryn T; Guérin, Gérard; Haase, Bianca; Hasegawa, Telhisa; Hemmann, Karin; Hill, Emmeline W; Leeb, Tosso; Lindgren, Gabriella; Lohi, Hannes; Lopes, Maria Susana; McGivney, Beatrice A; Mikko, Sofia; Orr, Nicholas; Penedo, M Cecilia T; Piercy, Richard J; Raekallio, Marja; Rieder, Stefan; Røed, Knut H; Swinburne, June; Tozaki, Teruaki; Vaudin, Mark; Wade, Claire M; McCue, Molly E

    2013-01-01

    Intense selective pressures applied over short evolutionary time have resulted in homogeneity within, but substantial variation among, horse breeds. Utilizing this population structure, 744 individuals from 33 breeds, and a 54,000 SNP genotyping array, breed-specific targets of selection were identified using an F(ST)-based statistic calculated in 500-kb windows across the genome. A 5.5-Mb region of ECA18, in which the myostatin (MSTN) gene was centered, contained the highest signature of selection in both the Paint and Quarter Horse. Gene sequencing and histological analysis of gluteal muscle biopsies showed a promoter variant and intronic SNP of MSTN were each significantly associated with higher Type 2B and lower Type 1 muscle fiber proportions in the Quarter Horse, demonstrating a functional consequence of selection at this locus. Signatures of selection on ECA23 in all gaited breeds in the sample led to the identification of a shared, 186-kb haplotype including two doublesex related mab transcription factor genes (DMRT2 and 3). The recent identification of a DMRT3 mutation within this haplotype, which appears necessary for the ability to perform alternative gaits, provides further evidence for selection at this locus. Finally, putative loci for the determination of size were identified in the draft breeds and the Miniature horse on ECA11, as well as when signatures of selection surrounding candidate genes at other loci were examined. This work provides further evidence of the importance of MSTN in racing breeds, provides strong evidence for selection upon gait and size, and illustrates the potential for population-based techniques to find genomic regions driving important phenotypes in the modern horse. PMID:23349635

  7. Genome-Wide Analysis Reveals Selection for Important Traits in Domestic Horse Breeds

    PubMed Central

    Petersen, Jessica L.; Mickelson, James R.; Rendahl, Aaron K.; Valberg, Stephanie J.; Andersson, Lisa S.; Axelsson, Jeanette; Bailey, Ernie; Bannasch, Danika; Binns, Matthew M.; Borges, Alexandre S.; Brama, Pieter; da Câmara Machado, Artur; Capomaccio, Stefano; Cappelli, Katia; Cothran, E. Gus; Distl, Ottmar; Fox-Clipsham, Laura; Graves, Kathryn T.; Guérin, Gérard; Haase, Bianca; Hasegawa, Telhisa; Hemmann, Karin; Hill, Emmeline W.; Leeb, Tosso; Lindgren, Gabriella; Lohi, Hannes; Lopes, Maria Susana; McGivney, Beatrice A.; Mikko, Sofia; Orr, Nicholas; Penedo, M. Cecilia T.; Piercy, Richard J.; Raekallio, Marja; Rieder, Stefan; Røed, Knut H.; Swinburne, June; Tozaki, Teruaki; Vaudin, Mark; Wade, Claire M.; McCue, Molly E.

    2013-01-01

    Intense selective pressures applied over short evolutionary time have resulted in homogeneity within, but substantial variation among, horse breeds. Utilizing this population structure, 744 individuals from 33 breeds, and a 54,000 SNP genotyping array, breed-specific targets of selection were identified using an FST-based statistic calculated in 500-kb windows across the genome. A 5.5-Mb region of ECA18, in which the myostatin (MSTN) gene was centered, contained the highest signature of selection in both the Paint and Quarter Horse. Gene sequencing and histological analysis of gluteal muscle biopsies showed a promoter variant and intronic SNP of MSTN were each significantly associated with higher Type 2B and lower Type 1 muscle fiber proportions in the Quarter Horse, demonstrating a functional consequence of selection at this locus. Signatures of selection on ECA23 in all gaited breeds in the sample led to the identification of a shared, 186-kb haplotype including two doublesex related mab transcription factor genes (DMRT2 and 3). The recent identification of a DMRT3 mutation within this haplotype, which appears necessary for the ability to perform alternative gaits, provides further evidence for selection at this locus. Finally, putative loci for the determination of size were identified in the draft breeds and the Miniature horse on ECA11, as well as when signatures of selection surrounding candidate genes at other loci were examined. This work provides further evidence of the importance of MSTN in racing breeds, provides strong evidence for selection upon gait and size, and illustrates the potential for population-based techniques to find genomic regions driving important phenotypes in the modern horse. PMID:23349635

  8. Population genomic structure and linkage disequilibrium analysis of South African goat breeds using genome-wide SNP data.

    PubMed

    Mdladla, K; Dzomba, E F; Huson, H J; Muchadeyi, F C

    2016-08-01

    The sustainability of goat farming in marginal areas of southern Africa depends on local breeds that are adapted to specific agro-ecological conditions. Unimproved non-descript goats are the main genetic resources used for the development of commercial meat-type breeds of South Africa. Little is known about genetic diversity and the genetics of adaptation of these indigenous goat populations. This study investigated the genetic diversity, population structure and breed relations, linkage disequilibrium, effective population size and persistence of gametic phase in goat populations of South Africa. Three locally developed meat-type breeds of the Boer (n = 33), Savanna (n = 31), Kalahari Red (n = 40), a feral breed of Tankwa (n = 25) and unimproved non-descript village ecotypes (n = 110) from four goat-producing provinces of the Eastern Cape, KwaZulu-Natal, Limpopo and North West were assessed using the Illumina Goat 50K SNP Bead Chip assay. The proportion of SNPs with minor allele frequencies >0.05 ranged from 84.22% in the Tankwa to 97.58% in the Xhosa ecotype, with a mean of 0.32 ± 0.13 across populations. Principal components analysis, admixture and pairwise FST identified Tankwa as a genetically distinct population and supported clustering of the populations according to their historical origins. Genome-wide FST identified 101 markers potentially under positive selection in the Tankwa. Average linkage disequilibrium was highest in the Tankwa (r(2)  = 0.25 ± 0.26) and lowest in the village ecotypes (r(2) range = 0.09 ± 0.12 to 0.11 ± 0.14). We observed an effective population size of <150 for all populations 13 generations ago. The estimated correlations for all breed pairs were lower than 0.80 at marker distances >100 kb with the exception of those in Savanna and Tswana populations. This study highlights the high level of genetic diversity in South African indigenous goats as well as the utility of the genome-wide SNP marker panels in

  9. Genome-wide Association Mapping of Fusarium Head Blight Resistance in Contemporary Barley Breeding Germplasm

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Utilization of quantitative trait loci (QTL) identified in bi-parental mapping populations has had limited success for complex quantitative traits. The use of association mapping in contemporary breeding germplasm may lead to more effective marker strategies for crop improvement. To map Fusarium he...

  10. Genome-wide association study for longevity with whole-genome sequencing in 3 cattle breeds.

    PubMed

    Zhang, Qianqian; Guldbrandtsen, Bernt; Thomasen, Jørn Rind; Lund, Mogens Sandø; Sahana, Goutam

    2016-09-01

    Longevity is an important economic trait in dairy production. Improvements in longevity could increase the average number of lactations per cow, thereby affecting the profitability of the dairy cattle industry. Improved longevity for cows reduces the replacement cost of stock and enables animals to achieve the highest production period. Moreover, longevity is an indirect indicator of animal welfare. Using whole-genome sequencing variants in 3 dairy cattle breeds, we carried out an association study and identified 7 genomic regions in Holstein and 5 regions in Red Dairy Cattle that were associated with longevity. Meta-analyses of 3 breeds revealed 2 significant genomic regions, located on chromosomes 6 (META-CHR6-88MB) and 18 (META-CHR18-58MB). META-CHR6-88MB overlaps with 2 known genes: neuropeptide G-protein coupled receptor (NPFFR2; 89,052,210-89,059,348 bp) and vitamin D-binding protein precursor (GC; 88,695,940-88,739,180 bp). The NPFFR2 gene was previously identified as a candidate gene for mastitis resistance. META-CHR18-58MB overlaps with zinc finger protein 717 (ZNF717; 58,130,465-58,141,877 bp) and zinc finger protein 613 (ZNF613; 58,115,782-58,117,110 bp), which have been associated with calving difficulties. Information on longevity-associated genomic regions could be used to find causal genes/variants influencing longevity and exploited to improve the reliability of genomic prediction. PMID:27289149

  11. A validated genome wide association study to breed cattle adapted to an environment altered by climate change.

    PubMed

    Hayes, Ben J; Bowman, Phil J; Chamberlain, Amanda J; Savin, Keith; van Tassell, Curt P; Sonstegard, Tad S; Goddard, Mike E

    2009-01-01

    Continued production of food in areas predicted to be most affected by climate change, such as dairy farming regions of Australia, will be a major challenge in coming decades. Along with rising temperatures and water shortages, scarcity of inputs such as high energy feeds is predicted. With the motivation of selecting cattle adapted to these changing environments, we conducted a genome wide association study to detect DNA markers (single nucleotide polymorphisms) associated with the sensitivity of milk production to environmental conditions. To do this we combined historical milk production and weather records with dense marker genotypes on dairy sires with many daughters milking across a wide range of production environments in Australia. Markers associated with sensitivity of milk production to feeding level and sensitivity of milk production to temperature humidity index on chromosome nine and twenty nine respectively were validated in two independent populations, one a different breed of cattle. As the extent of linkage disequilibrium across cattle breeds is limited, the underlying causative mutations have been mapped to a small genomic interval containing two promising candidate genes. The validated marker panels we have reported here will aid selection for high milk production under anticipated climate change scenarios, for example selection of sires whose daughters will be most productive at low levels of feeding. PMID:19688089

  12. Diversifying Selection Between Pure-Breed and Free-Breeding Dogs Inferred from Genome-Wide SNP Analysis.

    PubMed

    Pilot, Małgorzata; Malewski, Tadeusz; Moura, Andre E; Grzybowski, Tomasz; Oleński, Kamil; Kamiński, Stanisław; Fadel, Fernanda Ruiz; Alagaili, Abdulaziz N; Mohammed, Osama B; Bogdanowicz, Wiesław

    2016-01-01

    Domesticated species are often composed of distinct populations differing in the character and strength of artificial and natural selection pressures, providing a valuable model to study adaptation. In contrast to pure-breed dogs that constitute artificially maintained inbred lines, free-ranging dogs are typically free-breeding, i.e., unrestrained in mate choice. Many traits in free-breeding dogs (FBDs) may be under similar natural and sexual selection conditions to wild canids, while relaxation of sexual selection is expected in pure-breed dogs. We used a Bayesian approach with strict false-positive control criteria to identify FST-outlier SNPs between FBDs and either European or East Asian breeds, based on 167,989 autosomal SNPs. By identifying outlier SNPs located within coding genes, we found four candidate genes under diversifying selection shared by these two comparisons. Three of them are associated with the Hedgehog (HH) signaling pathway regulating vertebrate morphogenesis. A comparison between FBDs and East Asian breeds also revealed diversifying selection on the BBS6 gene, which was earlier shown to cause snout shortening and dental crowding via disrupted HH signaling. Our results suggest that relaxation of natural and sexual selection in pure-breed dogs as opposed to FBDs could have led to mild changes in regulation of the HH signaling pathway. HH inhibits adhesion and the migration of neural crest cells from the neural tube, and minor deficits of these cells during embryonic development have been proposed as the underlying cause of "domestication syndrome." This suggests that the process of breed formation involved the same genetic and developmental pathways as the process of domestication. PMID:27233669

  13. Diversifying Selection Between Pure-Breed and Free-Breeding Dogs Inferred from Genome-Wide SNP Analysis

    PubMed Central

    Pilot, Małgorzata; Malewski, Tadeusz; Moura, Andre E.; Grzybowski, Tomasz; Oleński, Kamil; Kamiński, Stanisław; Fadel, Fernanda Ruiz; Alagaili, Abdulaziz N.; Mohammed, Osama B.; Bogdanowicz, Wiesław

    2016-01-01

    Domesticated species are often composed of distinct populations differing in the character and strength of artificial and natural selection pressures, providing a valuable model to study adaptation. In contrast to pure-breed dogs that constitute artificially maintained inbred lines, free-ranging dogs are typically free-breeding, i.e., unrestrained in mate choice. Many traits in free-breeding dogs (FBDs) may be under similar natural and sexual selection conditions to wild canids, while relaxation of sexual selection is expected in pure-breed dogs. We used a Bayesian approach with strict false-positive control criteria to identify FST-outlier SNPs between FBDs and either European or East Asian breeds, based on 167,989 autosomal SNPs. By identifying outlier SNPs located within coding genes, we found four candidate genes under diversifying selection shared by these two comparisons. Three of them are associated with the Hedgehog (HH) signaling pathway regulating vertebrate morphogenesis. A comparison between FBDs and East Asian breeds also revealed diversifying selection on the BBS6 gene, which was earlier shown to cause snout shortening and dental crowding via disrupted HH signaling. Our results suggest that relaxation of natural and sexual selection in pure-breed dogs as opposed to FBDs could have led to mild changes in regulation of the HH signaling pathway. HH inhibits adhesion and the migration of neural crest cells from the neural tube, and minor deficits of these cells during embryonic development have been proposed as the underlying cause of “domestication syndrome.” This suggests that the process of breed formation involved the same genetic and developmental pathways as the process of domestication. PMID:27233669

  14. Genome-wide scan for visceral leishmaniasis in mixed-breed dogs identifies candidate genes involved in T helper cells and macrophage signaling

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We conducted a genome-wide scan for visceral leishmaniasis in mixed-breed dogs from a highly endemic area in Brazil using 149,648 single nucleotide polymorphism (SNP) markers genotyped in 20 cases and 28 controls. Using a mixed model approach, we found two candidate loci on canine autosomes 1 and 2....

  15. Genome-wide Association Study of Integrated Meat Quality-related Traits of the Duroc Pig Breed.

    PubMed

    Lee, Taeheon; Shin, Dong-Hyun; Cho, Seoae; Kang, Hyun Sung; Kim, Sung Hoon; Lee, Hak-Kyo; Kim, Heebal; Seo, Kang-Seok

    2014-03-01

    The increasing importance of meat quality has implications for animal breeding programs. Research has revealed much about the genetic background of pigs, and many studies have revealed the importance of various genetic factors. Since meat quality is a complex trait which is affected by many factors, consideration of the overall phenotype is very useful to study meat quality. For integrating the phenotypes, we used principle component analysis (PCA). The significant SNPs refer to results of the GRAMMAR method against PC1, PC2 and PC3 of 14 meat quality traits of 181 Duroc pigs. The Genome-wide association study (GWAS) found 26 potential SNPs affecting various meat quality traits. The loci identified are located in or near 23 genes. The SNPs associated with meat quality are in or near five genes (ANK1, BMP6, SHH, PIP4K2A, and FOXN2) and have been reported previously. Twenty-five of the significant SNPs also located in meat quality-related QTL regions, these result supported the QTL effect indirectly. Each single gene typically affects multiple traits. Therefore, it is a useful approach to use integrated traits for the various traits at the same time. This innovative approach using integrated traits could be applied on other GWAS of complex-traits including meat-quality, and the results will contribute to improving meat-quality of pork. PMID:25049955

  16. Genome-Wide Association Mapping for Yield and Other Agronomic Traits in an Elite Breeding Population of Tropical Rice (Oryza sativa)

    PubMed Central

    Lalusin, Antonio; Borromeo, Teresita; Gregorio, Glenn; Hernandez, Jose; Virk, Parminder; Collard, Bertrand; McCouch, Susan R.

    2015-01-01

    Genome-wide association mapping studies (GWAS) are frequently used to detect QTL in diverse collections of crop germplasm, based on historic recombination events and linkage disequilibrium across the genome. Generally, diversity panels genotyped with high density SNP panels are utilized in order to assay a wide range of alleles and haplotypes and to monitor recombination breakpoints across the genome. By contrast, GWAS have not generally been performed in breeding populations. In this study we performed association mapping for 19 agronomic traits including yield and yield components in a breeding population of elite irrigated tropical rice breeding lines so that the results would be more directly applicable to breeding than those from a diversity panel. The population was genotyped with 71,710 SNPs using genotyping-by-sequencing (GBS), and GWAS performed with the explicit goal of expediting selection in the breeding program. Using this breeding panel we identified 52 QTL for 11 agronomic traits, including large effect QTLs for flowering time and grain length/grain width/grain-length-breadth ratio. We also identified haplotypes that can be used to select plants in our population for short stature (plant height), early flowering time, and high yield, and thus demonstrate the utility of association mapping in breeding populations for informing breeding decisions. We conclude by exploring how the newly identified significant SNPs and insights into the genetic architecture of these quantitative traits can be leveraged to build genomic-assisted selection models. PMID:25785447

  17. Genome-wide analysis of Italian sheep diversity reveals a strong geographic pattern and cryptic relationships between breeds.

    PubMed

    Ciani, E; Crepaldi, P; Nicoloso, L; Lasagna, E; Sarti, F M; Moioli, B; Napolitano, F; Carta, A; Usai, G; D'Andrea, M; Marletta, D; Ciampolini, R; Riggio, V; Occidente, M; Matassino, D; Kompan, D; Modesto, P; Macciotta, N; Ajmone-Marsan, P; Pilla, F

    2014-04-01

    Italy counts several sheep breeds, arisen over centuries as a consequence of ancient and recent genetic and demographic events. To finely reconstruct genetic structure and relationships between Italian sheep, 496 subjects from 19 breeds were typed at 50K single nucleotide polymorphism loci. A subset of foreign breeds from the Sheep HapMap dataset was also included in the analyses. Genetic distances (as visualized either in a network or in a multidimensional scaling analysis of identical by state distances) closely reflected geographic proximity between breeds, with a clear north-south gradient, likely because of high levels of past gene flow and admixture all along the peninsula. Sardinian breeds diverged more from other breeds, a probable consequence of the combined effect of ancient sporadic introgression of feral mouflon and long-lasting genetic isolation from continental sheep populations. The study allowed the detection of previously undocumented episodes of recent introgression (Delle Langhe into the endangered Altamurana breed) as well as signatures of known, or claimed, historical introgression (Merino into Sopravissana and Gentile di Puglia; Bergamasca into Fabrianese, Appenninica and, to a lesser extent, Leccese). Arguments that would question, from a genomic point of view, the current breed classification of Bergamasca and Biellese into two separate breeds are presented. Finally, a role for traditional transhumance practices in shaping the genetic makeup of Alpine sheep breeds is proposed. The study represents the first exhaustive analysis of Italian sheep diversity in an European context, and it bridges the gap in the previous HapMap panel between Western Mediterranean and Swiss breeds. PMID:24303943

  18. The Shepherds’ Tale: A Genome-Wide Study across 9 Dog Breeds Implicates Two Loci in the Regulation of Fructosamine Serum Concentration in Belgian Shepherds

    PubMed Central

    Ljungvall, Ingrid; Merveille, Anne-Christine; Gouni, Vassiliki; Wiberg, Maria; Lundgren Willesen, Jakob; Hanås, Sofia; Lequarré, Anne-Sophie; Mejer Sørensen, Louise; Tiret, Laurent; McEntee, Kathleen; Seppälä, Eija; Koch, Jørgen; Battaille, Géraldine; Lohi, Hannes; Fredholm, Merete; Chetboul, Valerie; Häggström, Jens; Carlborg, Örjan; Lindblad-Toh, Kerstin; Höglund, Katja

    2015-01-01

    Diabetes mellitus is a serious health problem in both dogs and humans. Certain dog breeds show high prevalence of the disease, whereas other breeds are at low risk. Fructosamine and glycated haemoglobin (HbA1c) are two major biomarkers of glycaemia, where serum concentrations reflect glucose turnover over the past few weeks to months. In this study, we searched for genetic factors influencing variation in serum fructosamine concentration in healthy dogs using data from nine dog breeds. Considering all breeds together, we did not find any genome-wide significant associations to fructosamine serum concentration. However, by performing breed-specific analyses we revealed an association on chromosome 3 (pcorrected ≈ 1:68 × 10-6) in Belgian shepherd dogs of the Malinois subtype. The associated region and its close neighbourhood harbours interesting candidate genes such as LETM1 and GAPDH that are important in glucose metabolism and have previously been implicated in the aetiology of diabetes mellitus. To further explore the genetics of this breed specificity, we screened the genome for reduced heterozygosity stretches private to the Belgian shepherd breed. This revealed a region with reduced heterozygosity that shows a statistically significant interaction (p = 0.025) with the association region on chromosome 3. This region also harbours some interesting candidate genes and regulatory regions but the exact mechanisms underlying the interaction are still unknown. Nevertheless, this finding provides a plausible explanation for breed-specific genetic effects for complex traits in dogs. Shepherd breeds are at low risk of developing diabetes mellitus. The findings in Belgian shepherds could be connected to a protective mechanism against the disease. Further insight into the regulation of glucose metabolism could improve diagnostic and therapeutic methods for diabetes mellitus. PMID:25970163

  19. Effect of population size and unbalanced data sets on QTL detection using genome-wide association mapping in barley breeding germplasm.

    PubMed

    Wang, Hongyun; Smith, Kevin P; Combs, Emily; Blake, Tom; Horsley, Richard D; Muehlbauer, Gary J

    2012-01-01

    Over the past two decades many quantitative trait loci (QTL) have been detected; however, very few have been incorporated into breeding programs. The recent development of genome-wide association studies (GWAS) in plants provides the opportunity to detect QTL in germplasm collections such as unstructured populations from breeding programs. The overall goal of the barley Coordinated Agricultural Project was to conduct GWAS with the intent to couple QTL detection and breeding. The basic idea is that breeding programs generate a vast amount of phenotypic data and combined with cheap genotyping it should be possible to use GWAS to detect QTL that would be immediately accessible and used by breeding programs. There are several constraints to using breeding program-derived phenotype data for conducting GWAS namely: limited population size and unbalanced data sets. We chose the highly heritable trait heading date to study these two variables. We examined 766 spring barley breeding lines (panel #1) grown in balanced trials and a subset of 384 spring barley breeding lines (panel #2) grown in balanced and unbalanced trials. In panel #1, we detected three major QTL for heading date that have been detected in previous bi-parental mapping studies. Simulation studies showed that population sizes greater than 384 individuals are required to consistently detect QTL. We also showed that unbalanced data sets from panel #2 can be used to detect the three major QTL. However, unbalanced data sets resulted in an increase in the false-positive rate. Interestingly, one-step analysis performed better than two-step analysis in reducing the false-positive rate. The results of this work show that it is possible to use phenotypic data from breeding programs to detect QTL, but that careful consideration of population size and experimental design are required. PMID:21898052

  20. A genome-wide association study to detect genetic variation for postpartum dysgalactia syndrome in five commercial pig breeding lines.

    PubMed

    Preissler, Regine; Tetens, Jens; Reiners, Kerstin; Looft, Holger; Kemper, Nicole

    2013-08-01

    Postpartum dysgalactia syndrome (PDS) in sows is an important disease after parturition with a relevant economic impact, affecting the health and welfare of both sows and piglets. The genetic background of this disease has been discussed and its heritability estimated, but further genetic analyses are lacking in detail. The aim of the current study was to detect loci affecting the susceptibility to PDS through a genome-wide association approach. The study was designed as a family-based association study with matched sampling of affected sows and healthy half- or full-sib control sows on six farms. For the study, 597 sows (322 affected vs. 275 healthy control sows) were genotyped on 62 163 single nucleotide polymorphisms (SNPs) using the Illumina PorcineSNP60 BeadChip. After quality control, 585 sows (314 affected vs. 271 healthy control sows) and 49 740 SNPs remained for further analysis. Statistics were performed mainly with the r package genabel and included a principal component analysis. A statistically significant genome-wide associated SNP was identified on porcine chromosome (SSC) 17. Further promising results with moderate significance were detected on SSC 13 and on an unplaced scaffold with an older annotation on SSC 15. The PRICKLE2 and NRP2 genes were identified as candidate genes near associated SNPs. Several quantitative trait loci (QTL) have been previously described in these genomic regions, including QTL for mammary gland condition, as teat number and non-functional nipples QTL, as well as QTL for body temperature and gestation length. PMID:23742276

  1. A Multi-Breed Genome-Wide Association Analysis for Canine Hypothyroidism Identifies a Shared Major Risk Locus on CFA12

    PubMed Central

    Massey, Jonathan; Dietschi, Elisabeth; Kierczak, Marcin; Lund-Ziener, Martine; Sundberg, Katarina; Thoresen, Stein Istre; Kämpe, Olle; Andersson, Göran; Ollier, William E. R.; Hedhammar, Åke; Leeb, Tosso; Lindblad-Toh, Kerstin; Kennedy, Lorna J.; Lingaas, Frode; Rosengren Pielberg, Gerli

    2015-01-01

    Hypothyroidism is a complex clinical condition found in both humans and dogs, thought to be caused by a combination of genetic and environmental factors. In this study we present a multi-breed analysis of predisposing genetic risk factors for hypothyroidism in dogs using three high-risk breeds—the Gordon Setter, Hovawart and the Rhodesian Ridgeback. Using a genome-wide association approach and meta-analysis, we identified a major hypothyroidism risk locus shared by these breeds on chromosome 12 (p = 2.1x10-11). Further characterisation of the candidate region revealed a shared ~167 kb risk haplotype (4,915,018–5,081,823 bp), tagged by two SNPs in almost complete linkage disequilibrium. This breed-shared risk haplotype includes three genes (LHFPL5, SRPK1 and SLC26A8) and does not extend to the dog leukocyte antigen (DLA) class II gene cluster located in the vicinity. These three genes have not been identified as candidate genes for hypothyroid disease previously, but have functions that could potentially contribute to the development of the disease. Our results implicate the potential involvement of novel genes and pathways for the development of canine hypothyroidism, raising new possibilities for screening, breeding programmes and treatments in dogs. This study may also contribute to our understanding of the genetic etiology of human hypothyroid disease, which is one of the most common endocrine disorders in humans. PMID:26261983

  2. Genome-wide assessment of worldwide chicken SNP genetic diversity indicates significant absence of rare alleles in commercial breeds

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Breed utilization, genetic improvement, and industry consolidation are predicted to have major impacts on the genetic composition of commercial chickens. Consequently, the question arises as to whether sufficient genetic diversity remains within industry stocks to address future needs. With the ch...

  3. Genome-wide study on intramuscular fat in Italian Large White pig breed using the PorcineSNP60 BeadChip.

    PubMed

    Davoli, R; Luise, D; Mingazzini, V; Zambonelli, P; Braglia, S; Serra, A; Russo, V

    2016-08-01

    Genome-wide association study results are presented for intramuscular fat in Italian Large White pig breed. A total of 886 individuals were genotyped with PorcineSNP60 BeadChip. After quality control performed with plink software and in R environment, 49 208 markers remained for the association analysis. The genome-wide association studies was conducted using linear mixed model implemented in GenABEL. We detected seven new SNPs of genes till now not found associated to intramuscular fat (IMF). Three markers map in a wide intergenic region rich of QTL linked to fat traits, one map 388 kb upstream the gene SDK1, one map inside PPP3CA gene, one inside SCPEP1 gene and the last is not mapped in the porcine genome yet. Associations here presented indicate a moderate effect of these genes on IMF. In particular, PPP3CA, that is involved in the oxidative metabolism of skeletal muscle, could be considerated as an interesting candidate gene for IMF content in pigs. However, further studies are needed to clarify the role of these genes on the physiological processes involved in IMF regulation. These results may be useful to control this trait that is important in terms of nutritional, technological and organoleptic characteristics of fresh meat and processed products. PMID:26578072

  4. Genome-wide assessment of worldwide chicken SNP genetic diversity indicates significant absence of rare alleles in commercial breeds

    PubMed Central

    Muir, William M.; Wong, Gane Ka-Shu; Zhang, Yong; Wang, Jun; Groenen, Martien A. M.; Crooijmans, Richard P. M. A.; Megens, Hendrik-Jan; Zhang, Huanmin; Okimoto, Ron; Vereijken, Addie; Jungerius, Annemieke; Albers, Gerard A. A.; Lawley, Cindy Taylor; Delany, Mary E.; MacEachern, Sean; Cheng, Hans H.

    2008-01-01

    Breed utilization, genetic improvement, and industry consolidation are predicted to have major impacts on the genetic composition of commercial chickens. Consequently, the question arises as to whether sufficient genetic diversity remains within industry stocks to address future needs. With the chicken genome sequence and more than 2.8 million single-nucleotide polymorphisms (SNPs), it is now possible to address biodiversity using a previously unattainable metric: missing alleles. To achieve this assessment, 2551 informative SNPs were genotyped on 2580 individuals, including 1440 commercial birds. The proportion of alleles lacking in commercial populations was assessed by (1) estimating the global SNP allele frequency distribution from a hypothetical ancestral population as a reference, then determining the portion of the distribution lost, and then (2) determining the relationship between allele loss and the inbreeding coefficient. The results indicate that 50% or more of the genetic diversity in ancestral breeds is absent in commercial pure lines. The missing genetic diversity resulted from the limited number of incorporated breeds. As such, hypothetically combining stocks within a company could recover only preexisting within-breed variability, but not more rare ancestral alleles. We establish that SNP weights act as sentinels of biodiversity and provide an objective assessment of the strains that are most valuable for preserving genetic diversity. This is the first experimental analysis investigating the extant genetic diversity of virtually an entire agricultural commodity. The methods presented are the first to characterize biodiversity in terms of allelic diversity and to objectively link rate of allele loss with the inbreeding coefficient. PMID:18981413

  5. Using an Inbred Horse Breed in a High Density Genome-Wide Scan for Genetic Risk Factors of Insect Bite Hypersensitivity (IBH)

    PubMed Central

    Velie, Brandon D.; Shrestha, Merina; Franҫois, Liesbeth; Schurink, Anouk; Tesfayonas, Yohannes G.; Stinckens, Anneleen; Blott, Sarah; Ducro, Bart J.; Mikko, Sofia; Thomas, Ruth; Swinburne, June E.; Sundqvist, Marie; Eriksson, Susanne; Buys, Nadine; Lindgren, Gabriella

    2016-01-01

    While susceptibility to hypersensitive reactions is a common problem amongst humans and animals alike, the population structure of certain animal species and breeds provides a more advantageous route to better understanding the biology underpinning these conditions. The current study uses Exmoor ponies, a highly inbred breed of horse known to frequently suffer from insect bite hypersensitivity, to identify genomic regions associated with a type I and type IV hypersensitive reaction. A total of 110 cases and 170 controls were genotyped on the 670K Axiom Equine Genotyping Array. Quality control resulted in 452,457 SNPs and 268 individuals being tested for association. Genome-wide association analyses were performed using the GenABEL package in R and resulted in the identification of two regions of interest on Chromosome 8. The first region contained the most significant SNP identified, which was located in an intron of the DCC netrin 1 receptor gene. The second region identified contained multiple top SNPs and encompassed the PIGN, KIAA1468, TNFRSF11A, ZCCHC2, and PHLPP1 genes. Although additional studies will be needed to validate the importance of these regions in horses and the relevance of these regions in other species, the knowledge gained from the current study has the potential to be a step forward in unraveling the complex nature of hypersensitive reactions. PMID:27070818

  6. Using an Inbred Horse Breed in a High Density Genome-Wide Scan for Genetic Risk Factors of Insect Bite Hypersensitivity (IBH).

    PubMed

    Velie, Brandon D; Shrestha, Merina; Franҫois, Liesbeth; Schurink, Anouk; Tesfayonas, Yohannes G; Stinckens, Anneleen; Blott, Sarah; Ducro, Bart J; Mikko, Sofia; Thomas, Ruth; Swinburne, June E; Sundqvist, Marie; Eriksson, Susanne; Buys, Nadine; Lindgren, Gabriella

    2016-01-01

    While susceptibility to hypersensitive reactions is a common problem amongst humans and animals alike, the population structure of certain animal species and breeds provides a more advantageous route to better understanding the biology underpinning these conditions. The current study uses Exmoor ponies, a highly inbred breed of horse known to frequently suffer from insect bite hypersensitivity, to identify genomic regions associated with a type I and type IV hypersensitive reaction. A total of 110 cases and 170 controls were genotyped on the 670K Axiom Equine Genotyping Array. Quality control resulted in 452,457 SNPs and 268 individuals being tested for association. Genome-wide association analyses were performed using the GenABEL package in R and resulted in the identification of two regions of interest on Chromosome 8. The first region contained the most significant SNP identified, which was located in an intron of the DCC netrin 1 receptor gene. The second region identified contained multiple top SNPs and encompassed the PIGN, KIAA1468, TNFRSF11A, ZCCHC2, and PHLPP1 genes. Although additional studies will be needed to validate the importance of these regions in horses and the relevance of these regions in other species, the knowledge gained from the current study has the potential to be a step forward in unraveling the complex nature of hypersensitive reactions. PMID:27070818

  7. Genome-wide insertion-deletion (InDel) marker discovery and genotyping for genomics-assisted breeding applications in chickpea.

    PubMed

    Das, Shouvik; Upadhyaya, Hari D; Srivastava, Rishi; Bajaj, Deepak; Gowda, C L L; Sharma, Shivali; Singh, Sube; Tyagi, Akhilesh K; Parida, Swarup K

    2015-10-01

    We developed 21,499 genome-wide insertion-deletion (InDel) markers (2- to 54-bp in silico fragment length polymorphism) by comparing the genomic sequences of four (desi, kabuli and wild C. reticulatum) chickpea [Cicer arietinum (L.)] accessions. InDel markers showing 2- to 6-bp fragment length polymorphism among accessions were abundant (76.8%) in the chickpea genome. The physically mapped 7,643 and 13,856 markers on eight chromosomes and unanchored scaffolds, respectively, were structurally and functionally annotated. The 4,506 coding (23% large-effect frameshift mutations) and regulatory InDel markers were identified from 3,228 genes (representing 11.7% of total 27,571 desi genes), suggesting their functional relevance for trait association/genetic mapping. High amplification (97%) and intra-specific polymorphic (60-83%) potential and wider genetic diversity (15-89%) were detected by genome-wide 6,254 InDel markers among desi, kabuli and wild accessions using even a simpler cost-effective agarose gel-based assay. This signifies added advantages of this user-friendly genetic marker system for manifold large-scale genotyping applications in laboratories with limited infrastructure and resources. Utilizing 6,254 InDel markers-based high-density (inter-marker distance: 0.212 cM) inter-specific genetic linkage map (ICC 4958 × ICC 17160) of chickpea as a reference, three major genomic regions harboring six flowering and maturity time robust QTLs (16.4-27.5% phenotypic variation explained, 8.1-11.5 logarithm of odds) were identified. Integration of genetic and physical maps at these target QTL intervals mapped on three chromosomes delineated five InDel markers-containing candidate genes tightly linked to the QTLs governing flowering and maturity time in chickpea. Taken together, our study demonstrated the practical utility of developing and high-throughput genotyping of such beneficial InDel markers at a genome-wide scale to expedite genomics-assisted breeding

  8. Genome-wide insertion–deletion (InDel) marker discovery and genotyping for genomics-assisted breeding applications in chickpea

    PubMed Central

    Das, Shouvik; Upadhyaya, Hari D.; Srivastava, Rishi; Bajaj, Deepak; Gowda, C.L.L.; Sharma, Shivali; Singh, Sube; Tyagi, Akhilesh K.; Parida, Swarup K.

    2015-01-01

    We developed 21,499 genome-wide insertion–deletion (InDel) markers (2- to 54-bp in silico fragment length polymorphism) by comparing the genomic sequences of four (desi, kabuli and wild C. reticulatum) chickpea [Cicer arietinum (L.)] accessions. InDel markers showing 2- to 6-bp fragment length polymorphism among accessions were abundant (76.8%) in the chickpea genome. The physically mapped 7,643 and 13,856 markers on eight chromosomes and unanchored scaffolds, respectively, were structurally and functionally annotated. The 4,506 coding (23% large-effect frameshift mutations) and regulatory InDel markers were identified from 3,228 genes (representing 11.7% of total 27,571 desi genes), suggesting their functional relevance for trait association/genetic mapping. High amplification (97%) and intra-specific polymorphic (60–83%) potential and wider genetic diversity (15–89%) were detected by genome-wide 6,254 InDel markers among desi, kabuli and wild accessions using even a simpler cost-effective agarose gel-based assay. This signifies added advantages of this user-friendly genetic marker system for manifold large-scale genotyping applications in laboratories with limited infrastructure and resources. Utilizing 6,254 InDel markers-based high-density (inter-marker distance: 0.212 cM) inter-specific genetic linkage map (ICC 4958 × ICC 17160) of chickpea as a reference, three major genomic regions harboring six flowering and maturity time robust QTLs (16.4–27.5% phenotypic variation explained, 8.1–11.5 logarithm of odds) were identified. Integration of genetic and physical maps at these target QTL intervals mapped on three chromosomes delineated five InDel markers-containing candidate genes tightly linked to the QTLs governing flowering and maturity time in chickpea. Taken together, our study demonstrated the practical utility of developing and high-throughput genotyping of such beneficial InDel markers at a genome-wide scale to expedite genomics

  9. Genome-Wide Study of Structural Variants in Bovine Holstein, Montbéliarde and Normande Dairy Breeds

    PubMed Central

    Boussaha, Mekki; Esquerré, Diane; Barbieri, Johanna; Djari, Anis; Pinton, Alain; Letaief, Rabia; Salin, Gérald; Escudié, Frédéric; Roulet, Alain; Fritz, Sébastien; Samson, Franck; Grohs, Cécile; Bernard, Maria; Klopp, Christophe; Boichard, Didier; Rocha, Dominique

    2015-01-01

    High-throughput sequencing technologies have offered in recent years new opportunities to study genome variations. These studies have mostly focused on single nucleotide polymorphisms, small insertions or deletions and on copy number variants. Other structural variants, such as large insertions or deletions, tandem duplications, translocations, and inversions are less well-studied, despite that some have an important impact on phenotypes. In the present study, we performed a large-scale survey of structural variants in cattle. We report the identification of 6,426 putative structural variants in cattle extracted from whole-genome sequence data of 62 bulls representing the three major French dairy breeds. These genomic variants affect DNA segments greater than 50 base pairs and correspond to deletions, inversions and tandem duplications. Out of these, we identified a total of 547 deletions and 410 tandem duplications which could potentially code for CNVs. Experimental validation was carried out on 331 structural variants using a novel high-throughput genotyping method. Out of these, 255 structural variants (77%) generated good quality genotypes and 191 (75%) of them were validated. Gene content analyses in structural variant regions revealed 941 large deletions removing completely one or several genes, including 10 single-copy genes. In addition, some of the structural variants are located within quantitative trait loci for dairy traits. This study is a pan-genome assessment of genomic variations in cattle and may provide a new glimpse into the bovine genome architecture. Our results may also help to study the effects of structural variants on gene expression and consequently their effect on certain phenotypes of interest. PMID:26317361

  10. Genome-Wide Scan for Visceral Leishmaniasis in Mixed-Breed Dogs Identifies Candidate Genes Involved in T Helper Cells and Macrophage Signaling

    PubMed Central

    Utsunomiya, Yuri T.; Ribeiro, Érica S.; Quintal, Amanda P. N.; Sangalli, Juliano R.; Gazola, Valquiria R.; Paula, Henrique B.; Trinconi, Cristiana M.; Lima, Valéria M. F.; Perri, Silvia H. V.; Taylor, Jeremy F.; Schnabel, Robert D.; Sonstegard, Tad S.; Garcia, José F.; Nunes, Cáris M.

    2015-01-01

    We conducted a genome-wide scan for visceral leishmaniasis in mixed-breed dogs from a highly endemic area in Brazil using 149,648 single nucleotide polymorphism (SNP) markers genotyped in 20 cases and 28 controls. Using a mixed model approach, we found two candidate loci on canine autosomes 1 and 2. The positional association on chromosome 2 mapped to a predicted DNAse sensitive site in CD14+ monocytes that serve as a cis-regulatory element for the expression of interleukin alpha receptors 2 (IL2RA) and 15 (IL15RA). Both interleukins were previously found to lead to protective T helper 1 cell (Th1) response against Leishmania spp. in humans and mice. The associated marker on chromosome 1 was located between two predicted transcription factor binding sites regulating the expression of the transducin-like enhancer of split 1 gene (TLE1), an important player in Notch signaling. This pathway is critical for macrophage activity and CD4+ T cell differentiation into Th1 and T helper 2. Together, these findings suggest that the human and mouse model for protective response against Leishmania spp., which involves Th1 and macrophage modulation by interleukins 2, 15, gamma interferon and Notch signaling, may also hold for the canine model. PMID:26348501

  11. Cassava Breeding I: The Value of Breeding Value

    PubMed Central

    Ceballos, Hernán; Pérez, Juan C.; Joaqui Barandica, Orlando; Lenis, Jorge I.; Morante, Nelson; Calle, Fernando; Pino, Lizbeth; Hershey, Clair H.

    2016-01-01

    Breeding cassava relies on several selection stages (single row trial-SRT; preliminary; advanced; and uniform yield trials—UYT). This study uses data from 14 years of evaluations. From more than 20,000 genotypes initially evaluated only 114 reached the last stage. The objective was to assess how the data at SRT could be used to predict the probabilities of genotypes reaching the UYT. Phenotypic data from each genotype at SRT was integrated into the selection index (SIN) used by the cassava breeding program. Average SIN from all the progenies derived from each progenitor was then obtained. Average SIN is an approximation of the breeding value of each progenitor. Data clearly suggested that some genotypes were better progenitors than others (e.g., high number of their progenies reaching the UYT), suggesting important variation in breeding values of progenitors. However, regression of average SIN of each parental genotype on the number of their respective progenies reaching UYT resulted in a negligible coefficient of determination (r2 = 0.05). Breeding value (e.g., average SIN) at SRT was not efficient predicting which genotypes were more likely to reach the UYT stage. Number of families and progenies derived from a given progenitor were more efficient predicting the probabilities of the progeny from a given parent reaching the UYT stage. Large within-family genetic variation tends to mask the true breeding value of each progenitor. The use of partially inbred progenitors (e.g., S1 or S2 genotypes) would reduce the within-family genetic variation thus making the assessment of breeding value more accurate. Moreover, partial inbreeding of progenitors can improve the breeding value of the original (S0) parental material and sharply accelerate genetic gains. For instance, homozygous S1 genotypes for the dominant resistance to cassava mosaic disease (CMD) could be generated and selected. All gametes from these selected S1 genotypes would carry the desirable allele and

  12. Cassava Breeding I: The Value of Breeding Value.

    PubMed

    Ceballos, Hernán; Pérez, Juan C; Joaqui Barandica, Orlando; Lenis, Jorge I; Morante, Nelson; Calle, Fernando; Pino, Lizbeth; Hershey, Clair H

    2016-01-01

    Breeding cassava relies on several selection stages (single row trial-SRT; preliminary; advanced; and uniform yield trials-UYT). This study uses data from 14 years of evaluations. From more than 20,000 genotypes initially evaluated only 114 reached the last stage. The objective was to assess how the data at SRT could be used to predict the probabilities of genotypes reaching the UYT. Phenotypic data from each genotype at SRT was integrated into the selection index (SIN) used by the cassava breeding program. Average SIN from all the progenies derived from each progenitor was then obtained. Average SIN is an approximation of the breeding value of each progenitor. Data clearly suggested that some genotypes were better progenitors than others (e.g., high number of their progenies reaching the UYT), suggesting important variation in breeding values of progenitors. However, regression of average SIN of each parental genotype on the number of their respective progenies reaching UYT resulted in a negligible coefficient of determination (r (2) = 0.05). Breeding value (e.g., average SIN) at SRT was not efficient predicting which genotypes were more likely to reach the UYT stage. Number of families and progenies derived from a given progenitor were more efficient predicting the probabilities of the progeny from a given parent reaching the UYT stage. Large within-family genetic variation tends to mask the true breeding value of each progenitor. The use of partially inbred progenitors (e.g., S1 or S2 genotypes) would reduce the within-family genetic variation thus making the assessment of breeding value more accurate. Moreover, partial inbreeding of progenitors can improve the breeding value of the original (S0) parental material and sharply accelerate genetic gains. For instance, homozygous S1 genotypes for the dominant resistance to cassava mosaic disease (CMD) could be generated and selected. All gametes from these selected S1 genotypes would carry the desirable allele and

  13. Genome-wide DNA methylation profiling in triple-negative breast cancer reveals epigenetic signatures with important clinical value

    PubMed Central

    Stirzaker, Clare; Zotenko, Elena; Clark, Susan J

    2016-01-01

    abstract Analysis of cancer methylomes has dramatically changed our concept of the potential of diagnostic and prognostic methylation biomarkers in disease stratification. Through whole-genome methylation capture sequencing of triple-negative breast cancers (TNBCs) we recently identified differentially methylated regions with diagnostic and prognostic value that promise to stratify TNBCs for more personalized management. PMID:27308556

  14. Genome-wide DNA methylation profiling in triple-negative breast cancer reveals epigenetic signatures with important clinical value.

    PubMed

    Stirzaker, Clare; Zotenko, Elena; Clark, Susan J

    2016-01-01

    Analysis of cancer methylomes has dramatically changed our concept of the potential of diagnostic and prognostic methylation biomarkers in disease stratification. Through whole-genome methylation capture sequencing of triple-negative breast cancers (TNBCs) we recently identified differentially methylated regions with diagnostic and prognostic value that promise to stratify TNBCs for more personalized management. PMID:27308556

  15. Genome-wide differential expression of genes and small RNAs in testis of two different porcine breeds and at two different ages.

    PubMed

    Li, Yao; Li, Jialian; Fang, Chengchi; Shi, Liang; Tan, Jiajian; Xiong, Yuanzhu; Bin Fan; Li, Changchun

    2016-01-01

    Some documented evidences proved small RNAs (sRNA) and targeted genes are involved in mammalian testicular development and spermatogenesis. However, the detailed molecular regulation mechanisms of them remain largely unknown so far. In this study, we obtained a total of 10,716 mRNAs, 67 miRNAs and 16,953 piRNAs which were differentially expressed between LC and LW pig breeds or between the two sexual maturity stages. Of which, we identified 16 miRNAs and 28 targeted genes possibly related to spermatogenesis; 14 miRNA and 18 targeted genes probably associated with cell adhesion related testis development. We also annotated 579 piRNAs which could potentially regulate cell death, nucleosome organization and other basic biology process, which implied that those piRNAs might be involved in sexual maturation difference. The integrated network analysis results suggested that some differentially expressed genes were involved in spermatogenesis through the ECM-receptor interaction, focal adhesion, Wnt and PI3K-Akt signaling pathways, some particular miRNAs have the negative regulation roles and some special piRNAs have the positive and negative regulation roles in testicular development. Our data provide novel insights into the molecular expression and regulation similarities and diversities of spermatogenesis and testicular development in different pig breeds at different stages of sexual maturity. PMID:27229484

  16. Genome-wide differential expression of genes and small RNAs in testis of two different porcine breeds and at two different ages

    PubMed Central

    Li, Yao; Li, Jialian; Fang, Chengchi; Shi, Liang; Tan, Jiajian; Xiong, Yuanzhu; Bin Fan; Li, Changchun

    2016-01-01

    Some documented evidences proved small RNAs (sRNA) and targeted genes are involved in mammalian testicular development and spermatogenesis. However, the detailed molecular regulation mechanisms of them remain largely unknown so far. In this study, we obtained a total of 10,716 mRNAs, 67 miRNAs and 16,953 piRNAs which were differentially expressed between LC and LW pig breeds or between the two sexual maturity stages. Of which, we identified 16 miRNAs and 28 targeted genes possibly related to spermatogenesis; 14 miRNA and 18 targeted genes probably associated with cell adhesion related testis development. We also annotated 579 piRNAs which could potentially regulate cell death, nucleosome organization and other basic biology process, which implied that those piRNAs might be involved in sexual maturation difference. The integrated network analysis results suggested that some differentially expressed genes were involved in spermatogenesis through the ECM–receptor interaction, focal adhesion, Wnt and PI3K–Akt signaling pathways, some particular miRNAs have the negative regulation roles and some special piRNAs have the positive and negative regulation roles in testicular development. Our data provide novel insights into the molecular expression and regulation similarities and diversities of spermatogenesis and testicular development in different pig breeds at different stages of sexual maturity. PMID:27229484

  17. Prediction of total genetic value using genome-wide dense marker in Holstein breed by Bayesian method

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Marker-assisted selection (MAS) can be based on molecular markers in linkage equilibrium with quantitative trait loci, molecular markers in linkage disequilibrium with QTL, or on selection of the actual mutations causing the QTL effect. However, one problem in relation to all of them is that only a ...

  18. Genome-Wide Gene Expression Profiles in Lung Tissues of Pig Breeds Differing in Resistance to Porcine Reproductive and Respiratory Syndrome Virus

    PubMed Central

    Zhang, Chenhua; Zhang, Yujie; Wang, Nan; Li, Yanping; Yang, Lijuan; Jiang, Chenglan; Zhang, Chaoyang; Wen, Changhong; Jiang, Yunliang

    2014-01-01

    Porcine reproductive and respiratory syndrome (PRRS) caused by PRRS virus (PRRSV) is an infectious disease characterized by severe reproductive deficiency in pregnant sows, typical respiratory symptoms in piglets, and high mortality rate of piglets. In this study, we employed an Affymetrix microarray chip to compare the gene expression profiles of lung tissue samples from Dapulian (DPL) pigs (a Chinese indigenous pig breed) and Duroc×Landrace×Yorkshire (DLY) pigs after infection with PRRSV. During infection with PRRSV, the DLY pigs exhibited a range of clinical features that typify the disease, whereas the DPL pigs showed only mild signs of the disease. Overall, the DPL group had a lower percentage of CD4+ cells and lower CD4+/CD8+ratios than the DLY group (p<0.05). For both IL-10 and TNF-α, the DLY pigs had significantly higher levels than the DPL pigs (p<0.01). The DLY pigs have lower serum IFN-γ levels than the DPL pigs (p<0.01). The serum IgG levels increased slightly from 0 dpi to 7 dpi, and peaked at 14 dpi (p<0.0001). Microarray data analysis revealed 16 differentially expressed (DE) genes in the lung tissue samples from the DLY and DPL pigs (q≤5%), of which LOC100516029 and LOC100523005 were up-regulated in the PRRSV-infected DPL pigs, while the other 14 genes were down-regulated in the PRRSV-infected DPL pigs compared with the PRRSV-infected DLY pigs. The mRNA expression levels of 10 out of the 16 DE genes were validated by real-time quantitative RT-PCR and their fold change was consistent with the result of microarray data analysis. We further analyzed the mRNA expression level of 8 differentially expressed genes between the DPL and DLY pigs for both uninfected and infected groups, and found that TF and USP18 genes were important in underlying porcine resistance or susceptibility to PRRSV. PMID:24465897

  19. Comparison of molecular breeding values based on within- and across-breed training in beef cattle

    PubMed Central

    2013-01-01

    Background Although the efficacy of genomic predictors based on within-breed training looks promising, it is necessary to develop and evaluate across-breed predictors for the technology to be fully applied in the beef industry. The efficacies of genomic predictors trained in one breed and utilized to predict genetic merit in differing breeds based on simulation studies have been reported, as have the efficacies of predictors trained using data from multiple breeds to predict the genetic merit of purebreds. However, comparable studies using beef cattle field data have not been reported. Methods Molecular breeding values for weaning and yearling weight were derived and evaluated using a database containing BovineSNP50 genotypes for 7294 animals from 13 breeds in the training set and 2277 animals from seven breeds (Angus, Red Angus, Hereford, Charolais, Gelbvieh, Limousin, and Simmental) in the evaluation set. Six single-breed and four across-breed genomic predictors were trained using pooled data from purebred animals. Molecular breeding values were evaluated using field data, including genotypes for 2227 animals and phenotypic records of animals born in 2008 or later. Accuracies of molecular breeding values were estimated based on the genetic correlation between the molecular breeding value and trait phenotype. Results With one exception, the estimated genetic correlations of within-breed molecular breeding values with trait phenotype were greater than 0.28 when evaluated in the breed used for training. Most estimated genetic correlations for the across-breed trained molecular breeding values were moderate (> 0.30). When molecular breeding values were evaluated in breeds that were not in the training set, estimated genetic correlations clustered around zero. Conclusions Even for closely related breeds, within- or across-breed trained molecular breeding values have limited prediction accuracy for breeds that were not in the training set. For breeds in the training

  20. Genome-wide Association Study of Chicken Plumage Pigmentation.

    PubMed

    Park, Mi Na; Choi, Jin Ae; Lee, Kyung-Tai; Lee, Hyun-Jeong; Choi, Bong-Hwan; Kim, Heebal; Kim, Tae-Hun; Cho, Seoae; Lee, Taeheon

    2013-11-01

    To increase plumage color uniformity and understand the genetic background of Korean chickens, we performed a genome-wide association study of different plumage color in Korean native chickens. We analyzed 60K SNP chips on 279 chickens with GEMMA methods for GWAS and estimated the genetic heritability for plumage color. The estimated heritability suggests that plumage coloration is a polygenic trait. We found new loci associated with feather pigmentation at the genome-wide level and from the results infer that there are additional genetic effect for plumage color. The results will be used for selecting and breeding chicken for plumage color uniformity. PMID:25049737

  1. Genome-wide association studies in pharmacogenomics.

    PubMed

    Daly, Ann K

    2010-04-01

    Genome-wide association (GWA) studies for pharmacogenomics-related traits are increasingly being performed to identify loci that affect either drug response or susceptibility to adverse drug reactions. Until now, only the largest effects have been detected, partly because of the challenges of obtaining large numbers of cases for pharmacogenomic studies. Since 2007, a range of pharmacogenomics GWA studies have been published that have identified several interesting and novel associations between drug responses or reactions and clinically relevant loci, showing the value of this approach. PMID:20300088

  2. Genome-wide association study for semen quality traits in German Warmblood stallions.

    PubMed

    Gottschalk, Maren; Metzger, Julia; Martinsson, Gunilla; Sieme, Harald; Distl, Ottmar

    2016-08-01

    We performed a genome-wide association study for semen quality traits in 139 German Warmblood stallions. Stallions were genotyped using the Illumina equine SNP50 Beadchip. Traits analysed were de-regressed estimated breeding values (EBVs) for gel-free volume, sperm concentration, total number of sperm, progressive motility and the total number of progressively motile sperm. The GWAS revealed 29 SNPs on 12 different chromosomes as genome-wide significantly associated with semen quality traits. For ten genomic regions we could retrieve candidate genes influencing stallion fertility. Among the candidate genes, we could find the genes encoding cysteine-rich secretory proteins (CRISP1, CRISP2 and CRISP3). This was the first GWAS in horses performed for semen quality traits. PMID:27334685

  3. Genome-wide SNP detection, validation, and development of an 8K SNP array for apple

    Technology Transfer Automated Retrieval System (TEKTRAN)

    As high-throughput genetic marker screening systems are essential for a range of genetics studies and plant breeding applications, the International RosBREED SNP Consortium (IRSC) has utilized the Illumina Infinium® II system to develop a medium- to high-throughput SNP screening tool for genome-wide...

  4. Genome-Wide Detection of CNVs and Their Association with Meat Tenderness in Nelore Cattle

    PubMed Central

    da Silva, Vinicius Henrique; Regitano, Luciana Correia de Almeida; Geistlinger, Ludwig; Pértille, Fábio; Morosini, Natália Silva; Zimmer, Ralf; Coutinho, Luiz Lehmann

    2016-01-01

    Brazil is one of the largest beef producers and exporters in the world with the Nelore breed representing the vast majority of Brazilian cattle (Bos taurus indicus). Despite the great adaptability of the Nelore breed to tropical climate, meat tenderness (MT) remains to be improved. Several factors including genetic composition can influence MT. In this article, we report a genome-wide analysis of copy number variation (CNV) inferred from Illumina® High Density SNP-chip data for a Nelore population of 723 males. We detected >2,600 CNV regions (CNVRs) representing ≈6.5% of the genome. Comparing our results with previous studies revealed an overlap in ≈1400 CNVRs (>50%). A total of 1,155 CNVRs (43.6%) overlapped 2,750 genes. They were enriched for processes involving guanosine triphosphate (GTP), previously reported to influence skeletal muscle physiology and morphology. Nelore CNVRs also overlapped QTLs for MT reported in other breeds (8.9%, 236 CNVRs) and from a previous study with this population (4.1%, 109 CNVRs). Two CNVRs were also proximal to glutathione metabolism genes that were previously associated with MT. Genome-wide association study of CN state with estimated breeding values derived from meat shear force identified 6 regions, including a region on BTA3 that contains genes of the cAMP and cGMP pathway. Ten CNVRs that overlapped regions associated with MT were successfully validated by qPCR. Our results represent the first comprehensive CNV study in Bos taurus indicus cattle and identify regions in which copy number changes are potentially of importance for the MT phenotype. PMID:27348523

  5. Genome-Wide Detection of CNVs and Their Association with Meat Tenderness in Nelore Cattle.

    PubMed

    Silva, Vinicius Henrique da; Regitano, Luciana Correia de Almeida; Geistlinger, Ludwig; Pértille, Fábio; Giachetto, Poliana Fernanda; Brassaloti, Ricardo Augusto; Morosini, Natália Silva; Zimmer, Ralf; Coutinho, Luiz Lehmann

    2016-01-01

    Brazil is one of the largest beef producers and exporters in the world with the Nelore breed representing the vast majority of Brazilian cattle (Bos taurus indicus). Despite the great adaptability of the Nelore breed to tropical climate, meat tenderness (MT) remains to be improved. Several factors including genetic composition can influence MT. In this article, we report a genome-wide analysis of copy number variation (CNV) inferred from Illumina® High Density SNP-chip data for a Nelore population of 723 males. We detected >2,600 CNV regions (CNVRs) representing ≈6.5% of the genome. Comparing our results with previous studies revealed an overlap in ≈1400 CNVRs (>50%). A total of 1,155 CNVRs (43.6%) overlapped 2,750 genes. They were enriched for processes involving guanosine triphosphate (GTP), previously reported to influence skeletal muscle physiology and morphology. Nelore CNVRs also overlapped QTLs for MT reported in other breeds (8.9%, 236 CNVRs) and from a previous study with this population (4.1%, 109 CNVRs). Two CNVRs were also proximal to glutathione metabolism genes that were previously associated with MT. Genome-wide association study of CN state with estimated breeding values derived from meat shear force identified 6 regions, including a region on BTA3 that contains genes of the cAMP and cGMP pathway. Ten CNVRs that overlapped regions associated with MT were successfully validated by qPCR. Our results represent the first comprehensive CNV study in Bos taurus indicus cattle and identify regions in which copy number changes are potentially of importance for the MT phenotype. PMID:27348523

  6. Genetic Diversity in the Modern Horse Illustrated from Genome-Wide SNP Data

    PubMed Central

    Petersen, Jessica L.; Mickelson, James R.; Cothran, E. Gus; Andersson, Lisa S.; Axelsson, Jeanette; Bailey, Ernie; Bannasch, Danika; Binns, Matthew M.; Borges, Alexandre S.; Brama, Pieter; da Câmara Machado, Artur; Distl, Ottmar; Felicetti, Michela; Fox-Clipsham, Laura; Graves, Kathryn T.; Guérin, Gérard; Haase, Bianca; Hasegawa, Telhisa; Hemmann, Karin; Hill, Emmeline W.; Leeb, Tosso; Lindgren, Gabriella; Lohi, Hannes; Lopes, Maria Susana; McGivney, Beatrice A.; Mikko, Sofia; Orr, Nicholas; Penedo, M. Cecilia T; Piercy, Richard J.; Raekallio, Marja; Rieder, Stefan; Røed, Knut H.; Silvestrelli, Maurizio; Swinburne, June; Tozaki, Teruaki; Vaudin, Mark; M. Wade, Claire; McCue, Molly E.

    2013-01-01

    Horses were domesticated from the Eurasian steppes 5,000–6,000 years ago. Since then, the use of horses for transportation, warfare, and agriculture, as well as selection for desired traits and fitness, has resulted in diverse populations distributed across the world, many of which have become or are in the process of becoming formally organized into closed, breeding populations (breeds). This report describes the use of a genome-wide set of autosomal SNPs and 814 horses from 36 breeds to provide the first detailed description of equine breed diversity. FST calculations, parsimony, and distance analysis demonstrated relationships among the breeds that largely reflect geographic origins and known breed histories. Low levels of population divergence were observed between breeds that are relatively early on in the process of breed development, and between those with high levels of within-breed diversity, whether due to large population size, ongoing outcrossing, or large within-breed phenotypic diversity. Populations with low within-breed diversity included those which have experienced population bottlenecks, have been under intense selective pressure, or are closed populations with long breed histories. These results provide new insights into the relationships among and the diversity within breeds of horses. In addition these results will facilitate future genome-wide association studies and investigations into genomic targets of selection. PMID:23383025

  7. Genetic diversity in the modern horse illustrated from genome-wide SNP data.

    PubMed

    Petersen, Jessica L; Mickelson, James R; Cothran, E Gus; Andersson, Lisa S; Axelsson, Jeanette; Bailey, Ernie; Bannasch, Danika; Binns, Matthew M; Borges, Alexandre S; Brama, Pieter; da Câmara Machado, Artur; Distl, Ottmar; Felicetti, Michela; Fox-Clipsham, Laura; Graves, Kathryn T; Guérin, Gérard; Haase, Bianca; Hasegawa, Telhisa; Hemmann, Karin; Hill, Emmeline W; Leeb, Tosso; Lindgren, Gabriella; Lohi, Hannes; Lopes, Maria Susana; McGivney, Beatrice A; Mikko, Sofia; Orr, Nicholas; Penedo, M Cecilia T; Piercy, Richard J; Raekallio, Marja; Rieder, Stefan; Røed, Knut H; Silvestrelli, Maurizio; Swinburne, June; Tozaki, Teruaki; Vaudin, Mark; M Wade, Claire; McCue, Molly E

    2013-01-01

    Horses were domesticated from the Eurasian steppes 5,000-6,000 years ago. Since then, the use of horses for transportation, warfare, and agriculture, as well as selection for desired traits and fitness, has resulted in diverse populations distributed across the world, many of which have become or are in the process of becoming formally organized into closed, breeding populations (breeds). This report describes the use of a genome-wide set of autosomal SNPs and 814 horses from 36 breeds to provide the first detailed description of equine breed diversity. F(ST) calculations, parsimony, and distance analysis demonstrated relationships among the breeds that largely reflect geographic origins and known breed histories. Low levels of population divergence were observed between breeds that are relatively early on in the process of breed development, and between those with high levels of within-breed diversity, whether due to large population size, ongoing outcrossing, or large within-breed phenotypic diversity. Populations with low within-breed diversity included those which have experienced population bottlenecks, have been under intense selective pressure, or are closed populations with long breed histories. These results provide new insights into the relationships among and the diversity within breeds of horses. In addition these results will facilitate future genome-wide association studies and investigations into genomic targets of selection. PMID:23383025

  8. Genome-wide association analysis identifies loci for left-sided displacement of the abomasum in German Holstein cattle.

    PubMed

    Mömke, S; Sickinger, M; Lichtner, P; Doll, K; Rehage, J; Distl, O

    2013-06-01

    Left-sided displacement of the abomasum (LDA) is one of the most common disorders of the digestive system in many dairy breeds and particularly in Holstein dairy cows. We performed a genome-wide association study for 854 German Holstein cows, including 225 cases and 629 controls. All cows were genotyped using the Illumina Bovine SNP50 BeadChip (Illumina Inc., San Diego, CA). After quality control of genotypes, a total of 36,226 informative single nucleotide polymorphisms (SNP) were left for analysis. We used a mixed linear model approach for a genome-wide association study of LDA. In total, 36 SNP located on 17 bovine (Bos taurus) chromosomes (BTA) showed associations with LDA at nominal -log10P-values >3.0. Two of these SNP, located on BTA11 at 46.70 Mb and BTA20 at 16.67 Mb, showed genome-wide significant associations with LDA at -log10P-values >4.6. Pathway analyses indicated genes involved in calcium metabolism and insulin-dependent diabetes mellitus to be factors in the pathogenesis of LDA in German Holstein cows. PMID:23548285

  9. Efficient estimation of breeding values from dense genomic data

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genomic, phenotypic, and pedigree data can be combined to produce estimated breeding values (EBV) with higher reliability. If coefficient matrix Z includes genotypes for many loci and marker effects (u) are normally distributed with equal variance at each, estimation of u by mixed model equations or...

  10. Genome Wide Analysis of Fertility and Production Traits in Italian Holstein Cattle

    PubMed Central

    Stella, Alessandra; Biffani, Stefano; Negrini, Riccardo; Lazzari, Barbara; Ajmone-Marsan, Paolo; Williams, John L .

    2013-01-01

    A genome wide scan was performed on a total of 2093 Italian Holstein proven bulls genotyped with 50K single nucleotide polymorphisms (SNPs), with the objective of identifying loci associated with fertility related traits and to test their effects on milk production traits. The analysis was carried out using estimated breeding values for the aggregate fertility index and for each trait contributing to the index: angularity, calving interval, non-return rate at 56 days, days to first service, and 305 day first parity lactation. In addition, two production traits not included in the aggregate fertility index were analysed: fat yield and protein yield. Analyses were carried out using all SNPs treated separately, further the most significant marker on BTA14 associated to milk quality located in the DGAT1 region was treated as fixed effect. Genome wide association analysis identified 61 significant SNPs and 75 significant marker-trait associations. Eight additional SNP associations were detected when SNP located near DGAT1 was included as a fixed effect. As there were no obvious common SNPs between the traits analyzed independently in this study, a network analysis was carried out to identify unforeseen relationships that may link production and fertility traits. PMID:24265800

  11. Genome-wide association study on reproductive traits in Jinghai Yellow Chicken.

    PubMed

    Zhang, G X; Fan, Q C; Wang, J Y; Zhang, T; Xue, Q; Shi, H Q

    2015-12-01

    To identify molecular markers and candidate genes associated with reproductive traits, a genome-wide analysis was performed in Jinghai Yellow Chickens to analyze body weight at first oviposition (BWF), age at first oviposition (AFE), weight of the egg at first oviposition (FEW), egg weight at the age of 300 days (EW300), number of eggs produced by 300 days of age (EN300), egg hatchability (HA) and multiple selection index for egg production (MSI). The results showed that seven single nucleotide polymorphisms (SNPs) were associated with reproductive traits (P<1.80E-6, Bonferroni correction). The P-values of the seven SNPs were 5.62E-10, 3.45E-08, 9.76E-07, 8.90E-07, 1.12E-06, 1.42E-07 and 1.48E-07, respectively. These SNPs were located in close proximity to or within the sequence of the five candidate genes, including FAM184B, TTL, RGS1, FBLN5 and PCNX. An additional 46 SNPs that could be associated with reproductive traits were identified (P<3.59E-5, Bonferroni correction). Identification of the candidate genes as well as genome-wide SNPs that may be associated with reproductive traits will greatly advance the understanding of the genetic basis and molecular mechanisms underlying reproductive traits and may have practical significance in breeding programs for the improvements of reproductive traits in the Jinghai Yellow Chicken. PMID:26498507

  12. Accuracy of genomic breeding values in multibreed beef cattle populations derived from deregressed breeding values and phenotypes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genomic selection involves the assessment of genetic merit through prediction equations that allocate genetic variation with dense marker genotypes. It has the potential to provide accurate breeding values for selection candidates at an early age and facilitate selection for expensive or difficult ...

  13. Genome-wide association study of schizophrenia in Ashkenazi Jews.

    PubMed

    Goes, Fernando S; McGrath, John; Avramopoulos, Dimitrios; Wolyniec, Paula; Pirooznia, Mehdi; Ruczinski, Ingo; Nestadt, Gerald; Kenny, Eimear E; Vacic, Vladimir; Peters, Inga; Lencz, Todd; Darvasi, Ariel; Mulle, Jennifer G; Warren, Stephen T; Pulver, Ann E

    2015-12-01

    Schizophrenia is a common, clinically heterogeneous disorder associated with lifelong morbidity and early mortality. Several genetic variants associated with schizophrenia have been identified, but the majority of the heritability remains unknown. In this study, we report on a case-control sample of Ashkenazi Jews (AJ), a founder population that may provide additional insights into genetic etiology of schizophrenia. We performed a genome-wide association analysis (GWAS) of 592 cases and 505 controls of AJ ancestry ascertained in the US. Subsequently, we performed a meta-analysis with an Israeli AJ sample of 913 cases and 1640 controls, followed by a meta-analysis and polygenic risk scoring using summary results from Psychiatric GWAS Consortium 2 schizophrenia study. The U.S. AJ sample showed strong evidence of polygenic inheritance (pseudo-R(2) ∼9.7%) and a SNP-heritability estimate of 0.39 (P = 0.00046). We found no genome-wide significant associations in the U.S. sample or in the combined US/Israeli AJ meta-analysis of 1505 cases and 2145 controls. The strongest AJ specific associations (P-values in 10(-6) -10(-7) range) were in the 22q 11.2 deletion region and included the genes TBX1, GLN1, and COMT. Supportive evidence (meta P < 1 × 10(-4) ) was also found for several previously identified genome-wide significant findings, including the HLA region, CNTN4, IMMP2L, and GRIN2A. The meta-analysis of the U.S. sample with the PGC2 results provided initial genome-wide significant evidence for six new loci. Among the novel potential susceptibility genes is PEPD, a gene involved in proline metabolism, which is associated with a Mendelian disorder characterized by developmental delay and cognitive deficits. PMID:26198764

  14. Methods for meta-analysis of genome-wide association studies

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A limitation of many genome-wide association studies (GWA) in animal breeding is that there are many loci with small effect sizes; thus, larger sample sizes (N) are required to guarantee suitable power of detection. For increasing N, results from different GWA can be combined in a meta-analysis (MA-...

  15. Meta-analysis of genome-wide association from genomic prediction models

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A limitation of many genome-wide association studies (GWA) in animal breeding is that there are many loci with small effect sizes; thus, larger sample sizes (N) are required to guarantee suitable power of detection. To increase sample size, results from different GWA can be combined in a meta-analys...

  16. Genomic selection & association mapping in rice: effect of trait genetic architecture, training population composition, marker number & statistical model on accuracy of rice genomic selection in elite, tropical rice breeding

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genomic Selection (GS) is a new breeding method in which genome-wide markers are used to predict the breeding value of individuals in a breeding population. GS has been shown to improve breeding efficiency in dairy cattle and several crop plant species, and here we evaluate for the first time its ef...

  17. Genome-Wide Estimates of Coancestry, Inbreeding and Effective Population Size in the Spanish Holstein Population

    PubMed Central

    Rodríguez-Ramilo, Silvia Teresa; Fernández, Jesús; Toro, Miguel Angel; Hernández, Delfino; Villanueva, Beatriz

    2015-01-01

    Estimates of effective population size in the Holstein cattle breed have usually been low despite the large number of animals that constitute this breed. Effective population size is inversely related to the rates at which coancestry and inbreeding increase and these rates have been high as a consequence of intense and accurate selection. Traditionally, coancestry and inbreeding coefficients have been calculated from pedigree data. However, the development of genome-wide single nucleotide polymorphisms has increased the interest of calculating these coefficients from molecular data in order to improve their accuracy. In this study, genomic estimates of coancestry, inbreeding and effective population size were obtained in the Spanish Holstein population and then compared with pedigree-based estimates. A total of 11,135 animals genotyped with the Illumina BovineSNP50 BeadChip were available for the study. After applying filtering criteria, the final genomic dataset included 36,693 autosomal SNPs and 10,569 animals. Pedigree data from those genotyped animals included 31,203 animals. These individuals represented only the last five generations in order to homogenise the amount of pedigree information across animals. Genomic estimates of coancestry and inbreeding were obtained from identity by descent segments (coancestry) or runs of homozygosity (inbreeding). The results indicate that the percentage of variance of pedigree-based coancestry estimates explained by genomic coancestry estimates was higher than that for inbreeding. Estimates of effective population size obtained from genome-wide and pedigree information were consistent and ranged from about 66 to 79. These low values emphasize the need of controlling the rate of increase of coancestry and inbreeding in Holstein selection programmes. PMID:25880228

  18. Genome-wide prediction models that incorporate de novo GWAS are a powerful new tool for tropical rice improvement.

    PubMed

    Spindel, J E; Begum, H; Akdemir, D; Collard, B; Redoña, E; Jannink, J-L; McCouch, S

    2016-04-01

    To address the multiple challenges to food security posed by global climate change, population growth and rising incomes, plant breeders are developing new crop varieties that can enhance both agricultural productivity and environmental sustainability. Current breeding practices, however, are unable to keep pace with demand. Genomic selection (GS) is a new technique that helps accelerate the rate of genetic gain in breeding by using whole-genome data to predict the breeding value of offspring. Here, we describe a new GS model that combines RR-BLUP with markers fit as fixed effects selected from the results of a genome-wide-association study (GWAS) on the RR-BLUP training data. We term this model GS + de novo GWAS. In a breeding population of tropical rice, GS + de novo GWAS outperformed six other models for a variety of traits and in multiple environments. On the basis of these results, we propose an extended, two-part breeding design that can be used to efficiently integrate novel variation into elite breeding populations, thus expanding genetic diversity and enhancing the potential for sustainable productivity gains. PMID:26860200

  19. Genome-wide prediction models that incorporate de novo GWAS are a powerful new tool for tropical rice improvement

    PubMed Central

    Spindel, J E; Begum, H; Akdemir, D; Collard, B; Redoña, E; Jannink, J-L; McCouch, S

    2016-01-01

    To address the multiple challenges to food security posed by global climate change, population growth and rising incomes, plant breeders are developing new crop varieties that can enhance both agricultural productivity and environmental sustainability. Current breeding practices, however, are unable to keep pace with demand. Genomic selection (GS) is a new technique that helps accelerate the rate of genetic gain in breeding by using whole-genome data to predict the breeding value of offspring. Here, we describe a new GS model that combines RR-BLUP with markers fit as fixed effects selected from the results of a genome-wide-association study (GWAS) on the RR-BLUP training data. We term this model GS + de novo GWAS. In a breeding population of tropical rice, GS + de novo GWAS outperformed six other models for a variety of traits and in multiple environments. On the basis of these results, we propose an extended, two-part breeding design that can be used to efficiently integrate novel variation into elite breeding populations, thus expanding genetic diversity and enhancing the potential for sustainable productivity gains. PMID:26860200

  20. Progress of genome wide association study in domestic animals

    PubMed Central

    2012-01-01

    Domestic animals are invaluable resources for study of the molecular architecture of complex traits. Although the mapping of quantitative trait loci (QTL) responsible for economically important traits in domestic animals has achieved remarkable results in recent decades, not all of the genetic variation in the complex traits has been captured because of the low density of markers used in QTL mapping studies. The genome wide association study (GWAS), which utilizes high-density single-nucleotide polymorphism (SNP), provides a new way to tackle this issue. Encouraging achievements in dissection of the genetic mechanisms of complex diseases in humans have resulted from the use of GWAS. At present, GWAS has been applied to the field of domestic animal breeding and genetics, and some advances have been made. Many genes or markers that affect economic traits of interest in domestic animals have been identified. In this review, advances in the use of GWAS in domestic animals are described. PMID:22958308

  1. Genome-wide association studies in neurology

    PubMed Central

    Tan, Meng-Shan; Jiang, Teng

    2014-01-01

    Genome-wide association studies (GWAS) are a powerful tool for understanding the genetic underpinnings of human disease. In this article, we briefly review the role and findings of GWAS in common neurological diseases, including Stroke, Alzheimer’s disease, Parkinson’s disease, epilepsy, multiple sclerosis, migraine, amyotrophic lateral sclerosis, frontotemporal lobar degeneration, restless legs syndrome, intracranial aneurysm, human prion diseases and moyamoya disease. We then discuss the present and future implications of these findings with regards to disease prediction, uncovering basic biology, and the development of potential therapeutic agents. PMID:25568877

  2. Genome-Wide Association Studies: A Primer

    PubMed Central

    Corvin, Aiden; Craddock, Nick; Sullivan, Patrick F.

    2014-01-01

    There have been nearly 400genome-wide association studies published since 2005. The GWAS approach has been exceptionally successful in identifying common genetic variants that predispose to a variety of complex human diseases and biochemical and anthropometric traits. Although this approach is relatively new, there are many excellent reviews of different aspects of the GWAS method. Here, we provide a primer, an annotated overview of the GWAS method with particular reference to psychiatric genetics. We dissect the GWAS methodology into its components and provide a brief description with citations and links to reviews that cover the topic in detail. PMID:19895722

  3. Multiple trait genomic selection methods increase genetic value prediction accuracy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genomic selection predicts genetic values with genome-wide markers. It is rapidly emerging in plant breeding and is widely implemented in animal breeding. Genetic correlations between quantitative traits are pervasive in many breeding programs. These correlations indicate that measurements of one tr...

  4. Genome-wide identification of enhancer elements.

    PubMed

    Tulin, Sarah; Barsi, Julius C; Bocconcelli, Carlo; Smith, Joel

    2016-01-01

    We present a prospective genome-wide regulatory element database for the sea urchin embryo and the modified chromosome capture-related methodology used to create it. The method we developed is termed GRIP-seq for genome-wide regulatory element immunoprecipitation and combines features of chromosome conformation capture, chromatin immunoprecipitation, and paired-end next-generation sequencing with molecular steps that enrich for active cis-regulatory elements associated with basal transcriptional machinery. The first GRIP-seq database, available to the community, comes from S. purpuratus 24 hpf embryos and takes advantage of the extremely well-characterized cis-regulatory elements in this system for validation. In addition, using the GRIP-seq database, we identify and experimentally validate a novel, intronic cis-regulatory element at the onecut locus. We find GRIP-seq signal sensitively identifies active cis-regulatory elements with a high signal-to-noise ratio for both distal and intronic elements. This promising GRIP-seq protocol has the potential to address a rate-limiting step in resolving comprehensive, predictive network models in all systems. PMID:27389984

  5. Effect of breed and body weight on echocardiographic values in four breeds of dogs of differing somatotype.

    PubMed

    Morrison, S A; Moise, N S; Scarlett, J; Mohammed, H; Yeager, A E

    1992-01-01

    Eighty normal dogs of four morphologically disparate breeds (Pembroke Welsh Corgi, Miniature Poodle, Afghan Hound, Golden Retriever) (twenty of each breed), were studied by echocardiography to determine the importance of breed and weight in establishing normal echocardiographic reference ranges. Echocardiographic measurements included left-ventricular chamber dimension at systole and end-diastole, right-ventricular chamber dimension at end-diastole, interventricular septal thickness at systole and end-diastole, left-ventricular free wall thickness at systole and end-diastole, E-point septal separation, aortic root dimension at end-diastole, left atrial dimension, and fractional shortening. Analyses of covariance indicated that for all measurements except right-ventricular chamber dimension, the means were significantly different among breeds, after the differences in weight were taken into account. Echocardiographic measurements are variable even within the same breed. Breed must be considered in establishing echocardiographic measurement reference ranges. Echocardiographic values for each breed are presented. PMID:1522552

  6. Genome-Wide Association Study of Metabolic Syndrome in Koreans

    PubMed Central

    Jeong, Seok Won; Chung, Myungguen; Park, Soo-Jung; Cho, Seong Beom

    2014-01-01

    Metabolic syndrome (METS) is a disorder of energy utilization and storage and increases the risk of developing cardiovascular disease and diabetes. To identify the genetic risk factors of METS, we carried out a genome-wide association study (GWAS) for 2,657 cases and 5,917 controls in Korean populations. As a result, we could identify 2 single nucleotide polymorphisms (SNPs) with genome-wide significance level p-values (<5 × 10-8), 8 SNPs with genome-wide suggestive p-values (5 × 10-8 ≤ p < 1 × 10-5), and 2 SNPs of more functional variants with borderline p-values (5 × 10-5 ≤ p < 1 × 10-4). On the other hand, the multiple correction criteria of conventional GWASs exclude false-positive loci, but simultaneously, they discard many true-positive loci. To reconsider the discarded true-positive loci, we attempted to include the functional variants (nonsynonymous SNPs [nsSNPs] and expression quantitative trait loci [eQTL]) among the top 5,000 SNPs based on the proportion of phenotypic variance explained by genotypic variance. In total, 159 eQTLs and 18 nsSNPs were presented in the top 5,000 SNPs. Although they should be replicated in other independent populations, 6 eQTLs and 2 nsSNP loci were located in the molecular pathways of LPL, APOA5, and CHRM2, which were the significant or suggestive loci in the METS GWAS. Conclusively, our approach using the conventional GWAS, reconsidering functional variants and pathway-based interpretation, suggests a useful method to understand the GWAS results of complex traits and can be expanded in other genomewide association studies. PMID:25705157

  7. Genome-wide association study of obsessive-compulsive disorder.

    PubMed

    Stewart, S E; Yu, D; Scharf, J M; Neale, B M; Fagerness, J A; Mathews, C A; Arnold, P D; Evans, P D; Gamazon, E R; Davis, L K; Osiecki, L; McGrath, L; Haddad, S; Crane, J; Hezel, D; Illman, C; Mayerfeld, C; Konkashbaev, A; Liu, C; Pluzhnikov, A; Tikhomirov, A; Edlund, C K; Rauch, S L; Moessner, R; Falkai, P; Maier, W; Ruhrmann, S; Grabe, H-J; Lennertz, L; Wagner, M; Bellodi, L; Cavallini, M C; Richter, M A; Cook, E H; Kennedy, J L; Rosenberg, D; Stein, D J; Hemmings, S M J; Lochner, C; Azzam, A; Chavira, D A; Fournier, E; Garrido, H; Sheppard, B; Umaña, P; Murphy, D L; Wendland, J R; Veenstra-VanderWeele, J; Denys, D; Blom, R; Deforce, D; Van Nieuwerburgh, F; Westenberg, H G M; Walitza, S; Egberts, K; Renner, T; Miguel, E C; Cappi, C; Hounie, A G; Conceição do Rosário, M; Sampaio, A S; Vallada, H; Nicolini, H; Lanzagorta, N; Camarena, B; Delorme, R; Leboyer, M; Pato, C N; Pato, M T; Voyiaziakis, E; Heutink, P; Cath, D C; Posthuma, D; Smit, J H; Samuels, J; Bienvenu, O J; Cullen, B; Fyer, A J; Grados, M A; Greenberg, B D; McCracken, J T; Riddle, M A; Wang, Y; Coric, V; Leckman, J F; Bloch, M; Pittenger, C; Eapen, V; Black, D W; Ophoff, R A; Strengman, E; Cusi, D; Turiel, M; Frau, F; Macciardi, F; Gibbs, J R; Cookson, M R; Singleton, A; Hardy, J; Crenshaw, A T; Parkin, M A; Mirel, D B; Conti, D V; Purcell, S; Nestadt, G; Hanna, G L; Jenike, M A; Knowles, J A; Cox, N; Pauls, D L

    2013-07-01

    Obsessive-compulsive disorder (OCD) is a common, debilitating neuropsychiatric illness with complex genetic etiology. The International OCD Foundation Genetics Collaborative (IOCDF-GC) is a multi-national collaboration established to discover the genetic variation predisposing to OCD. A set of individuals affected with DSM-IV OCD, a subset of their parents, and unselected controls, were genotyped with several different Illumina SNP microarrays. After extensive data cleaning, 1465 cases, 5557 ancestry-matched controls and 400 complete trios remained, with a common set of 469,410 autosomal and 9657 X-chromosome single nucleotide polymorphisms (SNPs). Ancestry-stratified case-control association analyses were conducted for three genetically-defined subpopulations and combined in two meta-analyses, with and without the trio-based analysis. In the case-control analysis, the lowest two P-values were located within DLGAP1 (P=2.49 × 10(-6) and P=3.44 × 10(-6)), a member of the neuronal postsynaptic density complex. In the trio analysis, rs6131295, near BTBD3, exceeded the genome-wide significance threshold with a P-value=3.84 × 10(-8). However, when trios were meta-analyzed with the case-control samples, the P-value for this variant was 3.62 × 10(-5), losing genome-wide significance. Although no SNPs were identified to be associated with OCD at a genome-wide significant level in the combined trio-case-control sample, a significant enrichment of methylation QTLs (P<0.001) and frontal lobe expression quantitative trait loci (eQTLs) (P=0.001) was observed within the top-ranked SNPs (P<0.01) from the trio-case-control analysis, suggesting these top signals may have a broad role in gene expression in the brain, and possibly in the etiology of OCD. PMID:22889921

  8. A genome-wide DNA methylation study in colorectal carcinoma

    PubMed Central

    2011-01-01

    Background We performed a genome-wide scan of 27,578 CpG loci covering 14,475 genes to identify differentially methylated loci (DML) in colorectal carcinoma (CRC). Methods We used Illumina's Infinium methylation assay in paired DNA samples extracted from 24 fresh frozen CRC tissues and their corresponding normal colon tissues from 24 consecutive diagnosed patients at a tertiary medical center. Results We found a total of 627 DML in CRC covering 513 genes, of which 535 are novel DML covering 465 genes. We also validated the Illumina Infinium methylation data for top-ranking genes by non-bisulfite conversion q-PCR-based methyl profiler assay in a subset of the same samples. We also carried out integration of genome-wide copy number and expression microarray along with methylation profiling to see the functional effect of methylation. Gene Set Enrichment Analysis (GSEA) showed that among the major "gene sets" that are hypermethylated in CRC are the sets: "inhibition of adenylate cyclase activity by G-protein signaling", "Rac guanyl-nucleotide exchange factor activity", "regulation of retinoic acid receptor signaling pathway" and "estrogen receptor activity". Two-level nested cross validation showed that DML-based predictive models may offer reasonable sensitivity (around 89%), specificity (around 95%), positive predictive value (around 95%) and negative predictive value (around 89%), suggesting that these markers may have potential clinical application. Conclusion Our genome-wide methylation study in CRC clearly supports most of the previous findings; additionally we found a large number of novel DML in CRC tissue. If confirmed in future studies, these findings may lead to identification of genomic markers for potential clinical application. PMID:21699707

  9. Genome-Wide Association Study of Parity in Bangladeshi Women

    PubMed Central

    Aschebrook-Kilfoy, Briseis; Argos, Maria; Pierce, Brandon L.; Tong, Lin; Jasmine, Farzana; Roy, Shantanu; Parvez, Faruque; Ahmed, Alauddin; Islam, Tariqul; Kibriya, Muhammad G.; Ahsan, Habibul

    2015-01-01

    Human fertility is a complex trait determined by gene-environment interactions in which genetic factors represent a significant component. To better understand inter-individual variability in fertility, we performed one of the first genome-wide association studies (GWAS) of common fertility phenotypes, lifetime number of pregnancies and number of children in a developing country population. The fertility phenotype data and DNA samples were obtained at baseline recruitment from individuals participating in a large prospective cohort study in Bangladesh. GWAS analyses of fertility phenotypes were conducted among 1,686 married women. One SNP on chromosome 4 was non-significantly associated with number of children at P <10-7 and number of pregnancies at P <10-6. This SNP is located in a region without a gene within 1 Mb. One SNP on chromosome 6 was non-significantly associated with extreme number of children at P <10-6. The closest gene to this SNP is HDGFL1, a hepatoma-derived growth factor. When we excluded hormonal contraceptive users, a SNP on chromosome 5 was non-significantly associated at P <10-5 for number of children and number of pregnancies. This SNP is located near C5orf64, an open reading frame, and ZSWIM6, a zinc ion binding gene. We also estimated the heritability of these phenotypes from our genotype data using GCTA (Genome-wide Complex Trait Analysis) for number of children (hg2 = 0.149, SE = 0.24, p-value = 0.265) and number of pregnancies (hg2 = 0.007, SE = 0.22, p-value = 0.487). Our genome-wide association study and heritability estimates of number of pregnancies and number of children in Bangladesh did not confer strong evidence of common variants for parity variation. However, our results suggest that future studies may want to consider the role of 3 notable SNPs in their analysis. PMID:25742292

  10. Genome-wide association study of parity in Bangladeshi women.

    PubMed

    Aschebrook-Kilfoy, Briseis; Argos, Maria; Pierce, Brandon L; Tong, Lin; Jasmine, Farzana; Roy, Shantanu; Parvez, Faruque; Ahmed, Alauddin; Islam, Tariqul; Kibriya, Muhammad G; Ahsan, Habibul

    2015-01-01

    Human fertility is a complex trait determined by gene-environment interactions in which genetic factors represent a significant component. To better understand inter-individual variability in fertility, we performed one of the first genome-wide association studies (GWAS) of common fertility phenotypes, lifetime number of pregnancies and number of children in a developing country population. The fertility phenotype data and DNA samples were obtained at baseline recruitment from individuals participating in a large prospective cohort study in Bangladesh. GWAS analyses of fertility phenotypes were conducted among 1,686 married women. One SNP on chromosome 4 was non-significantly associated with number of children at P <10(-7) and number of pregnancies at P <10(-6). This SNP is located in a region without a gene within 1 Mb. One SNP on chromosome 6 was non-significantly associated with extreme number of children at P <10(-6). The closest gene to this SNP is HDGFL1, a hepatoma-derived growth factor. When we excluded hormonal contraceptive users, a SNP on chromosome 5 was non-significantly associated at P <10(-5) for number of children and number of pregnancies. This SNP is located near C5orf64, an open reading frame, and ZSWIM6, a zinc ion binding gene. We also estimated the heritability of these phenotypes from our genotype data using GCTA (Genome-wide Complex Trait Analysis) for number of children (hg2 = 0.149, SE = 0.24, p-value = 0.265) and number of pregnancies (hg2 = 0.007, SE = 0.22, p-value = 0.487). Our genome-wide association study and heritability estimates of number of pregnancies and number of children in Bangladesh did not confer strong evidence of common variants for parity variation. However, our results suggest that future studies may want to consider the role of 3 notable SNPs in their analysis. PMID:25742292

  11. GWIDD: Genome-wide protein docking database

    PubMed Central

    Kundrotas, Petras J.; Zhu, Zhengwei; Vakser, Ilya A.

    2010-01-01

    Structural information on interacting proteins is important for understanding life processes at the molecular level. Genome-wide docking database is an integrated resource for structural studies of protein–protein interactions on the genome scale, which combines the available experimental data with models obtained by docking techniques. Current database version (August 2009) contains 25 559 experimental and modeled 3D structures for 771 organisms spanned over the entire universe of life from viruses to humans. Data are organized in a relational database with user-friendly search interface allowing exploration of the database content by a number of parameters. Search results can be interactively previewed and downloaded as PDB-formatted files, along with the information relevant to the specified interactions. The resource is freely available at http://gwidd.bioinformatics.ku.edu. PMID:19900970

  12. Genome-wide Membrane Protein Structure Prediction

    PubMed Central

    Piccoli, Stefano; Suku, Eda; Garonzi, Marianna; Giorgetti, Alejandro

    2013-01-01

    Transmembrane proteins allow cells to extensively communicate with the external world in a very accurate and specific way. They form principal nodes in several signaling pathways and attract large interest in therapeutic intervention, as the majority pharmaceutical compounds target membrane proteins. Thus, according to the current genome annotation methods, a detailed structural/functional characterization at the protein level of each of the elements codified in the genome is also required. The extreme difficulty in obtaining high-resolution three-dimensional structures, calls for computational approaches. Here we review to which extent the efforts made in the last few years, combining the structural characterization of membrane proteins with protein bioinformatics techniques, could help describing membrane proteins at a genome-wide scale. In particular we analyze the use of comparative modeling techniques as a way of overcoming the lack of high-resolution three-dimensional structures in the human membrane proteome. PMID:24403851

  13. Genome-Wide Association Studies of Cancer

    PubMed Central

    Stadler, Zsofia K.; Thom, Peter; Robson, Mark E.; Weitzel, Jeffrey N.; Kauff, Noah D.; Hurley, Karen E.; Devlin, Vincent; Gold, Bert; Klein, Robert J.; Offit, Kenneth

    2010-01-01

    Knowledge of the inherited risk for cancer is an important component of preventive oncology. In addition to well-established syndromes of cancer predisposition, much remains to be discovered about the genetic variation underlying susceptibility to common malignancies. Increased knowledge about the human genome and advances in genotyping technology have made possible genome-wide association studies (GWAS) of human diseases. These studies have identified many important regions of genetic variation associated with an increased risk for human traits and diseases including cancer. Understanding the principles, major findings, and limitations of GWAS is becoming increasingly important for oncologists as dissemination of genomic risk tests directly to consumers is already occurring through commercial companies. GWAS have contributed to our understanding of the genetic basis of cancer and will shed light on biologic pathways and possible new strategies for targeted prevention. To date, however, the clinical utility of GWAS-derived risk markers remains limited. PMID:20585100

  14. Assessing Predictive Properties of Genome-Wide Selection in Soybeans.

    PubMed

    Xavier, Alencar; Muir, William M; Rainey, Katy Martin

    2016-01-01

    Many economically important traits in plant breeding have low heritability or are difficult to measure. For these traits, genomic selection has attractive features and may boost genetic gains. Our goal was to evaluate alternative scenarios to implement genomic selection for yield components in soybean (Glycine max L. merr). We used a nested association panel with cross validation to evaluate the impacts of training population size, genotyping density, and prediction model on the accuracy of genomic prediction. Our results indicate that training population size was the factor most relevant to improvement in genome-wide prediction, with greatest improvement observed in training sets up to 2000 individuals. We discuss assumptions that influence the choice of the prediction model. Although alternative models had minor impacts on prediction accuracy, the most robust prediction model was the combination of reproducing kernel Hilbert space regression and BayesB. Higher genotyping density marginally improved accuracy. Our study finds that breeding programs seeking efficient genomic selection in soybeans would best allocate resources by investing in a representative training set. PMID:27317786

  15. Assessing Predictive Properties of Genome-Wide Selection in Soybeans

    PubMed Central

    Xavier, Alencar; Muir, William M.; Rainey, Katy Martin

    2016-01-01

    Many economically important traits in plant breeding have low heritability or are difficult to measure. For these traits, genomic selection has attractive features and may boost genetic gains. Our goal was to evaluate alternative scenarios to implement genomic selection for yield components in soybean (Glycine max L. merr). We used a nested association panel with cross validation to evaluate the impacts of training population size, genotyping density, and prediction model on the accuracy of genomic prediction. Our results indicate that training population size was the factor most relevant to improvement in genome-wide prediction, with greatest improvement observed in training sets up to 2000 individuals. We discuss assumptions that influence the choice of the prediction model. Although alternative models had minor impacts on prediction accuracy, the most robust prediction model was the combination of reproducing kernel Hilbert space regression and BayesB. Higher genotyping density marginally improved accuracy. Our study finds that breeding programs seeking efficient genomic selection in soybeans would best allocate resources by investing in a representative training set. PMID:27317786

  16. Genome-Wide Association Studies for Comb Traits in Chickens

    PubMed Central

    Ma, Meng; Dou, Taocun; Lu, Jian; Guo, Jun; Hu, Yuping; Yi, Guoqiang; Yuan, Jingwei; Sun, Congjiao; Wang, Kehua; Yang, Ning

    2016-01-01

    The comb, as a secondary sexual character, is an important trait in chicken. Indicators of comb length (CL), comb height (CH), and comb weight (CW) are often selected in production. DNA-based marker-assisted selection could help chicken breeders to accelerate genetic improvement for comb or related economic characters by early selection. Although a number of quantitative trait loci (QTL) and candidate genes have been identified with advances in molecular genetics, candidate genes underlying comb traits are limited. The aim of the study was to use genome-wide association (GWA) studies by 600 K Affymetrix chicken SNP arrays to detect genes that are related to comb, using an F2 resource population. For all comb characters, comb exhibited high SNP-based heritability estimates (0.61–0.69). Chromosome 1 explained 20.80% genetic variance, while chromosome 4 explained 6.89%. Independent univariate genome-wide screens for each character identified 127, 197, and 268 novel significant SNPs with CL, CH, and CW, respectively. Three candidate genes, VPS36, AR, and WNT11B, were determined to have a plausible function in all comb characters. These genes are important to the initiation of follicle development, gonadal growth, and dermal development, respectively. The current study provides the first GWA analysis for comb traits. Identification of the genetic basis as well as promising candidate genes will help us understand the underlying genetic architecture of comb development and has practical significance in breeding programs for the selection of comb as an index for sexual maturity or reproduction. PMID:27427764

  17. Genome-Wide Association Studies for Comb Traits in Chickens.

    PubMed

    Shen, Manman; Qu, Liang; Ma, Meng; Dou, Taocun; Lu, Jian; Guo, Jun; Hu, Yuping; Yi, Guoqiang; Yuan, Jingwei; Sun, Congjiao; Wang, Kehua; Yang, Ning

    2016-01-01

    The comb, as a secondary sexual character, is an important trait in chicken. Indicators of comb length (CL), comb height (CH), and comb weight (CW) are often selected in production. DNA-based marker-assisted selection could help chicken breeders to accelerate genetic improvement for comb or related economic characters by early selection. Although a number of quantitative trait loci (QTL) and candidate genes have been identified with advances in molecular genetics, candidate genes underlying comb traits are limited. The aim of the study was to use genome-wide association (GWA) studies by 600 K Affymetrix chicken SNP arrays to detect genes that are related to comb, using an F2 resource population. For all comb characters, comb exhibited high SNP-based heritability estimates (0.61-0.69). Chromosome 1 explained 20.80% genetic variance, while chromosome 4 explained 6.89%. Independent univariate genome-wide screens for each character identified 127, 197, and 268 novel significant SNPs with CL, CH, and CW, respectively. Three candidate genes, VPS36, AR, and WNT11B, were determined to have a plausible function in all comb characters. These genes are important to the initiation of follicle development, gonadal growth, and dermal development, respectively. The current study provides the first GWA analysis for comb traits. Identification of the genetic basis as well as promising candidate genes will help us understand the underlying genetic architecture of comb development and has practical significance in breeding programs for the selection of comb as an index for sexual maturity or reproduction. PMID:27427764

  18. Genome-wide Association Study Identifies Shared Risk Loci Common to Two Malignancies in Golden Retrievers

    PubMed Central

    Tonomura, Noriko; Elvers, Ingegerd; Thomas, Rachael; Megquier, Kate; Turner-Maier, Jason; Howald, Cedric; Sarver, Aaron L.; Swofford, Ross; Frantz, Aric M.; Ito, Daisuke; Mauceli, Evan; Arendt, Maja; Noh, Hyun Ji; Koltookian, Michele; Biagi, Tara; Fryc, Sarah; Williams, Christina; Avery, Anne C.; Kim, Jong-Hyuk; Barber, Lisa; Burgess, Kristine; Lander, Eric S.; Karlsson, Elinor K.; Azuma, Chieko

    2015-01-01

    Dogs, with their breed-determined limited genetic background, are great models of human disease including cancer. Canine B-cell lymphoma and hemangiosarcoma are both malignancies of the hematologic system that are clinically and histologically similar to human B-cell non-Hodgkin lymphoma and angiosarcoma, respectively. Golden retrievers in the US show significantly elevated lifetime risk for both B-cell lymphoma (6%) and hemangiosarcoma (20%). We conducted genome-wide association studies for hemangiosarcoma and B-cell lymphoma, identifying two shared predisposing loci. The two associated loci are located on chromosome 5, and together contribute ~20% of the risk of developing these cancers. Genome-wide p-values for the top SNP of each locus are 4.6×10-7 and 2.7×10-6, respectively. Whole genome resequencing of nine cases and controls followed by genotyping and detailed analysis identified three shared and one B-cell lymphoma specific risk haplotypes within the two loci, but no coding changes were associated with the risk haplotypes. Gene expression analysis of B-cell lymphoma tumors revealed that carrying the risk haplotypes at the first locus is associated with down-regulation of several nearby genes including the proximal gene TRPC6, a transient receptor Ca2+-channel involved in T-cell activation, among other functions. The shared risk haplotype in the second locus overlaps the vesicle transport and release gene STX8. Carrying the shared risk haplotype is associated with gene expression changes of 100 genes enriched for pathways involved in immune cell activation. Thus, the predisposing germ-line mutations in B-cell lymphoma and hemangiosarcoma appear to be regulatory, and affect pathways involved in T-cell mediated immune response in the tumor. This suggests that the interaction between the immune system and malignant cells plays a common role in the tumorigenesis of these relatively different cancers. PMID:25642983

  19. Genome-wide association study identifies shared risk loci common to two malignancies in golden retrievers.

    PubMed

    Tonomura, Noriko; Elvers, Ingegerd; Thomas, Rachael; Megquier, Kate; Turner-Maier, Jason; Howald, Cedric; Sarver, Aaron L; Swofford, Ross; Frantz, Aric M; Ito, Daisuke; Mauceli, Evan; Arendt, Maja; Noh, Hyun Ji; Koltookian, Michele; Biagi, Tara; Fryc, Sarah; Williams, Christina; Avery, Anne C; Kim, Jong-Hyuk; Barber, Lisa; Burgess, Kristine; Lander, Eric S; Karlsson, Elinor K; Azuma, Chieko; Modiano, Jaime F; Breen, Matthew; Lindblad-Toh, Kerstin

    2015-02-01

    Dogs, with their breed-determined limited genetic background, are great models of human disease including cancer. Canine B-cell lymphoma and hemangiosarcoma are both malignancies of the hematologic system that are clinically and histologically similar to human B-cell non-Hodgkin lymphoma and angiosarcoma, respectively. Golden retrievers in the US show significantly elevated lifetime risk for both B-cell lymphoma (6%) and hemangiosarcoma (20%). We conducted genome-wide association studies for hemangiosarcoma and B-cell lymphoma, identifying two shared predisposing loci. The two associated loci are located on chromosome 5, and together contribute ~20% of the risk of developing these cancers. Genome-wide p-values for the top SNP of each locus are 4.6×10-7 and 2.7×10-6, respectively. Whole genome resequencing of nine cases and controls followed by genotyping and detailed analysis identified three shared and one B-cell lymphoma specific risk haplotypes within the two loci, but no coding changes were associated with the risk haplotypes. Gene expression analysis of B-cell lymphoma tumors revealed that carrying the risk haplotypes at the first locus is associated with down-regulation of several nearby genes including the proximal gene TRPC6, a transient receptor Ca2+-channel involved in T-cell activation, among other functions. The shared risk haplotype in the second locus overlaps the vesicle transport and release gene STX8. Carrying the shared risk haplotype is associated with gene expression changes of 100 genes enriched for pathways involved in immune cell activation. Thus, the predisposing germ-line mutations in B-cell lymphoma and hemangiosarcoma appear to be regulatory, and affect pathways involved in T-cell mediated immune response in the tumor. This suggests that the interaction between the immune system and malignant cells plays a common role in the tumorigenesis of these relatively different cancers. PMID:25642983

  20. Genomic selection accuracy using multi-family prediction models in a wheat breeding program

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genomic selection (GS) uses genome-wide molecular marker data to predict the genetic value of selection candidates in breeding programs. In plant breeding, the ability to produce large numbers of progeny per cross allows GS to be conducted within each family. However, this approach requires phenotyp...

  1. Genome-Wide Association Study for Indicator Traits of Sexual Precocity in Nellore Cattle

    PubMed Central

    Irano, Natalia; de Camargo, Gregório Miguel Ferreira; Costa, Raphael Bermal; Terakado, Ana Paula Nascimento; Magalhães, Ana Fabrícia Braga; Silva, Rafael Medeiros de Oliveira; Dias, Marina Mortati; Bignardi, Annaiza Braga; Baldi, Fernando; Carvalheiro, Roberto; de Oliveira, Henrique Nunes; de Albuquerque, Lucia Galvão

    2016-01-01

    The objective of this study was to perform a genome-wide association study (GWAS) to detect chromosome regions associated with indicator traits of sexual precocity in Nellore cattle. Data from Nellore animals belonging to farms which participate in the DeltaGen® and Paint® animal breeding programs, were used. The traits used in this study were the occurrence of early pregnancy (EP) and scrotal circumference (SC). Data from 72,675 females and 83,911 males with phenotypes were used; of these, 1,770 females and 1,680 males were genotyped. The SNP effects were estimated with a single-step procedure (WssGBLUP) and the observed phenotypes were used as dependent variables. All animals with available genotypes and phenotypes, in addition to those with only phenotypic information, were used. A single-trait animal model was applied to predict breeding values and the solutions of SNP effects were obtained from these breeding values. The results of GWAS are reported as the proportion of variance explained by windows with 150 adjacent SNPs. The 10 windows that explained the highest proportion of variance were identified. The results of this study indicate the polygenic nature of EP and SC, demonstrating that the indicator traits of sexual precocity studied here are probably controlled by many genes, including some of moderate effect. The 10 windows with large effects obtained for EP are located on chromosomes 5, 6, 7, 14, 18, 21 and 27, and together explained 7.91% of the total genetic variance. For SC, these windows are located on chromosomes 4, 8, 11, 13, 14, 19, 22 and 23, explaining 6.78% of total variance. GWAS permitted to identify chromosome regions associated with EP and SC. The identification of these regions contributes to a better understanding and evaluation of these traits, and permits to indicate candidate genes for future investigation of causal mutations. PMID:27494397

  2. Genome-Wide Association Study for Indicator Traits of Sexual Precocity in Nellore Cattle.

    PubMed

    Irano, Natalia; de Camargo, Gregório Miguel Ferreira; Costa, Raphael Bermal; Terakado, Ana Paula Nascimento; Magalhães, Ana Fabrícia Braga; Silva, Rafael Medeiros de Oliveira; Dias, Marina Mortati; Bignardi, Annaiza Braga; Baldi, Fernando; Carvalheiro, Roberto; de Oliveira, Henrique Nunes; de Albuquerque, Lucia Galvão

    2016-01-01

    The objective of this study was to perform a genome-wide association study (GWAS) to detect chromosome regions associated with indicator traits of sexual precocity in Nellore cattle. Data from Nellore animals belonging to farms which participate in the DeltaGen® and Paint® animal breeding programs, were used. The traits used in this study were the occurrence of early pregnancy (EP) and scrotal circumference (SC). Data from 72,675 females and 83,911 males with phenotypes were used; of these, 1,770 females and 1,680 males were genotyped. The SNP effects were estimated with a single-step procedure (WssGBLUP) and the observed phenotypes were used as dependent variables. All animals with available genotypes and phenotypes, in addition to those with only phenotypic information, were used. A single-trait animal model was applied to predict breeding values and the solutions of SNP effects were obtained from these breeding values. The results of GWAS are reported as the proportion of variance explained by windows with 150 adjacent SNPs. The 10 windows that explained the highest proportion of variance were identified. The results of this study indicate the polygenic nature of EP and SC, demonstrating that the indicator traits of sexual precocity studied here are probably controlled by many genes, including some of moderate effect. The 10 windows with large effects obtained for EP are located on chromosomes 5, 6, 7, 14, 18, 21 and 27, and together explained 7.91% of the total genetic variance. For SC, these windows are located on chromosomes 4, 8, 11, 13, 14, 19, 22 and 23, explaining 6.78% of total variance. GWAS permitted to identify chromosome regions associated with EP and SC. The identification of these regions contributes to a better understanding and evaluation of these traits, and permits to indicate candidate genes for future investigation of causal mutations. PMID:27494397

  3. Breeding value estimation in the Hungarian Sport Horse population.

    PubMed

    Posta, János; Komlósi, István; Mihók, Sándor

    2009-07-01

    The aims of this study were to estimate phenotypic and genetic parameters for a range of traits in Hungarian Sport Horses, and to compare several methods of estimating breeding value (BV) in this breed. The analyses were based on the Hungarian Sport Horse Studbook, results of self-performance tests (SPTs) and show-jumping competition results. An SPT comprises subjective judgement of conformation traits, movement analysis traits and free-jumping performance, assessed via ordinal scores. Genetic parameters of SPTs were estimated with an animal model. Different measurements of the competition performance were compared using the same repeatability model. Estimates of BV for sport were made with random regression models using a first-order Legendre polynomial. Heritability was found to increase and permanent environmental variance to decrease continuously with age. BVs can be estimated at different ages and from these a composite BV index can be computed. It is possible to weight BVs for the specific age of a horse. PMID:19375365

  4. Comparison of molecular breeding values based on within- and across-breed training in beef cattle

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background Although the efficacy of genomic predictors based on within-breed training looks promising, it is necessary to develop and evaluate across-breed predictors for the technology to be fully applied in the beef industry. The efficacies of genomic predictors trained in one breed and utilized ...

  5. Genome-wide gene-based association study.

    PubMed

    Yang, Hsin-Chou; Liang, Yu-Jen; Chung, Chia-Min; Chen, Jia-Wei; Pan, Wen-Harn

    2009-01-01

    Genome-wide association studies, which analyzes hundreds of thousands of single-nucleotide polymorphisms to identify disease susceptibility genes, are challenging because the work involves intensive computation and complex modeling. We propose a two-stage genome-wide association scanning procedure, consisting of a single-locus association scan for the first stage and a gene-based association scan for the second stage. Marginal effects of single-nucleotide polymorphisms are examined by using the exact Armitage trend test or logistic regression, and gene effects are examined by using a p-value combination method. Compared with some existing single-locus and multilocus methods, the proposed method has the following merits: 1) convenient for definition of biologically meaningful regions, 2) powerful for detection of minor-effect genes, 3) helpful for alleviation of a multiple-testing problem, and 4) convenient for result interpretation. The method was applied to study Genetic Analysis Workshop 16 Problem 1 rheumatoid arthritis data, and strong association signals were found. The results show that the human major histocompatibility complex region is the most important genomic region associated with rheumatoid arthritis. Moreover, previously reported genes including PTPN22, C5, and IL2RB were confirmed; novel genes including HLA-DRA, BTNL2, C6orf10, NOTCH4, TAP2, and TNXB were identified by our analysis. PMID:20018002

  6. A Pooled Genome-Wide Association Study of Asperger Syndrome

    PubMed Central

    Warrier, Varun; Chakrabarti, Bhismadev; Murphy, Laura; Chan, Allen; Craig, Ian; Mallya, Uma; Lakatošová, Silvia; Rehnstrom, Karola; Wheelwright, Sally; Allison, Carrie; Fisher, Simon E.; Baron-Cohen, Simon

    2015-01-01

    Asperger Syndrome (AS) is a neurodevelopmental condition characterized by impairments in social interaction and communication, alongside the presence of unusually repetitive, restricted interests and stereotyped behaviour. Individuals with AS have no delay in cognitive and language development. It is a subset of Autism Spectrum Conditions (ASC), which are highly heritable and has a population prevalence of approximately 1%. Few studies have investigated the genetic basis of AS. To address this gap in the literature, we performed a genome-wide pooled DNA association study to identify candidate loci in 612 individuals (294 cases and 318 controls) of Caucasian ancestry, using the Affymetrix GeneChip Human Mapping version 6.0 array. We identified 11 SNPs that had a p-value below 1x10-5. These SNPs were independently genotyped in the same sample. Three of the SNPs (rs1268055, rs7785891 and rs2782448) were nominally significant, though none remained significant after Bonferroni correction. Two of our top three SNPs (rs7785891 and rs2782448) lie in loci previously implicated in ASC. However, investigation of the three SNPs in the ASC genome-wide association dataset from the Psychiatric Genomics Consortium indicated that these three SNPs were not significantly associated with ASC. The effect sizes of the variants were modest, indicating that our study was not sufficiently powered to identify causal variants with precision. PMID:26176695

  7. Genome-wide analysis correlates Ayurveda Prakriti

    PubMed Central

    Govindaraj, Periyasamy; Nizamuddin, Sheikh; Sharath, Anugula; Jyothi, Vuskamalla; Rotti, Harish; Raval, Ritu; Nayak, Jayakrishna; Bhat, Balakrishna K.; Prasanna, B. V.; Shintre, Pooja; Sule, Mayura; Joshi, Kalpana S.; Dedge, Amrish P.; Bharadwaj, Ramachandra; Gangadharan, G. G.; Nair, Sreekumaran; Gopinath, Puthiya M.; Patwardhan, Bhushan; Kondaiah, Paturu; Satyamoorthy, Kapaettu; Valiathan, Marthanda Varma Sankaran; Thangaraj, Kumarasamy

    2015-01-01

    The practice of Ayurveda, the traditional medicine of India, is based on the concept of three major constitutional types (Vata, Pitta and Kapha) defined as “Prakriti”. To the best of our knowledge, no study has convincingly correlated genomic variations with the classification of Prakriti. In the present study, we performed genome-wide SNP (single nucleotide polymorphism) analysis (Affymetrix, 6.0) of 262 well-classified male individuals (after screening 3416 subjects) belonging to three Prakritis. We found 52 SNPs (p ≤ 1 × 10−5) were significantly different between Prakritis, without any confounding effect of stratification, after 106 permutations. Principal component analysis (PCA) of these SNPs classified 262 individuals into their respective groups (Vata, Pitta and Kapha) irrespective of their ancestry, which represent its power in categorization. We further validated our finding with 297 Indian population samples with known ancestry. Subsequently, we found that PGM1 correlates with phenotype of Pitta as described in the ancient text of Caraka Samhita, suggesting that the phenotypic classification of India’s traditional medicine has a genetic basis; and its Prakriti-based practice in vogue for many centuries resonates with personalized medicine. PMID:26511157

  8. Genome-wide methylation profiling of schizophrenia.

    PubMed

    Rukova, B; Staneva, R; Hadjidekova, S; Stamenov, G; Milanova; Toncheva, D

    2014-12-01

    Schizophrenia is one of the major psychiatric disorders. It is a disorder of complex inheritance, involving both heritable and environmental factors. DNA methylation is an inheritable epigenetic modification that stably alters gene expression. We reasoned that genetic modifications that are a result of environmental stimuli could also make a contribution. We have performed 26 high-resolution genome-wide methylation array analyses to determine the methylation status of 27,627 CpG islands and compared the data between patients and healthy controls. Methylation profiles of DNAs were analyzed in six pools: 220 schizophrenia patients; 220 age-matched healthy controls; 110 female schizophrenia patients; 110 age-matched healthy females; 110 male schizophrenia patients; 110 age-matched healthy males. We also investigated the methylation status of 20 individual patient DNA samples (eight females and 12 males. We found significant differences in the methylation profile between schizophrenia and control DNA pools. We found new candidate genes that principally participate in apoptosis, synaptic transmission and nervous system development (GABRA2, LIN7B, CASP3). Methylation profiles differed between the genders. In females, the most important genes participate in apoptosis and synaptic transmission (XIAP, GABRD, OXT, KRT7), whereas in the males, the implicated genes in the molecular pathology of the disease were DHX37, MAP2K2, FNDC4 and GIPC1. Data from the individual methylation analyses confirmed, the gender-specific pools results. Our data revealed major differences in methylation profiles between schizophrenia patients and controls and between male and female patients. The dysregulated activity of the candidate genes could play a role in schizophrenia pathogenesis. PMID:25937794

  9. Genome-Wide Methylation Profiling of Schizophrenia

    PubMed Central

    Rukova, B; Staneva, R; Hadjidekova, S; Stamenov, G; Milanova; Toncheva, D

    2014-01-01

    Schizophrenia is one of the major psychiatric disorders. It is a disorder of complex inheritance, involving both heritable and environmental factors. DNA methylation is an inheritable epigenetic modification that stably alters gene expression. We reasoned that genetic modifications that are a result of environmental stimuli could also make a contribution. We have performed 26 high-resolution genome-wide methylation array analyses to determine the methylation status of 27,627 CpG islands and compared the data between patients and healthy controls. Methylation profiles of DNAs were analyzed in six pools: 220 schizophrenia patients; 220 age-matched healthy controls; 110 female schizophrenia patients; 110 age-matched healthy females; 110 male schizophrenia patients; 110 age-matched healthy males. We also investigated the methylation status of 20 individual patient DNA samples (eight females and 12 males. We found significant differences in the methylation profile between schizophrenia and control DNA pools. We found new candidate genes that principally participate in apoptosis, synaptic transmission and nervous system development (GABRA2, LIN7B, CASP3). Methylation profiles differed between the genders. In females, the most important genes participate in apoptosis and synaptic transmission (XIAP, GABRD, OXT, KRT7), whereas in the males, the implicated genes in the molecular pathology of the disease were DHX37, MAP2K2, FNDC4 and GIPC1. Data from the individual methylation analyses confirmed, the gender-specific pools results. Our data revealed major differences in methylation profiles between schizophrenia patients and controls and between male and female patients. The dysregulated activity of the candidate genes could play a role in schizophrenia pathogenesis. PMID:25937794

  10. Genome Wide Methylome Alterations in Lung Cancer.

    PubMed

    Mullapudi, Nandita; Ye, Bin; Suzuki, Masako; Fazzari, Melissa; Han, Weiguo; Shi, Miao K; Marquardt, Gaby; Lin, Juan; Wang, Tao; Keller, Steven; Zhu, Changcheng; Locker, Joseph D; Spivack, Simon D

    2015-01-01

    Aberrant cytosine 5-methylation underlies many deregulated elements of cancer. Among paired non-small cell lung cancers (NSCLC), we sought to profile DNA 5-methyl-cytosine features which may underlie genome-wide deregulation. In one of the more dense interrogations of the methylome, we sampled 1.2 million CpG sites from twenty-four NSCLC tumor (T)-non-tumor (NT) pairs using a methylation-sensitive restriction enzyme- based HELP-microarray assay. We found 225,350 differentially methylated (DM) sites in adenocarcinomas versus adjacent non-tumor tissue that vary in frequency across genomic compartment, particularly notable in gene bodies (GB; p<2.2E-16). Further, when DM was coupled to differential transcriptome (DE) in the same samples, 37,056 differential loci in adenocarcinoma emerged. Approximately 90% of the DM-DE relationships were non-canonical; for example, promoter DM associated with DE in the same direction. Of the canonical changes noted, promoter (PR) DM loci with reciprocal changes in expression in adenocarcinomas included HBEGF, AGER, PTPRM, DPT, CST1, MELK; DM GB loci with concordant changes in expression included FOXM1, FERMT1, SLC7A5, and FAP genes. IPA analyses showed adenocarcinoma-specific promoter DMxDE overlay identified familiar lung cancer nodes [tP53, Akt] as well as less familiar nodes [HBEGF, NQO1, GRK5, VWF, HPGD, CDH5, CTNNAL1, PTPN13, DACH1, SMAD6, LAMA3, AR]. The unique findings from this study include the discovery of numerous candidate The unique findings from this study include the discovery of numerous candidate methylation sites in both PR and GB regions not previously identified in NSCLC, and many non-canonical relationships to gene expression. These DNA methylation features could potentially be developed as risk or diagnostic biomarkers, or as candidate targets for newer methylation locus-targeted preventive or therapeutic agents. PMID:26683690

  11. Genome Wide Methylome Alterations in Lung Cancer

    PubMed Central

    Suzuki, Masako; Fazzari, Melissa; Han, Weiguo; Shi, Miao K.; Marquardt, Gaby; Lin, Juan; Wang, Tao; Keller, Steven; Zhu, Changcheng; Locker, Joseph D.; Spivack, Simon D.

    2015-01-01

    Aberrant cytosine 5-methylation underlies many deregulated elements of cancer. Among paired non-small cell lung cancers (NSCLC), we sought to profile DNA 5-methyl-cytosine features which may underlie genome-wide deregulation. In one of the more dense interrogations of the methylome, we sampled 1.2 million CpG sites from twenty-four NSCLC tumor (T)–non-tumor (NT) pairs using a methylation-sensitive restriction enzyme- based HELP-microarray assay. We found 225,350 differentially methylated (DM) sites in adenocarcinomas versus adjacent non-tumor tissue that vary in frequency across genomic compartment, particularly notable in gene bodies (GB; p<2.2E-16). Further, when DM was coupled to differential transcriptome (DE) in the same samples, 37,056 differential loci in adenocarcinoma emerged. Approximately 90% of the DM-DE relationships were non-canonical; for example, promoter DM associated with DE in the same direction. Of the canonical changes noted, promoter (PR) DM loci with reciprocal changes in expression in adenocarcinomas included HBEGF, AGER, PTPRM, DPT, CST1, MELK; DM GB loci with concordant changes in expression included FOXM1, FERMT1, SLC7A5, and FAP genes. IPA analyses showed adenocarcinoma-specific promoter DMxDE overlay identified familiar lung cancer nodes [tP53, Akt] as well as less familiar nodes [HBEGF, NQO1, GRK5, VWF, HPGD, CDH5, CTNNAL1, PTPN13, DACH1, SMAD6, LAMA3, AR]. The unique findings from this study include the discovery of numerous candidate The unique findings from this study include the discovery of numerous candidate methylation sites in both PR and GB regions not previously identified in NSCLC, and many non-canonical relationships to gene expression. These DNA methylation features could potentially be developed as risk or diagnostic biomarkers, or as candidate targets for newer methylation locus-targeted preventive or therapeutic agents. PMID:26683690

  12. Genome-wide distribution of genetic diversity and linkage disequilibrium in elite sugar beet germplasm

    PubMed Central

    2011-01-01

    Background Characterization of population structure and genetic diversity of germplasm is essential for the efficient organization and utilization of breeding material. The objectives of this study were to (i) explore the patterns of population structure in the pollen parent heterotic pool using different methods, (ii) investigate the genome-wide distribution of genetic diversity, and (iii) assess the extent and genome-wide distribution of linkage disequilibrium (LD) in elite sugar beet germplasm. Results A total of 264 and 238 inbred lines from the yield type and sugar type inbreds of the pollen parent heterotic gene pools, respectively, which had been genotyped with 328 SNP markers, were used in this study. Two distinct subgroups were detected based on different statistical methods within the elite sugar beet germplasm set, which was in accordance with its breeding history. MCLUST based on principal components, principal coordinates, or lapvectors had high correspondence with the germplasm type information as well as the assignment by STRUCTURE, which indicated that these methods might be alternatives to STRUCTURE for population structure analysis. Gene diversity and modified Roger's distance between the examined germplasm types varied considerably across the genome, which might be due to artificial selection. This observation indicates that population genetic approaches could be used to identify candidate genes for the traits under selection. Due to the fact that r2 >0.8 is required to detect marker-phenotype association explaining less than 1% of the phenotypic variance, our observation of a low proportion of SNP loci pairs showing such levels of LD suggests that the number of markers has to be dramatically increased for powerful genome-wide association mapping. Conclusions We provided a genome-wide distribution map of genetic diversity and linkage disequilibrium for the elite sugar beet germplasm, which is useful for the application of genome-wide association

  13. Integration of DNA marker information into breeding value predictions

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Calves from seven breeds including 20 herds were genotyped with a reduced DNA marker panel for weaning weight. The marker panel used was derived using USMARC Cycle VII animals. The results from the current study suggest marker effects are not robust across breeds and that methodology exists to integ...

  14. Chronic Periodontitis Genome-wide Association Studies

    PubMed Central

    Rhodin, K.; Divaris, K.; North, K.E.; Barros, S.P.; Moss, K.; Beck, J.D.; Offenbacher, S.

    2014-01-01

    Recent genome-wide association studies (GWAS) of chronic periodontitis (CP) offer rich data sources for the investigation of candidate genes, functional elements, and pathways. We used GWAS data of CP (n = 4,504) and periodontal pathogen colonization (n = 1,020) from a cohort of adult Americans of European descent participating in the Atherosclerosis Risk in Communities study and employed a MAGENTA approach (i.e., meta-analysis gene set enrichment of variant associations) to obtain gene-centric and gene set association results corrected for gene size, number of single-nucleotide polymorphisms, and local linkage disequilibrium characteristics based on the human genome build 18 (National Center for Biotechnology Information build 36). We used the Gene Ontology, Ingenuity, KEGG, Panther, Reactome, and Biocarta databases for gene set enrichment analyses. Six genes showed evidence of statistically significant association: 4 with severe CP (NIN, p = 1.6 × 10−7; ABHD12B, p = 3.6 × 10−7; WHAMM, p = 1.7 × 10−6; AP3B2, p = 2.2 × 10−6) and 2 with high periodontal pathogen colonization (red complex–KCNK1, p = 3.4 × 10−7; Porphyromonas gingivalis–DAB2IP, p = 1.0 × 10−6). Top-ranked genes for moderate CP were HGD (p = 1.4 × 10−5), ZNF675 (p = 1.5 × 10−5), TNFRSF10C (p = 2.0 × 10−5), and EMR1 (p = 2.0 × 10−5). Loci containing NIN, EMR1, KCNK1, and DAB2IP had showed suggestive evidence of association in the earlier single-nucleotide polymorphism–based analyses, whereas WHAMM and AP2B2 emerged as novel candidates. The top gene sets included severe CP (“endoplasmic reticulum membrane,” “cytochrome P450,” “microsome,” and “oxidation reduction”) and moderate CP (“regulation of gene expression,” “zinc ion binding,” “BMP signaling pathway,” and “ruffle”). Gene-centric analyses offer a promising avenue for efficient interrogation of large-scale GWAS data. These results highlight genes in previously identified loci and

  15. Incorporating molecular breeding values with variable call rates into genetic evaluations

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A partial genotype for an animal can result from panels with low call rates used to calculate a molecular breeding value. A molecular breeding value can still be calculated using a partial genotype by replacing the missing marker covariates with their mean value. This approach is expected to chang...

  16. Assessing genomic selection prediction accuracy in a dynamic barley breeding

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genomic selection is a method to improve quantitative traits in crops and livestock by estimating breeding values of selection candidates using phenotype and genome-wide marker data sets. Prediction accuracy has been evaluated through simulation and cross-validation, however validation based on prog...

  17. Systems-Level Analysis of Genome-Wide Association Data

    PubMed Central

    Farber, Charles R.

    2013-01-01

    Genome-wide association studies (GWAS) have emerged as the method of choice for identifying common variants affecting complex disease. In a GWAS, particular attention is placed, for obvious reasons, on single-nucleotide polymorphisms (SNPs) that exceed stringent genome-wide significance thresholds. However, it is expected that many SNPs with only nominal evidence of association (e.g., P < 0.05) truly influence disease. Efforts to extract additional biological information from entire GWAS datasets have primarily focused on pathway-enrichment analyses. However, these methods suffer from a number of limitations and typically fail to lead to testable hypotheses. To evaluate alternative approaches, we performed a systems-level analysis of GWAS data using weighted gene coexpression network analysis. A weighted gene coexpression network was generated for 1918 genes harboring SNPs that displayed nominal evidence of association (P ≤ 0.05) from a GWAS of bone mineral density (BMD) using microarray data on circulating monocytes isolated from individuals with extremely low or high BMD. Thirteen distinct gene modules were identified, each comprising coexpressed and highly interconnected GWAS genes. Through the characterization of module content and topology, we illustrate how network analysis can be used to discover disease-associated subnetworks and characterize novel interactions for genes with a known role in the regulation of BMD. In addition, we provide evidence that network metrics can be used as a prioritizing tool when selecting genes and SNPs for replication studies. Our results highlight the advantages of using systems-level strategies to add value to and inform GWAS. PMID:23316444

  18. Beef cattle body temperature during climatic stress: a genome-wide association study

    NASA Astrophysics Data System (ADS)

    Howard, Jeremy T.; Kachman, Stephen D.; Snelling, Warren M.; Pollak, E. John; Ciobanu, Daniel C.; Kuehn, Larry A.; Spangler, Matthew L.

    2014-09-01

    Cattle are reared in diverse environments and collecting phenotypic body temperature (BT) measurements to characterize BT variation across diverse environments is difficult and expensive. To better understand the genetic basis of BT regulation, a genome-wide association study was conducted utilizing crossbred steers and heifers totaling 239 animals of unknown pedigree and breed fraction. During predicted extreme heat and cold stress events, hourly tympanic and vaginal BT devices were placed in steers and heifers, respectively. Individuals were genotyped with the BovineSNP50K_v2 assay and data analyzed using Bayesian models for area under the curve (AUC), a measure of BT over time, using hourly BT observations summed across 5-days (AUC summer 5-day (AUCS5D) and AUC winter 5-day (AUCW5D)). Posterior heritability estimates were moderate to high and were estimated to be 0.68 and 0.21 for AUCS5D and AUCW5D, respectively. Moderately positive correlations between direct genomic values for AUCS5D and AUCW5D (0.40) were found, although a small percentage of the top 5 % 1-Mb windows were in common. Different sets of genes were associated with BT during winter and summer, thus simultaneous selection for animals tolerant to both heat and cold appears possible.

  19. Genome-wide association study for jumping performances in French sport horses.

    PubMed

    Brard, S; Ricard, A

    2015-02-01

    A genome-wide association study was performed to identify single nucleotide polymorphisms (SNPs) associated with jumping performances of warmbloods in France. The 999 horses included in the study for jumping performances were sport horses [mostly Selle Français (68%), Anglo-Arabians (13%) and horses from the other European studbooks]. Horses were genotyped using the Illumina EquineSNP50 BeadChip. Of the 54,602 SNPs available on this chip, 44,424 were retained after quality testing. Phenotypes were obtained by deregressing official breeding values for jumping competitions to use all available information, that is, the performances of each horse as well as those of its relatives. Two models were used to test the effects of the genotypes on deregressed phenotypes: a single-marker mixed model and a haplotype-based mixed model (significant: P < 1E-05; suggestive: P < 1E-04). Both models included a polygenic effect to take into account familial structures. For jumping performances, one suggestive quantitative trait locus (QTL) located on chromosome 1 (BIEC2_31196 and BIEC2_31198) was detected with both models. This QTL explains 0.7% of the phenotypic variance. RYR2, a gene encoding a major calcium channel in cardiac muscle in humans and mice, is located 0.55 Mb from this potential QTL. PMID:25515185

  20. Genome-wide association mapping of cadmium accumulation in different organs of barley.

    PubMed

    Wu, Dezhi; Sato, Kazuhiro; Ma, Jian Feng

    2015-11-01

    The threshold value of cadmium (Cd) concentration in grains of barley (Hordeum vulgare) is the lowest among cereal crops; however, it is poorly understood how Cd accumulation in barley grain is genetically controlled. We investigated genotypic variation in Cd accumulation of different organs in 100 accessions from a subset of the barley core collection using both hydroponic and Cd-contaminated soil culture. We also performed a genome-wide association (GWA) mapping for Cd accumulation in different organs. A large genotypic variation in the Cd concentration was found in all organs. There was a good correlation between shoot Cd of solution and soil culture, the shoot Cd and grain Cd, but no correlation between the root Cd and grain Cd. GWA mapping detected 9 quantitative trait loci (QTL) for root Cd, 21 for shoot Cd, 14 for root-to-shoot translocation and 15 for grain Cd. A common QTL for the shoot Cd and root-to-shoot translocation was found at 132.6 cM on chromosome 5H. Two major QTL for grain Cd were identified on chromosome 2H and chromosome 5H. The genetic variation in Cd accumulation and major QTL detected provide useful information helpful for cloning candidate genes for Cd accumulation and breeding low-Cd barley cultivars in future. PMID:26061418

  1. Genome-Wide Association Study of a Varroa-Specific Defense Behavior in Honeybees (Apis mellifera).

    PubMed

    Spötter, Andreas; Gupta, Pooja; Mayer, Manfred; Reinsch, Norbert; Bienefeld, Kaspar

    2016-05-01

    Honey bees are exposed to many damaging pathogens and parasites. The most devastating is Varroa destructor, which mainly affects the brood. A promising approach for preventing its spread is to breed Varroa-resistant honey bees. One trait that has been shown to provide significant resistance against the Varroa mite is hygienic behavior, which is a behavioral response of honeybee workers to brood diseases in general. Here, we report the use of an Affymetrix 44K SNP array to analyze SNPs associated with detection and uncapping of Varroa-parasitized brood by individual worker bees (Apis mellifera). For this study, 22 000 individually labeled bees were video-monitored and a sample of 122 cases and 122 controls was collected and analyzed to determine the dependence/independence of SNP genotypes from hygienic and nonhygienic behavior on a genome-wide scale. After false-discovery rate correction of the P values, 6 SNP markers had highly significant associations with the trait investigated (α < 0.01). Inspection of the genomic regions around these SNPs led to the discovery of putative candidate genes. PMID:26774061

  2. Beef cattle body temperature during climatic stress: a genome-wide association study.

    PubMed

    Howard, Jeremy T; Kachman, Stephen D; Snelling, Warren M; Pollak, E John; Ciobanu, Daniel C; Kuehn, Larry A; Spangler, Matthew L

    2014-09-01

    Cattle are reared in diverse environments and collecting phenotypic body temperature (BT) measurements to characterize BT variation across diverse environments is difficult and expensive. To better understand the genetic basis of BT regulation, a genome-wide association study was conducted utilizing crossbred steers and heifers totaling 239 animals of unknown pedigree and breed fraction. During predicted extreme heat and cold stress events, hourly tympanic and vaginal BT devices were placed in steers and heifers, respectively. Individuals were genotyped with the BovineSNP50K_v2 assay and data analyzed using Bayesian models for area under the curve (AUC), a measure of BT over time, using hourly BT observations summed across 5-days (AUC summer 5-day (AUCS5D) and AUC winter 5-day (AUCW5D)). Posterior heritability estimates were moderate to high and were estimated to be 0.68 and 0.21 for AUCS5D and AUCW5D, respectively. Moderately positive correlations between direct genomic values for AUCS5D and AUCW5D (0.40) were found, although a small percentage of the top 5% 1-Mb windows were in common. Different sets of genes were associated with BT during winter and summer, thus simultaneous selection for animals tolerant to both heat and cold appears possible. PMID:24362770

  3. Identification and characterization of a genome-wide significant region associated with red blood cell phenotypes in domestic sheep

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A genome wide association study (GWAS) investigating red blood cell (RBC) phenotypes was performed with over 500 domestic sheep (Ovis aries) from three economically important breeds in the US (Columbia, Polypay, and Rambouillet). A single nucleotide polymorphism (SNP, hereafter the discovery SNP) sh...

  4. Genome-wide SNP discovery in walnut with an AGSNP pipeline updated for SNP discovery in allogamous organisms

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: A genome-wide set of single nucleotide polymorphisms (SNPs) is a valuable resource in genetic research and breeding and is usually developed by re-sequencing a genome. If a genome sequence is not available, an alternative strategy must be used. We previously reported the development of a...

  5. Genome-wide SNP discovery in walnut with an AGSNP pipeline updated for SNP discovery in allogamous organisms

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background A genome-wide set of single nucleotide polymorphisms (SNPs) is a valuable resource in genetic research and breeding and is usually developed by re-sequencing a genome. If a genome sequence is not available, an alternative strategy must be used. We previously reported the development of a ...

  6. Genome-wide association mapping of fusarium head blight resistance in wheat (Triticum aestivum L.) using genotyping by sequencing

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Fusarium head blight (FHB) is one of the most important wheat diseases worldwide and host resistance displays complex genetic control. A genome-wide association study (GWAS) was performed on 273 winter wheat breeding lines from the mid-western and eastern regions of the US to identify chromosomal re...

  7. Estimated breeding values for meat characteristics of crossbred cattle with an animal model.

    PubMed

    Van Vleck, L D; Hakim, A F; Cundiff, L V; Koch, R M; Crouse, J D; Boldman, K G

    1992-02-01

    Longissimus muscle area, shear force measure, and sensory panel scores for flavor, juiciness, and tenderness, and marbling score were obtained from 682 steer carcasses, resulting from crosses among five Bos taurus and Bos indicus breeds. The single-trait model used included birth year and as covariates breed fractions, weaning age, and days on feed. The numerator relationship matrix was for 1,350 animals (682 steers, 74 pure breed and 52 F1-cross sires and 542 dams). The coefficient matrix was inverted to examine standard errors of prediction. Estimated breeding value is the sum of the estimate of genetic deviation and the weighted (fractions) sum of estimates of breed effects. Heritabilities used in estimating breeding values were .62, .06, .05, .11, .05, and .43 for longissimus muscle area, shear force, flavor, juiciness, tenderness, and marbling score. Sires within a breed or crossbred group tended to rank similarly due to large differences among breed effects (e.g., the six Sahiwal sires ranked in the highest six places for shear force). These results illustrate that for traits with large breed differences, selection of the proper breed should be done before selection within that breed. PMID:1548197

  8. Genome-Wide Association Study of Insect Bite Hypersensitivity in Swedish-Born Icelandic Horses.

    PubMed

    Shrestha, Merina; Eriksson, Susanne; Schurink, Anouk; Andersson, Lisa S; Sundquist, Marie; Frey, Rebecka; Broström, Hans; Bergström, Tomas; Ducro, Bart; Lindgren, Gabriella

    2015-01-01

    Insect bite hypersensitivity (IBH) is the most common allergic skin disease in horses and is caused by biting midges, mainly of the genus Culicoides. The disease predominantly comprises a type I hypersensitivity reaction, causing severe itching and discomfort that reduce the welfare and commercial value of the horse. It is a multifactorial disorder influenced by both genetic and environmental factors, with heritability ranging from 0.16 to 0.27 in various horse breeds. The worldwide prevalence in different horse breeds ranges from 3% to 60%; it is more than 50% in Icelandic horses exported to the European continent and approximately 8% in Swedish-born Icelandic horses. To minimize the influence of environmental effects, we analyzed Swedish-born Icelandic horses to identify genomic regions that regulate susceptibility to IBH. We performed a genome-wide association (GWA) study on 104 affected and 105 unaffected Icelandic horses genotyped using Illumina® EquineSNP50 Genotyping BeadChip. Quality control and population stratification analyses were performed with the GenABEL package in R (λ = 0.81). The association analysis was performed using the Bayesian variable selection method, Bayes C, implemented in GenSel software. The highest percentage of genetic variance was explained by the windows on X chromosomes (0.51% and 0.36% by 73 and 74 mb), 17 (0.34% by 77 mb), and 18 (0.34% by 26 mb). Overlapping regions with previous GWA studies were observed on chromosomes 7, 9, and 17. The windows identified in our study on chromosomes 7, 10, and 17 harbored immune system genes and are priorities for further investigation. PMID:26026046

  9. Genome-Wide Association for Growth Traits in Canchim Beef Cattle

    PubMed Central

    Buzanskas, Marcos E.; Grossi, Daniela A.; Ventura, Ricardo V.; Schenkel, Flávio S.; Sargolzaei, Mehdi; Meirelles, Sarah L. C.; Mokry, Fabiana B.; Higa, Roberto H.; Mudadu, Maurício A.; da Silva, Marcos V. G. Barbosa.; Niciura, Simone C. M.; Júnior, Roberto A. A. Torres.; Alencar, Maurício M.; Regitano, Luciana C. A.; Munari, Danísio P.

    2014-01-01

    Studies are being conducted on the applicability of genomic data to improve the accuracy of the selection process in livestock, and genome-wide association studies (GWAS) provide valuable information to enhance the understanding on the genetics of complex traits. The aim of this study was to identify genomic regions and genes that play roles in birth weight (BW), weaning weight adjusted for 210 days of age (WW), and long-yearling weight adjusted for 420 days of age (LYW) in Canchim cattle. GWAS were performed by means of the Generalized Quasi-Likelihood Score (GQLS) method using genotypes from the BovineHD BeadChip and estimated breeding values for BW, WW, and LYW. Data consisted of 285 animals from the Canchim breed and 114 from the MA genetic group (derived from crossings between Charolais sires and ½ Canchim + ½ Zebu dams). After applying a false discovery rate correction at a 10% significance level, a total of 4, 12, and 10 SNPs were significantly associated with BW, WW, and LYW, respectively. These SNPs were surveyed to their corresponding genes or to surrounding genes within a distance of 250 kb. The genes DPP6 (dipeptidyl-peptidase 6) and CLEC3B (C-type lectin domain family 3 member B) were highlighted, considering its functions on the development of the brain and skeletal system, respectively. The GQLS method identified regions on chromosome associated with birth weight, weaning weight, and long-yearling weight in Canchim and MA animals. New candidate regions for body weight traits were detected and some of them have interesting biological functions, of which most have not been previously reported. The observation of QTL reports for body weight traits, covering areas surrounding the genes (SNPs) herein identified provides more evidence for these associations. Future studies targeting these areas could provide further knowledge to uncover the genetic architecture underlying growth traits in Canchim cattle. PMID:24733441

  10. Genome-wide association for heifer reproduction and calf performance traits in beef cattle.

    PubMed

    Akanno, Everestus C; Plastow, Graham; Fitzsimmons, Carolyn; Miller, Stephen P; Baron, Vern; Ominski, Kimberly; Basarab, John A

    2015-12-01

    The aim of this study was to identify SNP markers that associate with variation in beef heifer reproduction and performance of their calves. A genome-wide association study was performed by means of the generalized quasi-likelihood score (GQLS) method using heifer genotypes from the BovineSNP50 BeadChip and estimated breeding values for pre-breeding body weight (PBW), pregnancy rate (PR), calving difficulty (CD), age at first calving (AFC), calf birth weight (BWT), calf weaning weight (WWT), and calf pre-weaning average daily gain (ADG). Data consisted of 785 replacement heifers from three Canadian research herds, namely Brandon Research Centre, Brandon, Manitoba, University of Alberta Roy Berg Kinsella Ranch, Kinsella, Alberta, and Lacombe Research Centre, Lacombe, Alberta. After applying a false discovery rate correction at a 5% significance level, a total of 4, 3, 3, 9, 6, 2, and 1 SNPs were significantly associated with PBW, PR, CD, AFC, BWT, WWT, and ADG, respectively. These SNPs were located on chromosomes 1, 5-7, 9, 13-16, 19-21, 24, 25, and 27-29. Chromosomes 1, 5, and 24 had SNPs with pleiotropic effects. New significant SNPs that impact functional traits were detected, many of which have not been previously reported. The results of this study support quantitative genetic studies related to the inheritance of these traits, and provides new knowledge regarding beef cattle quantitative trait loci effects. The identification of these SNPs provides a starting point to identify genes affecting heifer reproduction traits and performance of their calves (BWT, WWT, and ADG). They also contribute to a better understanding of the biology underlying these traits and will be potentially useful in marker- and genome-assisted selection and management. PMID:26484575

  11. Genome Wide Association Study Identifies New Loci Associated with Undesired Coat Color Phenotypes in Saanen Goats

    PubMed Central

    Martin, Pauline Marie; Palhière, Isabelle; Ricard, Anne; Tosser-Klopp, Gwenola; Rupp, Rachel

    2016-01-01

    This paper reports a quantitative genetics and genomic analysis of undesirable coat color patterns in goats. Two undesirable coat colors have routinely been recorded for the past 15 years in French Saanen goats. One fifth of Saanen females have been phenotyped “pink” (8.0%) or “pink neck” (11.5%) and consequently have not been included in the breeding program as elite animals. Heritability of the binary “pink” and “pink neck” phenotype, estimated from 103,443 females was 0.26 for “pink” and 0.21 for “pink neck”. Genome wide association studies (using haplotypes or single SNPs) were implemented using a daughter design of 810 Saanen goats sired by 9 Artificial Insemination bucks genotyped with the goatSNP50 chip. A highly significant signal (-log10pvalue = 10.2) was associated with the “pink neck” phenotype on chromosome 11, suggesting the presence of a major gene. Highly significant signals for the “pink” phenotype were found on chromosomes 5 and 13 (-log10p values of 7.2 and, 7.7 respectively). The most significant SNP on chromosome 13 was in the ASIP gene region, well known for its association with coat color phenotypes. Nine significant signals were also found for both traits. The highest signal for each trait was detected by both single SNP and haplotype approaches, whereas the smaller signals were not consistently detected by the two methods. Altogether these results demonstrated a strong genetic control of the “pink” and “pink neck” phenotypes in French Saanen goats suggesting that SNP information could be used to identify and remove undesired colored animals from the breeding program. PMID:27030980

  12. Genome-wide Association Study and Meta-Analysis Identify ISL1 as Genome-wide Significant Susceptibility Gene for Bladder Exstrophy

    PubMed Central

    Draaken, Markus; Knapp, Michael; Pennimpede, Tracie; Schmidt, Johanna M.; Ebert, Anne-Karolin; Rösch, Wolfgang; Stein, Raimund; Utsch, Boris; Hirsch, Karin; Boemers, Thomas M.; Mangold, Elisabeth; Heilmann, Stefanie; Ludwig, Kerstin U.; Jenetzky, Ekkehart; Zwink, Nadine; Moebus, Susanne; Herrmann, Bernhard G.; Mattheisen, Manuel; Nöthen, Markus M.

    2015-01-01

    The bladder exstrophy-epispadias complex (BEEC) represents the severe end of the uro-rectal malformation spectrum, and is thought to result from aberrant embryonic morphogenesis of the cloacal membrane and the urorectal septum. The most common form of BEEC is isolated classic bladder exstrophy (CBE). To identify susceptibility loci for CBE, we performed a genome-wide association study (GWAS) of 110 CBE patients and 1,177 controls of European origin. Here, an association was found with a region of approximately 220kb on chromosome 5q11.1. This region harbors the ISL1 (ISL LIM homeobox 1) gene. Multiple markers in this region showed evidence for association with CBE, including 84 markers with genome-wide significance. We then performed a meta-analysis using data from a previous GWAS by our group of 98 CBE patients and 526 controls of European origin. This meta-analysis also implicated the 5q11.1 locus in CBE risk. A total of 138 markers at this locus reached genome-wide significance in the meta-analysis, and the most significant marker (rs9291768) achieved a P value of 2.13 × 10−12. No other locus in the meta-analysis achieved genome-wide significance. We then performed murine expression analyses to follow up this finding. Here, Isl1 expression was detected in the genital region within the critical time frame for human CBE development. Genital regions with Isl1 expression included the peri-cloacal mesenchyme and the urorectal septum. The present study identified the first genome-wide significant locus for CBE at chromosomal region 5q11.1, and provides strong evidence for the hypothesis that ISL1 is the responsible candidate gene in this region. PMID:25763902

  13. Genome wide signatures of positive selection: The comparison of independent samples and the identification of regions associated to traits

    PubMed Central

    Barendse, William; Harrison, Blair E; Bunch, Rowan J; Thomas, Merle B; Turner, Lex B

    2009-01-01

    Background The goal of genome wide analyses of polymorphisms is to achieve a better understanding of the link between genotype and phenotype. Part of that goal is to understand the selective forces that have operated on a population. Results In this study we compared the signals of selection, identified through population divergence in the Bovine HapMap project, to those found in an independent sample of cattle from Australia. Evidence for population differentiation across the genome, as measured by FST, was highly correlated in the two data sets. Nevertheless, 40% of the variance in FST between the two studies was attributed to the differences in breed composition. Seventy six percent of the variance in FST was attributed to differences in SNP composition and density when the same breeds were compared. The difference between FST of adjacent loci increased rapidly with the increase in distance between SNP, reaching an asymptote after 20 kb. Using 129 SNP that have highly divergent FST values in both data sets, we identified 12 regions that had additive effects on the traits residual feed intake, beef yield or intramuscular fatness measured in the Australian sample. Four of these regions had effects on more than one trait. One of these regions includes the R3HDM1 gene, which is under selection in European humans. Conclusion Firstly, many different populations will be necessary for a full description of selective signatures across the genome, not just a small set of highly divergent populations. Secondly, it is necessary to use the same SNP when comparing the signatures of selection from one study to another. Thirdly, useful signatures of selection can be obtained where many of the groups have only minor genetic differences and may not be clearly separated in a principal component analysis. Fourthly, combining analyses of genome wide selection signatures and genome wide associations to traits helps to define the trait under selection or the population group in which

  14. Genome-Wide Association Mapping of Anther Extrusion in Hexaploid Spring Wheat

    PubMed Central

    Muqaddasi, Quddoos H.; Lohwasser, Ulrike; Nagel, Manuela; Börner, Andreas; Pillen, Klaus; Röder, Marion S.

    2016-01-01

    In a number of crop species hybrids are able to outperform line varieties. The anthers of the autogamous bread wheat plant are normally extruded post anthesis, a trait which is unfavourable for the production of F1 hybrid grain. Higher anther extrusion (AE) promotes cross fertilization for more efficient hybrid seed production. Therefore, this study aimed at the genetic dissection of AE by genome wide association studies (GWAS) and determination of the main effect QTL. We applied GWAS approach to identify DArT markers potentially linked to AE to unfold its genetic basis in a panel of spring wheat accessions. Phenotypic data were collected for three years and best linear unbiased estimate (BLUE) values were calculated across all years. The extent of the AE correlation between growing years and BLUE values ranged from r = +0.56 (2013 vs 2015) to 0.91 (2014 vs BLUE values). The broad sense heritability was 0.84 across all years. Six accessions displayed stable AE >80% across all the years. Genotyping data included 2,575 DArT markers (with minimum of 0.05 minor allele frequency applied). AE was influenced both by genotype and by the growing environment. In all, 131 significant marker trait associations (MTAs) (|log10 (P)| >FDR) were established for AE. AE behaved as a quantitative trait, with five consistently significant markers (significant across at least two years with a significant BLUE value) contributing a minor to modest proportion (4.29% to 8.61%) of the phenotypic variance and affecting the trait either positively or negatively. For this reason, there is potential for breeding for improved AE by gene pyramiding. The consistently significant markers linked to AE could be helpful for marker assisted selection to transfer AE to high yielding varieties allowing to promote the exploitation of hybrid-heterosis in the key crop wheat. PMID:27191600

  15. Genome-Wide Association Mapping of Anther Extrusion in Hexaploid Spring Wheat.

    PubMed

    Muqaddasi, Quddoos H; Lohwasser, Ulrike; Nagel, Manuela; Börner, Andreas; Pillen, Klaus; Röder, Marion S

    2016-01-01

    In a number of crop species hybrids are able to outperform line varieties. The anthers of the autogamous bread wheat plant are normally extruded post anthesis, a trait which is unfavourable for the production of F1 hybrid grain. Higher anther extrusion (AE) promotes cross fertilization for more efficient hybrid seed production. Therefore, this study aimed at the genetic dissection of AE by genome wide association studies (GWAS) and determination of the main effect QTL. We applied GWAS approach to identify DArT markers potentially linked to AE to unfold its genetic basis in a panel of spring wheat accessions. Phenotypic data were collected for three years and best linear unbiased estimate (BLUE) values were calculated across all years. The extent of the AE correlation between growing years and BLUE values ranged from r = +0.56 (2013 vs 2015) to 0.91 (2014 vs BLUE values). The broad sense heritability was 0.84 across all years. Six accessions displayed stable AE >80% across all the years. Genotyping data included 2,575 DArT markers (with minimum of 0.05 minor allele frequency applied). AE was influenced both by genotype and by the growing environment. In all, 131 significant marker trait associations (MTAs) (|log10 (P)| >FDR) were established for AE. AE behaved as a quantitative trait, with five consistently significant markers (significant across at least two years with a significant BLUE value) contributing a minor to modest proportion (4.29% to 8.61%) of the phenotypic variance and affecting the trait either positively or negatively. For this reason, there is potential for breeding for improved AE by gene pyramiding. The consistently significant markers linked to AE could be helpful for marker assisted selection to transfer AE to high yielding varieties allowing to promote the exploitation of hybrid-heterosis in the key crop wheat. PMID:27191600

  16. Genome-Wide Scan Reveals Mutation Associated with Melanoma

    MedlinePlus

    ... 1999 Spotlight on Research 2012 July 2012 (historical) Genome-Wide Scan Reveals Mutation Associated with Melanoma A ... out to see if a technology called whole genome sequencing would help them find other genetic risk ...

  17. Multiple Genes Related to Muscle Identified through a Joint Analysis of a Two-stage Genome-wide Association Study for Racing Performance of 1,156 Thoroughbreds

    PubMed Central

    Shin, Dong-Hyun; Lee, Jin Woo; Park, Jong-Eun; Choi, Ik-Young; Oh, Hee-Seok; Kim, Hyeon Jeong; Kim, Heebal

    2015-01-01

    Thoroughbred, a relatively recent horse breed, is best known for its use in horse racing. Although myostatin (MSTN) variants have been reported to be highly associated with horse racing performance, the trait is more likely to be polygenic in nature. The purpose of this study was to identify genetic variants strongly associated with racing performance by using estimated breeding value (EBV) for race time as a phenotype. We conducted a two-stage genome-wide association study to search for genetic variants associated with the EBV. In the first stage of genome-wide association study, a relatively large number of markers (~54,000 single-nucleotide polymorphisms, SNPs) were evaluated in a small number of samples (240 horses). In the second stage, a relatively small number of markers identified to have large effects (170 SNPs) were evaluated in a much larger number of samples (1,156 horses). We also validated the SNPs related to MSTN known to have large effects on racing performance and found significant associations in the stage two analysis, but not in stage one. We identified 28 significant SNPs related to 17 genes. Among these, six genes have a function related to myogenesis and five genes are involved in muscle maintenance. To our knowledge, these genes are newly reported for the genetic association with racing performance of Thoroughbreds. It complements a recent horse genome-wide association studies of racing performance that identified other SNPs and genes as the most significant variants. These results will help to expand our knowledge of the polygenic nature of racing performance in Thoroughbreds. PMID:25925054

  18. Multiple Genes Related to Muscle Identified through a Joint Analysis of a Two-stage Genome-wide Association Study for Racing Performance of 1,156 Thoroughbreds.

    PubMed

    Shin, Dong-Hyun; Lee, Jin Woo; Park, Jong-Eun; Choi, Ik-Young; Oh, Hee-Seok; Kim, Hyeon Jeong; Kim, Heebal

    2015-06-01

    Thoroughbred, a relatively recent horse breed, is best known for its use in horse racing. Although myostatin (MSTN) variants have been reported to be highly associated with horse racing performance, the trait is more likely to be polygenic in nature. The purpose of this study was to identify genetic variants strongly associated with racing performance by using estimated breeding value (EBV) for race time as a phenotype. We conducted a two-stage genome-wide association study to search for genetic variants associated with the EBV. In the first stage of genome-wide association study, a relatively large number of markers (~54,000 single-nucleotide polymorphisms, SNPs) were evaluated in a small number of samples (240 horses). In the second stage, a relatively small number of markers identified to have large effects (170 SNPs) were evaluated in a much larger number of samples (1,156 horses). We also validated the SNPs related to MSTN known to have large effects on racing performance and found significant associations in the stage two analysis, but not in stage one. We identified 28 significant SNPs related to 17 genes. Among these, six genes have a function related to myogenesis and five genes are involved in muscle maintenance. To our knowledge, these genes are newly reported for the genetic association with racing performance of Thoroughbreds. It complements a recent horse genome-wide association studies of racing performance that identified other SNPs and genes as the most significant variants. These results will help to expand our knowledge of the polygenic nature of racing performance in Thoroughbreds. PMID:25925054

  19. Genome-wide Mapping Reveals Conservation of Promoter DNA Methylation Following Chicken Domestication

    PubMed Central

    Li, Qinghe; Wang, Yuanyuan; Hu, Xiaoxiang; Zhao, Yaofeng; Li, Ning

    2015-01-01

    It is well-known that environment influences DNA methylation, however, the extent of heritable DNA methylation variation following animal domestication remains largely unknown. Using meDIP-chip we mapped the promoter methylomes for 23,316 genes in muscle tissues of ancestral and domestic chickens. We systematically examined the variation of promoter DNA methylation in terms of different breeds, differentially expressed genes, SNPs and genes undergo genetic selection sweeps. While considerable changes in DNA sequence and gene expression programs were prevalent, we found that the inter-strain DNA methylation patterns were highly conserved in promoter region between the wild and domestic chicken breeds. Our data suggests a global preservation of DNA methylation between the wild and domestic chicken breeds in either a genome-wide or locus-specific scale in chick muscle tissues. PMID:25735894

  20. Genome wide identification of regulatory motifs in Bacillus subtilis

    PubMed Central

    Mwangi, Michael M; Siggia, Eric D

    2003-01-01

    Background To explain the vastly different phenotypes exhibited by the same organism under different conditions, it is essential that we understand how the organism's genes are coordinately regulated. While there are many excellent tools for predicting sequences encoding proteins or RNA genes, few algorithms exist to predict regulatory sequences on a genome wide scale with no prior information. Results To identify motifs involved in the control of transcription, an algorithm was developed that searches upstream of operons for improbably frequent dimers. The algorithm was applied to the B. subtilis genome, which is predicted to encode for approximately 200 DNA binding proteins. The dimers found to be over-represented could be clustered into 317 distinct groups, each thought to represent a class of motifs uniquely recognized by some transcription factor. For each cluster of dimers, a representative weight matrix was derived and scored over the regions upstream of the operons to predict the sites recognized by the cluster's factor, and a putative regulon of the operons immediately downstream of the sites was inferred. The distribution in number of operons per predicted regulon is comparable to that for well characterized transcription factors. The most highly over-represented dimers matched σA, the T-box, and σW sites. We have evidence to suggest that at least 52 of our clusters of dimers represent actual regulatory motifs, based on the groups' weight matrix matches to experimentally characterized sites, the functional similarity of the component operons of the groups' regulons, and the positional biases of the weight matrix matches. All predictions are assigned a significance value, and thresholds are set to avoid false positives. Where possible, we examine our false negatives, drawing examples from known regulatory motifs and regulons inferred from RNA expression data. Conclusions We have demonstrated that in the case of B. subtilis our algorithm allows for the

  1. Genome-wide association scan suggests basis for microtia in Awassi sheep.

    PubMed

    Jawasreh, K; Boettcher, P J; Stella, A

    2016-08-01

    Hereditary underdevelopment of the ear, a condition also known as microtia, has been observed in several sheep breeds as well as in humans and other species. Its genetic basis in sheep is unknown. The Awassi sheep, a breed native to southwest Asia, carries this phenotype and was targeted for molecular characterization via a genome-wide association study. DNA samples were collected from sheep in Jordan. Eight affected and 12 normal individuals were genotyped with the Illumina OvineSNP50(®) chip. Multilocus analyses failed to identify any genotypic association. In contrast, a single-locus analysis revealed a statistically significant association (P = 0.012, genome-wide) with a SNP at basepair 34 647 499 on OAR23. This marker is adjacent to the gene encoding transcription factor GATA-6, which has been shown to play a role in many developmental processes, including chondrogenesis. The lack of extended homozygosity in this region suggests a fairly ancient mutation, and the time of occurrence was estimated to be approximately 3000 years ago. Many of the earless sheep breeds may thus share the causative mutation, especially within the subgroup of fat-tailed, wool sheep. PMID:26990958

  2. Sparse principal component analysis for identifying ancestry-informative markers in genome-wide association studies.

    PubMed

    Lee, Seokho; Epstein, Michael P; Duncan, Richard; Lin, Xihong

    2012-05-01

    Genome-wide association studies (GWAS) routinely apply principal component analysis (PCA) to infer population structure within a sample to correct for confounding due to ancestry. GWAS implementation of PCA uses tens of thousands of single-nucleotide polymorphisms (SNPs) to infer structure, despite the fact that only a small fraction of such SNPs provides useful information on ancestry. The identification of this reduced set of ancestry-informative markers (AIMs) from a GWAS has practical value; for example, researchers can genotype the AIM set to correct for potential confounding due to ancestry in follow-up studies that utilize custom SNP or sequencing technology. We propose a novel technique to identify AIMs from genome-wide SNP data using sparse PCA. The procedure uses penalized regression methods to identify those SNPs in a genome-wide panel that significantly contribute to the principal components while encouraging SNPs that provide negligible loadings to vanish from the analysis. We found that sparse PCA leads to negligible loss of ancestry information compared to traditional PCA analysis of genome-wide SNP data. We further demonstrate the value of sparse PCA for AIM selection using real data from the International HapMap Project and a genomewide study of inflammatory bowel disease. We have implemented our approach in open-source R software for public use. PMID:22508067

  3. Genome wide association scan for chronic periodontitis implicates novel locus

    PubMed Central

    2014-01-01

    Background There is evidence for a genetic contribution to chronic periodontitis. In this study, we conducted a genome wide association study among 866 participants of the University of Pittsburgh Dental Registry and DNA Repository, whose periodontal diagnosis ranged from healthy (N = 767) to severe chronic periodontitis (N = 99). Methods Genotypingi of over half-million single nucleotide polymorphisms was determined. Analyses were done twice, first in the complete dataset of all ethnicities, and second including only samples defined as self-reported Whites. From the top 100 results, twenty single nucleotide polymorphisms had consistent results in both analyses (borderline p-values ranging from 1E-05 to 1E-6) and were selected to be tested in two independent datasets derived from 1,460 individuals from Porto Alegre, and 359 from Rio de Janeiro, Brazil. Meta-analyses of the Single nucleotide polymorphisms showing a trend for association in the independent dataset were performed. Results The rs1477403 marker located on 16q22.3 showed suggestive association in the discovery phase and in the Porto Alegre dataset (p = 0.05). The meta-analysis suggested the less common allele decreases the risk of chronic periodontitis. Conclusions Our data offer a clear hypothesis to be independently tested regarding the contribution of the 16q22.3 locus to chronic periodontitis. PMID:25008200

  4. Genome-Wide Association Study of Grain Appearance and Milling Quality in a Worldwide Collection of Indica Rice Germplasm.

    PubMed

    Qiu, Xianjin; Pang, Yunlong; Yuan, Zhihua; Xing, Danying; Xu, Jianlong; Dingkuhn, Michael; Li, Zhikang; Ye, Guoyou

    2015-01-01

    Grain appearance quality and milling quality are the main determinants of market value of rice. Breeding for improved grain quality is a major objective of rice breeding worldwide. Identification of genes/QTL controlling quality traits is the prerequisite for increasing breeding efficiency through marker-assisted selection. Here, we reported a genome-wide association study in indica rice to identify QTL associated with 10 appearance and milling quality related traits, including grain length, grain width, grain length to width ratio, grain thickness, thousand grain weight, degree of endosperm chalkiness, percentage of grains with chalkiness, brown rice rate, milled rice rate and head milled rice rate. A diversity panel consisting of 272 indica accessions collected worldwide was evaluated in four locations including Hangzhou, Jingzhou, Sanya and Shenzhen representing indica rice production environments in China and genotyped using genotyping-by-sequencing and Diversity Arrays Technology based on next-generation sequencing technique called DArTseq™. A wide range of variation was observed for all traits in all environments. A total of 16 different association analysis models were compared to determine the best model for each trait-environment combination. Association mapping based on 18,824 high quality markers yielded 38 QTL for the 10 traits. Five of the detected QTL corresponded to known genes or fine mapped QTL. Among the 33 novel QTL identified, qDEC1.1 (qGLWR1.1), qBRR2.2 (qGL2.1), qTGW2.1 (qGL2.2), qGW11.1 (qMRR11.1) and qGL7.1 affected multiple traits with relatively large effects and/or were detected in multiple environments. The research provided an insight of the genetic architecture of rice grain quality and important information for mining genes/QTL with large effects within indica accessions for rice breeding. PMID:26714258

  5. Genome-Wide Association Study of Grain Appearance and Milling Quality in a Worldwide Collection of Indica Rice Germplasm

    PubMed Central

    Yuan, Zhihua; Xing, Danying; Xu, Jianlong; Dingkuhn, Michael; Li, Zhikang; Ye, Guoyou

    2015-01-01

    Grain appearance quality and milling quality are the main determinants of market value of rice. Breeding for improved grain quality is a major objective of rice breeding worldwide. Identification of genes/QTL controlling quality traits is the prerequisite for increasing breeding efficiency through marker-assisted selection. Here, we reported a genome-wide association study in indica rice to identify QTL associated with 10 appearance and milling quality related traits, including grain length, grain width, grain length to width ratio, grain thickness, thousand grain weight, degree of endosperm chalkiness, percentage of grains with chalkiness, brown rice rate, milled rice rate and head milled rice rate. A diversity panel consisting of 272 indica accessions collected worldwide was evaluated in four locations including Hangzhou, Jingzhou, Sanya and Shenzhen representing indica rice production environments in China and genotyped using genotyping-by-sequencing and Diversity Arrays Technology based on next-generation sequencing technique called DArTseq™. A wide range of variation was observed for all traits in all environments. A total of 16 different association analysis models were compared to determine the best model for each trait-environment combination. Association mapping based on 18,824 high quality markers yielded 38 QTL for the 10 traits. Five of the detected QTL corresponded to known genes or fine mapped QTL. Among the 33 novel QTL identified, qDEC1.1 (qGLWR1.1), qBRR2.2 (qGL2.1), qTGW2.1 (qGL2.2), qGW11.1 (qMRR11.1) and qGL7.1 affected multiple traits with relatively large effects and/or were detected in multiple environments. The research provided an insight of the genetic architecture of rice grain quality and important information for mining genes/QTL with large effects within indica accessions for rice breeding. PMID:26714258

  6. Genome-wide association for grain morphology in synthetic hexaploid wheats using digital imaging analysis

    PubMed Central

    2014-01-01

    with TKW, grain width and thickness. In silico functional analysis predicted a range of biological functions for 32 DArT loci and receptor like kinase, known to affect plant development, appeared to be common protein family encoded by several loci responsible for grain size and shape. Conclusion Conclusively, we demonstrated the application and integration of multiple approaches including high throughput phenotyping using DI, genome wide association studies (GWAS) and in silico functional analysis of candidate loci to analyze target traits, and identify candidate genomic regions underlying these traits. These approaches provided great opportunity to understand the breeding value of SHWs for improving grain weight and enhanced our deep understanding on molecular genetics of grain weight in wheat. PMID:24884376

  7. Assisted Breeding in Sugar Beet

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Molecular insight and methods applied to plant breeding and germplasm enhancement is the goal of assisted breeding, also known as marker assisted breeding, marker assisted selection, molecular plant breeding, or genome-wide selection, among others. The basic idea is that most, if not all, heritable ...

  8. Genome-wide mining, characterization, and development of microsatellite markers in Marsupenaeus japonicus by genome survey sequencing

    NASA Astrophysics Data System (ADS)

    Lu, Xia; Luan, Sheng; Kong, Jie; Hu, Longyang; Mao, Yong; Zhong, Shengping

    2015-12-01

    The kuruma prawn, Marsupenaeus japonicus, is one of the most cultivated and consumed species of shrimp. However, very few molecular genetic/genomic resources are publically available for it. Thus, the characterization and distribution of simple sequence repeats (SSRs) remains ambiguous and the use of SSR markers in genomic studies and marker-assisted selection is limited. The goal of this study is to characterize and develop genome-wide SSR markers in M. japonicus by genome survey sequencing for application in comparative genomics and breeding. A total of 326 945 perfect SSRs were identifi ed, among which dinucleotide repeats were the most frequent class (44.08%), followed by mononucleotides (29.67%), trinucleotides (18.96%), tetranucleotides (5.66%), hexanucleotides (1.07%), and pentanucleotides (0.56%). In total, 151 541 SSR loci primers were successfully designed. A subset of 30 SSR primer pairs were synthesized and tested in 42 individuals from a wild population, of which 27 loci (90.0%) were successfully amplifi ed with specifi c products and 24 (80.0%) were polymorphic. For the amplifi ed polymorphic loci, the alleles ranged from 5 to 17 (with an average of 9.63), and the average PIC value was 0.796. A total of 58 256 SSR-containing sequences had signifi cant Gene Ontology annotation; these are good functional molecular marker candidates for association studies and comparative genomic analysis. The newly identifi ed SSRs signifi cantly contribute to the M. japonicus genomic resources and will facilitate a number of genetic and genomic studies, including high density linkage mapping, genome-wide association analysis, marker-aided selection, comparative genomics analysis, population genetics, and evolution.

  9. Assessing statistical significance in multivariable genome wide association analysis

    PubMed Central

    Buzdugan, Laura; Kalisch, Markus; Navarro, Arcadi; Schunk, Daniel; Fehr, Ernst; Bühlmann, Peter

    2016-01-01

    Motivation: Although Genome Wide Association Studies (GWAS) genotype a very large number of single nucleotide polymorphisms (SNPs), the data are often analyzed one SNP at a time. The low predictive power of single SNPs, coupled with the high significance threshold needed to correct for multiple testing, greatly decreases the power of GWAS. Results: We propose a procedure in which all the SNPs are analyzed in a multiple generalized linear model, and we show its use for extremely high-dimensional datasets. Our method yields P-values for assessing significance of single SNPs or groups of SNPs while controlling for all other SNPs and the family wise error rate (FWER). Thus, our method tests whether or not a SNP carries any additional information about the phenotype beyond that available by all the other SNPs. This rules out spurious correlations between phenotypes and SNPs that can arise from marginal methods because the ‘spuriously correlated’ SNP merely happens to be correlated with the ‘truly causal’ SNP. In addition, the method offers a data driven approach to identifying and refining groups of SNPs that jointly contain informative signals about the phenotype. We demonstrate the value of our method by applying it to the seven diseases analyzed by the Wellcome Trust Case Control Consortium (WTCCC). We show, in particular, that our method is also capable of finding significant SNPs that were not identified in the original WTCCC study, but were replicated in other independent studies. Availability and implementation: Reproducibility of our research is supported by the open-source Bioconductor package hierGWAS. Contact: peter.buehlmann@stat.math.ethz.ch Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27153677

  10. The First Pilot Genome-Wide Gene-Environment Study of Depression in the Japanese Population

    PubMed Central

    Otowa, Takeshi; Kawamura, Yoshiya; Tsutsumi, Akizumi; Kawakami, Norito; Kan, Chiemi; Shimada, Takafumi; Umekage, Tadashi; Kasai, Kiyoto; Tokunaga, Katsushi; Sasaki, Tsukasa

    2016-01-01

    Stressful events have been identified as a risk factor for depression. Although gene–environment (G × E) interaction in a limited number of candidate genes has been explored, no genome-wide search has been reported. The aim of the present study is to identify genes that influence the association of stressful events with depression. Therefore, we performed a genome-wide G × E interaction analysis in the Japanese population. A genome-wide screen with 320 subjects was performed using the Affymetrix Genome-Wide Human Array 6.0. Stressful life events were assessed using the Social Readjustment Rating Scale (SRRS) and depression symptoms were assessed with self-rating questionnaires using the Center for Epidemiologic Studies Depression (CES-D) scale. The p values for interactions between single nucleotide polymorphisms (SNPs) and stressful events were calculated using the linear regression model adjusted for sex and age. After quality control of genotype data, a total of 534,848 SNPs on autosomal chromosomes were further analyzed. Although none surpassed the level of the genome-wide significance, a marginal significant association of interaction between SRRS and rs10510057 with depression were found (p = 4.5 × 10−8). The SNP is located on 10q26 near Regulators of G-protein signaling 10 (RGS10), which encodes a regulatory molecule involved in stress response. When we investigated a similar G × E interaction between depression (K6 scale) and work-related stress in an independent sample (n = 439), a significant G × E effect on depression was observed (p = 0.015). Our findings suggest that rs10510057, interacting with stressors, may be involved in depression risk. Incorporating G × E interaction into GWAS can contribute to find susceptibility locus that are potentially missed by conventional GWAS. PMID:27529621

  11. The First Pilot Genome-Wide Gene-Environment Study of Depression in the Japanese Population.

    PubMed

    Otowa, Takeshi; Kawamura, Yoshiya; Tsutsumi, Akizumi; Kawakami, Norito; Kan, Chiemi; Shimada, Takafumi; Umekage, Tadashi; Kasai, Kiyoto; Tokunaga, Katsushi; Sasaki, Tsukasa

    2016-01-01

    Stressful events have been identified as a risk factor for depression. Although gene-environment (G × E) interaction in a limited number of candidate genes has been explored, no genome-wide search has been reported. The aim of the present study is to identify genes that influence the association of stressful events with depression. Therefore, we performed a genome-wide G × E interaction analysis in the Japanese population. A genome-wide screen with 320 subjects was performed using the Affymetrix Genome-Wide Human Array 6.0. Stressful life events were assessed using the Social Readjustment Rating Scale (SRRS) and depression symptoms were assessed with self-rating questionnaires using the Center for Epidemiologic Studies Depression (CES-D) scale. The p values for interactions between single nucleotide polymorphisms (SNPs) and stressful events were calculated using the linear regression model adjusted for sex and age. After quality control of genotype data, a total of 534,848 SNPs on autosomal chromosomes were further analyzed. Although none surpassed the level of the genome-wide significance, a marginal significant association of interaction between SRRS and rs10510057 with depression were found (p = 4.5 × 10-8). The SNP is located on 10q26 near Regulators of G-protein signaling 10 (RGS10), which encodes a regulatory molecule involved in stress response. When we investigated a similar G × E interaction between depression (K6 scale) and work-related stress in an independent sample (n = 439), a significant G × E effect on depression was observed (p = 0.015). Our findings suggest that rs10510057, interacting with stressors, may be involved in depression risk. Incorporating G × E interaction into GWAS can contribute to find susceptibility locus that are potentially missed by conventional GWAS. PMID:27529621

  12. Genome-wide association study identifies five new schizophrenia loci

    PubMed Central

    2012-01-01

    We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 × 10−11) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 × 10−9), ANK3 (rs10994359, P = 2.5 × 10−8) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 × 10−9). PMID:21926974

  13. A super powerful method for genome wide association study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genome-Wide Association Studies shed light on the identification of genes underlying human diseases and agriculturally important traits. This potential has been shadowed by false positive findings. The Mixed Linear Model (MLM) method is flexible enough to simultaneously incorporate population struct...

  14. Design and bioinformatics analysis of genome-wide CLIP experiments

    PubMed Central

    Wang, Tao; Xiao, Guanghua; Chu, Yongjun; Zhang, Michael Q.; Corey, David R.; Xie, Yang

    2015-01-01

    The past decades have witnessed a surge of discoveries revealing RNA regulation as a central player in cellular processes. RNAs are regulated by RNA-binding proteins (RBPs) at all post-transcriptional stages, including splicing, transportation, stabilization and translation. Defects in the functions of these RBPs underlie a broad spectrum of human pathologies. Systematic identification of RBP functional targets is among the key biomedical research questions and provides a new direction for drug discovery. The advent of cross-linking immunoprecipitation coupled with high-throughput sequencing (genome-wide CLIP) technology has recently enabled the investigation of genome-wide RBP–RNA binding at single base-pair resolution. This technology has evolved through the development of three distinct versions: HITS-CLIP, PAR-CLIP and iCLIP. Meanwhile, numerous bioinformatics pipelines for handling the genome-wide CLIP data have also been developed. In this review, we discuss the genome-wide CLIP technology and focus on bioinformatics analysis. Specifically, we compare the strengths and weaknesses, as well as the scopes, of various bioinformatics tools. To assist readers in choosing optimal procedures for their analysis, we also review experimental design and procedures that affect bioinformatics analyses. PMID:25958398

  15. Genome-wide association mapping of soybean aphid resistance traits

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Soybean aphid is the most damaging insect pest of soybean in the Upper Midwest and is primarily controlled by insecticides. Soybean aphid resistance (i.e., Rag genes) has been documented in some soybean lines at chromosomes 6, 7, 13, and 16, but more sources of resistance are needed. Genome-wide ass...

  16. Genome-wide characterization of maize miRNA genes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    MicroRNAs (miRNAs) are small non-coding RNAs that play essential roles in plant growth and development. We conducted a genome-wide survey of maize miRNA genes, characterizing their structure, expression, and evolution. Computational approaches based on homology and secondary structure modeling ident...

  17. Hot topic: Definition and implementation of a breeding value for feed efficiency in dairy cows.

    PubMed

    Pryce, J E; Gonzalez-Recio, O; Nieuwhof, G; Wales, W J; Coffey, M P; Hayes, B J; Goddard, M E

    2015-10-01

    A new breeding value that combines the amount of feed saved through improved metabolic efficiency with predicted maintenance requirements is described. The breeding value includes a genomic component for residual feed intake (RFI) combined with maintenance requirements calculated from either a genomic or pedigree estimated breeding value (EBV) for body weight (BW) predicted using conformation traits. Residual feed intake is only available for genotyped Holsteins; however, BW is available for all breeds. The RFI component of the "feed saved" EBV has 2 parts: Australian calf RFI and Australian lactating cow RFI. Genomic breeding values for RFI were estimated from a reference population of 2,036 individuals in a multi-trait analysis including Australian calf RFI (n=843), Australian lactating cow RFI (n=234), and UK and Dutch lactating cow RFI (n=958). In all cases, the RFI phenotypes were deviations from a mean of 0, calculated by correcting dry matter intake for BW, growth, and milk yield (in the case of lactating cows). Single nucleotide polymorphism effects were calculated from the output of genomic BLUP and used to predict breeding values of 4,106 Holstein sires that were genotyped but did not have RFI phenotypes themselves. These bulls already had BW breeding values calculated from type traits, from which maintenance requirements in kilograms of feed per year were inferred. Finally, RFI and the feed required for maintenance (through BW) were used to calculate a feed saved breeding value and expressed as the predicted amount of feed saved per year. Animals that were 1 standard deviation above the mean were predicted to eat 66 kg dry matter less per year at the same level of milk production. In a data set of genotyped Holstein sires, the mean reliability of the feed saved breeding value was 0.37. For Holsteins that are not genotyped and for breeds other than Holsteins, feed saved is calculated using BW only. From April 2015, feed saved has been included as part of

  18. Massively expedited genome-wide heritability analysis (MEGHA)

    PubMed Central

    Ge, Tian; Nichols, Thomas E.; Lee, Phil H.; Holmes, Avram J.; Roffman, Joshua L.; Buckner, Randy L.; Sabuncu, Mert R.; Smoller, Jordan W.

    2015-01-01

    The discovery and prioritization of heritable phenotypes is a computational challenge in a variety of settings, including neuroimaging genetics and analyses of the vast phenotypic repositories in electronic health record systems and population-based biobanks. Classical estimates of heritability require twin or pedigree data, which can be costly and difficult to acquire. Genome-wide complex trait analysis is an alternative tool to compute heritability estimates from unrelated individuals, using genome-wide data that are increasingly ubiquitous, but is computationally demanding and becomes difficult to apply in evaluating very large numbers of phenotypes. Here we present a fast and accurate statistical method for high-dimensional heritability analysis using genome-wide SNP data from unrelated individuals, termed massively expedited genome-wide heritability analysis (MEGHA) and accompanying nonparametric sampling techniques that enable flexible inferences for arbitrary statistics of interest. MEGHA produces estimates and significance measures of heritability with several orders of magnitude less computational time than existing methods, making heritability-based prioritization of millions of phenotypes based on data from unrelated individuals tractable for the first time to our knowledge. As a demonstration of application, we conducted heritability analyses on global and local morphometric measurements derived from brain structural MRI scans, using genome-wide SNP data from 1,320 unrelated young healthy adults of non-Hispanic European ancestry. We also computed surface maps of heritability for cortical thickness measures and empirically localized cortical regions where thickness measures were significantly heritable. Our analyses demonstrate the unique capability of MEGHA for large-scale heritability-based screening and high-dimensional heritability profile construction. PMID:25675487

  19. Massively expedited genome-wide heritability analysis (MEGHA).

    PubMed

    Ge, Tian; Nichols, Thomas E; Lee, Phil H; Holmes, Avram J; Roffman, Joshua L; Buckner, Randy L; Sabuncu, Mert R; Smoller, Jordan W

    2015-02-24

    The discovery and prioritization of heritable phenotypes is a computational challenge in a variety of settings, including neuroimaging genetics and analyses of the vast phenotypic repositories in electronic health record systems and population-based biobanks. Classical estimates of heritability require twin or pedigree data, which can be costly and difficult to acquire. Genome-wide complex trait analysis is an alternative tool to compute heritability estimates from unrelated individuals, using genome-wide data that are increasingly ubiquitous, but is computationally demanding and becomes difficult to apply in evaluating very large numbers of phenotypes. Here we present a fast and accurate statistical method for high-dimensional heritability analysis using genome-wide SNP data from unrelated individuals, termed massively expedited genome-wide heritability analysis (MEGHA) and accompanying nonparametric sampling techniques that enable flexible inferences for arbitrary statistics of interest. MEGHA produces estimates and significance measures of heritability with several orders of magnitude less computational time than existing methods, making heritability-based prioritization of millions of phenotypes based on data from unrelated individuals tractable for the first time to our knowledge. As a demonstration of application, we conducted heritability analyses on global and local morphometric measurements derived from brain structural MRI scans, using genome-wide SNP data from 1,320 unrelated young healthy adults of non-Hispanic European ancestry. We also computed surface maps of heritability for cortical thickness measures and empirically localized cortical regions where thickness measures were significantly heritable. Our analyses demonstrate the unique capability of MEGHA for large-scale heritability-based screening and high-dimensional heritability profile construction. PMID:25675487

  20. Passive hip laxity in Estrela Mountain Dog--distraction index, heritability and breeding values.

    PubMed

    Ginja, Mário M D; Silvestre, António M; Ferreira, António J A; Gonzalo-Orden, José M; Orden, Maria A; Melo-Pinto, Pedro; Llorens-Pena, Maria P; Colaço, Jorge

    2008-09-01

    Two hundred and fifteen Estrela Mountain Dogs (EMD) were examined using the PennHIP method between 2002 and 2006. Passive hip laxity (PHL) was estimated calculating the distraction index (DI). Pedigree information was obtained from the Portuguese Kennel Club. The heritability and breeding values were estimated using the linear Animal Model. The DI, using as reference the worst joint of each animal, ranged from 0.15 to 1.12 (0.55 +/- 0.19). The PHL was equal in right and left sides, and was higher in females than in males (P > 0.05 and P <0.01 in the t-test, respectively). The estimated heritability was 0.83 +/- 0.11. The mean breeding values for PHL were stable in EMD born between 1991 and 2003, and showed an improvement in 2004 and 2005. The data confirm high PHL in breeds with high prevalence and severity of canine hip dysplasia. The high heritability indicates that the DI could be reduced in the breed if PHL were used as a selection criterion. The early favourable evolution of DI breeding values could be related with the increase of voluntary radiographic hip screening in the last years, and the subsequent introduction of hip quality as a breeding criterion. PMID:18828482

  1. Insights into the genetic history of Green-legged Partridgelike fowl: mtDNA and genome-wide SNP analysis

    PubMed Central

    Siwek, M; Wragg, D; Sławińska, A; Malek, M; Hanotte, O; Mwacharo, JM

    2013-01-01

    The Green-legged Partridgelike (GP) fowl, an old native Polish breed, is characterised by reseda green-coloured shanks rather than yellow, white, slate or black commonly observed across most domestic breeds of chicken. Here, we investigate the origin, genetic relationships and structure of the GP fowl using mtDNA D-loop sequencing and genome-wide SNP analysis. Genome-wide association analysis between breeds enables us to verify the genetic control of the reseda green shank phenotype, a defining trait for the breed. Two mtDNA D-loop haplogroups and three autosomal genetic backgrounds are revealed. Significant associations of SNPs on chromosomes GGA24 and GGAZ indicate that the reseda green leg phenotype is associated with recessive alleles linked to the W and Id loci. Our results provide new insights into the genetic history of European chicken, indicating an admixd origin of East European traditional breeds of chicken on the continent, as supported by the presence of the reseda green phenotype and the knowledge that the GP fowl as a breed was developed before the advent of commercial stocks. PMID:23611337

  2. Accuracy of predicting genomic breeding values for residual feed intake in Angus and Charolais beef cattle.

    PubMed

    Chen, L; Schenkel, F; Vinsky, M; Crews, D H; Li, C

    2013-10-01

    In beef cattle, phenotypic data that are difficult and/or costly to measure, such as feed efficiency, and DNA marker genotypes are usually available on a small number of animals of different breeds or populations. To achieve a maximal accuracy of genomic prediction using the phenotype and genotype data, strategies for forming a training population to predict genomic breeding values (GEBV) of the selection candidates need to be evaluated. In this study, we examined the accuracy of predicting GEBV for residual feed intake (RFI) based on 522 Angus and 395 Charolais steers genotyped on SNP with the Illumina Bovine SNP50 Beadchip for 3 training population forming strategies: within breed, across breed, and by pooling data from the 2 breeds (i.e., combined). Two other scenarios with the training and validation data split by birth year and by sire family within a breed were also investigated to assess the impact of genetic relationships on the accuracy of genomic prediction. Three statistical methods including the best linear unbiased prediction with the relationship matrix defined based on the pedigree (PBLUP), based on the SNP genotypes (GBLUP), and a Bayesian method (BayesB) were used to predict the GEBV. The results showed that the accuracy of the GEBV prediction was the highest when the prediction was within breed and when the validation population had greater genetic relationships with the training population, with a maximum of 0.58 for Angus and 0.64 for Charolais. The within-breed prediction accuracies dropped to 0.29 and 0.38, respectively, when the validation populations had a minimal pedigree link with the training population. When the training population of a different breed was used to predict the GEBV of the validation population, that is, across-breed genomic prediction, the accuracies were further reduced to 0.10 to 0.22, depending on the prediction method used. Pooling data from the 2 breeds to form the training population resulted in accuracies increased

  3. Acetaminophen-NAPQI Hepatotoxicity: A Cell Line Model System Genome-Wide Association Study

    PubMed Central

    Moyer, Ann M.; Fridley, Brooke L.; Jenkins, Gregory D.; Batzler, Anthony J.; Pelleymounter, Linda L.; Kalari, Krishna R.; Ji, Yuan; Chai, Yubo; Nordgren, Kendra K. S.; Weinshilboum, Richard M.

    2011-01-01

    Acetaminophen is the leading cause of acute hepatic failure in many developed nations. Acetaminophen hepatotoxicity is mediated by the reactive metabolite N-acetyl-p-benzoquinonimine (NAPQI). We performed a “discovery” genome-wide association study using a cell line–based model system to study the possible contribution of genomics to NAPQI-induced cytotoxicity. A total of 176 lymphoblastoid cell lines from healthy subjects were treated with increasing concentrations of NAPQI. Inhibiting concentration 50 values were determined and were associated with “glutathione pathway” gene single nucleotide polymorphisms (SNPs) and genome-wide basal messenger RNA expression, as well as with 1.3 million genome-wide SNPs. A group of SNPs in linkage disequilibrium on chromosome 3 was highly associated with NAPQI toxicity. The p value for rs2880961, the SNP with the lowest p value, was 1.88 × 10−7. This group of SNPs mapped to a “gene desert,” but chromatin immunoprecipitation assays demonstrated binding of several transcription factor proteins including heat shock factor 1 (HSF1) and HSF2, at or near rs2880961. These chromosome 3 SNPs were not significantly associated with variation in basal expression for any of the genome-wide genes represented on the Affymetrix U133 Plus 2.0 GeneChip. We have used a cell line–based model system to identify a SNP signal associated with NAPQI cytotoxicity. If these observations are validated in future clinical studies, this SNP signal might represent a potential biomarker for risk of acetaminophen hepatotoxicity. The mechanisms responsible for this association remain unclear. PMID:21177773

  4. Genome-wide analytical approaches for reverse metabolic engineering of industrially relevant phenotypes in yeast

    PubMed Central

    Oud, Bart; Maris, Antonius J A; Daran, Jean-Marc; Pronk, Jack T

    2012-01-01

    Successful reverse engineering of mutants that have been obtained by nontargeted strain improvement has long presented a major challenge in yeast biotechnology. This paper reviews the use of genome-wide approaches for analysis of Saccharomyces cerevisiae strains originating from evolutionary engineering or random mutagenesis. On the basis of an evaluation of the strengths and weaknesses of different methods, we conclude that for the initial identification of relevant genetic changes, whole genome sequencing is superior to other analytical techniques, such as transcriptome, metabolome, proteome, or array-based genome analysis. Key advantages of this technique over gene expression analysis include the independency of genome sequences on experimental context and the possibility to directly and precisely reproduce the identified changes in naive strains. The predictive value of genome-wide analysis of strains with industrially relevant characteristics can be further improved by classical genetics or simultaneous analysis of strains derived from parallel, independent strain improvement lineages. PMID:22152095

  5. Genome-wide association analysis of canine atopic dermatitis and identification of disease related SNPs.

    PubMed

    Wood, Shona Hiedi; Ke, Xiayi; Nuttall, Tim; McEwan, Neil; Ollier, William E; Carter, Stuart D

    2009-12-01

    In humans, genome-wide association studies (GWAS) have been shown to be an effective and thorough approach for identifying polymorphisms associated with disease phenotypes. Here, we describe the first study to perform a genome-wide association study in canine atopic dermatitis (cAD) using the Illumina Canine SNP20 array, containing 22,362 single-nucleotide polymorphisms (SNPs). The aim of the study was to identify SNPs associated with cAD using affected and unaffected Golden Retrievers. Further validation studies were performed for potentially associated SNPs using Sequenom genotyping of larger numbers of cases and controls across eight breeds (Boxer, German Shepherd Dog, Labrador, Golden Retriever, Shiba Inu, Shih Tzu, Pit Bull, and West Highland White Terriers). Using meta-analysis, two SNPs were associated with cAD in all breeds tested. RS22114085 was identified as a susceptibility locus (p=0.00014, odds ratio=2) and RS23472497 as a protective locus (p=0.0015, odds ratio=0.6). Both of these SNPs were located in intergenic regions, and their effects have been demonstrated to be independent of each other, highlighting that further fine mapping and resequencing is required of these areas. Further, 12 SNPs were validated by Sequenom genotyping as associated with cAD, but these were not associated with all breeds. This study suggests that GWAS will be a useful approach for identifying genetic risk factors for cAD. Given the clinical heterogeneity within this condition and the likelihood that the relative genetic effect sizes are small, greater sample sizes and further studies will be required. PMID:19838693

  6. Genome-wide patterns of selection in 230 ancient Eurasians.

    PubMed

    Mathieson, Iain; Lazaridis, Iosif; Rohland, Nadin; Mallick, Swapan; Patterson, Nick; Roodenberg, Songül Alpaslan; Harney, Eadaoin; Stewardson, Kristin; Fernandes, Daniel; Novak, Mario; Sirak, Kendra; Gamba, Cristina; Jones, Eppie R; Llamas, Bastien; Dryomov, Stanislav; Pickrell, Joseph; Arsuaga, Juan Luís; de Castro, José María Bermúdez; Carbonell, Eudald; Gerritsen, Fokke; Khokhlov, Aleksandr; Kuznetsov, Pavel; Lozano, Marina; Meller, Harald; Mochalov, Oleg; Moiseyev, Vyacheslav; Guerra, Manuel A Rojo; Roodenberg, Jacob; Vergès, Josep Maria; Krause, Johannes; Cooper, Alan; Alt, Kurt W; Brown, Dorcas; Anthony, David; Lalueza-Fox, Carles; Haak, Wolfgang; Pinhasi, Ron; Reich, David

    2015-12-24

    Ancient DNA makes it possible to observe natural selection directly by analysing samples from populations before, during and after adaptation events. Here we report a genome-wide scan for selection using ancient DNA, capitalizing on the largest ancient DNA data set yet assembled: 230 West Eurasians who lived between 6500 and 300 bc, including 163 with newly reported data. The new samples include, to our knowledge, the first genome-wide ancient DNA from Anatolian Neolithic farmers, whose genetic material we obtained by extracting from petrous bones, and who we show were members of the population that was the source of Europe's first farmers. We also report a transect of the steppe region in Samara between 5600 and 300 bc, which allows us to identify admixture into the steppe from at least two external sources. We detect selection at loci associated with diet, pigmentation and immunity, and two independent episodes of selection on height. PMID:26595274

  7. Genome-wide patterns of selection in 230 ancient Eurasians

    PubMed Central

    Mathieson, Iain; Lazaridis, Iosif; Rohland, Nadin; Mallick, Swapan; Patterson, Nick; Roodenberg, Songül Alpaslan; Harney, Eadaoin; Stewardson, Kristin; Fernandes, Daniel; Novak, Mario; Sirak, Kendra; Gamba, Cristina; Jones, Eppie R.; Llamas, Bastien; Dryomov, Stanislav; Pickrel, Joseph; Arsuaga, Juan Luís; de Castro, José María Bermúdez; Carbonell, Eudald; Gerritsen, Fokke; Khokhlov, Aleksandr; Kuznetsov, Pavel; Lozano, Marina; Meller, Harald; Mochalov, Oleg; Moiseyev, Vayacheslav; Rojo Guerra, Manuel A.; Roodenberg, Jacob; Vergès, Josep Maria; Krause, Johannes; Cooper, Alan; Alt, Kurt W.; Brown, Dorcas; Anthony, David; Lalueza-Fox, Carles; Haak, Wolfgang; Pinhasi, Ron; Reich, David

    2016-01-01

    Ancient DNA makes it possible to directly witness natural selection by analyzing samples from populations before, during and after adaptation events. Here we report the first scan for selection using ancient DNA, capitalizing on the largest genome-wide dataset yet assembled: 230 West Eurasians dating to between 6500 and 1000 BCE, including 163 with newly reported data. The new samples include the first genome-wide data from the Anatolian Neolithic culture whose genetic material we extracted from the DNA-rich petrous bone and who we show were members of the population that was the source of Europe’s first farmers. We also report a complete transect of the steppe region in Samara between 5500 and 1200 BCE that allows us to recognize admixture from at least two external sources into steppe populations during this period. We detect selection at loci associated with diet, pigmentation and immunity, and two independent episodes of selection on height. PMID:26595274

  8. Genome-Wide Significant Loci: How Important Are They?

    PubMed Central

    Björkegren, Johan L.M.; Kovacic, Jason C.; Dudley, Joel T.; Schadt, Eric E.

    2015-01-01

    Genome-wide association studies (GWAS) have been extensively used to study common complex diseases such as coronary artery disease (CAD), revealing 153 suggestive CAD loci, of which at least 46 have been validated as having genome-wide significance. However, these loci collectively explain <10% of the genetic variance in CAD. Thus, we must address the key question of what factors constitute the remaining 90% of CAD heritability. We review possible limitations of GWAS, and contextually consider some candidate CAD loci identified by this method. Looking ahead, we propose systems genetics as a complementary approach to unlocking the CAD heritability and etiology. Systems genetics builds network models of relevant molecular processes by combining genetic and genomic datasets to ultimately identify key “drivers” of disease. By leveraging systems-based genetic approaches, we can help reveal the full genetic basis of common complex disorders, enabling novel diagnostic and therapeutic opportunities. PMID:25720628

  9. Genome-wide Association Study Identifies New Susceptibility Loci for Posttraumatic Stress Disorder

    PubMed Central

    Xie, Pingxing; Kranzler, Henry R.; Yang, Can; Zhao, Hongyu; Farrer, Lindsay A.; Gelernter, Joel

    2013-01-01

    Background Genetic factors influence the risk for posttraumatic stress disorder (PTSD), a potentially chronic and disabling psychiatric disorder that can arise after exposure to trauma. Candidate gene association studies have identified few genetic variants that contribute to PTSD risk. Methods We conducted genome-wide association analyses in 1578 European Americans (EAs), including 300 PTSD cases, and 2766 African Americans, including 444 PTSD cases, to find novel common risk alleles for PTSD. We used the Illumina Omni1-Quad microarray, which yielded approximately 870,000 single nucleotide polymorphisms (SNPs) suitable for analysis. Results In EAs, we observed that one SNP on chromosome 7p12, rs406001, exceeded genome-wide significance (p = 3.97×10−8). A SNP that maps to the first intron of the Tolloid-Like 1 gene (TLL1) showed the second strongest evidence of association, although no SNPs at this locus reached genome-wide significance. We then tested six SNPs in an independent sample of nearly 2000 EAs and successfully replicated the association findings for two SNPs in the first intron of TLL1, rs6812849 and rs7691872, with p values of 6.3×10−6 and 2.3×10−4, respectively. In the combined sample, rs6812849 had a p value of 3.1 ×10−9. No significant signals were observed in the African American part of the sample. Genome-wide association study analyses restricted to trauma-exposed individuals yielded very similar results. Conclusions This study identified TLL1 as a new susceptibility gene for PTSD. PMID:23726511

  10. A genome-wide scan for preeclampsia in the Netherlands.

    PubMed

    Lachmeijer, A M; Arngrímsson, R; Bastiaans, E J; Frigge, M L; Pals, G; Sigurdardóttir, S; Stéfansson, H; Pálsson, B; Nicolae, D; Kong, A; Aarnoudse, J G; Gulcher, J R; Dekker, G A; ten Kate, L P; Stéfansson, K

    2001-10-01

    Preeclampsia, hallmarked by de novo hypertension and proteinuria in pregnancy, has a familial tendency. Recently, a large Icelandic genome-wide scan provided evidence for a maternal susceptibility locus for preeclampsia on chromosome 2p13 which was confirmed by a genome scan from Australia and New Zealand (NZ). The current study reports on a genome-wide scan of Dutch affected sib-pair families. In total 67 Dutch affected sib-pair families, comprising at least two siblings with proteinuric preeclampsia, eclampsia or HELLP-syndrome, were typed for 293 polymorphic markers throughout the genome and linkage analysis was performed. The highest allele sharing lod score of 1.99 was seen on chromosome 12q at 109.5 cM. Two peaks overlapped in the same regions between the Dutch and Icelandic genome-wide scan at chromosome 3p and chromosome 15q. No overlap was seen on 2p. Re-analysis in 38 families without HELLP-syndrome (preeclampsia families) and 34 families with at least one sibling with HELLP syndrome (HELLP families), revealed two peaks with suggestive evidence for linkage in the non-HELLP families on chromosome 10q (lod score 2.38, D10S1432, 93.9 cM) and 22q (lod score 2.41, D22S685, 32.4 cM). The peak on 12q appeared to be associated with HELLP syndrome; it increased to a lod score of 2.1 in the HELLP families and almost disappeared in the preeclampsia families. A nominal peak on chromosome 11 in the preeclampsia families showed overlap with the second highest peak in the Australian/NZ study. Results from our Dutch genome-wide scan indicate that HELLP syndrome might have a different genetic background than preeclampsia. PMID:11781687

  11. Inference of Population Splits and Mixtures from Genome-Wide Allele Frequency Data

    PubMed Central

    Pickrell, Joseph K.; Pritchard, Jonathan K.

    2012-01-01

    Many aspects of the historical relationships between populations in a species are reflected in genetic data. Inferring these relationships from genetic data, however, remains a challenging task. In this paper, we present a statistical model for inferring the patterns of population splits and mixtures in multiple populations. In our model, the sampled populations in a species are related to their common ancestor through a graph of ancestral populations. Using genome-wide allele frequency data and a Gaussian approximation to genetic drift, we infer the structure of this graph. We applied this method to a set of 55 human populations and a set of 82 dog breeds and wild canids. In both species, we show that a simple bifurcating tree does not fully describe the data; in contrast, we infer many migration events. While some of the migration events that we find have been detected previously, many have not. For example, in the human data, we infer that Cambodians trace approximately 16% of their ancestry to a population ancestral to other extant East Asian populations. In the dog data, we infer that both the boxer and basenji trace a considerable fraction of their ancestry (9% and 25%, respectively) to wolves subsequent to domestication and that East Asian toy breeds (the Shih Tzu and the Pekingese) result from admixture between modern toy breeds and “ancient” Asian breeds. Software implementing the model described here, called TreeMix, is available at http://treemix.googlecode.com. PMID:23166502

  12. Genomic estimated breeding values using genomic relationship matrices in a cloned population of loblolly pine.

    PubMed

    Zapata-Valenzuela, Jaime; Whetten, Ross W; Neale, David; McKeand, Steve; Isik, Fikret

    2013-05-01

    Replacement of the average numerator relationship matrix derived from the pedigree with the realized genomic relationship matrix based on DNA markers might be an attractive strategy in forest tree breeding for predictions of genetic merit. We used genotypes from 3461 single-nucleotide polymorphism loci to estimate genomic relationships for a population of 165 loblolly pine (Pinus taeda L.) individuals. Phenotypes of the 165 individuals were obtained from clonally replicated field trials and were used to estimate breeding values for growth (stem volume). Two alternative methods, based on allele frequencies or regression, were used to generate the genomic relationship matrices. The accuracies of genomic estimated breeding values based on the genomic relationship matrices and breeding values estimated based on the average numerator relationship matrix were compared. On average, the accuracy of predictions based on genomic relationships ranged between 0.37 and 0.74 depending on the validation method. We did not detect differences in the accuracy of predictions based on genomic relationship matrices estimated by two different methods. Using genomic relationship matrices allowed modeling of Mendelian segregation within full-sib families, an important advantage over a traditional genetic evaluation system based on pedigree. We conclude that estimation of genomic relationships could be a powerful tool in forest tree breeding because it accurately accounts both for genetic relationships among individuals and for nuisance effects such as location and replicate effects, and makes more accurate selection possible within full-sib crosses. PMID:23585458

  13. Genome-Wide Detection and Analysis of Multifunctional Genes

    PubMed Central

    Pritykin, Yuri; Ghersi, Dario; Singh, Mona

    2015-01-01

    Many genes can play a role in multiple biological processes or molecular functions. Identifying multifunctional genes at the genome-wide level and studying their properties can shed light upon the complexity of molecular events that underpin cellular functioning, thereby leading to a better understanding of the functional landscape of the cell. However, to date, genome-wide analysis of multifunctional genes (and the proteins they encode) has been limited. Here we introduce a computational approach that uses known functional annotations to extract genes playing a role in at least two distinct biological processes. We leverage functional genomics data sets for three organisms—H. sapiens, D. melanogaster, and S. cerevisiae—and show that, as compared to other annotated genes, genes involved in multiple biological processes possess distinct physicochemical properties, are more broadly expressed, tend to be more central in protein interaction networks, tend to be more evolutionarily conserved, and are more likely to be essential. We also find that multifunctional genes are significantly more likely to be involved in human disorders. These same features also hold when multifunctionality is defined with respect to molecular functions instead of biological processes. Our analysis uncovers key features about multifunctional genes, and is a step towards a better genome-wide understanding of gene multifunctionality. PMID:26436655

  14. Genome-Wide Detection and Analysis of Multifunctional Genes.

    PubMed

    Pritykin, Yuri; Ghersi, Dario; Singh, Mona

    2015-10-01

    Many genes can play a role in multiple biological processes or molecular functions. Identifying multifunctional genes at the genome-wide level and studying their properties can shed light upon the complexity of molecular events that underpin cellular functioning, thereby leading to a better understanding of the functional landscape of the cell. However, to date, genome-wide analysis of multifunctional genes (and the proteins they encode) has been limited. Here we introduce a computational approach that uses known functional annotations to extract genes playing a role in at least two distinct biological processes. We leverage functional genomics data sets for three organisms--H. sapiens, D. melanogaster, and S. cerevisiae--and show that, as compared to other annotated genes, genes involved in multiple biological processes possess distinct physicochemical properties, are more broadly expressed, tend to be more central in protein interaction networks, tend to be more evolutionarily conserved, and are more likely to be essential. We also find that multifunctional genes are significantly more likely to be involved in human disorders. These same features also hold when multifunctionality is defined with respect to molecular functions instead of biological processes. Our analysis uncovers key features about multifunctional genes, and is a step towards a better genome-wide understanding of gene multifunctionality. PMID:26436655

  15. Genome-wide association study of periodontal pathogen colonization.

    PubMed

    Divaris, K; Monda, K L; North, K E; Olshan, A F; Lange, E M; Moss, K; Barros, S P; Beck, J D; Offenbacher, S

    2012-07-01

    Pathological shifts of the human microbiome are characteristic of many diseases, including chronic periodontitis. To date, there is limited evidence on host genetic risk loci associated with periodontal pathogen colonization. We conducted a genome-wide association (GWA) study among 1,020 white participants of the Atherosclerosis Risk in Communities Study, whose periodontal diagnosis ranged from healthy to severe chronic periodontitis, and for whom "checkerboard" DNA-DNA hybridization quantification of 8 periodontal pathogens was performed. We examined 3 traits: "high red" and "high orange" bacterial complexes, and "high" Aggregatibacter actinomycetemcomitans (Aa) colonization. Genotyping was performed on the Affymetrix 6.0 platform. Imputation to 2.5 million markers was based on HapMap II-CEU, and a multiple-test correction was applied (genome-wide threshold of p < 5 × 10(-8)). We detected no genome-wide significant signals. However, 13 loci, including KCNK1, FBXO38, UHRF2, IL33, RUNX2, TRPS1, CAMTA1, and VAMP3, provided suggestive evidence (p < 5 × 10(-6)) of association. All associations reported for "red" and "orange" complex microbiota, but not for Aa, had the same effect direction in a second sample of 123 African-American participants. None of these polymorphisms was associated with periodontitis diagnosis. Investigations replicating these findings may lead to an improved understanding of the complex nature of host-microbiome interactions that characterizes states of health and disease. PMID:22699663

  16. Genome-wide polymorphisms show unexpected targets of natural selection.

    PubMed

    Pespeni, Melissa H; Garfield, David A; Manier, Mollie K; Palumbi, Stephen R

    2012-04-01

    Natural selection can act on all the expressed genes of an individual, leaving signatures of genetic differentiation or diversity at many loci across the genome. New power to assay these genome-wide effects of selection comes from associating multi-locus patterns of polymorphism with gene expression and function. Here, we performed one of the first genome-wide surveys in a marine species, comparing purple sea urchins, Strongylocentrotus purpuratus, from two distant locations along the species' wide latitudinal range. We examined 9112 polymorphic loci from upstream non-coding and coding regions of genes for signatures of selection with respect to gene function and tissue- and ontogenetic gene expression. We found that genetic differentiation (F(ST)) varied significantly across functional gene classes. The strongest enrichment occurred in the upstream regions of E3 ligase genes, enzymes known to regulate protein abundance during development and environmental stress. We found enrichment for high heterozygosity in genes directly involved in immune response, particularly NALP genes, which mediate pro-inflammatory signals during bacterial infection. We also found higher heterozygosity in immune genes in the southern population, where disease incidence and pathogen diversity are greater. Similar to the major histocompatibility complex in mammals, balancing selection may enhance genetic diversity in the innate immune system genes of this invertebrate. Overall, our results show that how genome-wide polymorphism data coupled with growing databases on gene function and expression can combine to detect otherwise hidden signals of selection in natural populations. PMID:21993504

  17. A Genome-Wide Association Study of Depressive Symptoms

    PubMed Central

    Cornelis, Marilyn C.; Amin, Najaf; Bakshis, Erin; Baumert, Jens; Ding, Jingzhong; Liu, Yongmei; Marciante, Kristin; Meirelles, Osorio; Nalls, Michael A.; Sun, Yan V.; Vogelzangs, Nicole; Yu, Lei; Bandinelli, Stefania; Benjamin, Emelia J.; Bennett, David A.; Boomsma, Dorret; Cannas, Alessandra; Coker, Laura H.; de Geus, Eco; De Jager, Philip L.; Diez-Roux, Ana V.; Purcell, Shaun; Hu, Frank B.; Rimma, Eric B.; Hunter, David J.; Jensen, Majken K.; Curhan, Gary; Rice, Kenneth; Penman, Alan D.; Rotter, Jerome I.; Sotoodehnia, Nona; Emeny, Rebecca; Eriksson, Johan G.; Evans, Denis A.; Ferrucci, Luigi; Fornage, Myriam; Gudnason, Vilmundur; Hofman, Albert; Illig, Thomas; Kardia, Sharon; Kelly-Hayes, Margaret; Koenen, Karestan; Kraft, Peter; Kuningas, Maris; Massaro, Joseph M.; Melzer, David; Mulas, Antonella; Mulder, Cornelis L.; Murray, Anna; Oostra, Ben A.; Palotie, Aarno; Penninx, Brenda; Petersmann, Astrid; Pilling, Luke C.; Psaty, Bruce; Rawal, Rajesh; Reiman, Eric M.; Schulz, Andrea; Shulman, Joshua M.; Singleton, Andrew B.; Smith, Albert V.; Sutin, Angelina R.; Uitterlinden, André G.; Völzke, Henry; Widen, Elisabeth; Yaffe, Kristine; Zonderman, Alan B.; Cucca, Francesco; Harris, Tamara; Ladwig, Karl-Heinz; Llewellyn, David J.; Räikkönen, Katri; Tanaka, Toshiko

    2013-01-01

    Background Depression is a heritable trait that exists on a continuum of varying severity and duration. Yet, the search for genetic variants associated with depression has had few successes. We exploit the entire continuum of depression to find common variants for depressive symptoms. Methods In this genome-wide association study, we combined the results of 17 population-based studies assessing depressive symptoms with the Center for Epidemiological Studies Depression Scale. Replication of the independent top hits (p < 1 × 10−5) was performed in five studies assessing depressive symptoms with other instruments. In addition, we performed a combined meta-analysis of all 22 discovery and replication studies. Results The discovery sample comprised 34,549 individuals (mean age of 66.5) and no loci reached genome-wide significance (lowest p = 1.05 × 10−7). Seven independent single nucleotide polymorphisms were considered for replication. In the replication set (n = 16,709), we found suggestive association of one single nucleotide polymorphism with depressive symptoms (rs161645, 5q21, p = 9.19 × 10−3). This 5q21 region reached genome-wide significance (p = 4.78 × 10−8) in the overall meta-analysis combining discovery and replication studies (n = 51,258). Conclusions The results suggest that only a large sample comprising more than 50,000 subjects may be sufficiently powered to detect genes for depressive symptoms. PMID:23290196

  18. Disruptive selection without genome-wide evolution across a migratory divide.

    PubMed

    von Rönn, Jan A C; Shafer, Aaron B A; Wolf, Jochen B W

    2016-06-01

    Transcontinental migration is a fascinating example of how animals can respond to climatic oscillation. Yet, quantitative data on fitness components are scarce, and the resulting population genetic consequences are poorly understood. Migratory divides, hybrid zones with a transition in migratory behaviour, provide a natural setting to investigate the micro-evolutionary dynamics induced by migration under sympatric conditions. Here, we studied the effects of migratory programme on survival, trait evolution and genome-wide patterns of population differentiation in a migratory divide of European barn swallows. We sampled a total of 824 individuals from both allopatric European populations wintering in central and southern Africa, respectively, along with two mixed populations from within the migratory divide. While most morphological characters varied by latitude consistent with Bergmann's rule, wing length co-varied with distance to wintering grounds. Survival data collected during a 5-year period provided strong evidence that this covariance is repeatedly generated by disruptive selection against intermediate phenotypes. Yet, selection-induced divergence did not translate into genome-wide genetic differentiation as assessed by microsatellites, mtDNA and >20 000 genome-wide SNP markers; nor did we find evidence of local genomic selection between migratory types. Among breeding populations, a single outlier locus mapped to the BUB1 gene with a role in mitotic and meiotic organization. Overall, this study provides evidence for an adaptive response to variation in migration behaviour continuously eroded by gene flow under current conditions of nonassortative mating. It supports the theoretical prediction that population differentiation is difficult to achieve under conditions of gene flow despite measurable disruptive selection. PMID:26749140

  19. A Comparison of Phenotypic Traits Related to Trypanotolerance in Five West African Cattle Breeds Highlights the Value of Shorthorn Taurine Breeds

    PubMed Central

    Berthier, David; Peylhard, Moana; Dayo, Guiguigbaza-Kossigan; Flori, Laurence; Sylla, Souleymane; Bolly, Seydou; Sakande, Hassane; Chantal, Isabelle; Thevenon, Sophie

    2015-01-01

    Background Animal African Trypanosomosis particularly affects cattle and dramatically impairs livestock development in sub-Saharan Africa. African Zebu (AFZ) or European taurine breeds usually die of the disease in the absence of treatment, whereas West African taurine breeds (AFT), considered trypanotolerant, are able to control the pathogenic effects of trypanosomosis. Up to now, only one AFT breed, the longhorn N’Dama (NDA), has been largely studied and is considered as the reference trypanotolerant breed. Shorthorn taurine trypanotolerance has never been properly assessed and compared to NDA and AFZ breeds. Methodology/Principal Findings This study compared the trypanotolerant/susceptible phenotype of five West African local breeds that differ in their demographic history. Thirty-six individuals belonging to the longhorn taurine NDA breed, two shorthorn taurine Lagune (LAG) and Baoulé (BAO) breeds, the Zebu Fulani (ZFU) and the Borgou (BOR), an admixed breed between AFT and AFZ, were infected by Trypanosoma congolense IL1180. All the cattle were genetically characterized using dense SNP markers, and parameters linked to parasitaemia, anaemia and leukocytes were analysed using synthetic variables and mixed models. We showed that LAG, followed by NDA and BAO, displayed the best control of anaemia. ZFU showed the greatest anaemia and the BOR breed had an intermediate value, as expected from its admixed origin. Large differences in leukocyte counts were also observed, with higher leukocytosis for AFT. Nevertheless, no differences in parasitaemia were found, except a tendency to take longer to display detectable parasites in ZFU. Conclusions We demonstrated that LAG and BAO are as trypanotolerant as NDA. This study highlights the value of shorthorn taurine breeds, which display strong local adaptation to trypanosomosis. Thanks to further analyses based on comparisons of the genome or transcriptome of the breeds, these results open up the way for better knowledge

  20. Genome-wide association discoveries of alcohol dependence

    PubMed Central

    Zuo, Lingjun; Lu, Lingeng; Tan, Yunlong; Pan, Xinghua; Cai, Yiqiang; Wang, Xiaoping; Hong, Jiang; Zhong, Chunlong; Wang, Fei; Zhang, Xiang-yang; Vanderlinden, Lauren A.; Tabakoff, Boris; Luo, Xingguang

    2014-01-01

    Objective To report the genome-wide significant and/or replicable risk variants for alcohol dependence and explore their potential biological functions. Methods We searched in PubMed for all genome-wide association studies (GWASs) of alcohol dependence. The following three types of the results were extracted: (1) genome-wide significant associations in an individual sample, the combined samples, or the meta-analysis (p<5×10−8); (2) top-ranked associations in an individual sample (p<10−5) that were nominally replicated in other samples (p<0.05); and (3) nominally replicable associations across at least three independent GWAS samples (p<0.05). These results were meta-analyzed. cis-eQTLs in human, RNA expression in rat and mouse brain and bioinformatics properties of all of these risk variants were analyzed. Results The variants located within ADH cluster were significantly associated with alcohol dependence at genome-wide level (p<5×10−8) in at least one sample. Some associations with the ADH cluster were replicable across six independent GWAS samples. The variants located within or near SERINC2, KIAA0040, MREG-PECR or PKNOX2 were significantly associated with alcohol dependence at genome-wide level (p<5×10−8) in meta-analysis or combined samples, and these associations were replicable across at least one sample. The associations with the variants within NRD1, GPD1L-CMTM8 or MAP3K9-PCNX were suggestive (5×10−8

  1. Genome Wide Association Mapping for Arabinoxylan Content in a Collection of Tetraploid Wheats

    PubMed Central

    Marcotuli, Ilaria; Houston, Kelly; Waugh, Robbie; Fincher, Geoffrey B.; Burton, Rachel A.; Blanco, Antonio; Gadaleta, Agata

    2015-01-01

    Background Arabinoxylans (AXs) are major components of plant cell walls in bread wheat and are important in bread-making and starch extraction. Furthermore, arabinoxylans are components of soluble dietary fibre that has potential health-promoting effects in human nutrition. Despite their high value for human health, few studies have been carried out on the genetics of AX content in durum wheat. Results The genetic variability of AX content was investigated in a set of 104 tetraploid wheat genotypes and regions attributable to AX content were identified through a genome wide association study (GWAS). The amount of arabinoxylan, expressed as percentage (w/w) of the dry weight of the kernel, ranged from 1.8% to 5.5% with a mean value of 4.0%. The GWAS revealed a total of 37 significant marker-trait associations (MTA), identifying 19 quantitative trait loci (QTL) associated with AX content. The highest number of MTAs was identified on chromosome 5A (seven), where three QTL regions were associated with AX content, while the lowest number of MTAs was detected on chromosomes 2B and 4B, where only one MTA identified a single locus. Conservation of synteny between SNP marker sequences and the annotated genes and proteins in Brachypodium distachyon, Oryza sativa and Sorghum bicolor allowed the identification of nine QTL coincident with candidate genes. These included a glycosyl hydrolase GH35, which encodes Gal7 and a glucosyltransferase GT31 on chromosome 1A; a cluster of GT1 genes on chromosome 2B that includes TaUGT1 and cisZog1; a glycosyl hydrolase that encodes a CelC gene on chromosome 3A; Ugt12887 and TaUGT1genes on chromosome 5A; a (1,3)-β-D-glucan synthase (Gsl12 gene) and a glucosyl hydrolase (Cel8 gene) on chromosome 7A. Conclusions This study identifies significant MTAs for the AX content in the grain of tetraploid wheat genotypes. We propose that these may be used for molecular breeding of durum wheat varieties with higher soluble fibre content. PMID:26176552

  2. Genome-Wide Meta-Analysis of Longitudinal Alcohol Consumption Across Youth and Early Adulthood.

    PubMed

    Adkins, Daniel E; Clark, Shaunna L; Copeland, William E; Kennedy, Martin; Conway, Kevin; Angold, Adrian; Maes, Hermine; Liu, Youfang; Kumar, Gaurav; Erkanli, Alaattin; Patkar, Ashwin A; Silberg, Judy; Brown, Tyson H; Fergusson, David M; Horwood, L John; Eaves, Lindon; van den Oord, Edwin J C G; Sullivan, Patrick F; Costello, E J

    2015-08-01

    The public health burden of alcohol is unevenly distributed across the life course, with levels of use, abuse, and dependence increasing across adolescence and peaking in early adulthood. Here, we leverage this temporal patterning to search for common genetic variants predicting developmental trajectories of alcohol consumption. Comparable psychiatric evaluations measuring alcohol consumption were collected in three longitudinal community samples (N=2,126, obs=12,166). Consumption-repeated measurements spanning adolescence and early adulthood were analyzed using linear mixed models, estimating individual consumption trajectories, which were then tested for association with Illumina 660W-Quad genotype data (866,099 SNPs after imputation and QC). Association results were combined across samples using standard meta-analysis methods. Four meta-analysis associations satisfied our pre-determined genome-wide significance criterion (FDR<0.1) and six others met our 'suggestive' criterion (FDR<0.2). Genome-wide significant associations were highly biological plausible, including associations within GABA transporter 1, SLC6A1 (solute carrier family 6, member 1), and exonic hits in LOC100129340 (mitofusin-1-like). Pathway analyses elaborated single marker results, indicating significant enriched associations to intuitive biological mechanisms, including neurotransmission, xenobiotic pharmacodynamics, and nuclear hormone receptors (NHR). These findings underscore the value of combining longitudinal behavioral data and genome-wide genotype information in order to study developmental patterns and improve statistical power in genomic studies. PMID:26081443

  3. Genome-wide meta-analysis of longitudinal alcohol consumption across youth and early adulthood

    PubMed Central

    Adkins, Daniel E.; Clark, Shaunna L.; Copeland, William E.; Kennedy, Martin; Conway, Kevin; Angold, Adrian; Maes, Hermine; Liu, Youfang; Kumar, Gaurav; Erkanli, Alaattin; Patkar, Ashwin A.; Silberg, Judy; Brown, Tyson H.; Fergusson, David M.; Horwood, L. John; Eaves, Lindon; van den Oord, Edwin J.C.G.; Sullivan, Patrick F.; Costello, E. J.

    2016-01-01

    The public health burden of alcohol is unevenly distributed across the life course, with levels of use, abuse and dependence increasing across adolescence and peaking in early adulthood. Here we leverage this temporal patterning to search for common genetic variants predicting developmental trajectories of alcohol consumption. Comparable psychiatric evaluations measuring alcohol consumption were collected in three, longitudinal community samples (N=2,126, obs=12,166). Consumption repeated measurements spanning adolescence and early adulthood were analyzed using linear mixed models, estimating individual consumption trajectories, which were then tested for association with Illumina 660W-Quad genotype data (866,099 SNPs after imputation and QC). Association results were combined across samples using standard meta-analysis methods. Four meta-analysis associations satisfied our pre-determined genome-wide significance criterion (FDR<0.1) and 6 others met our “suggestive” criterion (FDR<0.2). Genome-wide significant associations were highly biological plausible, including associations within GABA transporter 1, SLC6A1 (solute carrier family 6, member 1), and exonic hits in LOC100129340 (mitofusin-1-like). Pathway analyses elaborated single marker results, indicating significant enriched associations to intuitive biological mechanisms including neurotransmission, xenobiotic pharmacodynamics and nuclear hormone receptors. These findings underscore the value of combining longitudinal behavioral data and genome-wide genotype information in order to study developmental patterns and improve statistical power in genomic studies. PMID:26081443

  4. Simulation of genome-wide evolution under heterogeneous substitution models and complex multispecies coalescent histories.

    PubMed

    Arenas, Miguel; Posada, David

    2014-05-01

    Genomic evolution can be highly heterogeneous. Here, we introduce a new framework to simulate genome-wide sequence evolution under a variety of substitution models that may change along the genome and the phylogeny, following complex multispecies coalescent histories that can include recombination, demographics, longitudinal sampling, population subdivision/species history, and migration. A key aspect of our simulation strategy is that the heterogeneity of the whole evolutionary process can be parameterized according to statistical prior distributions specified by the user. We used this framework to carry out a study of the impact of variable codon frequencies across genomic regions on the estimation of the genome-wide nonsynonymous/synonymous ratio. We found that both variable codon frequencies across genes and rate variation among sites and regions can lead to severe underestimation of the global dN/dS values. The program SGWE-Simulation of Genome-Wide Evolution-is freely available from http://code.google.com/p/sgwe-project/, including extensive documentation and detailed examples. PMID:24557445

  5. Genome-wide association analysis to predict optimal antipsychotic dosage in schizophrenia: a pilot study.

    PubMed

    Koga, Arthur T; Strauss, John; Zai, Clement; Remington, Gary; De Luca, Vincenzo

    2016-03-01

    In recent years, several studies have investigated genetic polymorphisms of antipsychotic drug-metabolizing enzymes and receptors. However, most studies focused on drug response and very few have investigated the genetic influence on antipsychotic dosage. The aim of the present study is to test the association between antipsychotic dosages at genome-wide level. The current dosage of antipsychotic medications was collected from 79 schizophrenia patients. The dosage was standardized using three different methods: chlorpromazine equivalent (CPZe), defined daily dose (DDD), and percentage of maximum dose (PM %). The patients were then genotyped using the Illumina HumanOmni2.5-8 BeadChip Kit. All markers were screened for significance using linear regression, and the p values were visualized using a Manhattan plot. The genome-wide analysis showed that the top Single-Nucleotide Polymorphisms (SNPs) associated with dosage variation were rs981975 on chromosome 14 for CPZe, rs4470690 on chromosome 4 for PM %, and rs79323383 on chromosome 8 for DDD. However, no genome-wide significantly associated SNPs were identified. In this pilot sample, we found promising trends for pharmacodynamic targets associated with antipsychotic dosage. Therefore, studies combining large prescription databases may identify genetic predictors to adjust the dose of antipsychotic medication. PMID:26821981

  6. Common genetic variation and survival after colorectal cancer diagnosis: a genome-wide analysis.

    PubMed

    Phipps, Amanda I; Passarelli, Michael N; Chan, Andrew T; Harrison, Tabitha A; Jeon, Jihyoun; Hutter, Carolyn M; Berndt, Sonja I; Brenner, Hermann; Caan, Bette J; Campbell, Peter T; Chang-Claude, Jenny; Chanock, Stephen J; Cheadle, Jeremy P; Curtis, Keith R; Duggan, David; Fisher, David; Fuchs, Charles S; Gala, Manish; Giovannucci, Edward L; Hayes, Richard B; Hoffmeister, Michael; Hsu, Li; Jacobs, Eric J; Jansen, Lina; Kaplan, Richard; Kap, Elisabeth J; Maughan, Timothy S; Potter, John D; Schoen, Robert E; Seminara, Daniela; Slattery, Martha L; West, Hannah; White, Emily; Peters, Ulrike; Newcomb, Polly A

    2016-01-01

    Genome-wide association studies have identified several germline single nucleotide polymorphisms (SNPs) significantly associated with colorectal cancer (CRC) incidence. Common germline genetic variation may also be related to CRC survival. We used a discovery-based approach to identify SNPs related to survival outcomes after CRC diagnosis. Genome-wide genotyping arrays were conducted for 3494 individuals with invasive CRC enrolled in six prospective cohort studies (median study-specific follow-up = 4.2-8.1 years). In pooled analyses, we used Cox regression to assess SNP-specific associations with CRC-specific and overall survival, with additional analyses stratified by stage at diagnosis. Top findings were followed-up in independent studies. A P value threshold of P < 5×10(-8) in analyses combining discovery and follow-up studies was required for genome-wide significance. Among individuals with distant-metastatic CRC, several SNPs at 6p12.1, nearest the ELOVL5 gene, were statistically significantly associated with poorer survival, with the strongest associations noted for rs209489 [hazard ratio (HR) = 1.8, P = 7.6×10(-10) and HR = 1.8, P = 3.7×10(-9) for CRC-specific and overall survival, respectively). No SNPs were statistically significantly associated with survival among all cases combined or in cases without distant-metastases. SNPs in 6p12.1/ELOVL5 were associated with survival outcomes in individuals with distant-metastatic CRC, and merit further follow-up for functional significance. Findings from this genome-wide association study highlight the potential importance of genetic variation in CRC prognosis and provide clues to genomic regions of potential interest. PMID:26586795

  7. Genome-wide association study of drought-related resistance traits in Aegilops tauschii.

    PubMed

    Qin, Peng; Lin, Yu; Hu, Yaodong; Liu, Kun; Mao, Shuangshuang; Li, Zhanyi; Wang, Jirui; Liu, Yaxi; Wei, Yuming; Zheng, Youliang

    2016-07-01

    The D-genome progenitor of wheat (Triticum aestivum), Aegilops tauschii, possesses numerous genes for resistance to abiotic stresses, including drought. Therefore, information on the genetic architecture of A. tauschii can aid the development of drought-resistant wheat varieties. Here, we evaluated 13 traits in 373 A. tauschii accessions grown under normal and polyethylene glycol-simulated drought stress conditions and performed a genome-wide association study using 7,185 single nucleotide polymorphism (SNP) markers. We identified 208 and 28 SNPs associated with all traits using the general linear model and mixed linear model, respectively, while both models detected 25 significant SNPs with genome-wide distribution. Public database searches revealed several candidate/flanking genes related to drought resistance that were grouped into three categories according to the type of encoded protein (enzyme, storage protein, and drought-induced protein). This study provided essential information for SNPs and genes related to drought resistance in A. tauschii and wheat, and represents a foundation for breeding drought-resistant wheat cultivars using marker-assisted selection. PMID:27392238

  8. Genome-wide association studies for fatty acid metabolic traits in five divergent pig populations

    PubMed Central

    Zhang, Wanchang; Bin Yang; Zhang, Junjie; Cui, Leilei; Ma, Junwu; Chen, Congying; Ai, Huashui; Xiao, Shijun; Ren, Jun; Huang, Lusheng

    2016-01-01

    Fatty acid composition profiles are important indicators of meat quality and tasting flavor. Metabolic indices of fatty acids are more authentic to reflect meat nutrition and public acceptance. To investigate the genetic mechanism of fatty acid metabolic indices in pork, we conducted genome-wide association studies (GWAS) for 33 fatty acid metabolic traits in five pig populations. We identified a total of 865 single nucleotide polymorphisms (SNPs), corresponding to 11 genome-wide significant loci on nine chromosomes and 12 suggestive loci on nine chromosomes. Our findings not only confirmed seven previously reported QTL with stronger association strength, but also revealed four novel population-specific loci, showing that investigations on intermediate phenotypes like the metabolic traits of fatty acids can increase the statistical power of GWAS for end-point phenotypes. We proposed a list of candidate genes at the identified loci, including three novel genes (FADS2, SREBF1 and PLA2G7). Further, we constructed the functional networks involving these candidate genes and deduced the potential fatty acid metabolic pathway. These findings advance our understanding of the genetic basis of fatty acid composition in pigs. The results from European hybrid commercial pigs can be immediately transited into breeding practice for beneficial fatty acid composition. PMID:27097669

  9. Genome-wide association study of drought-related resistance traits in Aegilops tauschii

    PubMed Central

    Qin, Peng; Lin, Yu; Hu, Yaodong; Liu, Kun; Mao, Shuangshuang; Li, Zhanyi; Wang, Jirui; Liu, Yaxi; Wei, Yuming; Zheng, Youliang

    2016-01-01

    Abstract The D-genome progenitor of wheat (Triticum aestivum), Aegilops tauschii, possesses numerous genes for resistance to abiotic stresses, including drought. Therefore, information on the genetic architecture of A. tauschii can aid the development of drought-resistant wheat varieties. Here, we evaluated 13 traits in 373 A. tauschii accessions grown under normal and polyethylene glycol-simulated drought stress conditions and performed a genome-wide association study using 7,185 single nucleotide polymorphism (SNP) markers. We identified 208 and 28 SNPs associated with all traits using the general linear model and mixed linear model, respectively, while both models detected 25 significant SNPs with genome-wide distribution. Public database searches revealed several candidate/flanking genes related to drought resistance that were grouped into three categories according to the type of encoded protein (enzyme, storage protein, and drought-induced protein). This study provided essential information for SNPs and genes related to drought resistance in A. tauschii and wheat, and represents a foundation for breeding drought-resistant wheat cultivars using marker-assisted selection. PMID:27560650

  10. Development and application of a novel genome-wide SNP array reveals domestication history in soybean

    PubMed Central

    Wang, Jiao; Chu, Shanshan; Zhang, Huairen; Zhu, Ying; Cheng, Hao; Yu, Deyue

    2016-01-01

    Domestication of soybeans occurred under the intense human-directed selections aimed at developing high-yielding lines. Tracing the domestication history and identifying the genes underlying soybean domestication require further exploration. Here, we developed a high-throughput NJAU 355 K SoySNP array and used this array to study the genetic variation patterns in 367 soybean accessions, including 105 wild soybeans and 262 cultivated soybeans. The population genetic analysis suggests that cultivated soybeans have tended to originate from northern and central China, from where they spread to other regions, accompanied with a gradual increase in seed weight. Genome-wide scanning for evidence of artificial selection revealed signs of selective sweeps involving genes controlling domestication-related agronomic traits including seed weight. To further identify genomic regions related to seed weight, a genome-wide association study (GWAS) was conducted across multiple environments in wild and cultivated soybeans. As a result, a strong linkage disequilibrium region on chromosome 20 was found to be significantly correlated with seed weight in cultivated soybeans. Collectively, these findings should provide an important basis for genomic-enabled breeding and advance the study of functional genomics in soybean. PMID:26856884

  11. Development and application of a novel genome-wide SNP array reveals domestication history in soybean.

    PubMed

    Wang, Jiao; Chu, Shanshan; Zhang, Huairen; Zhu, Ying; Cheng, Hao; Yu, Deyue

    2016-01-01

    Domestication of soybeans occurred under the intense human-directed selections aimed at developing high-yielding lines. Tracing the domestication history and identifying the genes underlying soybean domestication require further exploration. Here, we developed a high-throughput NJAU 355 K SoySNP array and used this array to study the genetic variation patterns in 367 soybean accessions, including 105 wild soybeans and 262 cultivated soybeans. The population genetic analysis suggests that cultivated soybeans have tended to originate from northern and central China, from where they spread to other regions, accompanied with a gradual increase in seed weight. Genome-wide scanning for evidence of artificial selection revealed signs of selective sweeps involving genes controlling domestication-related agronomic traits including seed weight. To further identify genomic regions related to seed weight, a genome-wide association study (GWAS) was conducted across multiple environments in wild and cultivated soybeans. As a result, a strong linkage disequilibrium region on chromosome 20 was found to be significantly correlated with seed weight in cultivated soybeans. Collectively, these findings should provide an important basis for genomic-enabled breeding and advance the study of functional genomics in soybean. PMID:26856884

  12. Genome-wide association studies for fatty acid metabolic traits in five divergent pig populations.

    PubMed

    Zhang, Wanchang; Bin Yang; Zhang, Junjie; Cui, Leilei; Ma, Junwu; Chen, Congying; Ai, Huashui; Xiao, Shijun; Ren, Jun; Huang, Lusheng

    2016-01-01

    Fatty acid composition profiles are important indicators of meat quality and tasting flavor. Metabolic indices of fatty acids are more authentic to reflect meat nutrition and public acceptance. To investigate the genetic mechanism of fatty acid metabolic indices in pork, we conducted genome-wide association studies (GWAS) for 33 fatty acid metabolic traits in five pig populations. We identified a total of 865 single nucleotide polymorphisms (SNPs), corresponding to 11 genome-wide significant loci on nine chromosomes and 12 suggestive loci on nine chromosomes. Our findings not only confirmed seven previously reported QTL with stronger association strength, but also revealed four novel population-specific loci, showing that investigations on intermediate phenotypes like the metabolic traits of fatty acids can increase the statistical power of GWAS for end-point phenotypes. We proposed a list of candidate genes at the identified loci, including three novel genes (FADS2, SREBF1 and PLA2G7). Further, we constructed the functional networks involving these candidate genes and deduced the potential fatty acid metabolic pathway. These findings advance our understanding of the genetic basis of fatty acid composition in pigs. The results from European hybrid commercial pigs can be immediately transited into breeding practice for beneficial fatty acid composition. PMID:27097669

  13. Genome-Wide Divergence in the West-African Malaria Vector Anopheles melas.

    PubMed

    Deitz, Kevin C; Athrey, Giridhar A; Jawara, Musa; Overgaard, Hans J; Matias, Abrahan; Slotman, Michel A

    2016-01-01

    Anopheles melas is a member of the recently diverged An. gambiae species complex, a model for speciation studies, and is a locally important malaria vector along the West-African coast where it breeds in brackish water. A recent population genetic study of An. melas revealed species-level genetic differentiation between three population clusters. An. melas West extends from The Gambia to the village of Tiko, Cameroon. The other mainland cluster, An. melas South, extends from the southern Cameroonian village of Ipono to Angola. Bioko Island, Equatorial Guinea An. melas populations are genetically isolated from mainland populations. To examine how genetic differentiation between these An. melas forms is distributed across their genomes, we conducted a genome-wide analysis of genetic differentiation and selection using whole genome sequencing data of pooled individuals (Pool-seq) from a representative population of each cluster. The An. melas forms exhibit high levels of genetic differentiation throughout their genomes, including the presence of numerous fixed differences between clusters. Although the level of divergence between the clusters is on a par with that of other species within the An. gambiae complex, patterns of genome-wide divergence and diversity do not provide evidence for the presence of pre- and/or postmating isolating mechanisms in the form of speciation islands. These results are consistent with an allopatric divergence process with little or no introgression. PMID:27466271

  14. Genome-wide association study of drought-related resistance traits in Aegilops tauschii.

    PubMed

    Qin, Peng; Lin, Yu; Hu, Yaodong; Liu, Kun; Mao, Shuangshuang; Li, Zhanyi; Wang, Jirui; Liu, Yaxi; Wei, Yuming; Zheng, Youliang

    2016-01-01

    The D-genome progenitor of wheat (Triticum aestivum), Aegilops tauschii, possesses numerous genes for resistance to abiotic stresses, including drought. Therefore, information on the genetic architecture of A. tauschii can aid the development of drought-resistant wheat varieties. Here, we evaluated 13 traits in 373 A. tauschii accessions grown under normal and polyethylene glycol-simulated drought stress conditions and performed a genome-wide association study using 7,185 single nucleotide polymorphism (SNP) markers. We identified 208 and 28 SNPs associated with all traits using the general linear model and mixed linear model, respectively, while both models detected 25 significant SNPs with genome-wide distribution. Public database searches revealed several candidate/flanking genes related to drought resistance that were grouped into three categories according to the type of encoded protein (enzyme, storage protein, and drought-induced protein). This study provided essential information for SNPs and genes related to drought resistance in A. tauschii and wheat, and represents a foundation for breeding drought-resistant wheat cultivars using marker-assisted selection. PMID:27560650

  15. Genome-wide association studies for multiple diseases of the German Shepherd Dog.

    PubMed

    Tsai, Kate L; Noorai, Rooksana E; Starr-Moss, Alison N; Quignon, Pascale; Rinz, Caitlin J; Ostrander, Elaine A; Steiner, Jörg M; Murphy, Keith E; Clark, Leigh Anne

    2012-02-01

    The German Shepherd Dog (GSD) is a popular working and companion breed for which over 50 hereditary diseases have been documented. Herein, SNP profiles for 197 GSDs were generated using the Affymetrix v2 canine SNP array for a genome-wide association study to identify loci associated with four diseases: pituitary dwarfism, degenerative myelopathy (DM), congenital megaesophagus (ME), and pancreatic acinar atrophy (PAA). A locus on Chr 9 is strongly associated with pituitary dwarfism and is proximal to a plausible candidate gene, LHX3. Results for DM confirm a major locus encompassing SOD1, in which an associated point mutation was previously identified, but do not suggest modifier loci. Several SNPs on Chr 12 are associated with ME and a 4.7 Mb haplotype block is present in affected dogs. Analysis of additional ME cases for a SNP within the haplotype provides further support for this association. Results for PAA indicate more complex genetic underpinnings. Several regions on multiple chromosomes reach genome-wide significance. However, no major locus is apparent and only two associated haplotype blocks, on Chrs 7 and 12 are observed. These data suggest that PAA may be governed by multiple loci with small effects, or it may be a heterogeneous disorder. PMID:22105877

  16. Genome-Wide Divergence in the West-African Malaria Vector Anopheles melas

    PubMed Central

    Deitz, Kevin C.; Athrey, Giridhar A.; Jawara, Musa; Overgaard, Hans J.; Matias, Abrahan; Slotman, Michel A.

    2016-01-01

    Anopheles melas is a member of the recently diverged An. gambiae species complex, a model for speciation studies, and is a locally important malaria vector along the West-African coast where it breeds in brackish water. A recent population genetic study of An. melas revealed species-level genetic differentiation between three population clusters. An. melas West extends from The Gambia to the village of Tiko, Cameroon. The other mainland cluster, An. melas South, extends from the southern Cameroonian village of Ipono to Angola. Bioko Island, Equatorial Guinea An. melas populations are genetically isolated from mainland populations. To examine how genetic differentiation between these An. melas forms is distributed across their genomes, we conducted a genome-wide analysis of genetic differentiation and selection using whole genome sequencing data of pooled individuals (Pool-seq) from a representative population of each cluster. The An. melas forms exhibit high levels of genetic differentiation throughout their genomes, including the presence of numerous fixed differences between clusters. Although the level of divergence between the clusters is on a par with that of other species within the An. gambiae complex, patterns of genome-wide divergence and diversity do not provide evidence for the presence of pre- and/or postmating isolating mechanisms in the form of speciation islands. These results are consistent with an allopatric divergence process with little or no introgression. PMID:27466271

  17. EVALUATION OF GENETIC DIVERSITY AND GENOME-WIDE LINKAGE DISEQUILIBRIUM AMOUNG US WHEAT (TRITICUM AETIVUM L.) GERMPLASM REPRESENTING DIFFERENT MARKET CLASSES

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genetic diversity and genome-wide linkage disequilibrium (LD) were investigated among forty-three US wheat (Triticum aestivum L.) elite cultivars and breeding lines representing seven US wheat market classes using 242 wheat genomic simple sequence repeat (SSR) markers distributed throughout the whea...

  18. Genome-wide association study reveals novel variants for growth and egg traits in Dongxiang blue-shelled and White Leghorn chickens.

    PubMed

    Liao, R; Zhang, X; Chen, Q; Wang, Z; Wang, Q; Yang, C; Pan, Y

    2016-10-01

    This study was designed to investigate the genetic basis of growth and egg traits in Dongxiang blue-shelled chickens and White Leghorn chickens. In this study, we employed a reduced representation sequencing approach called genotyping by genome reducing and sequencing to detect genome-wide SNPs in 252 Dongxiang blue-shelled chickens and 252 White Leghorn chickens. The Dongxiang blue-shelled chicken breed has many specific traits and is characterized by blue-shelled eggs, black plumage, black skin, black bone and black organs. The White Leghorn chicken is an egg-type breed with high productivity. As multibreed genome-wide association studies (GWASs) can improve precision due to less linkage disequilibrium across breeds, a multibreed GWAS was performed with 156 575 SNPs to identify the associated variants underlying growth and egg traits within the two chicken breeds. The analysis revealed 32 SNPs exhibiting a significant genome-wide association with growth and egg traits. Some of the significant SNPs are located in genes that are known to impact growth and egg traits, but nearly half of the significant SNPs are located in genes with unclear functions in chickens. To our knowledge, this is the first multibreed genome-wide report for the genetics of growth and egg traits in the Dongxiang blue-shelled and White Leghorn chickens. PMID:27166871

  19. Evaluation of genetic diversity and genome-wide linkage disequilibrium among US wheat (Triticum aestivum L.) germplasm representing different market classes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Genetic diversity and genome-wide linkage disequilibrium (LD) were investigated among forty-three U.S. wheat (Triticum aestivum L.) elite cultivars and breeding lines representing seven U.S. wheat market classes using 242 wheat genomic simple sequence repeat (SSR) markers distributed throughout the ...

  20. Phenotypic structures and breeding value of open-pollinated corn varietal hybrids

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The growing interest in using open-pollinated varieties (OPVs) and varietal hybrids (OPVhs) of corn (Zea mays L.) especially in breeding programs for organic and low-input farming reflects the value of large plasticity levels available in their plant, ear, and kernel traits. We estimated and partiti...

  1. Genetic Correlations Between Carcass Traits And Molecular Breeding Values In Angus Cattle

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This research elucidated genetic relationships between carcass traits, ultrasound indicator traits, and their respective molecular breeding values (MBV). Animals whose MBV data were used to estimate (co)variance components were not previously used in development of the MBV. Results are presented fo...

  2. Comparison of Bayesian models to estimate direct genomic values in multi-breed commercial beef cattle

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background Several studies have examined the accuracy of genomic selection both within and across purebred beef or dairy populations. However, the accuracy of direct genomic breeding values (DGVs) has been less well studied in crossbred or admixed cattle populations. We used a population of 3,240 cr...

  3. Genome-wide linkage and association analysis identifies major gene loci for guttural pouch tympany in Arabian and German warmblood horses.

    PubMed

    Metzger, Julia; Ohnesorge, Bernhard; Distl, Ottmar

    2012-01-01

    Equine guttural pouch tympany (GPT) is a hereditary condition affecting foals in their first months of life. Complex segregation analyses in Arabian and German warmblood horses showed the involvement of a major gene as very likely. Genome-wide linkage and association analyses including a high density marker set of single nucleotide polymorphisms (SNPs) were performed to map the genomic region harbouring the potential major gene for GPT. A total of 85 Arabian and 373 German warmblood horses were genotyped on the Illumina equine SNP50 beadchip. Non-parametric multipoint linkage analyses showed genome-wide significance on horse chromosomes (ECA) 3 for German warmblood at 16-26 Mb and 34-55 Mb and for Arabian on ECA15 at 64-65 Mb. Genome-wide association analyses confirmed the linked regions for both breeds. In Arabian, genome-wide association was detected at 64 Mb within the region with the highest linkage peak on ECA15. For German warmblood, signals for genome-wide association were close to the peak region of linkage at 52 Mb on ECA3. The odds ratio for the SNP with the highest genome-wide association was 0.12 for the Arabian. In conclusion, the refinement of the regions with the Illumina equine SNP50 beadchip is an important step to unravel the responsible mutations for GPT. PMID:22848553

  4. Genome-wide association study of insect bite hypersensitivity in two horse populations in the Netherlands

    PubMed Central

    2012-01-01

    Background Insect bite hypersensitivity is a common allergic disease in horse populations worldwide. Insect bite hypersensitivity is affected by both environmental and genetic factors. However, little is known about genes contributing to the genetic variance associated with insect bite hypersensitivity. Therefore, the aim of our study was to identify and quantify genomic associations with insect bite hypersensitivity in Shetland pony mares and Icelandic horses in the Netherlands. Methods Data on 200 Shetland pony mares and 146 Icelandic horses were collected according to a matched case–control design. Cases and controls were matched on various factors (e.g. region, sire) to minimize effects of population stratification. Breed-specific genome-wide association studies were performed using 70 k single nucleotide polymorphisms genotypes. Bayesian variable selection method Bayes-C with a threshold model implemented in GenSel software was applied. A 1 Mb non-overlapping window approach that accumulated contributions of adjacent single nucleotide polymorphisms was used to identify associated genomic regions. Results The percentage of variance explained by all single nucleotide polymorphisms was 13% in Shetland pony mares and 28% in Icelandic horses. The 20 non-overlapping windows explaining the largest percentages of genetic variance were found on nine chromosomes in Shetland pony mares and on 14 chromosomes in Icelandic horses. Overlap in identified associated genomic regions between breeds would suggest interesting candidate regions to follow-up on. Such regions common to both breeds (within 15 Mb) were found on chromosomes 3, 7, 11, 20 and 23. Positional candidate genes within 2 Mb from the associated windows were identified on chromosome 20 in both breeds. Candidate genes are within the equine lymphocyte antigen class II region, which evokes an immune response by recognizing many foreign molecules. Conclusions The genome-wide association study identified several

  5. Exploring genome wide bisulfite sequencing for DNA methylation analysis in livestock: a technical assessment.

    PubMed

    Doherty, Rachael; Couldrey, Christine

    2014-01-01

    Recent advances made in "omics" technologies are contributing to a revolution in livestock selection and breeding practices. Epigenetic mechanisms, including DNA methylation are important determinants for the control of gene expression in mammals. DNA methylation research will help our understanding of how environmental factors contribute to phenotypic variation of complex production and health traits. High-throughput sequencing is a vital tool for the comprehensive analysis of DNA methylation, and bisulfite-based strategies coupled with DNA sequencing allows for quantitative, site-specific methylation analysis at the genome level or genome wide. Reduced representation bisulfite sequencing (RRBS) and more recently whole genome bisulfite sequencing (WGBS) have proven to be effective techniques for studying DNA methylation in both humans and mice. Here we report the development of RRBS and WGBS for use in sheep, the first application of this technology in livestock species. Important technical issues associated with these methodologies including fragment size selection and sequence depth are examined and discussed. PMID:24860595

  6. Genome-wide Association Study Identifies Loci for the Polled Phenotype in Yak.

    PubMed

    Liang, Chunnian; Wang, Lizhong; Wu, Xiaoyun; Wang, Kun; Ding, Xuezhi; Wang, Mingcheng; Chu, Min; Xie, Xiuyue; Qiu, Qiang; Yan, Ping

    2016-01-01

    The absence of horns, known as the polled phenotype, is an economically important trait in modern yak husbandry, but the genomic structure and genetic basis of this phenotype have yet to be discovered. Here, we conducted a genome-wide association study with a panel of 10 horned and 10 polled yaks using whole genome sequencing. We mapped the POLLED locus to a 200-kb interval, which comprises three protein-coding genes. Further characterization of the candidate region showed recent artificial selection signals resulting from the breeding process. We suggest that expressional variations rather than structural variations in protein probably contribute to the polled phenotype. Our results not only represent the first and important step in establishing the genomic structure of the polled region in yak, but also add to our understanding of the polled trait in bovid species. PMID:27389700

  7. Genome-wide Association Study Identifies Loci for the Polled Phenotype in Yak

    PubMed Central

    Wu, Xiaoyun; Wang, Kun; Ding, Xuezhi; Wang, Mingcheng; Chu, Min; Xie, Xiuyue; Qiu, Qiang; Yan, Ping

    2016-01-01

    The absence of horns, known as the polled phenotype, is an economically important trait in modern yak husbandry, but the genomic structure and genetic basis of this phenotype have yet to be discovered. Here, we conducted a genome-wide association study with a panel of 10 horned and 10 polled yaks using whole genome sequencing. We mapped the POLLED locus to a 200-kb interval, which comprises three protein-coding genes. Further characterization of the candidate region showed recent artificial selection signals resulting from the breeding process. We suggest that expressional variations rather than structural variations in protein probably contribute to the polled phenotype. Our results not only represent the first and important step in establishing the genomic structure of the polled region in yak, but also add to our understanding of the polled trait in bovid species. PMID:27389700

  8. Genome-Wide Association Mapping for Tomato Volatiles Positively Contributing to Tomato Flavor

    PubMed Central

    Zhang, Jing; Zhao, Jiantao; Xu, Yao; Liang, Jing; Chang, Peipei; Yan, Fei; Li, Mingjun; Liang, Yan; Zou, Zhirong

    2015-01-01

    Tomato volatiles, mainly derived from essential nutrients and health-promoting precursors, affect tomato flavor. Taste volatiles present a major challenge for flavor improvement and quality breeding. In this study, we performed genome-wide association studies (GWAS) to investigate potential chromosome regions associated with the tomato flavor volatiles. We observed significant variation (1200x) among the selected 28 most important volatiles in tomato based on their concentration and odor threshold importance across our sampled accessions. Using 174 tomato accessions, GWAS identified 125 significant associations (P < 0.005) among 182 SSR markers and 28 volatiles (27 volatiles with at least one significant association). Several significant associations were co-localized in previously identified quantitative trait loci (QTL). This result provides new potential candidate loci affecting the metabolism of several volatiles. PMID:26640472

  9. Voxelwise genome-wide association study (vGWAS)

    PubMed Central

    Stein, Jason L.; Hua, Xue; Lee, Suh; Ho, April J.; Leow, Alex D.; Toga, Arthur W.; Saykin, Andrew J.; Shen, Li; Foroud, Tatiana; Pankratz, Nathan; Huentelman, Matthew J.; Craig, David W.; Gerber, Jill D.; Allen, April N.; Corneveaux, Jason J.; DeChairo, Bryan M.; Potkin, Steven G.; Weiner, Michael W.; Thompson, Paul M.

    2010-01-01

    The structure of the human brain is highly heritable, and is thought to be influenced by many common genetic variants, many of which are currently unknown. Recent advances in neuroimaging and genetics have allowed collection of both highly detailed structural brain scans and genome-wide genotype information. This wealth of information presents a new opportunity to find the genes influencing brain structure. Here we explore the relation between 448,293 single nucleotide polymorphisms in each of 31,622 voxels of the entire brain across 740 elderly subjects (mean age±s.d.: 75.52±6.82 years; 438 male) including subjects with Alzheimer's disease, Mild Cognitive Impairment, and healthy elderly controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We used tensor-based morphometry to measure individual differences in brain structure at the voxel level relative to a study-specific template based on healthy elderly subjects. We then conducted a genome-wide association at each voxel to identify genetic variants of interest. By studying only the most associated variant at each voxel, we developed a novel method to address the multiple comparisons problem and computational burden associated with the unprecedented amount of data. No variant survived the strict significance criterion, but several genes worthy of further exploration were identified, including CSMD2 and CADPS2. These genes have high relevance to brain structure. This is the first voxelwise genome wide association study to our knowledge, and offers a novel method to discover genetic influences on brain structure. PMID:20171287

  10. Genome-Wide Approaches to Drosophila Heart Development

    PubMed Central

    Frasch, Manfred

    2016-01-01

    The development of the dorsal vessel in Drosophila is one of the first systems in which key mechanisms regulating cardiogenesis have been defined in great detail at the genetic and molecular level. Due to evolutionary conservation, these findings have also provided major inputs into studies of cardiogenesis in vertebrates. Many of the major components that control Drosophila cardiogenesis were discovered based on candidate gene approaches and their functions were defined by employing the outstanding genetic tools and molecular techniques available in this system. More recently, approaches have been taken that aim to interrogate the entire genome in order to identify novel components and describe genomic features that are pertinent to the regulation of heart development. Apart from classical forward genetic screens, the availability of the thoroughly annotated Drosophila genome sequence made new genome-wide approaches possible, which include the generation of massive numbers of RNA interference (RNAi) reagents that were used in forward genetic screens, as well as studies of the transcriptomes and proteomes of the developing heart under normal and experimentally manipulated conditions. Moreover, genome-wide chromatin immunoprecipitation experiments have been performed with the aim to define the full set of genomic binding sites of the major cardiogenic transcription factors, their relevant target genes, and a more complete picture of the regulatory network that drives cardiogenesis. This review will give an overview on these genome-wide approaches to Drosophila heart development and on computational analyses of the obtained information that ultimately aim to provide a description of this process at the systems level. PMID:27294102

  11. Genome-wide mapping of DNA hydroxymethylation in osteoarthritic chondrocytes

    PubMed Central

    Taylor, Sarah E. B.; Li, Ye Henry; Wong, Wing H.; Bhutani, Nidhi

    2015-01-01

    Objective To examine genome-wide 5hmC distribution in osteoarthritic (OA) and normal chondrocytes to investigate the effect on OA-specific gene expression. Methods Cartilage was obtained from OA patients undergoing total knee arthroplasty or control patients undergoing anterior cruciate ligament reconstruction. Genome-wide sequencing of 5hmC-enriched DNA (5hmC-seq) was performed for a small cohort of normal and OA chondrocytes to identify differentially hydroxymethylated regions (DhMRs) in OA chondrocytes. 5hmC-seq data was intersected with global OA gene expression data to define subsets of genes and pathways potentially affected by increased 5hmC levels in OA chondrocytes. Results 70591 DhMRs were identified in OA chondrocytes compared to normal chondrocytes, 44288 (63%) of which were increased in OA chondrocytes. The majority of DhMRs (66%) were gained in gene bodies. Increased DhMRs were observed in ~50% of genes previously implicated in OA pathology including MMP3, LRP5, GDF5 and COL11A1. Furthermore, analyses of gene expression data revealed gene body gain of 5hmC appears to be preferentially associated with activated but not repressed genes in OA chondrocytes. Conclusion This study provides the first genome-wide profiling of 5hmC distribution in OA chondrocytes. We had previously reported a global increase in 5hmC levels in OA chondrocytes. Gain of 5hmC in the gene body is found to be characteristic of activated genes in OA chondrocytes, highlighting the influence of 5hmC as an epigenetic mark in OA. In addition, this study identifies multiple OA-associated genes that are potentially regulated either singularly by gain of DNA hydroxymethylation or in combination with loss of DNA methylation. PMID:25940674

  12. [Genome-wide association study for adolescent idiopathic scoliosis].

    PubMed

    Ogura, Yoji; Kou, Ikuyo; Scoliosis, Japan; Matsumoto, Morio; Watanabe, Kota; Ikegawa, Shiro

    2016-04-01

    Adolescent idiopathic scoliosis(AIS)is a polygenic disease. Genome-wide association studies(GWASs)have been performed for a lot of polygenic diseases. For AIS, we conducted GWAS and identified the first AIS locus near LBX1. After the discovery, we have extended our study by increasing the numbers of subjects and SNPs. In total, our Japanese GWAS has identified four susceptibility genes. GWASs for AIS have also been performed in the USA and China, which identified one and three susceptibility genes, respectively. Here we review GWASs in Japan and abroad and functional analysis to clarify the pathomechanism of AIS. PMID:27013625

  13. Genome-wide profiling of alternative splicing in Alzheimer's disease

    PubMed Central

    Lai, Mitchell K.P.; Esiri, Margaret M.; Tan, Michelle G.K.

    2014-01-01

    Alternative splicing is a highly regulated process which generates transcriptome and proteome diversity through the skipping or inclusion of exons within gene loci. Identification of aberrant alternative splicing associated with human diseases has become feasible with the development of new genomic technologies and powerful bioinformatics. We have previously reported genome-wide gene alterations in the neocortex of a well-characterized cohort of Alzheimer's disease (AD) patients and matched elderly controls using a commercial exon microarray platform [1]. Here, we provide detailed description of analyses aimed at identifying differential alternative splicing events associated with AD. PMID:26484111

  14. Genome-wide association studies in diverse populations

    PubMed Central

    Rosenberg, Noah A; Huang, Lucy; Jewett, Ethan M; Szpiech, Zachary A; Jankovic, Ivana; Boehnke, Michael

    2011-01-01

    Genome-wide association (GWA) studies have identified a large number of single-nucleotide polymorphisms (SNPs) associated with disease phenotypes. As most GWA studies have been performed primarily in populations of European descent, this review examines the issues involved in extending consideration of GWA studies to diverse worldwide populations. Although challenges exist with such issues as imputation, admixture, and replication, investigation of diverse populations in GWA studies has significant potential to advance the project of mapping the genetic determinants of complex diseases for the human population as a whole. PMID:20395969

  15. [New insight of genome-wide association study (GWAS)].

    PubMed

    Hotta, Kikuko

    2013-02-01

    The number of obese patients is increasing in Japan, due to the westernization of lifestyle. Obesity, especially visceral fat obesity, is important for the development of metabolic syndrome. Genetic factors are important for the development of obesity as well as environmental factors. Importance of genetic factors of fat distribution is also reported. Recent genome-wide association studies (GWASs) have revealed the obesity and fat distribution-related polymorphisms. GWAS will highlight a better understanding of the underlying molecular mechanisms in the regulation of obesity and distribution of body fat. PMID:23631198

  16. Genome-Wide Association Studies for Polycystic Ovary Syndrome.

    PubMed

    Liu, Hongbin; Zhao, Han; Chen, Zi-Jiang

    2016-07-01

    Over the past several years, the field of reproductive medicine has witnessed great advances in genome-wide association studies (GWASs) of polycystic ovary syndrome (PCOS), leading to identification of several promising genes involved in hormone action, type 2 diabetes, and cell proliferation. This review summarizes the key findings and discusses their potential implications with regard to genetic mechanisms of PCOS. Limitations of GWAS are evaluated, emphasizing the understanding of the reasons for variability in results between individual studies. Root causes of misinterpretations of GWASs are also addressed. Finally, the impact of GWAS on future directions of multi- and interdisciplinary studies is discussed. PMID:27513023

  17. Genome-wide analysis reveals adaptation to high altitudes in Tibetan sheep.

    PubMed

    Wei, Caihong; Wang, Huihua; Liu, Gang; Zhao, Fuping; Kijas, James W; Ma, Youji; Lu, Jian; Zhang, Li; Cao, Jiaxue; Wu, Mingming; Wang, Guangkai; Liu, Ruizao; Liu, Zhen; Zhang, Shuzhen; Liu, Chousheng; Du, Lixin

    2016-01-01

    Tibetan sheep have lived on the Tibetan Plateau for thousands of years; however, the process and consequences of adaptation to this extreme environment have not been elucidated for important livestock such as sheep. Here, seven sheep breeds, representing both highland and lowland breeds from different areas of China, were genotyped for a genome-wide collection of single-nucleotide polymorphisms (SNPs). The FST and XP-EHH approaches were used to identify regions harbouring local positive selection between these highland and lowland breeds, and 236 genes were identified. We detected selection events spanning genes involved in angiogenesis, energy production and erythropoiesis. In particular, several candidate genes were associated with high-altitude hypoxia, including EPAS1, CRYAA, LONP1, NF1, DPP4, SOD1, PPARG and SOCS2. EPAS1 plays a crucial role in hypoxia adaption; therefore, we investigated the exon sequences of EPAS1 and identified 12 mutations. Analysis of the relationship between blood-related phenotypes and EPAS1 genotypes in additional highland sheep revealed that a homozygous mutation at a relatively conserved site in the EPAS1 3' untranslated region was associated with increased mean corpuscular haemoglobin concentration and mean corpuscular volume. Taken together, our results provide evidence of the genetic diversity of highland sheep and indicate potential high-altitude hypoxia adaptation mechanisms, including the role of EPAS1 in adaptation. PMID:27230812

  18. Genome-wide analysis reveals adaptation to high altitudes in Tibetan sheep

    PubMed Central

    Wei, Caihong; Wang, Huihua; Liu, Gang; Zhao, Fuping; Kijas, James W.; Ma, Youji; Lu, Jian; Zhang, Li; Cao, Jiaxue; Wu, Mingming; Wang, Guangkai; Liu, Ruizao; Liu, Zhen; Zhang, Shuzhen; Liu, Chousheng; Du, Lixin

    2016-01-01

    Tibetan sheep have lived on the Tibetan Plateau for thousands of years; however, the process and consequences of adaptation to this extreme environment have not been elucidated for important livestock such as sheep. Here, seven sheep breeds, representing both highland and lowland breeds from different areas of China, were genotyped for a genome-wide collection of single-nucleotide polymorphisms (SNPs). The FST and XP-EHH approaches were used to identify regions harbouring local positive selection between these highland and lowland breeds, and 236 genes were identified. We detected selection events spanning genes involved in angiogenesis, energy production and erythropoiesis. In particular, several candidate genes were associated with high-altitude hypoxia, including EPAS1, CRYAA, LONP1, NF1, DPP4, SOD1, PPARG and SOCS2. EPAS1 plays a crucial role in hypoxia adaption; therefore, we investigated the exon sequences of EPAS1 and identified 12 mutations. Analysis of the relationship between blood-related phenotypes and EPAS1 genotypes in additional highland sheep revealed that a homozygous mutation at a relatively conserved site in the EPAS1 3′ untranslated region was associated with increased mean corpuscular haemoglobin concentration and mean corpuscular volume. Taken together, our results provide evidence of the genetic diversity of highland sheep and indicate potential high-altitude hypoxia adaptation mechanisms, including the role of EPAS1 in adaptation. PMID:27230812

  19. SUSCEPTIBILITY LOCI FOR UMBILICAL HERNIA IN SWINE DETECTED BY GENOME-WIDE ASSOCIATION.

    PubMed

    Liao, X J; Lia, L; Zhang, Z Y; Long, Y; Yang, B; Ruan, G R; Su, Y; Ai, H S; Zhang, W C; Deng, W Y; Xiao, S J; Ren, J; Ding, N S; Huang, L S

    2015-10-01

    Umbilical hernia (UH) is a complex disorder caused by both genetic and environmental factors. UH brings animal welfare problems and severe economic loss to the pig industry. Until now, the genetic basis of UH is poorly understood. The high-density 60K porcine SNP array enables the rapid application of genome-wide association study (GWAS) to identify genetic loci for phenotypic traits at genome wide scale in pigs. The objective of this research was to identify susceptibility loci for swine umbilical hernia using the GWAS approach. We genotyped 478 piglets from 142 families representing three Western commercial breeds with the Illumina PorcineSNP60 BeadChip. Then significant SNPs were detected by GWAS using ROADTRIPS (Robust Association-Detection Test for Related Individuals with Population Substructure) software base on a Bonferroni corrected threshold (P = 1.67E-06) or suggestive threshold (P = 3.34E-05) and false discovery rate (FDR = 0.05). After quality control, 29,924 qualified SNPs and 472 piglets were used for GWAS. Two suggestive loci predisposing to pig UH were identified at 44.25MB on SSC2 (rs81358018, P = 3.34E-06, FDR = 0.049933) and at 45.90MB on SSC17 (rs81479278, P = 3.30E-06, FDR = 0.049933) in Duroc population, respectively. And no SNP was detected to be associated with pig UH at significant level in neither Landrace nor Large White population. Furthermore, we carried out a meta-analysis in the combined pure-breed population containing all the 472 piglets. rs81479278 (P = 1.16E-06, FDR = 0.022475) was identified to associate with pig UH at genome-wide significant level. SRC was characterized as plausible candidate gene for susceptibility to pig UH according to its genomic position and biological functions. To our knowledge, this study gives the first description of GWAS identifying susceptibility loci for umbilical hernia in pigs. Our findings provide deeper insights to the genetic architecture of umbilical hernia in pigs. PMID:27169231

  20. The identification of 14 new genes for meat quality traits in chicken using a genome-wide association study

    PubMed Central

    2013-01-01

    Background Meat quality is an important economic trait in chickens. To identify loci and genes associated with meat quality traits, we conducted a genome-wide association study (GWAS) of F2 populations derived from a local Chinese breed (Beijing-You chickens) and a commercial fast-growing broiler line (Cobb-Vantress). Results In the present study, 33 association signals were detected from the compressed mixed linear model (MLM) for 10 meat quality traits: dry matter in breast muscle (DMBr), dry matter in thigh muscle (DMTh), intramuscular fat content in breast muscle (IMFBr), meat color lightness (L*) and yellowness (b*) values, skin color L*, a* (redness) and b* values, abdominal fat weight (AbFW) and AbFW as a percentage of eviscerated weight (AbFP). Relative expressions of candidate genes identified near significant signals were compared using samples of chickens with High and Low phenotypic values. A total of 14 genes associated with IMFBr, meat color L*, AbFW, and AbFP, were differentially expressed between the High and Low phenotypic groups. These genes are, therefore, prospective candidate genes for meat quality traits: protein tyrosine kinase (TYRO3) and microsomal glutathione S-transferase 1 (MGST1) for IMFBr; collagen, type I, alpha 2 (COL1A2) for meat color L*; and RET proto-oncogene (RET), natriuretic peptide B (NPPB) and sterol regulatory element binding transcription factor 1 (SREBF1) for the abdominal fat (AbF) traits. Conclusions Based on the association signals and differential expression of nearby genes, 14 candidate loci and genes for IMFBr, meat L* and b* values, and AbF are identified. The results provide new insight into the molecular mechanisms underlying meat quality traits in chickens. PMID:23834466

  1. A Genome-Wide Association Study of a Biomarker of Nicotine Metabolism

    PubMed Central

    Loukola, Anu; Buchwald, Jadwiga; Gupta, Richa; Palviainen, Teemu; Hällfors, Jenni; Tikkanen, Emmi; Korhonen, Tellervo; Ollikainen, Miina; Sarin, Antti-Pekka; Ripatti, Samuli; Lehtimäki, Terho; Raitakari, Olli; Salomaa, Veikko; Rose, Richard J.; Tyndale, Rachel F.; Kaprio, Jaakko

    2015-01-01

    Individuals with fast nicotine metabolism typically smoke more and thus have a greater risk for smoking-induced diseases. Further, the efficacy of smoking cessation pharmacotherapy is dependent on the rate of nicotine metabolism. Our objective was to use nicotine metabolite ratio (NMR), an established biomarker of nicotine metabolism rate, in a genome-wide association study (GWAS) to identify novel genetic variants influencing nicotine metabolism. A heritability estimate of 0.81 (95% CI 0.70–0.88) was obtained for NMR using monozygotic and dizygotic twins of the FinnTwin cohort. We performed a GWAS in cotinine-verified current smokers of three Finnish cohorts (FinnTwin, Young Finns Study, FINRISK2007), followed by a meta-analysis of 1518 subjects, and annotated the genome-wide significant SNPs with methylation quantitative loci (meQTL) analyses. We detected association on 19q13 with 719 SNPs exceeding genome-wide significance within a 4.2 Mb region. The strongest evidence for association emerged for CYP2A6 (min p = 5.77E-86, in intron 4), the main metabolic enzyme for nicotine. Other interesting genes with genome-wide significant signals included CYP2B6, CYP2A7, EGLN2, and NUMBL. Conditional analyses revealed three independent signals on 19q13, all located within or in the immediate vicinity of CYP2A6. A genetic risk score constructed using the independent signals showed association with smoking quantity (p = 0.0019) in two independent Finnish samples. Our meQTL results showed that methylation values of 16 CpG sites within the region are affected by genotypes of the genome-wide significant SNPs, and according to causal inference test, for some of the SNPs the effect on NMR is mediated through methylation. To our knowledge, this is the first GWAS on NMR. Our results enclose three independent novel signals on 19q13.2. The detected CYP2A6 variants explain a strikingly large fraction of variance (up to 31%) in NMR in these study samples. Further, we provide evidence

  2. First WNK4-Hypokalemia Animal Model Identified by Genome-Wide Association in Burmese Cats

    PubMed Central

    Gandolfi, Barbara; Gruffydd-Jones, Timothy J.; Malik, Richard; Cortes, Alejandro; Jones, Boyd R.; Helps, Chris R.; Prinzenberg, Eva M.; Erhardt, George; Lyons, Leslie A.

    2012-01-01

    Burmese is an old and popular cat breed, however, several health concerns, such as hypokalemia and a craniofacial defect, are prevalent, endangering the general health of the breed. Hypokalemia, a subnormal serum potassium ion concentration ([K+]), most often occurs as a secondary problem but can occur as a primary problem, such as hypokalaemic periodic paralysis in humans, and as feline hypokalaemic periodic polymyopathy primarily in Burmese. The most characteristic clinical sign of hypokalemia in Burmese is a skeletal muscle weakness that is frequently episodic in nature, either generalized, or sometimes localized to the cervical and thoracic limb girdle muscles. Burmese hypokalemia is suspected to be a single locus autosomal recessive trait. A genome wide case-control study using the illumina Infinium Feline 63K iSelect DNA array was performed using 35 cases and 25 controls from the Burmese breed that identified a locus on chromosome E1 associated with hypokalemia. Within approximately 1.2 Mb of the highest associated SNP, two candidate genes were identified, KCNH4 and WNK4. Direct sequencing of the genes revealed a nonsense mutation, producing a premature stop codon within WNK4 (c.2899C>T), leading to a truncated protein that lacks the C-terminal coiled-coil domain and the highly conserved Akt1/SGK phosphorylation site. All cases were homozygous for the mutation. Although the exact mechanism causing hypokalemia has not been determined, extrapolation from the homologous human and mouse genes suggests the mechanism may involve a potassium-losing nephropathy. A genetic test to screen for the genetic defect within the active breeding population has been developed, which should lead to eradication of the mutation and improved general health within the breed. Moreover, the identified mutation may help clarify the role of the protein in K+ regulation and the cat represents the first animal model for WNK4-associated hypokalemia. PMID:23285264

  3. Genome-wide analysis of DNA methylation in hepatoblastoma tissues

    PubMed Central

    Cui, Ximao; Liu, Baihui; Zheng, Shan; Dong, Kuiran; Dong, Rui

    2016-01-01

    DNA methylation has a crucial role in cancer biology. In the present study, a genome-wide analysis of DNA methylation in hepatoblastoma (HB) tissues was performed to verify differential methylation levels between HB and normal tissues. As alpha-fetoprotein (AFP) has a critical role in HB, AFP methylation levels were also detected using pyrosequencing. Normal and HB liver tissue samples (frozen tissue) were obtained from patients with HB. Genome-wide analysis of DNA methylation in these tissues was performed using an Infinium HumanMethylation450 BeadChip, and the results were confirmed with reverse transcription-quantitative polymerase chain reaction. The Infinium HumanMethylation450 BeadChip demonstrated distinctively less methylation in HB tissues than in non-tumor tissues. In addition, methylation enrichment was observed in positions near the transcription start site of AFP, which exhibited lower methylation levels in HB tissues than in non-tumor liver tissues. Lastly, a significant negative correlation was observed between AFP messenger RNA expression and DNA methylation percentage, using linear Pearson's R correlation coefficients. The present results demonstrate differential methylation levels between HB and normal tissues, and imply that aberrant methylation of AFP in HB could reflect HB development. Expansion of these findings could provide useful insight into HB biology. PMID:27446465

  4. Genome-wide association study of Tourette's syndrome.

    PubMed

    Scharf, J M; Yu, D; Mathews, C A; Neale, B M; Stewart, S E; Fagerness, J A; Evans, P; Gamazon, E; Edlund, C K; Service, S K; Tikhomirov, A; Osiecki, L; Illmann, C; Pluzhnikov, A; Konkashbaev, A; Davis, L K; Han, B; Crane, J; Moorjani, P; Crenshaw, A T; Parkin, M A; Reus, V I; Lowe, T L; Rangel-Lugo, M; Chouinard, S; Dion, Y; Girard, S; Cath, D C; Smit, J H; King, R A; Fernandez, T V; Leckman, J F; Kidd, K K; Kidd, J R; Pakstis, A J; State, M W; Herrera, L D; Romero, R; Fournier, E; Sandor, P; Barr, C L; Phan, N; Gross-Tsur, V; Benarroch, F; Pollak, Y; Budman, C L; Bruun, R D; Erenberg, G; Naarden, A L; Lee, P C; Weiss, N; Kremeyer, B; Berrío, G B; Campbell, D D; Cardona Silgado, J C; Ochoa, W C; Mesa Restrepo, S C; Muller, H; Valencia Duarte, A V; Lyon, G J; Leppert, M; Morgan, J; Weiss, R; Grados, M A; Anderson, K; Davarya, S; Singer, H; Walkup, J; Jankovic, J; Tischfield, J A; Heiman, G A; Gilbert, D L; Hoekstra, P J; Robertson, M M; Kurlan, R; Liu, C; Gibbs, J R; Singleton, A; Hardy, J; Strengman, E; Ophoff, R A; Wagner, M; Moessner, R; Mirel, D B; Posthuma, D; Sabatti, C; Eskin, E; Conti, D V; Knowles, J A; Ruiz-Linares, A; Rouleau, G A; Purcell, S; Heutink, P; Oostra, B A; McMahon, W M; Freimer, N B; Cox, N J; Pauls, D L

    2013-06-01

    Tourette's syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (P<5 × 10(-8)); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (P=1.85 × 10(-6)). A secondary analysis including an additional 211 cases and 285 controls from two closely related Latin American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (P=3.6 × 10(-7) for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder. PMID:22889924

  5. Genome-Wide Patterns of Nucleotide Polymorphism in Domesticated Rice

    PubMed Central

    Hernandez, Ryan D; Boyko, Adam; Fledel-Alon, Adi; York, Thomas L; Polato, Nicholas R; Olsen, Kenneth M; Nielsen, Rasmus; McCouch, Susan R; Bustamante, Carlos D; Purugganan, Michael D

    2007-01-01

    Domesticated Asian rice (Oryza sativa) is one of the oldest domesticated crop species in the world, having fed more people than any other plant in human history. We report the patterns of DNA sequence variation in rice and its wild ancestor, O. rufipogon, across 111 randomly chosen gene fragments, and use these to infer the evolutionary dynamics that led to the origins of rice. There is a genome-wide excess of high-frequency derived single nucleotide polymorphisms (SNPs) in O. sativa varieties, a pattern that has not been reported for other crop species. We developed several alternative models to explain contemporary patterns of polymorphisms in rice, including a (i) selectively neutral population bottleneck model, (ii) bottleneck plus migration model, (iii) multiple selective sweeps model, and (iv) bottleneck plus selective sweeps model. We find that a simple bottleneck model, which has been the dominant demographic model for domesticated species, cannot explain the derived nucleotide polymorphism site frequency spectrum in rice. Instead, a bottleneck model that incorporates selective sweeps, or a more complex demographic model that includes subdivision and gene flow, are more plausible explanations for patterns of variation in domesticated rice varieties. If selective sweeps are indeed the explanation for the observed nucleotide data of domesticated rice, it suggests that strong selection can leave its imprint on genome-wide polymorphism patterns, contrary to expectations that selection results only in a local signature of variation. PMID:17907810

  6. Genome-wide signals of positive selection in human evolution

    PubMed Central

    Enard, David; Messer, Philipp W.; Petrov, Dmitri A.

    2014-01-01

    The role of positive selection in human evolution remains controversial. On the one hand, scans for positive selection have identified hundreds of candidate loci, and the genome-wide patterns of polymorphism show signatures consistent with frequent positive selection. On the other hand, recent studies have argued that many of the candidate loci are false positives and that most genome-wide signatures of adaptation are in fact due to reduction of neutral diversity by linked deleterious mutations, known as background selection. Here we analyze human polymorphism data from the 1000 Genomes Project and detect signatures of positive selection once we correct for the effects of background selection. We show that levels of neutral polymorphism are lower near amino acid substitutions, with the strongest reduction observed specifically near functionally consequential amino acid substitutions. Furthermore, amino acid substitutions are associated with signatures of recent adaptation that should not be generated by background selection, such as unusually long and frequent haplotypes and specific distortions in the site frequency spectrum. We use forward simulations to argue that the observed signatures require a high rate of strongly adaptive substitutions near amino acid changes. We further demonstrate that the observed signatures of positive selection correlate better with the presence of regulatory sequences, as predicted by the ENCODE Project Consortium, than with the positions of amino acid substitutions. Our results suggest that adaptation was frequent in human evolution and provide support for the hypothesis of King and Wilson that adaptive divergence is primarily driven by regulatory changes. PMID:24619126

  7. Genome-wide association study of Tourette Syndrome

    PubMed Central

    Scharf, Jeremiah M.; Yu, Dongmei; Mathews, Carol A.; Neale, Benjamin M.; Stewart, S. Evelyn; Fagerness, Jesen A; Evans, Patrick; Gamazon, Eric; Edlund, Christopher K.; Service, Susan; Tikhomirov, Anna; Osiecki, Lisa; Illmann, Cornelia; Pluzhnikov, Anna; Konkashbaev, Anuar; Davis, Lea K; Han, Buhm; Crane, Jacquelyn; Moorjani, Priya; Crenshaw, Andrew T.; Parkin, Melissa A.; Reus, Victor I.; Lowe, Thomas L.; Rangel-Lugo, Martha; Chouinard, Sylvain; Dion, Yves; Girard, Simon; Cath, Danielle C; Smit, Jan H; King, Robert A.; Fernandez, Thomas; Leckman, James F.; Kidd, Kenneth K.; Kidd, Judith R.; Pakstis, Andrew J.; State, Matthew; Herrera, Luis Diego; Romero, Roxana; Fournier, Eduardo; Sandor, Paul; Barr, Cathy L; Phan, Nam; Gross-Tsur, Varda; Benarroch, Fortu; Pollak, Yehuda; Budman, Cathy L.; Bruun, Ruth D.; Erenberg, Gerald; Naarden, Allan L; Lee, Paul C; Weiss, Nicholas; Kremeyer, Barbara; Berrío, Gabriel Bedoya; Campbell, Desmond; Silgado, Julio C. Cardona; Ochoa, William Cornejo; Restrepo, Sandra C. Mesa; Muller, Heike; Duarte, Ana V. Valencia; Lyon, Gholson J; Leppert, Mark; Morgan, Jubel; Weiss, Robert; Grados, Marco A.; Anderson, Kelley; Davarya, Sarah; Singer, Harvey; Walkup, John; Jankovic, Joseph; Tischfield, Jay A.; Heiman, Gary A.; Gilbert, Donald L.; Hoekstra, Pieter J.; Robertson, Mary M.; Kurlan, Roger; Liu, Chunyu; Gibbs, J. Raphael; Singleton, Andrew; Hardy, John; Strengman, Eric; Ophoff, Roel; Wagner, Michael; Moessner, Rainald; Mirel, Daniel B.; Posthuma, Danielle; Sabatti, Chiara; Eskin, Eleazar; Conti, David V.; Knowles, James A.; Ruiz-Linares, Andres; Rouleau, Guy A.; Purcell, Shaun; Heutink, Peter; Oostra, Ben A.; McMahon, William; Freimer, Nelson; Cox, Nancy J.; Pauls, David L.

    2012-01-01

    Tourette Syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel, and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (p<5 × 10−8); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (p=1.85 × 10−6). A secondary analysis including an additional 211 cases and 285 controls from two closely-related Latin-American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (p=3.6 × 10−7 for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder. PMID:22889924

  8. Genome-wide association analysis identifies three psoriasis susceptibility loci

    PubMed Central

    Stuart, Philip E.; Nair, Rajan P.; Ellinghaus, Eva; Ding, Jun; Tejasvi, Trilokraj; Gudjonsson, Johann E.; Li, Yun; Weidinger, Stephan; Eberlein, Bernadette; Gieger, Christian; Wichmann, H. Erich; Kunz, Manfred; Ike, Robert; Krueger, Gerald G.; Bowcock, Anne M.; Mroweitz, Ulrich; Lim, Henry W.; Voorhees, John J.; Abecasis, Goncalo R.; Weichenthal, Michael; Franke, Andre; Rahman, Proton; Gladman, Dafna D.; Elder, James T.

    2010-01-01

    To identify novel psoriasis susceptibility loci, we carried out a meta-analysis of two recent genome-wide association studies 1,2, yielding a discovery sample of 1,831 cases and 2,546 controls. 102 of the most promising loci in the discovery analysis were followed up in a three-stage replication study using 4,064 cases and 4,685 controls from Michigan, Toronto, Newfoundland, and Germany. Association at a genome-wide level of significance for the combined discovery and replication samples was found for three genomic regions. One contains NOS2 (rs4795067, p = 4 × 10−11), another contains FBXL19 (rs10782001, p = 9 × 10−10), and a third contains PSMA6 and NFKBIA (rs12586317, p = 2 × 10−8). All three loci were also strongly associated with the subphenotypes of psoriatic arthritis and purely cutaneous psoriasis. Finally, we confirmed a recently identified3 association signal near RNF114. PMID:20953189

  9. A Genome-Wide Association Study of Aging

    PubMed Central

    Walter, Stefan; Atzmon, Gil; Demerath, Ellen W.; Garcia, Melissa E.; Kaplan, Robert C.; Kumari, Meena; Lunetta, Kathryn L.; Milaneschi, Yuri; Tanaka, Toshiko; Tranah, Gregory J.; Völker, Uwe; Yu, Lei; Arnold, Alice; Benjamin, Emelia J.; Biffar, Reiner; Buchman, Aron S.; Boerwinkle, Eric; Couper, David; De Jager, Philip L.; Evans, Denis A.; Harris, Tamara B.; Hoffmann, Wolfgang; Hofman, Albert; Karasik, David; Kiel, Douglas P.; Kocher, Thomas; Kuningas, Maris; Launer, Lenore J.; Lohman, Kurt K.; Lutsey, Pamela L.; Mackenbach, Johan; Marciante, Kristin; Psaty, Bruce M.; Reiman, Eric M.; Rotter, Jerome I.; Seshadri, Sudha; Shardell, Michelle D.; Smith, Albert V.; van Duijn, Cornelia; Walston, Jeremy; Zillikens, M. Carola; Bandinelli, Stefania; Baumeister, Sebastian E.; Bennett, David A.; Ferrucci, Luigi; Gudnason, Vilmundur; Kivimaki, Mika; Liu, Yongmei; Murabito, Joanne M.; Newman, Anne B.; Tiemeier, Henning; Franceschini, Nora

    2011-01-01

    Human longevity and healthy aging show moderate heritability (20–50%). We conducted a meta-analysis of genome-wide association studies from nine studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium for two outcomes: a) all-cause mortality and b) survival free of major disease or death. No single nucleotide polymorphism (SNP) was a genome-wide significant predictor of either outcome (p < 5 × 10−8). We found fourteen independent SNPs that predicted risk of death, and eight SNPs that predicted event-free survival (p < 10−5). These SNPs are in or near genes that are highly expressed in the brain (HECW2, HIP1, BIN2, GRIA1), genes involved in neural development and function (KCNQ4, LMO4, GRIA1, NETO1) and autophagy (ATG4C), and genes that are associated with risk of various diseases including cancer and Alzheimer’s disease. In addition to considerable overlap between the traits, pathway and network analysis corroborated these findings. These findings indicate that variation in genes involved in neurological processes may be an important factor in regulating aging free of major disease and achieving longevity. PMID:21782286

  10. Consistency of genome-wide associations across major ancestral groups.

    PubMed

    Ntzani, Evangelia E; Liberopoulos, George; Manolio, Teri A; Ioannidis, John P A

    2012-07-01

    It is not well known whether genetic markers identified through genome-wide association studies (GWAS) confer similar or different risks across people of different ancestry. We screened a regularly updated catalog of all published GWAS curated at the NHGRI website for GWAS-identified associations that had reached genome-wide significance (p ≤ 5 × 10(-8)) in at least one major ancestry group (European, Asian, African) and for which replication data were available for comparison in at least two different major ancestry groups. These groups were compared for the correlation between and differences in risk allele frequencies and genetic effects' estimates. Data on 108 eligible GWAS-identified associations with a total of 900 datasets (European, n = 624; Asian, n = 217; African, n = 60) were analyzed. Risk-allele frequencies were modestly correlated between ancestry groups, with >10% absolute differences in 75-89% of the three pairwise comparisons of ancestry groups. Genetic effect (odds ratio) point estimates between ancestry groups correlated modestly (pairwise comparisons' correlation coefficients: 0.20-0.33) and point estimates of risks were opposite in direction or differed more than twofold in 57%, 79%, and 89% of the European versus Asian, European versus African, and Asian versus African comparisons, respectively. The modest correlations, differing risk estimates, and considerable between-association heterogeneity suggest that differential ancestral effects can be anticipated and genomic risk markers may need separate further evaluation in different ancestry groups. PMID:22183176

  11. Phenome-wide analysis of genome-wide polygenic scores.

    PubMed

    Krapohl, E; Euesden, J; Zabaneh, D; Pingault, J-B; Rimfeld, K; von Stumm, S; Dale, P S; Breen, G; O'Reilly, P F; Plomin, R

    2016-09-01

    Genome-wide polygenic scores (GPS), which aggregate the effects of thousands of DNA variants from genome-wide association studies (GWAS), have the potential to make genetic predictions for individuals. We conducted a systematic investigation of associations between GPS and many behavioral traits, the behavioral phenome. For 3152 unrelated 16-year-old individuals representative of the United Kingdom, we created 13 GPS from the largest GWAS for psychiatric disorders (for example, schizophrenia, depression and dementia) and cognitive traits (for example, intelligence, educational attainment and intracranial volume). The behavioral phenome included 50 traits from the domains of psychopathology, personality, cognitive abilities and educational achievement. We examined phenome-wide profiles of associations for the entire distribution of each GPS and for the extremes of the GPS distributions. The cognitive GPS yielded stronger predictive power than the psychiatric GPS in our UK-representative sample of adolescents. For example, education GPS explained variation in adolescents' behavior problems (~0.6%) and in educational achievement (~2%) but psychiatric GPS were associated with neither. Despite the modest effect sizes of current GPS, quantile analyses illustrate the ability to stratify individuals by GPS and opportunities for research. For example, the highest and lowest septiles for the education GPS yielded a 0.5 s.d. difference in mean math grade and a 0.25 s.d. difference in mean behavior problems. We discuss the usefulness and limitations of GPS based on adult GWAS to predict genetic propensities earlier in development. PMID:26303664

  12. Genome-wide identification of hypoxia-induced enhancer regions

    PubMed Central

    Preston, Jessica L.; Randel, Melissa A.; Johnson, Eric A.

    2015-01-01

    Here we present a genome-wide method for de novo identification of enhancer regions. This approach enables massively parallel empirical investigation of DNA sequences that mediate transcriptional activation and provides a platform for discovery of regulatory modules capable of driving context-specific gene expression. The method links fragmented genomic DNA to the transcription of randomer molecule identifiers and measures the functional enhancer activity of the library by massively parallel sequencing. We transfected a Drosophila melanogaster library into S2 cells in normoxia and hypoxia, and assayed 4,599,881 genomic DNA fragments in parallel. The locations of the enhancer regions strongly correlate with genes up-regulated after hypoxia and previously described enhancers. Novel enhancer regions were identified and integrated with RNAseq data and transcription factor motifs to describe the hypoxic response on a genome-wide basis as a complex regulatory network involving multiple stress-response pathways. This work provides a novel method for high-throughput assay of enhancer activity and the genome-scale identification of 31 hypoxia-activated enhancers in Drosophila. PMID:26713262

  13. Advances in genome-wide DNA methylation analysis

    PubMed Central

    Gupta, Romi; Nagarajan, Arvindhan; Wajapeyee, Narendra

    2013-01-01

    The covalent DNA modification of cytosine at position 5 (5-methylcytosine; 5mC) has emerged as an important epigenetic mark most commonly present in the context of CpG dinucleotides in mammalian cells. In pluripotent stem cells and plants, it is also found in non-CpG and CpNpG contexts, respectively. 5mC has important implications in a diverse set of biological processes, including transcriptional regulation. Aberrant DNA methylation has been shown to be associated with a wide variety of human ailments and thus is the focus of active investigation. Methods used for detecting DNA methylation have revolutionized our understanding of this epigenetic mark and provided new insights into its role in diverse biological functions. Here we describe recent technological advances in genome-wide DNA methylation analysis and discuss their relative utility and drawbacks, providing specific examples from studies that have used these technologies for genome-wide DNA methylation analysis to address important biological questions. Finally, we discuss a newly identified covalent DNA modification, 5-hydroxymethylcytosine (5hmC), and speculate on its possible biological function, as well as describe a new methodology that can distinguish 5hmC from 5mC. PMID:20964631

  14. Measuring genome-wide nucleosome turnover using CATCH-IT.

    PubMed

    Teves, Sheila S; Deal, Roger B; Henikoff, Steven

    2012-01-01

    The dynamic interplay between DNA-binding proteins and nucleosomes underlies essential nuclear processes such as transcription, replication, and DNA repair. Manifestations of this interplay include the assembly, eviction, and replacement of nucleosomes. Hence, measurements of nucleosome turnover kinetics can lead to insights into the regulation of dynamic chromatin processes. In this chapter, we describe a genome-wide method for measuring nucleosome turnover that uses metabolic labeling followed by capture of newly synthesized histones, which we have termed Covalent Attachment of Tagged Histones to Capture and Identify Turnover (CATCH-IT). Although CATCH-IT can be used with any genome-wide mapping procedure, high-resolution profiling is attainable using paired-end sequencing of native chromatin. Our protocol also includes an efficient Solexa DNA sequencing library preparation protocol that can be used for single base-pair resolution mapping of both nucleosome and subnucleosomal particles. We not only describe the use of these protocols in the context of a Drosophila cell line but also provide the necessary changes for adaptation to other model systems. PMID:22929769

  15. Genome-wide association interaction analysis for Alzheimer's disease

    PubMed Central

    Gusareva, Elena S.; Carrasquillo, Minerva M.; Bellenguez, Céline; Cuyvers, Elise; Colon, Samuel; Graff-Radford, Neill R.; Petersen, Ronald C.; Dickson, Dennis W.; Mahachie Johna, Jestinah M.; Bessonov, Kyrylo; Van Broeckhoven, Christine; Williams, Julie; Amouyel, Philippe; Sleegers, Kristel; Ertekin-Taner, Nilüfer; Lambert, Jean-Charles; Van Steen, Kristel

    2015-01-01

    We propose a minimal protocol for exhaustive genome-wide association interaction analysis that involves screening for epistasis over large-scale genomic data combining strengths of different methods and statistical tools. The different steps of this protocol are illustrated on a real-life data application for Alzheimer's disease (AD) (2259 patients and 6017 controls from France). Particularly, in the exhaustive genome-wide epistasis screening we identified AD-associated interacting SNPs-pair from chromosome 6q11.1 (rs6455128, the KHDRBS2 gene) and 13q12.11 (rs7989332, the CRYL1 gene) (p = 0.006, corrected for multiple testing). A replication analysis in the independent AD cohort from Germany (555 patients and 824 controls) confirmed the discovered epistasis signal (p = 0.036). This signal was also supported by a meta-analysis approach in 5 independent AD cohorts that was applied in the context of epistasis for the first time. Transcriptome analysis revealed negative correlation between expression levels of KHDRBS2 and CRYL1 in both the temporal cortex (β = −0.19, p = 0.0006) and cerebellum (β = −0.23, p < 0.0001) brain regions. This is the first time a replicable epistasis associated with AD was identified using a hypothesis free screening approach. PMID:24958192

  16. Establishing an analytic pipeline for genome-wide DNA methylation.

    PubMed

    Wright, Michelle L; Dozmorov, Mikhail G; Wolen, Aaron R; Jackson-Cook, Colleen; Starkweather, Angela R; Lyon, Debra E; York, Timothy P

    2016-01-01

    The need for research investigating DNA methylation (DNAm) in clinical studies has increased, leading to the evolution of new analytic methods to improve accuracy and reproducibility of the interpretation of results from these studies. The purpose of this article is to provide clinical researchers with a summary of the major data processing steps routinely applied in clinical studies investigating genome-wide DNAm using the Illumina HumanMethylation 450K BeadChip. In most studies, the primary goal of employing DNAm analysis is to identify differential methylation at CpG sites among phenotypic groups. Experimental design considerations are crucial at the onset to minimize bias from factors related to sample processing and avoid confounding experimental variables with non-biological batch effects. Although there are currently no de facto standard methods for analyzing these data, we review the major steps in processing DNAm data recommended by several research studies. We describe several variations available for clinical researchers to process, analyze, and interpret DNAm data. These insights are applicable to most types of genome-wide DNAm array platforms and will be applicable for the next generation of DNAm array technologies (e.g., the 850K array). Selection of the DNAm analytic pipeline followed by investigators should be guided by the research question and supported by recently published methods. PMID:27127542

  17. Genome-Wide Scan for Methylation Profiles in Keloids

    PubMed Central

    Jones, Lamont R.; Young, William; Divine, George; Datta, Indrani; Chen, Kang Mei; Ozog, David; Worsham, Maria J.

    2015-01-01

    Keloids are benign fibroproliferative tumors of the skin which commonly occur after injury mainly in darker skinned patients. Medical treatment is fraught with high recurrence rates mainly because of an incomplete understanding of the biological mechanisms that lead to keloids. The purpose of this project was to examine keloid pathogenesis from the epigenome perspective of DNA methylation. Genome-wide profiling used the Infinium HumanMethylation450 BeadChip to interrogate DNA from 6 fresh keloid and 6 normal skin samples from 12 anonymous donors. A 3-tiered approach was used to call out genes most differentially methylated between keloid and normal. When compared to normal, of the 685 differentially methylated CpGs at Tier 3, 510 were hypomethylated and 175 were hypermethylated with 190 CpGs in promoter and 495 in nonpromoter regions. The 190 promoter region CpGs corresponded to 152 genes: 96 (63%) were hypomethylated and 56 (37%) hypermethylated. This exploratory genome-wide scan of the keloid methylome highlights a predominance of hypomethylated genomic landscapes, favoring nonpromoter regions. DNA methylation, as an additional mechanism for gene regulation in keloid pathogenesis, holds potential for novel treatments that reverse deleterious epigenetic changes. As an alternative mechanism for regulating genes, epigenetics may explain why gene mutations alone do not provide definitive mechanisms for keloid formation. PMID:26074660

  18. Genome-Wide Mapping of DNA Strand Breaks

    PubMed Central

    Leduc, Frédéric; Faucher, David; Bikond Nkoma, Geneviève; Grégoire, Marie-Chantal; Arguin, Mélina; Wellinger, Raymund J.; Boissonneault, Guylain

    2011-01-01

    Determination of cellular DNA damage has so far been limited to global assessment of genome integrity whereas nucleotide-level mapping has been restricted to specific loci by the use of specific primers. Therefore, only limited DNA sequences can be studied and novel regions of genomic instability can hardly be discovered. Using a well-characterized yeast model, we describe a straightforward strategy to map genome-wide DNA strand breaks without compromising nucleotide-level resolution. This technique, termed “damaged DNA immunoprecipitation” (dDIP), uses immunoprecipitation and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin end-labeling (TUNEL) to capture DNA at break sites. When used in combination with microarray or next-generation sequencing technologies, dDIP will allow researchers to map genome-wide DNA strand breaks as well as other types of DNA damage and to establish a clear profiling of altered genes and/or intergenic sequences in various experimental conditions. This mapping technique could find several applications for instance in the study of aging, genotoxic drug screening, cancer, meiosis, radiation and oxidative DNA damage. PMID:21364894

  19. Genome-wide association studies and prediction of 17 traits related to phenology, biomass and cell wall composition in the energy grass Miscanthus sinensis

    PubMed Central

    Slavov, Gancho T; Nipper, Rick; Robson, Paul; Farrar, Kerrie; Allison, Gordon G; Bosch, Maurice; Clifton-Brown, John C; Donnison, Iain S; Jensen, Elaine

    2014-01-01

    Increasing demands for food and energy require a step change in the effectiveness, speed and flexibility of crop breeding. Therefore, the aim of this study was to assess the potential of genome-wide association studies (GWASs) and genomic selection (i.e. phenotype prediction from a genome-wide set of markers) to guide fundamental plant science and to accelerate breeding in the energy grass Miscanthus. We generated over 100 000 single-nucleotide variants (SNVs) by sequencing restriction site-associated DNA (RAD) tags in 138 Micanthus sinensis genotypes, and related SNVs to phenotypic data for 17 traits measured in a field trial. Confounding by population structure and relatedness was severe in naïve GWAS analyses, but mixed-linear models robustly controlled for these effects and allowed us to detect multiple associations that reached genome-wide significance. Genome-wide prediction accuracies tended to be moderate to high (average of 0.57), but varied dramatically across traits. As expected, predictive abilities increased linearly with the size of the mapping population, but reached a plateau when the number of markers used for prediction exceeded 10 000–20 000, and tended to decline, but remain significant, when cross-validations were performed across subpopulations. Our results suggest that the immediate implementation of genomic selection in Miscanthus breeding programs may be feasible. PMID:24308815

  20. Economic values of body weight, reproduction and parasite resistance traits for a Creole goat breeding goal.

    PubMed

    Gunia, M; Mandonnet, N; Arquet, R; Alexandre, G; Gourdine, J-L; Naves, M; Angeon, V; Phocas, F

    2013-01-01

    A specific breeding goal definition was developed for Creole goats in Guadeloupe. This local breed is used for meat production. To ensure a balanced selection outcome, the breeding objective included two production traits, live weight (BW11) and dressing percentage (DP) at 11 months (the mating or selling age), one reproduction trait, fertility (FER), and two traits to assess animal response to parasite infection: packed cell volume (PCV), a resilience trait, and faecal worm eggs count (FEC), a resistance trait. A deterministic bio-economic model was developed to calculate the economic values based on the description of the profit of a Guadeloupean goat farm. The farm income came from the sale of animals for meat or as reproducers. The main costs were feeding and treatments against gastro-intestinal parasites. The economic values were 7.69€ per kg for BW11, 1.38€ per % for FER, 3.53€ per % for DP and 3 × 10(-4)€ per % for PCV. The economic value for FEC was derived by comparing the expected profit and average FEC in a normal situation and in an extreme situation where parasites had developed resistance to anthelmintics. This method yielded a maximum weighting for FEC, which was -18.85€ per log(eggs per gram). Alternative scenarios were tested to assess the robustness of the economic values to variations in the economic and environmental context. The economic values of PCV and DP were the most stable. Issues involved in paving the way for selective breeding on resistance or resilience to parasites are discussed. PMID:23031546

  1. A Genome-Wide Association Study of Optic Disc Parameters

    PubMed Central

    Jansonius, Nomdo M.; de Jong, Paulus T. V. M.; Bergen, Arthur A. B.; Isaacs, Aaron; Amin, Najaf; Aulchenko, Yurii S.; Wolfs, Roger C. W.; Hofman, Albert; Rivadeneira, Fernando; Oostra, Ben A.; Uitterlinden, Andre G.; Hysi, Pirro; Hammond, Christopher J.; Lemij, Hans G.; Vingerling, Johannes R.

    2010-01-01

    The optic nerve head is involved in many ophthalmic disorders, including common diseases such as myopia and open-angle glaucoma. Two of the most important parameters are the size of the optic disc area and the vertical cup-disc ratio (VCDR). Both are highly heritable but genetically largely undetermined. We performed a meta-analysis of genome-wide association (GWA) data to identify genetic variants associated with optic disc area and VCDR. The gene discovery included 7,360 unrelated individuals from the population-based Rotterdam Study I and Rotterdam Study II cohorts. These cohorts revealed two genome-wide significant loci for optic disc area, rs1192415 on chromosome 1p22 (p = 6.72×10−19) within 117 kb of the CDC7 gene and rs1900004 on chromosome 10q21.3-q22.1 (p = 2.67×10−33) within 10 kb of the ATOH7 gene. They revealed two genome-wide significant loci for VCDR, rs1063192 on chromosome 9p21 (p = 6.15×10−11) in the CDKN2B gene and rs10483727 on chromosome 14q22.3-q23 (p = 2.93×10−10) within 40 kbp of the SIX1 gene. Findings were replicated in two independent Dutch cohorts (Rotterdam Study III and Erasmus Rucphen Family study; N = 3,612), and the TwinsUK cohort (N = 843). Meta-analysis with the replication cohorts confirmed the four loci and revealed a third locus at 16q12.1 associated with optic disc area, and four other loci at 11q13, 13q13, 17q23 (borderline significant), and 22q12.1 for VCDR. ATOH7 was also associated with VCDR independent of optic disc area. Three of the loci were marginally associated with open-angle glaucoma. The protein pathways in which the loci of optic disc area are involved overlap with those identified for VCDR, suggesting a common genetic origin. PMID:20548946

  2. Genome-wide association study of antisocial personality disorder.

    PubMed

    Rautiainen, M-R; Paunio, T; Repo-Tiihonen, E; Virkkunen, M; Ollila, H M; Sulkava, S; Jolanki, O; Palotie, A; Tiihonen, J

    2016-01-01

    The pathophysiology of antisocial personality disorder (ASPD) remains unclear. Although the most consistent biological finding is reduced grey matter volume in the frontal cortex, about 50% of the total liability to developing ASPD has been attributed to genetic factors. The contributing genes remain largely unknown. Therefore, we sought to study the genetic background of ASPD. We conducted a genome-wide association study (GWAS) and a replication analysis of Finnish criminal offenders fulfilling DSM-IV criteria for ASPD (N=370, N=5850 for controls, GWAS; N=173, N=3766 for controls and replication sample). The GWAS resulted in suggestive associations of two clusters of single-nucleotide polymorphisms at 6p21.2 and at 6p21.32 at the human leukocyte antigen (HLA) region. Imputation of HLA alleles revealed an independent association with DRB1*01:01 (odds ratio (OR)=2.19 (1.53-3.14), P=1.9 × 10(-5)). Two polymorphisms at 6p21.2 LINC00951-LRFN2 gene region were replicated in a separate data set, and rs4714329 reached genome-wide significance (OR=1.59 (1.37-1.85), P=1.6 × 10(-9)) in the meta-analysis. The risk allele also associated with antisocial features in the general population conditioned for severe problems in childhood family (β=0.68, P=0.012). Functional analysis in brain tissue in open access GTEx and Braineac databases revealed eQTL associations of rs4714329 with LINC00951 and LRFN2 in cerebellum. In humans, LINC00951 and LRFN2 are both expressed in the brain, especially in the frontal cortex, which is intriguing considering the role of the frontal cortex in behavior and the neuroanatomical findings of reduced gray matter volume in ASPD. To our knowledge, this is the first study showing genome-wide significant and replicable findings on genetic variants associated with any personality disorder. PMID:27598967

  3. Genome-wide assessment of Parkinson's disease in a Southern Spanish population.

    PubMed

    Bandrés-Ciga, Sara; Price, Timothy Ryan; Barrero, Francisco Javier; Escamilla-Sevilla, Francisco; Pelegrina, Javier; Arepalli, Sampath; Hernández, Dena; Gutiérrez, Blanca; Cervilla, Jorge; Rivera, Margarita; Rivera, Alberto; Ding, Jing-Hui; Vives, Francisco; Nalls, Michael; Singleton, Andrew; Durán, Raquel

    2016-09-01

    Here, we set out to study the genetic architecture of Parkinson's disease (PD) through a Genome-Wide Association Study in a Southern Spanish population. About 240 PD cases and 192 controls were genotyped on the NeuroX array. We estimated genetic variation associated with PD risk and age at onset (AAO). Risk profile analyses for PD and AAO were performed using a weighted genetic risk score. Total heritability was estimated by genome-wide complex trait analysis. Rare variants were screened with single-variant and burden tests. We also screened for variation in known PD genes. Finally, we explored runs of homozygosity and structural genomic variations. We replicate PD association (uncorrected p-value < 0.05) at the following loci: ACMSD/TMEM163, MAPT, STK39, MIR4697, and SREBF/RAI1. Subjects in the highest genetic risk score quintile showed significantly increased risk of PD versus the lowest quintile (odds ratio = 3.6, p-value < 4e(-7)), but no significant difference in AAO. We found evidence of runs of homozygosity in 2 PD-associated regions: one intersecting the HLA-DQB1 gene in 6 patients and 1 control; and another intersecting the GBA-SYT11 gene in PD case. The GBA N370S and the LRRK2 G2019S variants were found in 8 and 7 cases, respectively, replicating previous work. A structural variant was found in 1 case in the PARK2 gene locus. This current work represents a comprehensive assessment at a genome-wide level characterizing a novel population in PD genetics. PMID:27393345

  4. Prediction of breeding values for dairy cattle using artificial neural networks and neuro-fuzzy systems.

    PubMed

    Shahinfar, Saleh; Mehrabani-Yeganeh, Hassan; Lucas, Caro; Kalhor, Ahmad; Kazemian, Majid; Weigel, Kent A

    2012-01-01

    Developing machine learning and soft computing techniques has provided many opportunities for researchers to establish new analytical methods in different areas of science. The objective of this study is to investigate the potential of two types of intelligent learning methods, artificial neural networks and neuro-fuzzy systems, in order to estimate breeding values (EBV) of Iranian dairy cattle. Initially, the breeding values of lactating Holstein cows for milk and fat yield were estimated using conventional best linear unbiased prediction (BLUP) with an animal model. Once that was established, a multilayer perceptron was used to build ANN to predict breeding values from the performance data of selection candidates. Subsequently, fuzzy logic was used to form an NFS, a hybrid intelligent system that was implemented via a local linear model tree algorithm. For milk yield the correlations between EBV and EBV predicted by the ANN and NFS were 0.92 and 0.93, respectively. Corresponding correlations for fat yield were 0.93 and 0.93, respectively. Correlations between multitrait predictions of EBVs for milk and fat yield when predicted simultaneously by ANN were 0.93 and 0.93, respectively, whereas corresponding correlations with reference EBV for multitrait NFS were 0.94 and 0.95, respectively, for milk and fat production. PMID:22991575

  5. Genome-Wide Patterns of Genetic Variation in Two Domestic Chickens

    PubMed Central

    Fan, Wen-Lang; Ng, Chen Siang; Chen, Chih-Feng; Lu, Mei-Yeh Jade; Chen, Yu-Hsiang; Liu, Chia-Jung; Wu, Siao-Man; Chen, Chih-Kuan; Chen, Jiun-Jie; Mao, Chi-Tang; Lai, Yu-Ting; Lo, Wen-Sui; Chang, Wei-Hua; Li, Wen-Hsiung

    2013-01-01

    Domestic chickens are excellent models for investigating the genetic basis of phenotypic diversity, as numerous phenotypic changes in physiology, morphology, and behavior in chickens have been artificially selected. Genomic study is required to study genome-wide patterns of DNA variation for dissecting the genetic basis of phenotypic traits. We sequenced the genomes of the Silkie and the Taiwanese native chicken L2 at ∼23- and 25-fold average coverage depth, respectively, using Illumina sequencing. The reads were mapped onto the chicken reference genome (including 5.1% Ns) to 92.32% genome coverage for the two breeds. Using a stringent filter, we identified ∼7.6 million single-nucleotide polymorphisms (SNPs) and 8,839 copy number variations (CNVs) in the mapped regions; 42% of the SNPs have not found in other chickens before. Among the 68,906 SNPs annotated in the chicken sequence assembly, 27,852 were nonsynonymous SNPs located in 13,537 genes. We also identified hundreds of shared and divergent structural and copy number variants in intronic and intergenic regions and in coding regions in the two breeds. Functional enrichments of identified genetic variants were discussed. Radical nsSNP-containing immunity genes were enriched in the QTL regions associated with some economic traits for both breeds. Moreover, genetic changes involved in selective sweeps were detected. From the selective sweeps identified in our two breeds, several genes associated with growth, appetite, and metabolic regulation were identified. Our study provides a framework for genetic and genomic research of domestic chickens and facilitates the domestic chicken as an avian model for genomic, biomedical, and evolutionary studies. PMID:23814129

  6. Genome-wide association studies in pediatric chronic kidney disease.

    PubMed

    Gupta, Jayanta; Kanetsky, Peter A; Wuttke, Matthias; Köttgen, Anna; Schaefer, Franz; Wong, Craig S

    2016-08-01

    The genome-wide association study (GWAS) has become an established scientific method that provides an unbiased screen for genetic loci potentially associated with phenotypes of clinical interest, such as chronic kidney disease (CKD). Thus, GWAS provides opportunities to gain new perspectives regarding the genetic architecture of CKD progression by identifying new candidate genes and targets for intervention. As such, it has become an important arm of translational science providing a complementary line of investigation to identify novel therapeutics to treat CKD. In this review, we describe the method and the challenges of performing GWAS in the pediatric CKD population. We also provide an overview of successful GWAS for kidney disease, and we discuss the established pediatric CKD cohorts in North America and Europe that are poised to identify genetic risk variants associated with CKD progression. PMID:26490952

  7. Ultrafast laser nanosurgery in microfluidics for genome-wide screenings

    PubMed Central

    Ben-Yakar, Adela; Bourgeois, Frederic

    2009-01-01

    Summary The use of ultrafast laser pulses in surgery has allowed for unprecedented precision with minimal collateral damage to surrounding tissues. For these reasons, ultrafast laser nanosurgery, as an injury model, has gained tremendous momentum in experimental biology ranging from in-vitro manipulations of subcellular structures to in-vivo studies in whole living organisms. For example, femtosecond laser nanosurgery on such model organism as the nematode Caenorhabditis elegans (C. elegans) has opened new opportunities for in-vivo nerve regeneration studies. Meanwhile, the development of novel microfluidic devices has brought the control in experimental environment to the level required for precise nanosurgery in various animal models. Merging microfluidics and laser nanosurgery has recently improved the specificities and increased the speed of laser surgeries enabling fast genome-wide screenings that can more readily decode the genetic map of various biological processes. PMID:19278850

  8. Genome-wide nucleosome positioning during embryonic stem cell development.

    PubMed

    Teif, Vladimir B; Vainshtein, Yevhen; Caudron-Herger, Maïwen; Mallm, Jan-Philipp; Marth, Caroline; Höfer, Thomas; Rippe, Karsten

    2012-11-01

    We determined genome-wide nucleosome occupancies in mouse embryonic stem cells and their neural progenitor and embryonic fibroblast counterparts to assess features associated with nucleosome positioning during lineage commitment. Cell-type- and protein-specific binding preferences of transcription factors to sites with either low (Myc, Klf4 and Zfx) or high (Nanog, Oct4 and Sox2) nucleosome occupancy as well as complex patterns for CTCF were identified. Nucleosome-depleted regions around transcription start and transcription termination sites were broad and more pronounced for active genes, with distinct patterns for promoters classified according to CpG content or histone methylation marks. Throughout the genome, nucleosome occupancy was correlated with certain histone methylation or acetylation modifications. In addition, the average nucleosome repeat length increased during differentiation by 5-7 base pairs, with local variations for specific regions. Our results reveal regulatory mechanisms of cell differentiation that involve nucleosome repositioning. PMID:23085715

  9. Quantitative prediction of genome-wide resource allocation in bacteria.

    PubMed

    Goelzer, Anne; Muntel, Jan; Chubukov, Victor; Jules, Matthieu; Prestel, Eric; Nölker, Rolf; Mariadassou, Mahendra; Aymerich, Stéphane; Hecker, Michael; Noirot, Philippe; Becher, Dörte; Fromion, Vincent

    2015-11-01

    Predicting resource allocation between cell processes is the primary step towards decoding the evolutionary constraints governing bacterial growth under various conditions. Quantitative prediction at genome-scale remains a computational challenge as current methods are limited by the tractability of the problem or by simplifying hypotheses. Here, we show that the constraint-based modeling method Resource Balance Analysis (RBA), calibrated using genome-wide absolute protein quantification data, accurately predicts resource allocation in the model bacterium Bacillus subtilis for a wide range of growth conditions. The regulation of most cellular processes is consistent with the objective of growth rate maximization except for a few suboptimal processes which likely integrate more complex objectives such as coping with stressful conditions and survival. As a proof of principle by using simulations, we illustrated how calibrated RBA could aid rational design of strains for maximizing protein production, offering new opportunities to investigate design principles in prokaryotes and to exploit them for biotechnological applications. PMID:26498510

  10. Metabolite-based genome-wide association studies in plants.

    PubMed

    Luo, Jie

    2015-04-01

    The plant metabolome is the readout of plant physiological status and is regarded as the bridge between the genome and the phenome of plants. Unraveling the natural variation and the underlying genetic basis of plant metabolism has received increasing interest from plant biologists. Enabled by the recent advances in high-throughput profiling and genotyping technologies, metabolite-based genome-wide association study (mGWAS) has emerged as a powerful alternative forward genetics strategy to dissect the genetic and biochemical bases of metabolism in model and crop plants. In this review, recent progress and applications of mGWAS in understanding the genetic control of plant metabolism and in interactive functional genomics and metabolomics are presented. Further directions and perspectives of mGWAS in plants are also discussed. PMID:25637954

  11. Genome-wide DNA methylation profiling in zebrafish.

    PubMed

    Murphy, P J; Cairns, B R

    2016-01-01

    Genomic DNA methylation functions to repress gene expression by interfering with transcription factor binding and/or recruiting repressive chromatin machinery. Recent data support contribution of regulated DNA methylation to embryonic pluripotency, development, and tissue differentiation; this important epigenetic mark is chemically stable yet enzymatically reversible-and heritable through the germline. Importantly, all the major components involved in dynamic DNA methylation are conserved in zebrafish, including the factors that "write, read, and erase" this mark. Therefore, the zebrafish has become an excellent model for studying most biological processes associated with DNA methylation in mammals. Here we briefly review the zebrafish model for studying DNA methylation and describe a series of methods for performing genome-wide DNA methylation analysis. We address and provide methods for methylated DNA immunoprecipitation followed by sequencing (MeDIP-Seq), bisulfite sequencing (BS-Seq), and reduced representation bisulfite sequencing (RRBS-Seq). PMID:27443935

  12. Quality control procedures for genome-wide association studies.

    PubMed

    Turner, Stephen; Armstrong, Loren L; Bradford, Yuki; Carlson, Christopher S; Crawford, Dana C; Crenshaw, Andrew T; de Andrade, Mariza; Doheny, Kimberly F; Haines, Jonathan L; Hayes, Geoffrey; Jarvik, Gail; Jiang, Lan; Kullo, Iftikhar J; Li, Rongling; Ling, Hua; Manolio, Teri A; Matsumoto, Martha; McCarty, Catherine A; McDavid, Andrew N; Mirel, Daniel B; Paschall, Justin E; Pugh, Elizabeth W; Rasmussen, Luke V; Wilke, Russell A; Zuvich, Rebecca L; Ritchie, Marylyn D

    2011-01-01

    Genome-wide association studies (GWAS) are being conducted at an unprecedented rate in population-based cohorts and have increased our understanding of the pathophysiology of complex disease. Regardless of context, the practical utility of this information will ultimately depend upon the quality of the original data. Quality control (QC) procedures for GWAS are computationally intensive, operationally challenging, and constantly evolving. Here we enumerate some of the challenges in QC of GWAS data and describe the approaches that the electronic MEdical Records and Genomics (eMERGE) network is using for quality assurance in GWAS data, thereby minimizing potential bias and error in GWAS results. We discuss common issues associated with QC of GWAS data, including data file formats, software packages for data manipulation and analysis, sex chromosome anomalies, sample identity, sample relatedness, population substructure, batch effects, and marker quality. We propose best practices and discuss areas of ongoing and future research. PMID:21234875

  13. Accuracy of genomic breeding values for meat tenderness in Polled Nellore cattle.

    PubMed

    Magnabosco, C U; Lopes, F B; Fragoso, R C; Eifert, E C; Valente, B D; Rosa, G J M; Sainz, R D

    2016-07-01

    Zebu () cattle, mostly of the Nellore breed, comprise more than 80% of the beef cattle in Brazil, given their tolerance of the tropical climate and high resistance to ectoparasites. Despite their advantages for production in tropical environments, zebu cattle tend to produce tougher meat than Bos taurus breeds. Traditional genetic selection to improve meat tenderness is constrained by the difficulty and cost of phenotypic evaluation for meat quality. Therefore, genomic selection may be the best strategy to improve meat quality traits. This study was performed to compare the accuracies of different Bayesian regression models in predicting molecular breeding values for meat tenderness in Polled Nellore cattle. The data set was composed of Warner-Bratzler shear force (WBSF) of longissimus muscle from 205, 141, and 81 animals slaughtered in 2005, 2010, and 2012, respectively, which were selected and mated so as to create extreme segregation for WBSF. The animals were genotyped with either the Illumina BovineHD (HD; 777,000 from 90 samples) chip or the GeneSeek Genomic Profiler (GGP Indicus HD; 77,000 from 337 samples). The quality controls of SNP were Hard-Weinberg Proportion -value ≥ 0.1%, minor allele frequency > 1%, and call rate > 90%. The FImpute program was used for imputation from the GGP Indicus HD chip to the HD chip. The effect of each SNP was estimated using ridge regression, least absolute shrinkage and selection operator (LASSO), Bayes A, Bayes B, and Bayes Cπ methods. Different numbers of SNP were used, with 1, 2, 3, 4, 5, 7, 10, 20, 40, 60, 80, or 100% of the markers preselected based on their significance test (-value from genomewide association studies [GWAS]) or randomly sampled. The prediction accuracy was assessed by the correlation between genomic breeding value and the observed WBSF phenotype, using a leave-one-out cross-validation methodology. The prediction accuracies using all markers were all very similar for all models, ranging from 0

  14. Genome Wide Association Identifies Novel Loci Involved in Fungal Communication

    PubMed Central

    Kowbel, David; Welch, Juliet; Taylor, John W.; Brem, Rachel B.; Glass, N. Louise

    2013-01-01

    Understanding how genomes encode complex cellular and organismal behaviors has become the outstanding challenge of modern genetics. Unlike classical screening methods, analysis of genetic variation that occurs naturally in wild populations can enable rapid, genome-scale mapping of genotype to phenotype with a medium-throughput experimental design. Here we describe the results of the first genome-wide association study (GWAS) used to identify novel loci underlying trait variation in a microbial eukaryote, harnessing wild isolates of the filamentous fungus Neurospora crassa. We genotyped each of a population of wild Louisiana strains at 1 million genetic loci genome-wide, and we used these genotypes to map genetic determinants of microbial communication. In N. crassa, germinated asexual spores (germlings) sense the presence of other germlings, grow toward them in a coordinated fashion, and fuse. We evaluated germlings of each strain for their ability to chemically sense, chemotropically seek, and undergo cell fusion, and we subjected these trait measurements to GWAS. This analysis identified one gene, NCU04379 (cse-1, encoding a homolog of a neuronal calcium sensor), at which inheritance was strongly associated with the efficiency of germling communication. Deletion of cse-1 significantly impaired germling communication and fusion, and two genes encoding predicted interaction partners of CSE1 were also required for the communication trait. Additionally, mining our association results for signaling and secretion genes with a potential role in germling communication, we validated six more previously unknown molecular players, including a secreted protease and two other genes whose deletion conferred a novel phenotype of increased communication and multi-germling fusion. Our results establish protein secretion as a linchpin of germling communication in N. crassa and shed light on the regulation of communication molecules in this fungus. Our study demonstrates the power

  15. The genome-wide structure of the Jewish people.

    PubMed

    Behar, Doron M; Yunusbayev, Bayazit; Metspalu, Mait; Metspalu, Ene; Rosset, Saharon; Parik, Jüri; Rootsi, Siiri; Chaubey, Gyaneshwer; Kutuev, Ildus; Yudkovsky, Guennady; Khusnutdinova, Elza K; Balanovsky, Oleg; Semino, Ornella; Pereira, Luisa; Comas, David; Gurwitz, David; Bonne-Tamir, Batsheva; Parfitt, Tudor; Hammer, Michael F; Skorecki, Karl; Villems, Richard

    2010-07-01

    Contemporary Jews comprise an aggregate of ethno-religious communities whose worldwide members identify with each other through various shared religious, historical and cultural traditions. Historical evidence suggests common origins in the Middle East, followed by migrations leading to the establishment of communities of Jews in Europe, Africa and Asia, in what is termed the Jewish Diaspora. This complex demographic history imposes special challenges in attempting to address the genetic structure of the Jewish people. Although many genetic studies have shed light on Jewish origins and on diseases prevalent among Jewish communities, including studies focusing on uniparentally and biparentally inherited markers, genome-wide patterns of variation across the vast geographic span of Jewish Diaspora communities and their respective neighbours have yet to be addressed. Here we use high-density bead arrays to genotype individuals from 14 Jewish Diaspora communities and compare these patterns of genome-wide diversity with those from 69 Old World non-Jewish populations, of which 25 have not previously been reported. These samples were carefully chosen to provide comprehensive comparisons between Jewish and non-Jewish populations in the Diaspora, as well as with non-Jewish populations from the Middle East and north Africa. Principal component and structure-like analyses identify previously unrecognized genetic substructure within the Middle East. Most Jewish samples form a remarkably tight subcluster that overlies Druze and Cypriot samples but not samples from other Levantine populations or paired Diaspora host populations. In contrast, Ethiopian Jews (Beta Israel) and Indian Jews (Bene Israel and Cochini) cluster with neighbouring autochthonous populations in Ethiopia and western India, respectively, despite a clear paternal link between the Bene Israel and the Levant. These results cast light on the variegated genetic architecture of the Middle East, and trace the origins

  16. A genome-wide association study of anorexia nervosa.

    PubMed

    Boraska, V; Franklin, C S; Floyd, J A B; Thornton, L M; Huckins, L M; Southam, L; Rayner, N W; Tachmazidou, I; Klump, K L; Treasure, J; Lewis, C M; Schmidt, U; Tozzi, F; Kiezebrink, K; Hebebrand, J; Gorwood, P; Adan, R A H; Kas, M J H; Favaro, A; Santonastaso, P; Fernández-Aranda, F; Gratacos, M; Rybakowski, F; Dmitrzak-Weglarz, M; Kaprio, J; Keski-Rahkonen, A; Raevuori, A; Van Furth, E F; Slof-Op 't Landt, M C T; Hudson, J I; Reichborn-Kjennerud, T; Knudsen, G P S; Monteleone, P; Kaplan, A S; Karwautz, A; Hakonarson, H; Berrettini, W H; Guo, Y; Li, D; Schork, N J; Komaki, G; Ando, T; Inoko, H; Esko, T; Fischer, K; Männik, K; Metspalu, A; Baker, J H; Cone, R D; Dackor, J; DeSocio, J E; Hilliard, C E; O'Toole, J K; Pantel, J; Szatkiewicz, J P; Taico, C; Zerwas, S; Trace, S E; Davis, O S P; Helder, S; Bühren, K; Burghardt, R; de Zwaan, M; Egberts, K; Ehrlich, S; Herpertz-Dahlmann, B; Herzog, W; Imgart, H; Scherag, A; Scherag, S; Zipfel, S; Boni, C; Ramoz, N; Versini, A; Brandys, M K; Danner, U N; de Kovel, C; Hendriks, J; Koeleman, B P C; Ophoff, R A; Strengman, E; van Elburg, A A; Bruson, A; Clementi, M; Degortes, D; Forzan, M; Tenconi, E; Docampo, E; Escaramís, G; Jiménez-Murcia, S; Lissowska, J; Rajewski, A; Szeszenia-Dabrowska, N; Slopien, A; Hauser, J; Karhunen, L; Meulenbelt, I; Slagboom, P E; Tortorella, A; Maj, M; Dedoussis, G; Dikeos, D; Gonidakis, F; Tziouvas, K; Tsitsika, A; Papezova, H; Slachtova, L; Martaskova, D; Kennedy, J L; Levitan, R D; Yilmaz, Z; Huemer, J; Koubek, D; Merl, E; Wagner, G; Lichtenstein, P; Breen, G; Cohen-Woods, S; Farmer, A; McGuffin, P; Cichon, S; Giegling, I; Herms, S; Rujescu, D; Schreiber, S; Wichmann, H-E; Dina, C; Sladek, R; Gambaro, G; Soranzo, N; Julia, A; Marsal, S; Rabionet, R; Gaborieau, V; Dick, D M; Palotie, A; Ripatti, S; Widén, E; Andreassen, O A; Espeseth, T; Lundervold, A; Reinvang, I; Steen, V M; Le Hellard, S; Mattingsdal, M; Ntalla, I; Bencko, V; Foretova, L; Janout, V; Navratilova, M; Gallinger, S; Pinto, D; Scherer, S W; Aschauer, H; Carlberg, L; Schosser, A; Alfredsson, L; Ding, B; Klareskog, L; Padyukov, L; Courtet, P; Guillaume, S; Jaussent, I; Finan, C; Kalsi, G; Roberts, M; Logan, D W; Peltonen, L; Ritchie, G R S; Barrett, J C; Estivill, X; Hinney, A; Sullivan, P F; Collier, D A; Zeggini, E; Bulik, C M

    2014-10-01

    Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10(-7)) in SOX2OT and rs17030795 (P=5.84 × 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10(-)(6)) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10(-)(6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field. PMID:24514567

  17. Genome-wide linkage in Utah autism pedigrees.

    PubMed

    Allen-Brady, K; Robison, R; Cannon, D; Varvil, T; Villalobos, M; Pingree, C; Leppert, M F; Miller, J; McMahon, W M; Coon, H

    2010-10-01

    Genetic studies of autism over the past decade suggest a complex landscape of multiple genes. In the face of this heterogeneity, studies that include large extended pedigrees may offer valuable insights, as the relatively few susceptibility genes within single large families may be more easily discerned. This genome-wide screen of 70 families includes 20 large extended pedigrees of 6-9 generations, 6 moderate-sized families of 4-5 generations and 44 smaller families of 2-3 generations. The Center for Inherited Disease Research (CIDR) provided genotyping using the Illumina Linkage Panel 12, a 6K single-nucleotide polymorphism (SNP) platform. Results from 192 subjects with an autism spectrum disorder (ASD) and 461 of their relatives revealed genome-wide significance on chromosome 15q, with three possibly distinct peaks: 15q13.1-q14 (heterogeneity LOD (HLOD)=4.09 at 29 459 872 bp); 15q14-q21.1 (HLOD=3.59 at 36 837 208 bp); and 15q21.1-q22.2 (HLOD=5.31 at 55 629 733 bp). Two of these peaks replicate earlier findings. There were additional suggestive results on chromosomes 2p25.3-p24.1 (HLOD=1.87), 7q31.31-q32.3 (HLOD=1.97) and 13q12.11-q12.3 (HLOD=1.93). Affected subjects in families supporting the linkage peaks found in this study did not reveal strong evidence for distinct phenotypic subgroups. PMID:19455147

  18. Genome wide association identifies novel loci involved in fungal communication.

    PubMed

    Palma-Guerrero, Javier; Hall, Charles R; Kowbel, David; Welch, Juliet; Taylor, John W; Brem, Rachel B; Glass, N Louise

    2013-01-01

    Understanding how genomes encode complex cellular and organismal behaviors has become the outstanding challenge of modern genetics. Unlike classical screening methods, analysis of genetic variation that occurs naturally in wild populations can enable rapid, genome-scale mapping of genotype to phenotype with a medium-throughput experimental design. Here we describe the results of the first genome-wide association study (GWAS) used to identify novel loci underlying trait variation in a microbial eukaryote, harnessing wild isolates of the filamentous fungus Neurospora crassa. We genotyped each of a population of wild Louisiana strains at 1 million genetic loci genome-wide, and we used these genotypes to map genetic determinants of microbial communication. In N. crassa, germinated asexual spores (germlings) sense the presence of other germlings, grow toward them in a coordinated fashion, and fuse. We evaluated germlings of each strain for their ability to chemically sense, chemotropically seek, and undergo cell fusion, and we subjected these trait measurements to GWAS. This analysis identified one gene, NCU04379 (cse-1, encoding a homolog of a neuronal calcium sensor), at which inheritance was strongly associated with the efficiency of germling communication. Deletion of cse-1 significantly impaired germling communication and fusion, and two genes encoding predicted interaction partners of CSE1 were also required for the communication trait. Additionally, mining our association results for signaling and secretion genes with a potential role in germling communication, we validated six more previously unknown molecular players, including a secreted protease and two other genes whose deletion conferred a novel phenotype of increased communication and multi-germling fusion. Our results establish protein secretion as a linchpin of germling communication in N. crassa and shed light on the regulation of communication molecules in this fungus. Our study demonstrates the power

  19. A genome-wide association study of anorexia nervosa

    PubMed Central

    Boraska, Vesna; Franklin, Christopher S; Floyd, James AB; Thornton, Laura M; Huckins, Laura M; Southam, Lorraine; Rayner, N William; Tachmazidou, Ioanna; Klump, Kelly L; Treasure, Janet; Lewis, Cathryn M; Schmidt, Ulrike; Tozzi, Federica; Kiezebrink, Kirsty; Hebebrand, Johannes; Gorwood, Philip; Adan, Roger AH; Kas, Martien JH; Favaro, Angela; Santonastaso, Paolo; Fernández-Aranda, Fernando; Gratacos, Monica; Rybakowski, Filip; Dmitrzak-Weglarz, Monika; Kaprio, Jaakko; Keski-Rahkonen, Anna; Raevuori, Anu; Van Furth, Eric F; Landt, Margarita CT Slof-Op t; Hudson, James I; Reichborn-Kjennerud, Ted; Knudsen, Gun Peggy S; Monteleone, Palmiero; Kaplan, Allan S; Karwautz, Andreas; Hakonarson, Hakon; Berrettini, Wade H; Guo, Yiran; Li, Dong; Schork, Nicholas J.; Komaki, Gen; Ando, Tetsuya; Inoko, Hidetoshi; Esko, Tõnu; Fischer, Krista; Männik, Katrin; Metspalu, Andres; Baker, Jessica H; Cone, Roger D; Dackor, Jennifer; DeSocio, Janiece E; Hilliard, Christopher E; O'Toole, Julie K; Pantel, Jacques; Szatkiewicz, Jin P; Taico, Chrysecolla; Zerwas, Stephanie; Trace, Sara E; Davis, Oliver SP; Helder, Sietske; Bühren, Katharina; Burghardt, Roland; de Zwaan, Martina; Egberts, Karin; Ehrlich, Stefan; Herpertz-Dahlmann, Beate; Herzog, Wolfgang; Imgart, Hartmut; Scherag, André; Scherag, Susann; Zipfel, Stephan; Boni, Claudette; Ramoz, Nicolas; Versini, Audrey; Brandys, Marek K; Danner, Unna N; de Kovel, Carolien; Hendriks, Judith; Koeleman, Bobby PC; Ophoff, Roel A; Strengman, Eric; van Elburg, Annemarie A; Bruson, Alice; Clementi, Maurizio; Degortes, Daniela; Forzan, Monica; Tenconi, Elena; Docampo, Elisa; Escaramís, Geòrgia; Jiménez-Murcia, Susana; Lissowska, Jolanta; Rajewski, Andrzej; Szeszenia-Dabrowska, Neonila; Slopien, Agnieszka; Hauser, Joanna; Karhunen, Leila; Meulenbelt, Ingrid; Slagboom, P Eline; Tortorella, Alfonso; Maj, Mario; Dedoussis, George; Dikeos, Dimitris; Gonidakis, Fragiskos; Tziouvas, Konstantinos; Tsitsika, Artemis; Papezova, Hana; Slachtova, Lenka; Martaskova, Debora; Kennedy, James L.; Levitan, Robert D.; Yilmaz, Zeynep; Huemer, Julia; Koubek, Doris; Merl, Elisabeth; Wagner, Gudrun; Lichtenstein, Paul; Breen, Gerome; Cohen-Woods, Sarah; Farmer, Anne; McGuffin, Peter; Cichon, Sven; Giegling, Ina; Herms, Stefan; Rujescu, Dan; Schreiber, Stefan; Wichmann, H-Erich; Dina, Christian; Sladek, Rob; Gambaro, Giovanni; Soranzo, Nicole; Julia, Antonio; Marsal, Sara; Rabionet, Raquel; Gaborieau, Valerie; Dick, Danielle M; Palotie, Aarno; Ripatti, Samuli; Widén, Elisabeth; Andreassen, Ole A; Espeseth, Thomas; Lundervold, Astri; Reinvang, Ivar; Steen, Vidar M; Le Hellard, Stephanie; Mattingsdal, Morten; Ntalla, Ioanna; Bencko, Vladimir; Foretova, Lenka; Janout, Vladimir; Navratilova, Marie; Gallinger, Steven; Pinto, Dalila; Scherer, Stephen; Aschauer, Harald; Carlberg, Laura; Schosser, Alexandra; Alfredsson, Lars; Ding, Bo; Klareskog, Lars; Padyukov, Leonid; Finan, Chris; Kalsi, Gursharan; Roberts, Marion; Logan, Darren W; Peltonen, Leena; Ritchie, Graham RS; Barrett, Jeffrey C; Estivill, Xavier; Hinney, Anke; Sullivan, Patrick F; Collier, David A; Zeggini, Eleftheria; Bulik, Cynthia M

    2015-01-01

    Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2,907 cases with AN from 14 countries (15 sites) and 14,860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery datasets. Seventy-six (72 independent) SNPs were taken forward for in silico (two datasets) or de novo (13 datasets) replication genotyping in 2,677 independent AN cases and 8,629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication datasets comprised 5,551 AN cases and 21,080 controls. AN subtype analyses (1,606 AN restricting; 1,445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01×10-7) in SOX2OT and rs17030795 (P=5.84×10-6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76×10-6) between CUL3 and FAM124B and rs1886797 (P=8.05×10-6) near SPATA13. Comparing discovery to replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4×10-6), strongly suggesting that true findings exist but that our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field. PMID:24514567

  20. A genome-wide association study of anorexia nervosa

    PubMed Central

    Boraska, Vesna; Franklin, Christopher S; Floyd, James AB; Thornton, Laura M; Huckins, Laura M; Southam, Lorraine; Rayner, N William; Tachmazidou, Ioanna; Klump, Kelly L; Treasure, Janet; Lewis, Cathryn M; Schmidt, Ulrike; Tozzi, Federica; Kiezebrink, Kirsty; Hebebrand, Johannes; Gorwood, Philip; Adan, Roger AH; Kas, Martien JH; Favaro, Angela; Santonastaso, Paolo; Fernández-Aranda, Fernando; Gratacos, Monica; Rybakowski, Filip; Dmitrzak-Weglarz, Monika; Kaprio, Jaakko; Keski-Rahkonen, Anna; Raevuori, Anu; Van Furth, Eric F; Slof-Op t Landt, Margarita CT; Hudson, James I; Reichborn-Kjennerud, Ted; Knudsen, Gun Peggy S; Monteleone, Palmiero; Kaplan, Allan S; Karwautz, Andreas; Hakonarson, Hakon; Berrettini, Wade H; Guo, Yiran; Li, Dong; Schork, Nicholas J.; Komaki, Gen; Ando, Tetsuya; Inoko, Hidetoshi; Esko, Tõnu; Fischer, Krista; Männik, Katrin; Metspalu, Andres; Baker, Jessica H; Cone, Roger D; Dackor, Jennifer; DeSocio, Janiece E; Hilliard, Christopher E; O’Toole, Julie K; Pantel, Jacques; Szatkiewicz, Jin P; Taico, Chrysecolla; Zerwas, Stephanie; Trace, Sara E; Davis, Oliver SP; Helder, Sietske; Bühren, Katharina; Burghardt, Roland; de Zwaan, Martina; Egberts, Karin; Ehrlich, Stefan; Herpertz-Dahlmann, Beate; Herzog, Wolfgang; Imgart, Hartmut; Scherag, André; Scherag, Susann; Zipfel, Stephan; Boni, Claudette; Ramoz, Nicolas; Versini, Audrey; Brandys, Marek K; Danner, Unna N; de Kovel, Carolien; Hendriks, Judith; Koeleman, Bobby PC; Ophoff, Roel A; Strengman, Eric; van Elburg, Annemarie A; Bruson, Alice; Clementi, Maurizio; Degortes, Daniela; Forzan, Monica; Tenconi, Elena; Docampo, Elisa; Escaramís, Geòrgia; Jiménez-Murcia, Susana; Lissowska, Jolanta; Rajewski, Andrzej; Szeszenia-Dabrowska, Neonila; Slopien, Agnieszka; Hauser, Joanna; Karhunen, Leila; Meulenbelt, Ingrid; Slagboom, P Eline; Tortorella, Alfonso; Maj, Mario; Dedoussis, George; Dikeos, Dimitris; Gonidakis, Fragiskos; Tziouvas, Konstantinos; Tsitsika, Artemis; Papezova, Hana; Slachtova, Lenka; Martaskova, Debora; Kennedy, James L.; Levitan, Robert D.; Yilmaz, Zeynep; Huemer, Julia; Koubek, Doris; Merl, Elisabeth; Wagner, Gudrun; Lichtenstein, Paul; Breen, Gerome; Cohen-Woods, Sarah; Farmer, Anne; McGuffin, Peter; Cichon, Sven; Giegling, Ina; Herms, Stefan; Rujescu, Dan; Schreiber, Stefan; Wichmann, H-Erich; Dina, Christian; Sladek, Rob; Gambaro, Giovanni; Soranzo, Nicole; Julia, Antonio; Marsal, Sara; Rabionet, Raquel; Gaborieau, Valerie; Dick, Danielle M; Palotie, Aarno; Ripatti, Samuli; Widén, Elisabeth; Andreassen, Ole A; Espeseth, Thomas; Lundervold, Astri; Reinvang, Ivar; Steen, Vidar M; Le Hellard, Stephanie; Mattingsdal, Morten; Ntalla, Ioanna; Bencko, Vladimir; Foretova, Lenka; Janout, Vladimir; Navratilova, Marie; Gallinger, Steven; Pinto, Dalila; Scherer, Stephen; Aschauer, Harald; Carlberg, Laura; Schosser, Alexandra; Alfredsson, Lars; Ding, Bo; Klareskog, Lars; Padyukov, Leonid; Finan, Chris; Kalsi, Gursharan; Roberts, Marion; Logan, Darren W; Peltonen, Leena; Ritchie, Graham RS; Barrett, Jeffrey C; Estivill, Xavier; Hinney, Anke; Sullivan, Patrick F; Collier, David A; Zeggini, Eleftheria; Bulik, Cynthia M

    2013-01-01

    Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2,907 cases with AN from 14 countries (15 sites) and 14,860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery datasets. Seventy-six (72 independent) SNPs were taken forward for in silico (two datasets) or de novo (13 datasets) replication genotyping in 2,677 independent AN cases and 8,629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication datasets comprised 5,551 AN cases and 21,080 controls. AN subtype analyses (1,606 AN restricting; 1,445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01×10−7) in SOX2OT and rs17030795 (P=5.84×10−6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76×10−6) between CUL3 and FAM124B and rs1886797 (P=8.05×10−6) near SPATA13. Comparing discovery to replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P= 4×10−6), strongly suggesting that true findings exist but that our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field. PMID:21079607

  1. Comparative analysis of genome-wide divergence, domestication footprints and genome-wide association study of root traits for Gossypium hirsutum and Gossypium barbadense

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Use of 10,129 singleton SNPs of known genomic location in tetraploid cotton provided unique opportunities to characterize genome-wide diversity among 440 Gossypium hirsutum and 219 G. barbadense cultivars and landrace accessions of widespread origin. Using genome-wide distributed SNPs, we examined ...

  2. Canine hip dysplasia: phenotypic scoring and the role of estimated breeding value analysis.

    PubMed

    Soo, M; Worth, Aj

    2015-03-01

    Canine hip dysplasia (CHD) is a developmental orthopaedic disease of the coxofemoral joints with a multifactorial mode of inheritance. Multiple gene effects are influenced by environmental factors; therefore, it is unlikely that a simple genetic screening test with which to identify susceptible individuals will be developed in the near future. In the absence of feasible methods for objectively quantifying clinical CHD, radiographic techniques have been developed and widely used to identify dogs for breeding which are less affected by the disease. A hip-extended ventrodorsal view of the pelvis has been traditionally used to identify dogs with subluxation and/or osteoarthritis of the coxofemoral joints. More recently, there has been emphasis on the role of coxofemoral joint laxity as a determinant of CHD and methods have been developed to measure passive hip laxity. Though well-established worldwide, the effectiveness of traditional phenotypic scoring schemes in reducing the prevalence of CHD has been variable. The most successful implementation of traditional CHD scoring has occurred in countries or breeding colonies with mandatory scoring and open registries with access to pedigree records. Several commentators have recommended that for quantitative traits like CHD, selection of breeding stock should be based on estimated breeding values (EBV) rather than individual hip score/grade. The EBV is a reflection of the genetic superiority of an animal compared to its counterparts and is calculated from the phenotype of an individual and its relatives and their pedigree relationship. Selecting breeding stock on the basis of a dog's genetic merit, ideally based on a highly predictive phenotype, will confer the breeder with greater selection power, accelerate genetic improvement towards better hip conformation and thus more likely decrease the prevalence of CHD. PMID:25072401

  3. Genome-Wide Association of the Laboratory-Based Nicotine Metabolite Ratio in Three Ancestries

    PubMed Central

    Baurley, James W.; Edlund, Christopher K.; Pardamean, Carissa I.; Conti, David V.; Krasnow, Ruth; Javitz, Harold S.; Hops, Hyman; Swan, Gary E.; Benowitz, Neal L.

    2016-01-01

    Introduction: Metabolic enzyme variation and other patient and environmental characteristics influence smoking behaviors, treatment success, and risk of related disease. Population-specific variation in metabolic genes contributes to challenges in developing and optimizing pharmacogenetic interventions. We applied a custom genome-wide genotyping array for addiction research (Smokescreen), to three laboratory-based studies of nicotine metabolism with oral or venous administration of labeled nicotine and cotinine, to model nicotine metabolism in multiple populations. The trans-3′-hydroxycotinine/cotinine ratio, the nicotine metabolite ratio (NMR), was the nicotine metabolism measure analyzed. Methods: Three hundred twelve individuals of self-identified European, African, and Asian American ancestry were genotyped and included in ancestry-specific genome-wide association scans (GWAS) and a meta-GWAS analysis of the NMR. We modeled natural-log transformed NMR with covariates: principal components of genetic ancestry, age, sex, body mass index, and smoking status. Results: African and Asian American NMRs were statistically significantly (P values ≤ 5E-5) lower than European American NMRs. Meta-GWAS analysis identified 36 genome-wide significant variants over a 43 kilobase pair region at CYP2A6 with minimum P = 2.46E-18 at rs12459249, proximal to CYP2A6. Additional minima were located in intron 4 (rs56113850, P = 6.61E-18) and in the CYP2A6-CYP2A7 intergenic region (rs34226463, P = 1.45E-12). Most (34/36) genome-wide significant variants suggested reduced CYP2A6 activity; functional mechanisms were identified and tested in knowledge-bases. Conditional analysis resulted in intergenic variants of possible interest (P values < 5E-5). Conclusions: This meta-GWAS of the NMR identifies CYP2A6 variants, replicates the top-ranked single nucleotide polymorphism from a recent Finnish meta-GWAS of the NMR, identifies functional mechanisms, and provides pan

  4. A genome-wide association study of copy number variations with umbilical hernia in swine.

    PubMed

    Long, Yi; Su, Ying; Ai, Huashui; Zhang, Zhiyan; Yang, Bin; Ruan, Guorong; Xiao, Shijun; Liao, Xinjun; Ren, Jun; Huang, Lusheng; Ding, Nengshui

    2016-06-01

    Umbilical hernia (UH) is one of the most common congenital defects in pigs, leading to considerable economic loss and serious animal welfare problems. To test whether copy number variations (CNVs) contribute to pig UH, we performed a case-control genome-wide CNV association study on 905 pigs from the Duroc, Landrace and Yorkshire breeds using the Porcine SNP60 BeadChip and penncnv algorithm. We first constructed a genomic map comprising 6193 CNVs that pertain to 737 CNV regions. Then, we identified eight CNVs significantly associated with the risk for UH in the three pig breeds. Six of seven significantly associated CNVs were validated using quantitative real-time PCR. Notably, a rare CNV (CNV14:13030843-13059455) encompassing the NUGGC gene was strongly associated with UH (permutation-corrected P = 0.0015) in Duroc pigs. This CNV occurred exclusively in seven Duroc UH-affected individuals. SNPs surrounding the CNV did not show association signals, indicating that rare CNVs may play an important role in complex pig diseases such as UH. The NUGGC gene has been implicated in human omphalocele and inguinal hernia. Our finding supports that CNVs, including the NUGGC CNV, contribute to the pathogenesis of pig UH. PMID:27028052

  5. Meta-analysis of genome-wide association from genomic prediction models.

    PubMed

    Bernal Rubio, Y L; Gualdrón Duarte, J L; Bates, R O; Ernst, C W; Nonneman, D; Rohrer, G A; King, A; Shackelford, S D; Wheeler, T L; Cantet, R J C; Steibel, J P

    2016-02-01

    Genome-wide association (GWA) studies based on GBLUP models are a common practice in animal breeding. However, effect sizes of GWA tests are small, requiring larger sample sizes to enhance power of detection of rare variants. Because of difficulties in increasing sample size in animal populations, one alternative is to implement a meta-analysis (MA), combining information and results from independent GWA studies. Although this methodology has been used widely in human genetics, implementation in animal breeding has been limited. Thus, we present methods to implement a MA of GWA, describing the proper approach to compute weights derived from multiple genomic evaluations based on animal-centric GBLUP models. Application to real datasets shows that MA increases power of detection of associations in comparison with population-level GWA, allowing for population structure and heterogeneity of variance components across populations to be accounted for. Another advantage of MA is that it does not require access to genotype data that is required for a joint analysis. Scripts related to the implementation of this approach, which consider the strength of association as well as the sign, are distributed and thus account for heterogeneity in association phase between QTL and SNPs. Thus, MA of GWA is an attractive alternative to summarizing results from multiple genomic studies, avoiding restrictions with genotype data sharing, definition of fixed effects and different scales of measurement of evaluated traits. PMID:26607299

  6. Employing genome-wide SNP discovery and genotyping strategy to extrapolate the natural allelic diversity and domestication patterns in chickpea

    PubMed Central

    Kujur, Alice; Bajaj, Deepak; Upadhyaya, Hari D.; Das, Shouvik; Ranjan, Rajeev; Shree, Tanima; Saxena, Maneesha S.; Badoni, Saurabh; Kumar, Vinod; Tripathi, Shailesh; Gowda, C. L. L.; Sharma, Shivali; Singh, Sube; Tyagi, Akhilesh K.; Parida, Swarup K.

    2015-01-01

    regulating important complex quantitative agronomic traits in chickpea. The numerous informative genome-wide SNPs, natural allelic diversity-led domestication pattern, and LD-based information generated in our study have got multidimensional applicability with respect to chickpea genomics-assisted breeding. PMID:25873920

  7. Genome-Wide Linkage Analysis Identifies Loci for Physical Appearance Traits in Chickens

    PubMed Central

    Sun, Yanfa; Liu, Ranran; Zhao, Guiping; Zheng, Maiqing; Sun, Yan; Yu, Xiaoqiong; Li, Peng; Wen, Jie

    2015-01-01

    Physical appearance traits, such as feather-crested head, comb size and type, beard, wattles size, and feathered feet, are used to distinguish between breeds of chicken and also may be associated with economic traits. In this study, a genome-wide linkage analysis was used to identify candidate regions and genes for physical appearance traits and to potentially provide further knowledge of the molecular mechanisms that underlie these traits. The linkage analysis was conducted with an F2 population derived from Beijing-You chickens and a commercial broiler line. Single-nucleotide polymorphisms were analyzed using the Illumina 60K Chicken SNP Beadchip. The data were used to map quantitative trait loci and genes for six physical appearance traits. A 10-cM/0.51-Mb region (0.0−10.0 cM/0.00−0.51 Mb) with 1% genome-wide significant level on LGE22C19W28_E50C23 linkage group (LGE22) for crest trait was identified, which is likely very closely linked to the HOXC8. A QTL with 5% chromosome-wide significant level for comb weight, which partly overlaps with a region identified in a previous study, was identified at 74 cM/25.55 Mb on chicken (Gallus gallus; GG) chromosome 3 (i.e., GGA3). For beard and wattles traits, an identical region 11 cM/2.23 Mb (0.0−11.0 cM/0.00−2.23 Mb) including WNT3 and GH genes on GGA27 was identified. Two QTL with 1% genome-wide significant level for feathered feet trait, one 9-cM/2.80-Mb (48.0-57.0/13.40-16.20 Mb) region on GGA13, and another 12-cM/1.45-Mb (41.0−53.0 cM/11.37−12.82 Mb) region on GGA15 were identified. These candidate regions and genes provide important genetic information for the physical appearance traits in chicken. PMID:26248982

  8. Family-Based Genome-Wide Association Scan of Attention-Deficit/Hyperactivity Disorder

    PubMed Central

    Mick, Eric; Todorov, Alexandre; Smalley, Susan; Hu, Xiaolan; Loo, Sandra; Todd, Richard D.; Biederman, Joseph; Byrne, Deirdre; Dechairo, Bryan; Guiney, Allan; McCracken, James; McGough, James; Nelson, Stanley F.; Reiersen, Angela M.; Wilens, Timothy E.; Wozniak, Janet; Neale, Benjamin M.; Faraone, Stephen V.

    2013-01-01

    Objective . Genes likely play a substantial role in the etiology of attention-deficit hyperactivity disorder (ADHD). However, the genetic architecture of the disorder is unknown, and prior genome-wide association studies have not identified a genome-wide significant association. We have conducted a third, independent multi-site GWAS of DSM-IV-TR ADHD. Method . Families were ascertained at Massachusetts General Hospital (MGH, N=309 trios), Washington University at St Louis (WASH-U, N=272 trios), and University of California at Los Angeles (UCLA, N=156 trios). Genotyping was conducted with the Illumina Human1M or Human1M-Duo BeadChip platforms. After applying quality control filters, association with ADHD was tested with 835,136 SNPs in 735 DSM-IV ADHD trios from 732 families. Results . Our smallest p-value (6.7E-07) did not reach the threshold for genome-wide statistical significance (5.0E-08) but one of the 20 most significant associations was located in a candidate gene of interest for ADHD, (SLC9A9, rs9810857, p=6.4E-6). We also conducted gene-based tests of candidate genes identified in the literature and found additional evidence of association with SLC9A9. Conclusion . We and our colleagues in the Psychiatric GWAS Consortium are working to pool together GWAS samples to establish the large data sets needed to follow-up on these results and to identify genes for ADHD and other disorders. PMID:20732626

  9. Identification of Promising Mutants Associated with Egg Production Traits Revealed by Genome-Wide Association Study

    PubMed Central

    Dou, Taocun; Yi, Guoqiang; Qu, LuJiang; Qu, Liang; Wang, Kehua; Yang, Ning

    2015-01-01

    Egg number (EN), egg laying rate (LR) and age at first egg (AFE) are important production traits related to egg production in poultry industry. To better understand the knowledge of genetic architecture of dynamic EN during the whole laying cycle and provide the precise positions of associated variants for EN, LR and AFE, laying records from 21 to 72 weeks of age were collected individually for 1,534 F2 hens produced by reciprocal crosses between White Leghorn and Dongxiang Blue-shelled chicken, and their genotypes were assayed by chicken 600 K Affymetrix high density genotyping arrays. Subsequently, pedigree and SNP-based genetic parameters were estimated and a genome-wide association study (GWAS) was conducted on EN, LR and AFE. The heritability estimates were similar between pedigree and SNP-based estimates varying from 0.17 to 0.36. In the GWA analysis, we identified nine genome-wide significant loci associated with EN of the laying periods from 21 to 26 weeks, 27 to 36 weeks and 37 to 72 weeks. Analysis of GTF2A1 and CLSPN suggested that they influenced the function of ovary and uterus, and may be considered as relevant candidates. The identified SNP rs314448799 for accumulative EN from 21 to 40 weeks on chromosome 5 created phenotypic differences of 6.86 eggs between two homozygous genotypes, which could be potentially applied to the molecular breeding for EN selection. Moreover, our finding showed that LR was a moderate polygenic trait. The suggestive significant region on chromosome 16 for AFE suggested the relationship between sex maturity and immune in the current population. The present study comprehensively evaluates the role of genetic variants in the development of egg laying. The findings will be helpful to investigation of causative genes function and future marker-assisted selection and genomic selection in chickens. PMID:26496084

  10. Development of genome-wide insertion/deletion markers in rice based on graphic pipeline platform.

    PubMed

    Lü, Yang; Cui, Xiao; Li, Rui; Huang, Piaopiao; Zong, Jie; Yao, Danqing; Li, Gang; Zhang, Dabing; Yuan, Zheng

    2015-11-01

    DNA markers play important roles in plant breeding and genetics. The Insertion/Deletion (InDel) marker is one kind of co-dominant DNA markers widely used due to its low cost and high precision. However, the canonical way of searching for InDel markers is time-consuming and labor-intensive. We developed an end-to-end computational solution (InDel Markers Development Platform, IMDP) to identify genome-wide InDel markers under a graphic pipeline environment. IMDP constitutes assembled genome sequences alignment pipeline (AGA-pipe) and next-generation re-sequencing data mapping pipeline (NGS-pipe). With AGA-pipe we are able to identify 12,944 markers between the genome of rice cultivars Nipponbare and 93-11. Using NGS-pipe, we reported 34,794 InDels from re-sequencing data of rice cultivars Wu-Yun-Geng7 and Guang-Lu-Ai4. Combining AGA-pipe and NGS-pipe, we developed 205,659 InDels in eight japonica and nine indica cultivars and 2,681 InDels showed a subgroup-specific pattern. Polymerase chain reaction (PCR) analysis of subgroup-specific markers indicated that the precision reached 90% (86 of 95). Finally, to make them available to the public, we have integrated the InDels/markers information into a website (Rice InDel Marker Database, RIMD, http://202.120.45.71/). The application of IMDP in rice will facilitate efficiency for development of genome-wide InDel markers, in addition it can be used in other species with reference genome sequences and NGS data. PMID:25809845

  11. Genome-Wide Association Identifies SLC2A9 and NLN Gene Regions as Associated with Entropion in Domestic Sheep.

    PubMed

    Mousel, Michelle R; Reynolds, James O; White, Stephen N

    2015-01-01

    Entropion is an inward rolling of the eyelid allowing contact between the eyelashes and cornea that may lead to blindness if not corrected. Although many mammalian species, including humans and dogs, are afflicted by congenital entropion, no specific genes or gene regions related to development of entropion have been reported in any mammalian species to date. Entropion in domestic sheep is known to have a genetic component therefore, we used domestic sheep as a model system to identify genomic regions containing genes associated with entropion. A genome-wide association was conducted with congenital entropion in 998 Columbia, Polypay, and Rambouillet sheep genotyped with 50,000 SNP markers. Prevalence of entropion was 6.01%, with all breeds represented. Logistic regression was performed in PLINK with additive allelic, recessive, dominant, and genotypic inheritance models. Two genome-wide significant (empirical P<0.05) SNP were identified, specifically markers in SLC2A9 (empirical P = 0.007; genotypic model) and near NLN (empirical P = 0.026; dominance model). Six additional genome-wide suggestive SNP (nominal P<1x10(-5)) were identified including markers in or near PIK3CB (P = 2.22x10(-6); additive model), KCNB1 (P = 2.93x10(-6); dominance model), ZC3H12C (P = 3.25x10(-6); genotypic model), JPH1 (P = 4.68x20(-6); genotypic model), and MYO3B (P = 5.74x10(-6); recessive model). This is the first report of specific gene regions associated with congenital entropion in any mammalian species, to our knowledge. Further, none of these genes have previously been associated with any eyelid traits. These results represent the first genome-wide analysis of gene regions associated with entropion and provide target regions for the development of sheep genetic markers for marker-assisted selection. PMID:26098909

  12. Genome-Wide Association Identifies SLC2A9 and NLN Gene Regions as Associated with Entropion in Domestic Sheep

    PubMed Central

    Mousel, Michelle R.; Reynolds, James O.; White, Stephen N.

    2015-01-01

    Entropion is an inward rolling of the eyelid allowing contact between the eyelashes and cornea that may lead to blindness if not corrected. Although many mammalian species, including humans and dogs, are afflicted by congenital entropion, no specific genes or gene regions related to development of entropion have been reported in any mammalian species to date. Entropion in domestic sheep is known to have a genetic component therefore, we used domestic sheep as a model system to identify genomic regions containing genes associated with entropion. A genome-wide association was conducted with congenital entropion in 998 Columbia, Polypay, and Rambouillet sheep genotyped with 50,000 SNP markers. Prevalence of entropion was 6.01%, with all breeds represented. Logistic regression was performed in PLINK with additive allelic, recessive, dominant, and genotypic inheritance models. Two genome-wide significant (empirical P<0.05) SNP were identified, specifically markers in SLC2A9 (empirical P = 0.007; genotypic model) and near NLN (empirical P = 0.026; dominance model). Six additional genome-wide suggestive SNP (nominal P<1x10-5) were identified including markers in or near PIK3CB (P = 2.22x10-6; additive model), KCNB1 (P = 2.93x10-6; dominance model), ZC3H12C (P = 3.25x10-6; genotypic model), JPH1 (P = 4.68x20-6; genotypic model), and MYO3B (P = 5.74x10-6; recessive model). This is the first report of specific gene regions associated with congenital entropion in any mammalian species, to our knowledge. Further, none of these genes have previously been associated with any eyelid traits. These results represent the first genome-wide analysis of gene regions associated with entropion and provide target regions for the development of sheep genetic markers for marker-assisted selection. PMID:26098909

  13. Genome-wide association analyses in East Asians identify new susceptibility loci for colorectal cancer

    PubMed Central

    Jia, Wei-Hua; Zhang, Ben; Matsuo, Keitaro; Shin, Aesun; Xiang, Yong-Bing; Jee, Sun Ha; Kim, Dong-Hyun; Ren, Zefang; Cai, Qiuyin; Long, Jirong; Shi, Jiajun; Wen, Wanqing; Yang, Gong; Delahanty, Ryan J.; Ji, Bu-Tian; Pan, Zhi-Zhong; Matsuda, Fumihiko; Gao, Yu-Tang; Oh, Jae Hwan; Ahn, Yoon-Ok; Park, Eun Jung; Li, Hong-Lan; Park, Ji Won; Jo, Jaeseong; Jeong, Jin-Young; Hosono, Satoyo; Casey, Graham; Peters, Ulrike; Shu, Xiao-Ou; Zeng, Yi-Xin; Zheng, Wei

    2013-01-01

    To identify novel genetic factors for colorectal cancer (CRC), we conducted a genome-wide association study in East Asians. By analyzing genome-wide data in 2,098 cases and 5,749 controls, we selected 64 promising SNPs for replication in an independent set of samples including up to 5,358 cases and 5,922 controls. We identified four SNPs with a P-value of 8.58 × 10−7 to 3.77 × 10−10 in the combined analysis of all East Asian samples. Three of the four SNPs were replicated in a study conducted among 26,060 European descendants with a combined P-value of 1.22 × 10−10 for rs647161 (5q31.1), 6.64 × 10−9 for rs2423279 (20p12.3), and 3.06 × 10−8 for rs10774214 (12p13.32 near the CCND2 gene), respectively, derived from the meta-analysis of data from both East Asian and European populations. This study identified three new CRC susceptibility loci and provides additional insight into the genetics and biology of CRC. PMID:23263487

  14. A powerful test of independent assortment that determines genome-wide significance quickly and accurately

    PubMed Central

    Stewart, W C L; Hager, V R

    2016-01-01

    In the analysis of DNA sequences on related individuals, most methods strive to incorporate as much information as possible, with little or no attention paid to the issue of statistical significance. For example, a modern workstation can easily handle the computations needed to perform a large-scale genome-wide inheritance-by-descent (IBD) scan, but accurate assessment of the significance of that scan is often hindered by inaccurate approximations and computationally intensive simulation. To address these issues, we developed gLOD—a test of co-segregation that, for large samples, models chromosome-specific IBD statistics as a collection of stationary Gaussian processes. With this simple model, the parametric bootstrap yields an accurate and rapid assessment of significance—the genome-wide corrected P-value. Furthermore, we show that (i) under the null hypothesis, the limiting distribution of the gLOD is the standard Gumbel distribution; (ii) our parametric bootstrap simulator is approximately 40 000 times faster than gene-dropping methods, and it is more powerful than methods that approximate the adjusted P-value; and, (iii) the gLOD has the same statistical power as the widely used maximum Kong and Cox LOD. Thus, our approach gives researchers the ability to determine quickly and accurately the significance of most large-scale IBD scans, which may contain multiple traits, thousands of families and tens of thousands of DNA sequences. PMID:27245422

  15. A Genome-Wide Association Study of Total Bilirubin and Cholelithiasis Risk in Sickle Cell Anemia

    PubMed Central

    Milton, Jacqueline N.; Sebastiani, Paola; Solovieff, Nadia; Hartley, Stephen W.; Bhatnagar, Pallav; Arking, Dan E.; Dworkis, Daniel A.; Casella, James F.; Barron-Casella, Emily; Bean, Christopher J.; Hooper, W. Craig; DeBaun, Michael R.; Garrett, Melanie E.; Soldano, Karen; Telen, Marilyn J.; Ashley-Koch, Allison; Gladwin, Mark T.; Baldwin, Clinton T.; Steinberg, Martin H.; Klings, Elizabeth S.

    2012-01-01

    Serum bilirubin levels have been associated with polymorphisms in the UGT1A1 promoter in normal populations and in patients with hemolytic anemias, including sickle cell anemia. When hemolysis occurs circulating heme increases, leading to elevated bilirubin levels and an increased incidence of cholelithiasis. We performed the first genome-wide association study (GWAS) of bilirubin levels and cholelithiasis risk in a discovery cohort of 1,117 sickle cell anemia patients. We found 15 single nucleotide polymorphisms (SNPs) associated with total bilirubin levels at the genome-wide significance level (p value <5×10−8). SNPs in UGT1A1, UGT1A3, UGT1A6, UGT1A8 and UGT1A10, different isoforms within the UGT1A locus, were identified (most significant rs887829, p = 9.08×10−25). All of these associations were validated in 4 independent sets of sickle cell anemia patients. We tested the association of the 15 SNPs with cholelithiasis in the discovery cohort and found a significant association (most significant p value 1.15×10−4). These results confirm that the UGT1A region is the major regulator of bilirubin metabolism in African Americans with sickle cell anemia, similar to what is observed in other ethnicities. PMID:22558097

  16. A powerful test of independent assortment that determines genome-wide significance quickly and accurately.

    PubMed

    Stewart, W C L; Hager, V R

    2016-08-01

    In the analysis of DNA sequences on related individuals, most methods strive to incorporate as much information as possible, with little or no attention paid to the issue of statistical significance. For example, a modern workstation can easily handle the computations needed to perform a large-scale genome-wide inheritance-by-descent (IBD) scan, but accurate assessment of the significance of that scan is often hindered by inaccurate approximations and computationally intensive simulation. To address these issues, we developed gLOD-a test of co-segregation that, for large samples, models chromosome-specific IBD statistics as a collection of stationary Gaussian processes. With this simple model, the parametric bootstrap yields an accurate and rapid assessment of significance-the genome-wide corrected P-value. Furthermore, we show that (i) under the null hypothesis, the limiting distribution of the gLOD is the standard Gumbel distribution; (ii) our parametric bootstrap simulator is approximately 40 000 times faster than gene-dropping methods, and it is more powerful than methods that approximate the adjusted P-value; and, (iii) the gLOD has the same statistical power as the widely used maximum Kong and Cox LOD. Thus, our approach gives researchers the ability to determine quickly and accurately the significance of most large-scale IBD scans, which may contain multiple traits, thousands of families and tens of thousands of DNA sequences. PMID:27245422

  17. Refining genome-wide linkage intervals using a meta-analysis of genome-wide association studies identifies loci influencing personality dimensions.

    PubMed

    Amin, Najaf; Hottenga, Jouke-Jan; Hansell, Narelle K; Janssens, A Cecile J W; de Moor, Marleen H M; Madden, Pamela A F; Zorkoltseva, Irina V; Penninx, Brenda W; Terracciano, Antonio; Uda, Manuela; Tanaka, Toshiko; Esko, Tonu; Realo, Anu; Ferrucci, Luigi; Luciano, Michelle; Davies, Gail; Metspalu, Andres; Abecasis, Goncalo R; Deary, Ian J; Raikkonen, Katri; Bierut, Laura J; Costa, Paul T; Saviouk, Viatcheslav; Zhu, Gu; Kirichenko, Anatoly V; Isaacs, Aaron; Aulchenko, Yurii S; Willemsen, Gonneke; Heath, Andrew C; Pergadia, Michele L; Medland, Sarah E; Axenovich, Tatiana I; de Geus, Eco; Montgomery, Grant W; Wright, Margaret J; Oostra, Ben A; Martin, Nicholas G; Boomsma, Dorret I; van Duijn, Cornelia M

    2013-08-01

    Personality traits are complex phenotypes related to psychosomatic health. Individually, various gene finding methods have not achieved much success in finding genetic variants associated with personality traits. We performed a meta-analysis of four genome-wide linkage scans (N=6149 subjects) of five basic personality traits assessed with the NEO Five-Factor Inventory. We compared the significant regions from the meta-analysis of linkage scans with the results of a meta-analysis of genome-wide association studies (GWAS) (N∼17 000). We found significant evidence of linkage of neuroticism to chromosome 3p14 (rs1490265, LOD=4.67) and to chromosome 19q13 (rs628604, LOD=3.55); of extraversion to 14q32 (ATGG002, LOD=3.3); and of agreeableness to 3p25 (rs709160, LOD=3.67) and to two adjacent regions on chromosome 15, including 15q13 (rs970408, LOD=4.07) and 15q14 (rs1055356, LOD=3.52) in the individual scans. In the meta-analysis, we found strong evidence of linkage of extraversion to 4q34, 9q34, 10q24 and 11q22, openness to 2p25, 3q26, 9p21, 11q24, 15q26 and 19q13 and agreeableness to 4q34 and 19p13. Significant evidence of association in the GWAS was detected between openness and rs677035 at 11q24 (P-value=2.6 × 10(-06), KCNJ1). The findings of our linkage meta-analysis and those of the GWAS suggest that 11q24 is a susceptible locus for openness, with KCNJ1 as the possible candidate gene. PMID:23211697

  18. Genome-wide pathway analysis of genome-wide association studies on systemic lupus erythematosus and rheumatoid arthritis.

    PubMed

    Lee, Young Ho; Bae, Sang-Cheol; Choi, Sung Jae; Ji, Jong Dae; Song, Gwan Gyu

    2012-12-01

    The aim of this study was to explore candidate single nucleotide polymorphisms (SNPs) and candidate mechanisms of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Two SLE genome-wide association studies (GWASs) datasets were included in this study. Meta-analysis was conducted using 737,984 SNPs in 1,527 SLE cases and 3,421 controls of European ancestry, and 4,429 SNPs that met a threshold of p < 0.01 in a Korean RA GWAS dataset was used. ICSNPathway (identify candidate causal SNPs and pathways) analysis was applied to the meta-analysis results of the SLE GWAS datasets, and a RA GWAS dataset. The most significant result of SLE GWAS meta-analysis concerned rs2051549 in the human leukocyte antigen (HLA) region (p = 3.36E-22). In the non-HLA region, meta-analysis identified 6 SNPs associated with SLE with genome-wide significance (STAT4, TNPO3, BLK, FAM167A, and IRF5). ICSNPathway identified five candidate causal SNPs and 13 candidate causal pathways. This pathway-based analysis provides three hypotheses of the biological mechanism involved. First, rs8084 and rs7192 → HLA-DRA → bystander B cell activation. Second, rs1800629 → TNF → cytokine network. Third, rs1150752 and rs185819 → TNXB → collagen metabolic process. ICSNPathway analysis identified three candidate causal non-HLA SNPs and four candidate causal pathways involving the PADI4, MTR, PADI2, and TPH2 genes of RA. We identified five candidate SNPs and thirteen pathways, involving bystander B cell activation, cytokine network, and collagen metabolic processing, which may contribute to SLE susceptibility, and we revealed candidate causal non-HLA SNPs, genes, and pathways of RA. PMID:23053960

  19. Analysis of genome-wide structure, diversity and fine mapping of Mendelian traits in traditional and village chickens

    PubMed Central

    Wragg, D; Mwacharo, J M; Alcalde, J A; Hocking, P M; Hanotte, O

    2012-01-01

    Extensive phenotypic variation is a common feature among village chickens found throughout much of the developing world, and in traditional chicken breeds that have been artificially selected for traits such as plumage variety. We present here an assessment of traditional and village chicken populations, for fine mapping of Mendelian traits using genome-wide single-nucleotide polymorphism (SNP) genotyping while providing information on their genetic structure and diversity. Bayesian clustering analysis reveals two main genetic backgrounds in traditional breeds, Kenyan, Ethiopian and Chilean village chickens. Analysis of linkage disequilibrium (LD) reveals useful LD (r2⩾0.3) in both traditional and village chickens at pairwise marker distances of ∼10 Kb; while haplotype block analysis indicates a median block size of 11–12 Kb. Association mapping yielded refined mapping intervals for duplex comb (Gga 2:38.55–38.89 Mb) and rose comb (Gga 7:18.41–22.09 Mb) phenotypes in traditional breeds. Combined mapping information from traditional breeds and Chilean village chicken allows the oocyan phenotype to be fine mapped to two small regions (Gga 1:67.25–67.28 Mb, Gga 1:67.28–67.32 Mb) totalling ∼75 Kb. Mapping the unmapped earlobe pigmentation phenotype supports previous findings that the trait is sex-linked and polygenic. A critical assessment of the number of SNPs required to map simple traits indicate that between 90 and 110K SNPs are required for full genome-wide analysis of haplotype block structure/ancestry, and for association mapping in both traditional and village chickens. Our results demonstrate the importance and uniqueness of phenotypic diversity and genetic structure of traditional chicken breeds for fine-scale mapping of Mendelian traits in the species, with village chicken populations providing further opportunities to enhance mapping resolutions. PMID:22395157

  20. Analysis of genome-wide structure, diversity and fine mapping of Mendelian traits in traditional and village chickens.

    PubMed

    Wragg, D; Mwacharo, J M; Alcalde, J A; Hocking, P M; Hanotte, O

    2012-07-01

    Extensive phenotypic variation is a common feature among village chickens found throughout much of the developing world, and in traditional chicken breeds that have been artificially selected for traits such as plumage variety. We present here an assessment of traditional and village chicken populations, for fine mapping of Mendelian traits using genome-wide single-nucleotide polymorphism (SNP) genotyping while providing information on their genetic structure and diversity. Bayesian clustering analysis reveals two main genetic backgrounds in traditional breeds, Kenyan, Ethiopian and Chilean village chickens. Analysis of linkage disequilibrium (LD) reveals useful LD (r(2) ≥ 0.3) in both traditional and village chickens at pairwise marker distances of ~10 Kb; while haplotype block analysis indicates a median block size of 11-12 Kb. Association mapping yielded refined mapping intervals for duplex comb (Gga 2:38.55-38.89 Mb) and rose comb (Gga 7:18.41-22.09 Mb) phenotypes in traditional breeds. Combined mapping information from traditional breeds and Chilean village chicken allows the oocyan phenotype to be fine mapped to two small regions (Gga 1:67.25-67.28 Mb, Gga 1:67.28-67.32 Mb) totalling ~75 Kb. Mapping the unmapped earlobe pigmentation phenotype supports previous findings that the trait is sex-linked and polygenic. A critical assessment of the number of SNPs required to map simple traits indicate that between 90 and 110K SNPs are required for full genome-wide analysis of haplotype block structure/ancestry, and for association mapping in both traditional and village chickens. Our results demonstrate the importance and uniqueness of phenotypic diversity and genetic structure of traditional chicken breeds for fine-scale mapping of Mendelian traits in the species, with village chicken populations providing further opportunities to enhance mapping resolutions. PMID:22395157

  1. Genome-wide Association Study to Identify Quantitative Trait Loci for Meat and Carcass Quality Traits in Berkshire.

    PubMed

    Iqbal, Asif; Kim, You-Sam; Kang, Jun-Mo; Lee, Yun-Mi; Rai, Rajani; Jung, Jong-Hyun; Oh, Dong-Yup; Nam, Ki-Chang; Lee, Hak-Kyo; Kim, Jong-Joo

    2015-11-01

    Meat and carcass quality attributes are of crucial importance influencing consumer preference and profitability in the pork industry. A set of 400 Berkshire pigs were collected from Dasan breeding farm, Namwon, Chonbuk province, Korea that were born between 2012 and 2013. To perform genome wide association studies (GWAS), eleven meat and carcass quality traits were considered, including carcass weight, backfat thickness, pH value after 24 hours (pH24), Commission Internationale de l'Eclairage lightness in meat color (CIE L), redness in meat color (CIE a), yellowness in meat color (CIE b), filtering, drip loss, heat loss, shear force and marbling score. All of the 400 animals were genotyped with the Porcine 62K SNP BeadChips (Illumina Inc., USA). A SAS general linear model procedure (SAS version 9.2) was used to pre-adjust the animal phenotypes before GWAS with sire and sex effects as fixed effects and slaughter age as a covariate. After fitting the fixed and covariate factors in the model, the residuals of the phenotype regressed on additive effects of each single nucleotide polymorphism (SNP) under a linear regression model (PLINK version 1.07). The significant SNPs after permutation testing at a chromosome-wise level were subjected to stepwise regression analysis to determine the best set of SNP markers. A total of 55 significant (p<0.05) SNPs or quantitative trait loci (QTL) were detected on various chromosomes. The QTLs explained from 5.06% to 8.28% of the total phenotypic variation of the traits. Some QTLs with pleiotropic effect were also identified. A pair of significant QTL for pH24 was also found to affect both CIE L and drip loss percentage. The significant QTL after characterization of the functional candidate genes on the QTL or around the QTL region may be effectively and efficiently used in marker assisted selection to achieve enhanced genetic improvement of the trait considered. PMID:26580276

  2. Genome-wide Association Study to Identify Quantitative Trait Loci for Meat and Carcass Quality Traits in Berkshire

    PubMed Central

    Iqbal, Asif; Kim, You-Sam; Kang, Jun-Mo; Lee, Yun-Mi; Rai, Rajani; Jung, Jong-Hyun; Oh, Dong-Yup; Nam, Ki-Chang; Lee, Hak-Kyo; Kim, Jong-Joo

    2015-01-01

    Meat and carcass quality attributes are of crucial importance influencing consumer preference and profitability in the pork industry. A set of 400 Berkshire pigs were collected from Dasan breeding farm, Namwon, Chonbuk province, Korea that were born between 2012 and 2013. To perform genome wide association studies (GWAS), eleven meat and carcass quality traits were considered, including carcass weight, backfat thickness, pH value after 24 hours (pH24), Commission Internationale de l’Eclairage lightness in meat color (CIE L), redness in meat color (CIE a), yellowness in meat color (CIE b), filtering, drip loss, heat loss, shear force and marbling score. All of the 400 animals were genotyped with the Porcine 62K SNP BeadChips (Illumina Inc., USA). A SAS general linear model procedure (SAS version 9.2) was used to pre-adjust the animal phenotypes before GWAS with sire and sex effects as fixed effects and slaughter age as a covariate. After fitting the fixed and covariate factors in the model, the residuals of the phenotype regressed on additive effects of each single nucleotide polymorphism (SNP) under a linear regression model (PLINK version 1.07). The significant SNPs after permutation testing at a chromosome-wise level were subjected to stepwise regression analysis to determine the best set of SNP markers. A total of 55 significant (p<0.05) SNPs or quantitative trait loci (QTL) were detected on various chromosomes. The QTLs explained from 5.06% to 8.28% of the total phenotypic variation of the traits. Some QTLs with pleiotropic effect were also identified. A pair of significant QTL for pH24 was also found to affect both CIE L and drip loss percentage. The significant QTL after characterization of the functional candidate genes on the QTL or around the QTL region may be effectively and efficiently used in marker assisted selection to achieve enhanced genetic improvement of the trait considered. PMID:26580276

  3. The Genetic Architecture of Seed Composition in Soybean Is Refined by Genome-Wide Association Scans Across Multiple Populations

    PubMed Central

    Vaughn, Justin N.; Nelson, Randall L.; Song, Qijian; Cregan, Perry B.; Li, Zenglu

    2014-01-01

    Soybean oil and meal are major contributors to world-wide food production. Consequently, the genetic basis for soybean seed composition has been intensely studied using family-based mapping. Population-based mapping approaches, in the form of genome-wide association (GWA) scans, have been able to resolve loci controlling moderately complex quantitative traits (QTL) in numerous crop species. Yet, it is still unclear how soybean’s unique population history will affect GWA scans. Using one of the populations in this study, we simulated phenotypes resulting from a range of genetic architectures. We found that with a heritability of 0.5, ∼100% and ∼33% of the 4 and 20 simulated QTL can be recovered, respectively, with a false-positive rate of less than ∼6×10−5 per marker tested. Additionally, we demonstrated that combining information from multi-locus mixed models and compressed linear-mixed models improves QTL identification and interpretation. We applied these insights to exploring seed composition in soybean, refining the linkage group I (chromosome 20) protein QTL and identifying additional oil QTL that may allow some decoupling of highly correlated oil and protein phenotypes. Because the value of protein meal is closely related to its essential amino acid profile, we attempted to identify QTL underlying methionine, threonine, cysteine, and lysine content. Multiple QTL were found that have not been observed in family-based mapping studies, and each trait exhibited associations across multiple populations. Chromosomes 1 and 8 contain strong candidate alleles for essential amino acid increases. Overall, we present these and additional data that will be useful in determining breeding strategies for the continued improvement of soybean’s nutrient portfolio. PMID:25246241

  4. Genome-wide SNP validation and mantle tissue transcriptome analysis in the silver-lipped pearl oyster, Pinctada maxima.

    PubMed

    Jones, David B; Jerry, Dean R; Forêt, Sylvain; Konovalov, Dmitry A; Zenger, Kyall R

    2013-12-01

    Pearl oysters are not only farmed for their gemstone quality pearls worldwide, but they are also becoming important model organisms for investigating genetic mechanisms of biomineralisation. Despite their economic and scientific significance, limited genomic resources are available for this important group of bivalves, hampering investigations into identifying genes that regulate important pearl quality traits and unique biological characteristics (i.e. biomineralisation). The silver-lipped pearl oyster, Pinctada maxima, is one species where there is interest in understanding genes that regulate commercially important pearl traits, but presently, there is a dearth of genomic information. The objective of this study was to develop and validate a large number of type I genome-wide single nucleotide polymorphisms (SNPs) for P. maxima suitable for high-throughput genotyping. In addition, sequence annotations and Gene Ontology terms were assigned to a large mantle tissue 454 expressed sequence tag assembly (96,794 contigs) and information on known bivalve biomineralisation genes was incorporated into SNP discovery. The SNP discovery effort resulted in the de novo identification of 172,625 SNPs, of which 9,108 were identified as high value [minor allele frequency (MAF)≥ 0.15, read depth  ≥ 8]. Validation of 2,782 of these SNPs using Illumina iSelect Infinium genotyping technology returned some of the highest assay conversion (86.6 %) and validation (59.9 %; mean MAF 0.28) rates observed in aquaculture species to date. Genomic resources presented here will be pivotal to future research investigating the biological mechanisms behind biomineralisation and will form a strong foundation for genetic selective breeding programs in the P. maxima pearling industry. PMID:23715808

  5. Genome-Wide Association Study for Endothelial Growth Factors

    PubMed Central

    Lieb, Wolfgang; Chen, Ming-Huei; Larson, Martin G.; Safa, Radwan; Teumer, Alexander; Baumeister, Sebastian E.; Lin, Honghuang; Smith, Holly M.; Koch, Manja; Lorbeer, Roberto; Völker, Uwe; Nauck, Matthias; Völzke, Henry; Wallaschofski, Henri; Sawyer, Douglas B.; Vasan, Ramachandran S.

    2015-01-01

    Background Endothelial growth factors including angiopoietin-2 (Ang-2), its soluble receptor Tie-2 (sTie-2) and hepatocyte growth factor (HGF) play important roles in angiogenesis, vascular remodeling, local tumor growth and metastatic potential of various cancers. Circulating levels of these biomarkers have a heritable component (between 13% and 56%), but the underlying genetic variation influencing these biomarker levels is largely unknown. Methods and Results We performed a genome-wide association study for circulating Ang-2, sTie-2, and HGF in 3571 Framingham Heart Study (FHS) participants and assessed replication of the top hits for Ang-2 and sTie-2 in 3184 participants of the Study of Health in Pomerania (SHIP). In multivariable-adjusted models, sTie-2 and HGF concentrations were associated with single nucleotide polymorphisms (SNPs) in the genes encoding the respective biomarkers (top p=2.40×10−65 [rs2273720] and 3.64×10−19 [rs5745687], respectively). Likewise, rs2442517 in the MCPH1 gene (in which the Ang-2 gene is embedded) was associated with Ang-2 levels (p=5.05×10−8 in FHS and 8.39×10−5 in SHIP). Furthermore, SNPs in the AB0 gene were associated with sTie-2 (top SNP rs8176693 with p=1.84×10−33 in FHS; p=2.53×10−30 in SHIP) and Ang-2 (rs8176746 with p=2.07×10−8 in FHS; p=0.001 in SHIP) levels on a genome-wide significant level. The top genetic loci explained between 1.7% (Ang-2) and 11.2% (sTie-2) of the inter-individual variation in biomarker levels. Conclusions Genetic variation contributes to the inter-individual variation in growth factor levels and explains a modest proportion of circulating HGF, Ang-2, and Tie-2. This may potentially contribute to the familial susceptibility to cancer, a premise that warrants further studies. PMID:25552591

  6. Minimalist ensemble algorithms for genome-wide protein localization prediction

    PubMed Central

    2012-01-01

    Background Computational prediction of protein subcellular localization can greatly help to elucidate its functions. Despite the existence of dozens of protein localization prediction algorithms, the prediction accuracy and coverage are still low. Several ensemble algorithms have been proposed to improve the prediction performance, which usually include as many as 10 or more individual localization algorithms. However, their performance is still limited by the running complexity and redundancy among individual prediction algorithms. Results This paper proposed a novel method for rational design of minimalist ensemble algorithms for practical genome-wide protein subcellular localization prediction. The algorithm is based on combining a feature selection based filter and a logistic regression classifier. Using a novel concept of contribution scores, we analyzed issues of algorithm redundancy, consensus mistakes, and algorithm complementarity in designing ensemble algorithms. We applied the proposed minimalist logistic regression (LR) ensemble algorithm to two genome-wide datasets of Yeast and Human and compared its performance with current ensemble algorithms. Experimental results showed that the minimalist ensemble algorithm can achieve high prediction accuracy with only 1/3 to 1/2 of individual predictors of current ensemble algorithms, which greatly reduces computational complexity and running time. It was found that the high performance ensemble algorithms are usually composed of the predictors that together cover most of available features. Compared to the best individual predictor, our ensemble algorithm improved the prediction accuracy from AUC score of 0.558 to 0.707 for the Yeast dataset and from 0.628 to 0.646 for the Human dataset. Compared with popular weighted voting based ensemble algorithms, our classifier-based ensemble algorithms achieved much better performance without suffering from inclusion of too many individual predictors. Conclusions We

  7. Genome-wide association reveals the locus responsible for four-horned ruminant.

    PubMed

    Kijas, James W; Hadfield, Tracy; Naval Sanchez, Marina; Cockett, Noelle

    2016-04-01

    Phenotypic variability in horn characteristics, such as their size, number and shape, offers the opportunity to elucidate the molecular basis of horn development. The objective of this study was to map the genetic determinant controlling the production of four horns in two breeds, Jacob sheep and Navajo-Churro, and examine whether an eyelid abnormality occurring in the same populations is related. Genome-wide association mapping was performed using 125 animals from the two breeds that contain two- and four-horned individuals. A case-control design analysis of 570 712 SNPs genotyped with the ovine HD SNP Beadchip revealed a strong association signal on sheep chromosome 2. The 10 most strongly associated SNPs were all located in a region spanning Mb positions 131.9-132.6, indicating the genetic architecture underpinning the production of four horns is likely to involve a single gene. The closest genes to the most strongly associated marker (OAR2_132568092) were MTX2 and the HOXD cluster, located approximately 93 Kb and 251 Kb upstream respectively. The occurrence of an eyelid malformation across both breeds was restricted to polled animals and those carrying more than two horns. This suggests the eyelid abnormality may be associated with departures from the normal developmental production of two-horned animals and that the two conditions are developmentally linked. This study demonstrated the presence of separate loci responsible for the polled and four-horned phenotypes in sheep and advanced our understanding of the complexity that underpins horn morphology in ruminants. PMID:26767438

  8. Marker-trait associations in Virginia Tech winter barley identified using genome-wide mapping.

    PubMed

    Berger, Gregory L; Liu, Shuyu; Hall, Marla D; Brooks, Wynse S; Chao, Shiaoman; Muehlbauer, Gary J; Baik, B-K; Steffenson, Brian; Griffey, Carl A

    2013-03-01

    Genome-wide association studies (GWAS) provide an opportunity to examine the genetic architecture of quantitatively inherited traits in breeding populations. The objectives of this study were to use GWAS to identify chromosome regions governing traits of importance in six-rowed winter barley (Hordeum vulgare L.) germplasm and to identify single-nucleotide polymorphisms (SNPs) markers that can be implemented in a marker-assisted breeding program. Advanced hulled and hulless lines (329 total) were screened using 3,072 SNPs as a part of the US. Barley Coordinated Agricultural Project (CAP). Phenotypic data collected over 4 years for agronomic and food quality traits and resistance to leaf rust (caused by Puccinia hordei G. Otth), powdery mildew [caused by Blumeria graminis (DC.) E.O. Speer f. sp. hordei Em. Marchal], net blotch (caused by Pyrenophora teres), and spot blotch [caused by Cochliobolus sativus (Ito and Kuribayashi) Drechsler ex Dastur] were analyzed with SNP genotypic data in a GWAS to determine marker-trait associations. Significant SNPs associated with previously described quantitative trait loci (QTL) or genes were identified for heading date on chromosome 3H, test weight on 2H, yield on 7H, grain protein on 5H, polyphenol oxidase activity on 2H and resistance to leaf rust on 2H and 3H, powdery mildew on 1H, 2H and 4H, net blotch on 5H, and spot blotch on 7H. Novel QTL also were identified for agronomic, quality, and disease resistance traits. These SNP-trait associations provide the opportunity to directly select for QTL contributing to multiple traits in breeding programs. PMID:23139143

  9. Genome-wide association for grain yield under rainfed conditions in historical wheat cultivars from Pakistan

    PubMed Central

    Ain, Qurat-ul; Rasheed, Awais; Anwar, Alia; Mahmood, Tariq; Imtiaz, Muhammad; Mahmood, Tariq; Xia, Xianchun; He, Zhonghu; Quraishi, Umar M.

    2015-01-01

    Genome-wide association studies (GWAS) were undertaken to identify SNP markers associated with yield and yield-related traits in 123 Pakistani historical wheat cultivars evaluated during 2011–2014 seasons under rainfed field conditions. The population was genotyped by using high-density Illumina iSelect 90K single nucleotide polymorphism (SNP) assay, and finally 14,960 high quality SNPs were used in GWAS. Population structure examined using 1000 unlinked markers identified seven subpopulations (K = 7) that were representative of different breeding programs in Pakistan, in addition to local landraces. Forty four stable marker-trait associations (MTAs) with -log p > 4 were identified for nine yield-related traits. Nine multi-trait MTAs were found on chromosomes 1AL, 1BS, 2AL, 2BS, 2BL, 4BL, 5BL, 6AL, and 6BL, and those on 5BL and 6AL were stable across two seasons. Gene annotation and syntey identified that 14 trait-associated SNPs were linked to genes having significant importance in plant development. Favorable alleles for days to heading (DH), plant height (PH), thousand grain weight (TGW), and grain yield (GY) showed minor additive effects and their frequencies were slightly higher in cultivars released after 2000. However, no selection pressure on any favorable allele was identified. These genomic regions identified have historically contributed to achieve yield gains from 2.63 million tons in 1947 to 25.7 million tons in 2015. Future breeding strategies can be devised to initiate marker assisted breeding to accumulate these favorable alleles of SNPs associated with yield-related traits to increase grain yield. Additionally, in silico identification of 454-contigs corresponding to MTAs will facilitate fine mapping and subsequent cloning of candidate genes and functional marker development. PMID:26442056

  10. Genome-wide association study identifies four loci associated with eruption of permanent teeth.

    PubMed

    Geller, Frank; Feenstra, Bjarke; 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

    2011-09-01

    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

  11. Ancestry informative markers for distinguishing between Thai populations based on genome-wide association datasets.

    PubMed

    Vongpaisarnsin, Kornkiat; Listman, Jennifer Beth; Malison, Robert T; Gelernter, Joel

    2015-07-01

    The main purpose of this work was to identify a set of AIMs that stratify the genetic structure and diversity of the Thai population from a high-throughput autosomal genome-wide association study. In this study, more than one million SNPs from the international HapMap database and the Thai depression genome-wide association study have been examined to identify ancestry informative markers (AIMs) that distinguish between Thai populations. An efficient strategy is proposed to identify and characterize such SNPs and to test high-resolution SNP data from international HapMap populations. The best AIMs are identified to stratify the population and to infer genetic ancestry structure. A total of 124 AIMs were clearly clustered geographically across the continent, whereas only 89 AIMs stratified the Thai population from East Asian populations. Finally, a set of 273 AIMs was able to distinguish northern from southern Thai subpopulations. These markers will be of particular value in identifying the ethnic origins in regions where matching by self-reports is unavailable or unreliable, which usually occurs in real forensic cases. PMID:25759192

  12. Genome-wide association study on antipsychotic-induced weight gain in the CATIE sample.

    PubMed

    Brandl, E J; Tiwari, A K; Zai, C C; Nurmi, E L; Chowdhury, N I; Arenovich, T; Sanches, M; Goncalves, V F; Shen, J J; Lieberman, J A; Meltzer, H Y; Kennedy, J L; Müller, D J

    2016-08-01

    Antipsychotic-induced weight gain (AIWG) is a common side effect with a high genetic contribution. We reanalyzed genome-wide association study (GWAS) data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) selecting a refined subset of patients most suitable for AIWG studies. The final GWAS was conducted in N=189 individuals. The top polymorphisms were analyzed in a second cohort of N=86 patients. None of the single-nucleotide polymorphisms was significant at the genome-wide threshold of 5x10(-8). We observed interesting trends for rs9346455 (P=6.49x10(-6)) upstream of OGFRL1, the intergenic variants rs7336345 (P=1.31 × 10(-5)) and rs1012650 (P=1.47 × 10(-5)), and rs1059778 (P=1.49x10(-5)) in IBA57. In the second cohort, rs9346455 showed significant association with AIWG (P=0.005). The combined meta-analysis P-value for rs9346455 was 1.09 × 10(-7). Our reanalysis of the CATIE GWAS data revealed interesting new variants associated with AIWG. As the functional relevance of these polymorphisms is yet to be determined, further studies are needed.The Pharmacogenomics Journal advance online publication, 1 September 2015; doi:10.1038/tpj.2015.59. PMID:26323598

  13. Genome-wide investigation of schizophrenia associated plasma Ndel1 enzyme activity.

    PubMed

    Gadelha, Ary; Coleman, Jonathan; Breen, Gerome; Mazzoti, Diego Robles; Yonamine, Camila M; Pellegrino, Renata; Ota, Vanessa Kiyomi; Belangero, Sintia Iole; Glessner, Joseph; Sleiman, Patrick; Hakonarson, Hakon; Hayashi, Mirian A F; Bressan, Rodrigo A

    2016-04-01

    Ndel1 is a DISC1-interacting oligopeptidase that cleaves in vitro neuropeptides as neurotensin and bradykinin, and which has been associated with both neuronal migration and neurite outgrowth. We previously reported that plasma Ndel1 enzyme activity is lower in patients with schizophrenia (SCZ) compared to healthy controls (HCs). To our knowledge, no previous study has investigated the genetic factors associated with the plasma Ndel1 enzyme activity. In the current analyses, samples from 83 SCZ patients and 92 control subjects that were assayed for plasma Ndel1 enzyme activity were genotyped on Illumina Omni Express arrays. A genetic relationship matrix using genome-wide information was then used for ancestry correction, and association statistics were calculated genome-wide. Ndel1 enzyme activity was significantly lower in patients with SCZ (t=4.9; p<0.001) and was found to be associated with CAMK1D, MAGI2, CCDC25, and GABGR3, at a level of suggestive significance (p<10(-6)), independent of the clinical status. Then, we performed a model to investigate the observed differences for case/control measures. 2 SNPs at region 1p22.2 reached the p<10(-7) level. ZFPM2 and MAD1L1 were the only two genes with more than one hit at 10(-6) order of p value. Therefore, Ndel1 enzyme activity is a complex trait influenced by many different genetic variants that may contribute to SCZ physiopathology. PMID:26851141

  14. Genome-wide association study of tanning phenotype in a population of European ancestry.

    PubMed

    Nan, Hongmei; Kraft, Peter; Qureshi, Abrar A; Guo, Qun; Chen, Constance; Hankinson, Susan E; Hu, Frank B; Thomas, Gilles; Hoover, Robert N; Chanock, Stephen; Hunter, David J; Han, Jiali

    2009-09-01

    We conducted a multistage genome-wide association study (GWAS) of tanning response after exposure to sunlight in over 9,000 men and women of European ancestry who live in the United States. An initial analysis of 528,173 single-nucleotide polymorphisms (SNPs) genotyped on 2,287 women identified LOC401937 (rs966321) on chromosome 1 as a novel locus highly associated with tanning ability, and we confirmed this association in 870 women controls from a skin cancer case-control study with joint P-value=1.6 x 10(-9). We further genotyped this SNP in two subsequent replication studies (one with 3,750 women and the other with 2,405 men). This association was not replicated in either of these two studies. We found that several SNPs reaching the genome-wide significance level are located in or adjacent to the loci previously known as pigmentation genes: MATP, IRF4, TYR, OCA2, and MC1R. Overall, these tanning ability-related loci are similar to the hair color-related loci previously reported in the GWAS of hair color. PMID:19340012

  15. A genome-wide association study identifies multiple loci for variation in human ear morphology.

    PubMed

    Adhikari, Kaustubh; Reales, Guillermo; Smith, Andrew J P; Konka, Esra; Palmen, Jutta; Quinto-Sanchez, Mirsha; Acuña-Alonzo, Victor; Jaramillo, Claudia; Arias, William; Fuentes, Macarena; Pizarro, María; Barquera Lozano, Rodrigo; Macín Pérez, Gastón; Gómez-Valdés, Jorge; Villamil-Ramírez, Hugo; Hunemeier, Tábita; Ramallo, Virginia; Silva de Cerqueira, Caio C; Hurtado, Malena; Villegas, Valeria; Granja, Vanessa; Gallo, Carla; Poletti, Giovanni; Schuler-Faccini, Lavinia; Salzano, Francisco M; Bortolini, Maria-Cátira; Canizales-Quinteros, Samuel; Rothhammer, Francisco; Bedoya, Gabriel; Calderón, Rosario; Rosique, Javier; Cheeseman, Michael; Bhutta, Mahmood F; Humphries, Steve E; Gonzalez-José, Rolando; Headon, Denis; Balding, David; Ruiz-Linares, Andrés

    2015-01-01

    Here we report a genome-wide association study for non-pathological pinna morphology in over 5,000 Latin Americans. We find genome-wide significant association at seven genomic regions affecting: lobe size and attachment, folding of antihelix, helix rolling, ear protrusion and antitragus size (linear regression P values 2 × 10(-8) to 3 × 10(-14)). Four traits are associated with a functional variant in the Ectodysplasin A receptor (EDAR) gene, a key regulator of embryonic skin appendage development. We confirm expression of Edar in the developing mouse ear and that Edar-deficient mice have an abnormally shaped pinna. Two traits are associated with SNPs in a region overlapping the T-Box Protein 15 (TBX15) gene, a major determinant of mouse skeletal development. Strongest association in this region is observed for SNP rs17023457 located in an evolutionarily conserved binding site for the transcription factor Cartilage paired-class homeoprotein 1 (CART1), and we confirm that rs17023457 alters in vitro binding of CART1. PMID:26105758

  16. A genome-wide association study identifies multiple loci for variation in human ear morphology

    PubMed Central

    Adhikari, Kaustubh; Reales, Guillermo; Smith, Andrew J. P.; Konka, Esra; Palmen, Jutta; Quinto-Sanchez, Mirsha; Acuña-Alonzo, Victor; Jaramillo, Claudia; Arias, William; Fuentes, Macarena; Pizarro, María; Barquera Lozano, Rodrigo; Macín Pérez, Gastón; Gómez-Valdés, Jorge; Villamil-Ramírez, Hugo; Hunemeier, Tábita; Ramallo, Virginia; Silva de Cerqueira, Caio C.; Hurtado, Malena; Villegas, Valeria; Granja, Vanessa; Gallo, Carla; Poletti, Giovanni; Schuler-Faccini, Lavinia; Salzano, Francisco M.; Bortolini, Maria- Cátira; Canizales-Quinteros, Samuel; Rothhammer, Francisco; Bedoya, Gabriel; Calderón, Rosario; Rosique, Javier; Cheeseman, Michael; Bhutta, Mahmood F.; Humphries, Steve E.; Gonzalez-José, Rolando; Headon, Denis; Balding, David; Ruiz-Linares, Andrés

    2015-01-01

    Here we report a genome-wide association study for non-pathological pinna morphology in over 5,000 Latin Americans. We find genome-wide significant association at seven genomic regions affecting: lobe size and attachment, folding of antihelix, helix rolling, ear protrusion and antitragus size (linear regression P values 2 × 10−8 to 3 × 10−14). Four traits are associated with a functional variant in the Ectodysplasin A receptor (EDAR) gene, a key regulator of embryonic skin appendage development. We confirm expression of Edar in the developing mouse ear and that Edar-deficient mice have an abnormally shaped pinna. Two traits are associated with SNPs in a region overlapping the T-Box Protein 15 (TBX15) gene, a major determinant of mouse skeletal development. Strongest association in this region is observed for SNP rs17023457 located in an evolutionarily conserved binding site for the transcription factor Cartilage paired-class homeoprotein 1 (CART1), and we confirm that rs17023457 alters in vitro binding of CART1. PMID:26105758

  17. Comparative analysis of methods for genome-wide nucleosome cartography.

    PubMed

    Quintales, Luis; Vázquez, Enrique; Antequera, Francisco

    2015-07-01

    Nucleosomes contribute to compacting the genome into the nucleus and regulate the physical access of regulatory proteins to DNA either directly or through the epigenetic modifications of the histone tails. Precise mapping of nucleosome positioning across the genome is, therefore, essential to understanding the genome regulation. In recent years, several experimental protocols have been developed for this purpose that include the enzymatic digestion, chemical cleavage or immunoprecipitation of chromatin followed by next-generation sequencing of the resulting DNA fragments. Here, we compare the performance and resolution of these methods from the initial biochemical steps through the alignment of the millions of short-sequence reads to a reference genome to the final computational analysis to generate genome-wide maps of nucleosome occupancy. Because of the lack of a unified protocol to process data sets obtained through the different approaches, we have developed a new computational tool (NUCwave), which facilitates their analysis, comparison and assessment and will enable researchers to choose the most suitable method for any particular purpose. NUCwave is freely available at http://nucleosome.usal.es/nucwave along with a step-by-step protocol for its use. PMID:25296770

  18. Genome-Wide Association Studies of the Human Gut Microbiota.

    PubMed

    Davenport, Emily R; Cusanovich, Darren A; Michelini, Katelyn; Barreiro, Luis B; Ober, Carole; Gilad, Yoav

    2015-01-01

    The bacterial composition of the human fecal microbiome is influenced by many lifestyle factors, notably diet. It is less clear, however, what role host genetics plays in dictating the composition of bacteria living in the gut. In this study, we examined the association of ~200K host genotypes with the relative abundance of fecal bacterial taxa in a founder population, the Hutterites, during two seasons (n = 91 summer, n = 93 winter, n = 57 individuals collected in both). These individuals live and eat communally, minimizing variation due to environmental exposures, including diet, which could potentially mask small genetic effects. Using a GWAS approach that takes into account the relatedness between subjects, we identified at least 8 bacterial taxa whose abundances were associated with single nucleotide polymorphisms in the host genome in each season (at genome-wide FDR of 20%). For example, we identified an association between a taxon known to affect obesity (genus Akkermansia) and a variant near PLD1, a gene previously associated with body mass index. Moreover, we replicate a previously reported association from a quantitative trait locus (QTL) mapping study of fecal microbiome abundance in mice (genus Lactococcus, rs3747113, P = 3.13 x 10-7). Finally, based on the significance distribution of the associated microbiome QTLs in our study with respect to chromatin accessibility profiles, we identified tissues in which host genetic variation may be acting to influence bacterial abundance in the gut. PMID:26528553

  19. Genome-wide association study of aggressive behaviour in chicken.

    PubMed

    Li, Zhenhui; Zheng, Ming; Abdalla, Bahareldin Ali; Zhang, Zhe; Xu, Zhenqiang; Ye, Qiao; Xu, Haiping; Luo, Wei; Nie, Qinghua; Zhang, Xiquan

    2016-01-01

    In the poultry industry, aggressive behaviour is a large animal welfare issue all over the world. To date, little is known about the underlying genetics of the aggressive behaviour. Here, we performed a genome-wide association study (GWAS) to explore the genetic mechanism associated with aggressive behaviour in chickens. The GWAS results showed that a total of 33 SNPs were associated with aggressive behaviour traits (P < 4.6E-6). rs312463697 on chromosome 4 was significantly associated with aggression (P = 2.10905E-07), and it was in the intron region of the sortilin-related VPS10 domain containing receptor 2 (SORCS2) gene. In addition, biological function analysis of the nearest 26 genes around the significant SNPs was performed with Ingenuity Pathway Analysis. An interaction network contained 17 genes was obtained and SORCS2 was involved in this network, interacted with nerve growth factor (NGF), nerve growth factor receptor (NGFR), dopa decarboxylase (L-dopa) and dopamine. After knockdown of SORCS2, the mRNA levels of NGF, L-dopa and dopamine receptor genes DRD1, DRD2, DRD3 and DRD4 were significantly decreased (P < 0.05). In summary, our data indicated that SORCS2 might play an important role in chicken aggressive behaviour through the regulation of dopaminergic pathways and NGF. PMID:27485826

  20. Genome-Wide Discriminatory Information Patterns of Cytosine DNA Methylation.

    PubMed

    Sanchez, Robersy; Mackenzie, Sally A

    2016-01-01

    Cytosine DNA methylation (CDM) is a highly abundant, heritable but reversible chemical modification to the genome. Herein, a machine learning approach was applied to analyze the accumulation of epigenetic marks in methylomes of 152 ecotypes and 85 silencing mutants of Arabidopsis thaliana. In an information-thermodynamics framework, two measurements were used: (1) the amount of information gained/lost with the CDM changes I R and (2) the uncertainty of not observing a SNP L C R . We hypothesize that epigenetic marks are chromosomal footprints accounting for different ontogenetic and phylogenetic histories of individual populations. A machine learning approach is proposed to verify this hypothesis. Results support the hypothesis by the existence of discriminatory information (DI) patterns of CDM able to discriminate between individuals and between individual subpopulations. The statistical analyses revealed a strong association between the topologies of the structured population of Arabidopsis ecotypes based on I R and on LCR, respectively. A statistical-physical relationship between I R and L C R was also found. Results to date imply that the genome-wide distribution of CDM changes is not only part of the biological signal created by the methylation regulatory machinery, but ensures the stability of the DNA molecule, preserving the integrity of the genetic message under continuous stress from thermal fluctuations in the cell environment. PMID:27322251

  1. Imputing Phenotypes for Genome-wide Association Studies.

    PubMed

    Hormozdiari, Farhad; Kang, Eun Yong; Bilow, Michael; Ben-David, Eyal; Vulpe, Chris; McLachlan, Stela; Lusis, Aldons J; Han, Buhm; Eskin, Eleazar

    2016-07-01

    Genome-wide association studies (GWASs) have been successful in detecting variants correlated with phenotypes of clinical interest. However, the power to detect these variants depends on the number of individuals whose phenotypes are collected, and for phenotypes that are difficult to collect, the sample size might be insufficient to achieve the desired statistical power. The phenotype of interest is often difficult to collect, whereas surrogate phenotypes or related phenotypes are easier to collect and have already been collected in very large samples. This paper demonstrates how we take advantage of these additional related phenotypes to impute the phenotype of interest or target phenotype and then perform association analysis. Our approach leverages the correlation structure between phenotypes to perform the imputation. The correlation structure can be estimated from a smaller complete dataset for which both the target and related phenotypes have been collected. Under some assumptions, the statistical power can be computed analytically given the correlation structure of the phenotypes used in imputation. In addition, our method can impute the summary statistic of the target phenotype as a weighted linear combination of the summary statistics of related phenotypes. Thus, our method is applicable to datasets for which we have access only to summary statistics and not to the raw genotypes. We illustrate our approach by analyzing associated loci to triglycerides (TGs), body mass index (BMI), and systolic blood pressure (SBP) in the Northern Finland Birth Cohort dataset. PMID:27292110

  2. Genome-Wide Association Studies of the Human Gut Microbiota

    PubMed Central

    Davenport, Emily R.; Cusanovich, Darren A.; Michelini, Katelyn; Barreiro, Luis B.; Ober, Carole; Gilad, Yoav

    2015-01-01

    The bacterial composition of the human fecal microbiome is influenced by many lifestyle factors, notably diet. It is less clear, however, what role host genetics plays in dictating the composition of bacteria living in the gut. In this study, we examined the association of ~200K host genotypes with the relative abundance of fecal bacterial taxa in a founder population, the Hutterites, during two seasons (n = 91 summer, n = 93 winter, n = 57 individuals collected in both). These individuals live and eat communally, minimizing variation due to environmental exposures, including diet, which could potentially mask small genetic effects. Using a GWAS approach that takes into account the relatedness between subjects, we identified at least 8 bacterial taxa whose abundances were associated with single nucleotide polymorphisms in the host genome in each season (at genome-wide FDR of 20%). For example, we identified an association between a taxon known to affect obesity (genus Akkermansia) and a variant near PLD1, a gene previously associated with body mass index. Moreover, we replicate a previously reported association from a quantitative trait locus (QTL) mapping study of fecal microbiome abundance in mice (genus Lactococcus, rs3747113, P = 3.13 x 10−7). Finally, based on the significance distribution of the associated microbiome QTLs in our study with respect to chromatin accessibility profiles, we identified tissues in which host genetic variation may be acting to influence bacterial abundance in the gut. PMID:26528553

  3. Quality Control Procedures for Genome Wide Association Studies

    PubMed Central

    Turner, Stephen; Armstrong, Loren L.; Bradford, Yuki; Carlson, Christopher S.; Crawford, Dana C.; Crenshaw, Andrew T.; de Andrade, Mariza; Doheny, Kimberly F.; Haines, Jonathan L.; Hayes, Geoffrey; Jarvik, Gail; Jiang, Lan; Kullo, Iftikhar J.; Li, Rongling; Ling, Hua; Manolio, Teri A.; Matsumoto, Martha; McCarty, Catherine A.; McDavid, Andrew N.; Mirel, Daniel B.; Paschall, Justin E.; Pugh, Elizabeth W.; Rasmussen, Luke V.; Wilke, Russell A.; Zuvich, Rebecca L.; Ritchie, Marylyn D.

    2011-01-01

    Genome-wide association studies (GWAS) are being conducted at an unprecedented rate in population-based cohorts and have increased our understanding of the pathophysiology of complex disease. The recent application of GWAS to clinic-based cohorts has also yielded genetic predictors of clinical outcomes. Regardless of context, the practical utility of this information will ultimately depend upon the quality of the original data. Quality control (QC) procedures for GWAS are computationally intensive, operationally challenging, and constantly evolving. With each new dataset, new realities are discovered about GWAS data and best practices continue to be developed. The Genomics Workgroup of the National Human Genome Research Institute (NHGRI) funded electronic Medical Records and Genomics (eMERGE) network has invested considerable effort in developing strategies for QC of these data. The lessons learned by this group will be valuable for other investigators dealing with large scale genomic datasets. Here we enumerate some of the challenges in QC of GWAS data and describe the approaches that the eMERGE network is using for quality assurance in GWAS data, thereby minimizing potential bias and error in GWAS results. In this protocol we discuss common issues associated with QC of GWAS data, including data file formats, software packages for data manipulation and analysis, sex chromosome anomalies, sample identity, sample relatedness, population substructure, batch effects, and marker quality. We propose best practices and discuss areas of ongoing and future research. PMID:21234875

  4. Insights into kidney diseases from genome-wide association studies.

    PubMed

    Wuttke, Matthias; Köttgen, Anna

    2016-09-01

    Over the past decade, genome-wide association studies (GWAS) have considerably improved our understanding of the genetic basis of kidney function and disease. Population-based studies, used to investigate traits that define chronic kidney disease (CKD), have identified >50 genomic regions in which common genetic variants associate with estimated glomerular filtration rate or urinary albumin-to-creatinine ratio. Case-control studies, used to study specific CKD aetiologies, have yielded risk loci for specific kidney diseases such as IgA nephropathy and membranous nephropathy. In this Review, we summarize important findings from GWAS and clinical and experimental follow-up studies. We also compare risk allele frequency, effect sizes, and specificity in GWAS of CKD-defining traits and GWAS of specific CKD aetiologies and the implications for study design. Genomic regions identified in GWAS of CKD-defining traits can contain causal genes for monogenic kidney diseases. Population-based research on kidney function traits can therefore generate insights into more severe forms of kidney diseases. Experimental follow-up studies have begun to identify causal genes and variants, which are potential therapeutic targets, and suggest mechanisms underlying the high allele frequency of causal variants. GWAS are thus a useful approach to advance knowledge in nephrology. PMID:27477491

  5. Reconstructing Roma History from Genome-Wide Data

    PubMed Central

    Moorjani, Priya; Patterson, Nick; Loh, Po-Ru; Lipson, Mark; Kisfali, Péter; Melegh, Bela I.; Bonin, Michael; Kádaši, Ľudevít; Rieß, Olaf; Berger, Bonnie; Reich, David; Melegh, Béla

    2013-01-01

    The Roma people, living throughout Europe and West Asia, are a diverse population linked by the Romani language and culture. Previous linguistic and genetic studies have suggested that the Roma migrated into Europe from South Asia about 1,000–1,500 years ago. Genetic inferences about Roma history have mostly focused on the Y chromosome and mitochondrial DNA. To explore what additional information can be learned from genome-wide data, we analyzed data from six Roma groups that we genotyped at hundreds of thousands of single nucleotide polymorphisms (SNPs). We estimate that the Roma harbor about 80% West Eurasian ancestry–derived from a combination of European and South Asian sources–and that the date of admixture of South Asian and European ancestry was about 850 years before present. We provide evidence for Eastern Europe being a major source of European ancestry, and North-west India being a major source of the South Asian ancestry in the Roma. By computing allele sharing as a measure of linkage disequilibrium, we estimate that the migration of Roma out of the Indian subcontinent was accompanied by a severe founder event, which appears to have been followed by a major demographic expansion after the arrival in Europe. PMID:23516520

  6. Optical mapping discerns genome wide DNA methylation profiles

    PubMed Central

    Ananiev, Gene E; Goldstein, Steve; Runnheim, Rod; Forrest, Dan K; Zhou, Shiguo; Potamousis, Konstantinos; Churas, Chris P; Bergendahl, Veit; Thomson, James A; Schwartz, David C

    2008-01-01

    Background Methylation of CpG dinucleotides is a fundamental mechanism of epigenetic regulation in eukaryotic genomes. Development of methods for rapid genome wide methylation profiling will greatly facilitate both hypothesis and discovery driven research in the field of epigenetics. In this regard, a single molecule approach to methylation profiling offers several unique advantages that include elimination of chemical DNA modification steps and PCR amplification. Results A single molecule approach is presented for the discernment of methylation profiles, based on optical mapping. We report results from a series of pilot studies demonstrating the capabilities of optical mapping as a platform for methylation profiling of whole genomes. Optical mapping was used to discern the methylation profile from both an engineered and wild type Escherichia coli. Furthermore, the methylation status of selected loci within the genome of human embryonic stem cells was profiled using optical mapping. Conclusion The optical mapping platform effectively detects DNA methylation patterns. Due to single molecule detection, optical mapping offers significant advantages over other technologies. This advantage stems from obviation of DNA modification steps, such as bisulfite treatment, and the ability of the platform to assay repeat dense regions within mammalian genomes inaccessible to techniques using array-hybridization technologies. PMID:18667073

  7. Genome-wide significant risk associations for mucinous ovarian carcinoma

    PubMed Central

    Kelemen, Linda E.; Lawrenson, Kate; Tyrer, Jonathan; Li, Qiyuan; M. Lee, Janet; Seo, Ji-Heui; Phelan, Catherine M.; Beesley, Jonathan; Chen, Xiaoqin; Spindler, Tassja J.; Aben, Katja K.H.; Anton-Culver, Hoda; Antonenkova, Natalia; Baker, Helen; Bandera, Elisa V.; Bean, Yukie; Beckmann, Matthias W.; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A.; Brooks-Wilson, Angela; Bruinsma, Fiona; Butzow, Ralf; Campbell, Ian G.; Carty, Karen; Chang-Claude, Jenny; Chen, Y. Ann; Chen, Zhihua; Cook, Linda S.; Cramer, Daniel W.; Cunningham, Julie M.; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Dennis, Joe; Dicks, Ed; Doherty, Jennifer A.; Dörk, Thilo; du Bois, Andreas; Dürst, Matthias; Eccles, Diana; Easton, Douglas T.; Edwards, Robert P.; Eilber, Ursula; Ekici, Arif B.; Engelholm, Svend Aage; Fasching, Peter A.; Fridley, Brooke L.; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G.; Glasspool, Rosalind; Goode, Ellen L.; Goodman, Marc T.; Grownwald, Jacek; Harrington, Patricia; Harter, Philipp; Hasmad, Hanis Nazihah; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A.T.; Hillemanns, Peter; Hogdall, Estrid; Hogdall, Claus; Hosono, Satoyo; Iversen, Edwin S.; Jakubowska, Anna; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y; Kellar, Melissa; Kelley, Joseph L.; Kiemeney, Lambertus A.; Krakstad, Camilla; Kjaer, Susanne K.; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D.; Lee, Alice W.; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A.; Liang, Dong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F.A.G.; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R.; McNeish, Iain; Menon, Usha; Modugno, Francesmary; Moes-Sosnowska, Joanna; Moysich, Kirsten B.; Narod, Steven A.; Nedergaard, Lotte; Ness, Roberta B.; Nevanlinna, Heli; Azmi, Mat Adenan Noor; Odunsi, Kunle; Olson, Sara H.; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Paul, James; Pearce, Celeste Leigh; Pejovic, Tanja; Pelttari, Liisa M.; Permuth-Wey, Jennifer; Pike, Malcolm C.; Poole, Elizabeth M.; Ramus, Susan J.; Risch, Harvey A.; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H.; Rudolph, Anja; Runnebaum, Ingo B.; Rzepecka, Iwona K.; Salvesen, Helga B.; Schildkraut, Joellen M.; Schwaab, Ira; Shu, Xiao-Ou; Shvetsov, Yurii B; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C.; Sucheston, Lara; Tangen, Ingvild L.; Teo, Soo-Hwang; Terry, Kathryn L.; Thompson, Pamela J; Tworoger, Shelley S.; van Altena, Anne M.; Van Nieuwenhuysen, Els; Vergote, Ignace; Vierkant, Robert A.; Wang-Gohrke, Shan; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S.; Wicklund, Kristine G.; Wilkens, Lynne R.; Wlodzimierz, Sawicki; Woo, Yin-Ling; Wu, Xifeng; Wu, Anna H.; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Sellers, Thomas A.; Freedman, Matthew L.; Chenevix-Trench, Georgia; Pharoah, Paul D.; Gayther, Simon A.; Berchuck, Andrew

    2015-01-01

    Genome-wide association studies have identified several risk associations for ovarian carcinomas (OC) but not for mucinous ovarian carcinomas (MOC). Genotypes from OC cases and controls were imputed into the 1000 Genomes Project reference panel. Analysis of 1,644 MOC cases and 21,693 controls identified three novel risk associations: rs752590 at 2q13 (P = 3.3 × 10−8), rs711830 at 2q31.1 (P = 7.5 × 10−12) and rs688187 at 19q13.2 (P = 6.8 × 10−13). Expression Quantitative Trait Locus (eQTL) analysis in ovarian and colorectal tumors (which are histologically similar to MOC) identified significant eQTL associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10−4, FDR = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors, and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease. PMID:26075790

  8. Genome-Wide Mapping of Yeast RNA Polymerase II Termination

    PubMed Central

    Schaughency, Paul; Merran, Jonathan; Corden, Jeffry L.

    2014-01-01

    Yeast RNA polymerase II (Pol II) terminates transcription of coding transcripts through the polyadenylation (pA) pathway and non-coding transcripts through the non-polyadenylation (non-pA) pathway. We have used PAR-CLIP to map the position of Pol II genome-wide in living yeast cells after depletion of components of either the pA or non-pA termination complexes. We show here that Ysh1, responsible for cleavage at the pA site, is required for efficient removal of Pol II from the template. Depletion of Ysh1 from the nucleus does not, however, lead to readthrough transcription. In contrast, depletion of the termination factor Nrd1 leads to widespread runaway elongation of non-pA transcripts. Depletion of Sen1 also leads to readthrough at non-pA terminators, but in contrast to Nrd1, this readthrough is less processive, or more susceptible to pausing. The data presented here provide delineation of in vivo Pol II termination regions and highlight differences in the sequences that signal termination of different classes of non-pA transcripts. PMID:25299594

  9. Reconstructing Roma history from genome-wide data.

    PubMed

    Moorjani, Priya; Patterson, Nick; Loh, Po-Ru; Lipson, Mark; Kisfali, Péter; Melegh, Bela I; Bonin, Michael; Kádaši, Ludevít; Rieß, Olaf; Berger, Bonnie; Reich, David; Melegh, Béla

    2013-01-01

    The Roma people, living throughout Europe and West Asia, are a diverse population linked by the Romani language and culture. Previous linguistic and genetic studies have suggested that the Roma migrated into Europe from South Asia about 1,000-1,500 years ago. Genetic inferences about Roma history have mostly focused on the Y chromosome and mitochondrial DNA. To explore what additional information can be learned from genome-wide data, we analyzed data from six Roma groups that we genotyped at hundreds of thousands of single nucleotide polymorphisms (SNPs). We estimate that the Roma harbor about 80% West Eurasian ancestry-derived from a combination of European and South Asian sources-and that the date of admixture of South Asian and European ancestry was about 850 years before present. We provide evidence for Eastern Europe being a major source of European ancestry, and North-west India being a major source of the South Asian ancestry in the Roma. By computing allele sharing as a measure of linkage disequilibrium, we estimate that the migration of Roma out of the Indian subcontinent was accompanied by a severe founder event, which appears to have been followed by a major demographic expansion after the arrival in Europe. PMID:23516520

  10. Genome-wide association study of aggressive behaviour in chicken

    PubMed Central

    Li, Zhenhui; Zheng, Ming; Abdalla, Bahareldin Ali; Zhang, Zhe; Xu, Zhenqiang; Ye, Qiao; Xu, Haiping; Luo, Wei; Nie, Qinghua; Zhang, Xiquan

    2016-01-01

    In the poultry industry, aggressive behaviour is a large animal welfare issue all over the world. To date, little is known about the underlying genetics of the aggressive behaviour. Here, we performed a genome-wide association study (GWAS) to explore the genetic mechanism associated with aggressive behaviour in chickens. The GWAS results showed that a total of 33 SNPs were associated with aggressive behaviour traits (P < 4.6E-6). rs312463697 on chromosome 4 was significantly associated with aggression (P = 2.10905E-07), and it was in the intron region of the sortilin-related VPS10 domain containing receptor 2 (SORCS2) gene. In addition, biological function analysis of the nearest 26 genes around the significant SNPs was performed with Ingenuity Pathway Analysis. An interaction network contained 17 genes was obtained and SORCS2 was involved in this network, interacted with nerve growth factor (NGF), nerve growth factor receptor (NGFR), dopa decarboxylase (L-dopa) and dopamine. After knockdown of SORCS2, the mRNA levels of NGF, L-dopa and dopamine receptor genes DRD1, DRD2, DRD3 and DRD4 were significantly decreased (P < 0.05). In summary, our data indicated that SORCS2 might play an important role in chicken aggressive behaviour through the regulation of dopaminergic pathways and NGF. PMID:27485826

  11. A SUPER Powerful Method for Genome Wide Association Study

    PubMed Central

    Pan, Yuchun; Buckler, Edward S.; Zhang, Zhiwu

    2014-01-01

    Genome-Wide Association Studies shed light on the identification of genes underlying human diseases and agriculturally important traits. This potential has been shadowed by false positive findings. The Mixed Linear Model (MLM) method is flexible enough to simultaneously incorporate population structure and cryptic relationships to reduce false positives. However, its intensive computational burden is prohibitive in practice, especially for large samples. The newly developed algorithm, FaST-LMM, solved the computational problem, but requires that the number of SNPs be less than the number of individuals to derive a rank-reduced relationship. This restriction potentially leads to less statistical power when compared to using all SNPs. We developed a method to extract a small subset of SNPs and use them in FaST-LMM. This method not only retains the computational advantage of FaST-LMM, but also remarkably increases statistical power even when compared to using the entire set of SNPs. We named the method SUPER (Settlement of MLM Under Progressively Exclusive Relationship) and made it available within an implementation of the GAPIT software package. PMID:25247812

  12. cgmisc: enhanced genome-wide association analyses and visualization

    PubMed Central

    Kierczak, Marcin; Jabłońska, Jagoda; Forsberg, Simon K. G.; Bianchi, Matteo; Tengvall, Katarina; Pettersson, Mats; Scholz, Veronika; Meadows, Jennifer R. S.; Jern, Patric; Carlborg, Örjan; Lindblad-Toh, Kerstin

    2015-01-01

    Summary: High-throughput genotyping and sequencing technologies facilitate studies of complex genetic traits and provide new research opportunities. The increasing popularity of genome-wide association studies (GWAS) leads to the discovery of new associated loci and a better understanding of the genetic architecture underlying not only diseases, but also other monogenic and complex phenotypes. Several softwares are available for performing GWAS analyses, R environment being one of them. Results: We present cgmisc, an R package that enables enhanced data analysis and visualization of results from GWAS. The package contains several utilities and modules that complement and enhance the functionality of the existing software. It also provides several tools for advanced visualization of genomic data and utilizes the power of the R language to aid in preparation of publication-quality figures. Some of the package functions are specific for the domestic dog (Canis familiaris) data. Availability and implementation: The package is operating system-independent and is available from: https://github.com/cgmisc-team/cgmisc Contact: marcin.kierczak@imbim.uu.se Supplementary information: Supplementary data are available at Bioinformatics online. PMID:26249815

  13. Genome-wide association study of selenium concentrations

    PubMed Central

    Cornelis, Marilyn C.; Fornage, Myriam; Foy, Millennia; Xun, Pengcheng; Gladyshev, Vadim N.; Morris, Steve; Chasman, Daniel I.; Hu, Frank B.; Rimm, Eric B.; Kraft, Peter; Jordan, Joanne M.; Mozaffarian, Dariush; He, Ka

    2015-01-01

    Selenium (Se) is an essential trace element in human nutrition, but its role in certain health conditions, particularly among Se sufficient populations, is controversial. A genome-wide association study (GWAS) of blood Se concentrations previously identified a locus at 5q14 near BHMT. We performed a GW meta-analysis of toenail Se concentrations, which reflect a longer duration of exposure than blood Se concentrations, including 4162 European descendants from four US cohorts. Toenail Se was measured using neutron activation analysis. We identified a GW-significant locus at 5q14 (P < 1 × 10−16), the same locus identified in the published GWAS of blood Se based on independent cohorts. The lead single-nucleotide polymorphism (SNP) explained ∼1% of the variance in toenail Se concentrations. Using GW-summary statistics from both toenail and blood Se, we observed statistical evidence of polygenic overlap (P < 0.001) and meta-analysis of results from studies of either trait (n = 9639) yielded a second GW-significant locus at 21q22.3, harboring CBS (P < 4 × 10−8). Proteins encoded by genes at 5q14 and 21q22.3 function in homocysteine (Hcy) metabolism, and index SNPs for each have previously been associated with betaine and Hcy levels in GWAS. Our findings show evidence of a genetic link between Se and Hcy pathways, both involved in cardiometabolic disease. PMID:25343990

  14. Realizing privacy preserving genome-wide association studies

    PubMed Central

    Simmons, Sean; Berger, Bonnie

    2016-01-01

    Motivation: As genomics moves into the clinic, there has been much interest in using this medical data for research. At the same time the use of such data raises many privacy concerns. These circumstances have led to the development of various methods to perform genome-wide association studies (GWAS) on patient records while ensuring privacy. In particular, there has been growing interest in applying differentially private techniques to this challenge. Unfortunately, up until now all methods for finding high scoring SNPs in a differentially private manner have had major drawbacks in terms of either accuracy or computational efficiency. Results: Here we overcome these limitations with a substantially modified version of the neighbor distance method for performing differentially private GWAS, and thus are able to produce a more viable mechanism. Specifically, we use input perturbation and an adaptive boundary method to overcome accuracy issues. We also design and implement a convex analysis based algorithm to calculate the neighbor distance for each SNP in constant time, overcoming the major computational bottleneck in the neighbor distance method. It is our hope that methods such as ours will pave the way for more widespread use of patient data in biomedical research. Availability and implementation: A python implementation is available at http://groups.csail.mit.edu/cb/DiffPriv/. Contact: bab@csail.mit.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:26769317

  15. Genome-wide significant risk associations for mucinous ovarian carcinoma.

    PubMed

    Kelemen, Linda E; Lawrenson, Kate; Tyrer, Jonathan; Li, Qiyuan; Lee, Janet M; Seo, Ji-Heui; Phelan, Catherine M; Beesley, Jonathan; Chen, Xiaoqing; Spindler, Tassja J; Aben, Katja K H; Anton-Culver, Hoda; Antonenkova, Natalia

    2015-08-01

    Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 × 10(-8)), rs711830 at 2q31.1 (P = 7.5 × 10(-12)) and rs688187 at 19q13.2 (P = 6.8 × 10(-13)). We identified significant expression quantitative trait locus (eQTL) associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10(-4), false discovery rate (FDR) = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk-associated SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease. PMID:26075790

  16. Genome wide association study on early puberty in Bos indicus.

    PubMed

    Nascimento, A V; Matos, M C; Seno, L O; Romero, A R S; Garcia, J F; Grisolia, A B

    2016-01-01

    The aim of this study was to evaluate a genome wide association study (GWAS) approach to identify single nucleotide polymorphisms (SNPs) associated with fertility traits (early puberty) in Nellore cattle (Bos indicus). Fifty-five Nellore cows were selected from a herd monitored for early puberty onset (positive pregnancy at 18 months of age). Extremes of this phenotype were selected; 30 and 25 individuals were pregnant and non-pregnant, respectively, at that age. DNA samples were genotyped using a high-density SNP chip (>777.000 SNP). GWAS using a case-control strategy highlighted a number of significant markers based on their proximity with the Bonferroni correction line. Results indicated that chromosomes 5, 6, 9, 10, and 22 were associated with the traits of interest. The most significant SNPs on these chromosomes were rs133039577, rs110013280, rs134702839, rs109551605, and rs41639155. Candidate genes, as well as quantitative trait loci (QTL) previously reported in the Ensembl and Cattle QTLdb databases, were further investigated. Analysis of the regions close to the SNP on chromosomes 9 and 10 revealed that four QTL had been previously classified under the reproduction category. In conclusion, we have identified SNPs in close proximity to genes associated with reproductive traits. Moreover, U6 spliceosomal RNA was present on three different chromosomes, which is possibly associated with age at first calving, suggesting that it might be a strong candidate for future studies. PMID:26909970

  17. Genome-wide DNA Methylation Profiles in Hepatocellular Carcinoma

    PubMed Central

    Shen, Jing; Wang, Shuang; Zhang, Yu-Jing; Kappil, Maya; Wu, Hui-Chen; Kibriya, Muhammad G.; Wang, Qiao; Jasmine, Farzana; Ahsan, Habib; Lee, Po-Huang; Yu, Ming-Whei; Chen, Chien-Jen; Santella, Regina M.

    2012-01-01

    Alterations in DNA methylation frequently occur in hepatocellular cancer (HCC). We have previously demonstrated that hypermethylation in candidate genes can be detected in plasma DNA prior to HCC diagnosis. To identify with a genome-wide approach additional genes hypermethylated in HCC that could be used for more accurate analysis of plasma DNA for early diagnosis, we analyzed tumor and adjacent non-tumor tissues from 62 Taiwanese HCC cases using Illumina methylation arrays that screen 26,486 autosomal CpG sites. After Bonferroni adjustment, a total of 2,324 CpG sites significantly differed in methylation level, with 684 CpG sites significantly hypermethylated and 1,640 hypomethylated in tumor compared to non-tumor tissues. Array data were validated with pyrosequencing in a subset of 5 of these genes; correlation coefficients ranged from 0.92 to 0.97. Analysis of plasma DNA from 38 cases demonstrated that 37% to 63% of cases had detectable hypermethylated DNA (≥5% methylation) for these 5 genes individually. At least one of these genes was hypermethylated in 87% of cases, suggesting that measurement of DNA methylation in plasma samples is feasible. The panel of methylated genes indentified in the current study will be further tested in large cohort of prospectively collected samples to determine their utility as early biomarkers of hepatocellular carcinoma. PMID:22234943

  18. Genome-wide footprinting: ready for prime time?

    PubMed

    Sung, Myong-Hee; Baek, Songjoon; Hager, Gordon L

    2016-03-01

    High-throughput sequencing technologies have allowed many gene locus-level molecular biology assays to become genome-wide profiling methods. DNA-cleaving enzymes such as DNase I have been used to probe accessible chromatin. The accessible regions contain functional regulatory sites, including promoters, insulators and enhancers. Deep sequencing of DNase-seq libraries and computational analysis of the cut profiles have been used to infer protein occupancy in the genome at the nucleotide level, a method introduced as 'digital genomic footprinting'. The approach has been proposed as an attractive alternative to the analysis of transcription factors (TFs) by chromatin immunoprecipitation followed by sequencing (ChIP-seq), and in theory it should overcome antibody issues, poor resolution and batch effects. Recent reports point to limitations of the DNase-based genomic footprinting approach and call into question the scope of detectable protein occupancy, especially for TFs with short-lived chromatin binding. The genomics community is grappling with issues concerning the utility of genomic footprinting and is reassessing the proposed approaches in terms of robust deliverables. Here we summarize the consensus as well as different views emerging from recent reports, and we describe the remaining issues and hurdles for genomic footprinting. PMID:26914206

  19. Genome-wide DNA methylation analysis in hepatocellular carcinoma.

    PubMed

    Yamada, Nobuhisa; Yasui, Kohichiroh; Dohi, Osamu; Gen, Yasuyuki; Tomie, Akira; Kitaichi, Tomoko; Iwai, Naoto; Mitsuyoshi, Hironori; Sumida, Yoshio; Moriguchi, Michihisa; Yamaguchi, Kanji; Nishikawa, Taichiro; Umemura, Atsushi; Naito, Yuji; Tanaka, Shinji; Arii, Shigeki; Itoh, Yoshito

    2016-04-01

    Epigenetic changes as well as genetic changes are mechanisms of tumorigenesis. We aimed to identify novel genes that are silenced by DNA hypermethylation in hepatocellular carcinoma (HCC). We screened for genes with promoter DNA hypermethylation using a genome-wide methylation microarray analysis in primary HCC (the discovery set). The microarray analysis revealed that there were 2,670 CpG sites that significantly differed in regards to the methylation level between the tumor and non-tumor liver tissues; 875 were significantly hypermethylated and 1,795 were significantly hypomethylated in the HCC tumors compared to the non‑tumor tissues. Further analyses using methylation-specific PCR, combined with expression analysis, in the validation set of primary HCC showed that, in addition to three known tumor-suppressor genes (APC, CDKN2A, and GSTP1), eight genes (AKR1B1, GRASP, MAP9, NXPE3, RSPH9, SPINT2, STEAP4, and ZNF154) were significantly hypermethylated and downregulated in the HCC tumors compared to the non-tumor liver tissues. Our results suggest that epigenetic silencing of these genes may be associated with HCC. PMID:26883180

  20. Genome-wide association study of selenium concentrations.

    PubMed

    Cornelis, Marilyn C; Fornage, Myriam; Foy, Millennia; Xun, Pengcheng; Gladyshev, Vadim N; Morris, Steve; Chasman, Daniel I; Hu, Frank B; Rimm, Eric B; Kraft, Peter; Jordan, Joanne M; Mozaffarian, Dariush; He, Ka

    2015-03-01

    Selenium (Se) is an essential trace element in human nutrition, but its role in certain health conditions, particularly among Se sufficient populations, is controversial. A genome-wide association study (GWAS) of blood Se concentrations previously identified a locus at 5q14 near BHMT. We performed a GW meta-analysis of toenail Se concentrations, which reflect a longer duration of exposure than blood Se concentrations, including 4162 European descendants from four US cohorts. Toenail Se was measured using neutron activation analysis. We identified a GW-significant locus at 5q14 (P < 1 × 10(-16)), the same locus identified in the published GWAS of blood Se based on independent cohorts. The lead single-nucleotide polymorphism (SNP) explained ∼1% of the variance in toenail Se concentrations. Using GW-summary statistics from both toenail and blood Se, we observed statistical evidence of polygenic overlap (P < 0.001) and meta-analysis of results from studies of either trait (n = 9639) yielded a second GW-significant locus at 21q22.3, harboring CBS (P < 4 × 10(-8)). Proteins encoded by genes at 5q14 and 21q22.3 function in homocysteine (Hcy) metabolism, and index SNPs for each have previously been associated with betaine and Hcy levels in GWAS. Our findings show evidence of a genetic link between Se and Hcy pathways, both involved in cardiometabolic disease. PMID:25343990

  1. Genome-wide association studies in pharmacogenetics research debate

    PubMed Central

    Bailey, Kent R; Cheng, Cheng

    2016-01-01

    Will genome-wide association studies (GWAS) ‘work’ for pharmacogenetics research? This question was the topic of a staged debate, with pro and con sides, aimed to bring out the strengths and weaknesses of GWAS for pharmacogenetics studies. After a full day of seminars at the Fifth Statistical Analysis Workshop of the Pharmacogenetics Research Network, the lively debate was held – appropriately – at Goonies Comedy Club in Rochester (MN, USA). The pro side emphasized that the many GWAS successes for identifying genetic variants associated with disease risk show that it works; that the current genotyping platforms are efficient, with good imputation methods to fill in missing data; that its global assessment is always a success even if no significant associations are detected; and that genetic effects are likely to be large because humans have not evolved in a drug-therapy environment. By contrast, the con side emphasized that we have limited knowledge of the complexity of the genome; limited clinical phenotypes compromise studies; the likely multifactorial nature of drug response clouding the small genetic effects; and limitations of sample size and replication studies in pharmacogenetic studies. Lively and insightful discussions emphasized further research efforts that might benefit GWAS in pharmacogenetics. PMID:20235786

  2. Genome-Wide Association Studies in Primary Biliary Cirrhosis.

    PubMed

    Gulamhusein, Aliya F; Juran, Brian D; Lazaridis, Konstantinos N

    2015-11-01

    Genome-wide association studies (GWASs) have been a significant technological advance in our ability to evaluate the genetic architecture of complex diseases such as primary biliary cirrhosis (PBC). To date, six large-scale studies have been performed that have identified 27 risk loci in addition to human leukocyte antigen (HLA) associated with PBC. The identified risk variants emphasize important disease concepts; namely, that disturbances in immunoregulatory pathways are important in the pathogenesis of PBC and that such perturbations are shared among a diverse number of autoimmune diseases-suggesting the risk architecture may confer a generalized propensity to autoimmunity not necessarily specific to PBC. Furthermore, the impact of non-HLA risk variants, particularly in genes involved with interleukin-12 signaling, and ethnic variation in conferring susceptibility to PBC have been highlighted. Although GWASs have been a critical stepping stone in understanding common genetic variation contributing to PBC, limitations pertaining to power, sample availability, and strong linkage disequilibrium across genes have left us with an incomplete understanding of the genetic underpinnings of disease pathogenesis. Future efforts to gain insight into this missing heritability, the genetic variation that contributes to important disease outcomes, and the functional consequences of associated variants will be critical if practical clinical translation is to be realized. PMID:26676814

  3. Genome-Wide Analysis of Human Metapneumovirus Evolution

    PubMed Central

    Kim, Jin Il; Park, Sehee; Lee, Ilseob; Park, Kwang Sook; Kwak, Eun Jung; Moon, Kwang Mee; Lee, Chang Kyu; Bae, Joon-Yong; Park, Man-Seong; Song, Ki-Joon

    2016-01-01

    Human metapneumovirus (HMPV) has been described as an important etiologic agent of upper and lower respiratory tract infections, especially in young children and the elderly. Most of school-aged children might be introduced to HMPVs, and exacerbation with other viral or bacterial super-infection is common. However, our understanding of the molecular evolution of HMPVs remains limited. To address the comprehensive evolutionary dynamics of HMPVs, we report a genome-wide analysis of the eight genes (N, P, M, F, M2, SH, G, and L) using 103 complete genome sequences. Phylogenetic reconstruction revealed that the eight genes from one HMPV strain grouped into the same genetic group among the five distinct lineages (A1, A2a, A2b, B1, and B2). A few exceptions of phylogenetic incongruence might suggest past recombination events, and we detected possible recombination breakpoints in the F, SH, and G coding regions. The five genetic lineages of HMPVs shared quite remote common ancestors ranging more than 220 to 470 years of age with the most recent origins for the A2b sublineage. Purifying selection was common, but most protein genes except the F and M2-2 coding regions also appeared to experience episodic diversifying selection. Taken together, these suggest that the five lineages of HMPVs maintain their individual evolutionary dynamics and that recombination and selection forces might work on shaping the genetic diversity of HMPVs. PMID:27046055

  4. Genome-wide transcriptome analysis of human epidermal melanocytes

    PubMed Central

    Haltaufderhyde, Kirk D.; Oancea, Elena

    2015-01-01

    Because human epidermal melanocytes (HEMs) provide critical protection against skin cancer, sunburn, and photoaging, a genome-wide perspective of gene expression in these cells is vital to understanding human skin physiology. In this study we performed high throughput sequencing of HEMs to obtain a complete data set of transcript sizes, abundances, and splicing. As expected, we found that melanocyte specific genes that function in pigmentation were among the highest expressed genes. We analyzed receptor, ion channel and transcription factor gene families to get a better understanding of the cell signalling pathways used by melanocytes. We also performed a comparative transcriptomic analysis of lightly versus darkly pigmented HEMs and found 16 genes differentially expressed in the two pigmentation phenotypes; of those, only one putative melanosomal transporter (SLC45A2) has known function in pigmentation. In addition, we found 166 genes with splice isoforms expressed exclusively in one pigmentation phenotype, 17 of which are genes involved in signal transduction. Our melanocyte transcriptome study provides a comprehensive view and may help identify novel pigmentation genes and potential pharmacological targets. PMID:25451175

  5. Genome-wide linkage-disequilibrium profiles from single individuals.

    PubMed

    Lynch, Michael; Xu, Sen; Maruki, Takahiro; Jiang, Xiaoqian; Pfaffelhuber, Peter; Haubold, Bernhard

    2014-09-01

    Although the analysis of linkage disequilibrium (LD) plays a central role in many areas of population genetics, the sampling variance of LD is known to be very large with high sensitivity to numbers of nucleotide sites and individuals sampled. Here we show that a genome-wide analysis of the distribution of heterozygous sites within a single diploid genome can yield highly informative patterns of LD as a function of physical distance. The proposed statistic, the correlation of zygosity, is closely related to the conventional population-level measure of LD, but is agnostic with respect to allele frequencies and hence likely less prone to outlier artifacts. Application of the method to several vertebrate species leads to the conclusion that >80% of recombination events are typically resolved by gene-conversion-like processes unaccompanied by crossovers, with the average lengths of conversion patches being on the order of one to several kilobases in length. Thus, contrary to common assumptions, the recombination rate between sites does not scale linearly with distance, often even up to distances of 100 kb. In addition, the amount of LD between sites separated by <200 bp is uniformly much greater than can be explained by the conventional neutral model, possibly because of the nonindependent origin of mutations within this spatial scale. These results raise questions about the application of conventional population-genetic interpretations to LD on short spatial scales and also about the use of spatial patterns of LD to infer demographic histories. PMID:24948778

  6. Genome-Wide Discriminatory Information Patterns of Cytosine DNA Methylation

    PubMed Central

    Sanchez, Robersy; Mackenzie, Sally A.

    2016-01-01

    Cytosine DNA methylation (CDM) is a highly abundant, heritable but reversible chemical modification to the genome. Herein, a machine learning approach was applied to analyze the accumulation of epigenetic marks in methylomes of 152 ecotypes and 85 silencing mutants of Arabidopsis thaliana. In an information-thermodynamics framework, two measurements were used: (1) the amount of information gained/lost with the CDM changes IR and (2) the uncertainty of not observing a SNP LCR. We hypothesize that epigenetic marks are chromosomal footprints accounting for different ontogenetic and phylogenetic histories of individual populations. A machine learning approach is proposed to verify this hypothesis. Results support the hypothesis by the existence of discriminatory information (DI) patterns of CDM able to discriminate between individuals and between individual subpopulations. The statistical analyses revealed a strong association between the topologies of the structured population of Arabidopsis ecotypes based on IR and on LCR, respectively. A statistical-physical relationship between IR and LCR was also found. Results to date imply that the genome-wide distribution of CDM changes is not only part of the biological signal created by the methylation regulatory machinery, but ensures the stability of the DNA molecule, preserving the integrity of the genetic message under continuous stress from thermal fluctuations in the cell environment. PMID:27322251

  7. Meta-analysis of New Genome-wide Association Studies of Colorectal Cancer Risk

    PubMed Central

    Peters, Ulrike; Hutter, Carolyn M.; Hsu, Li; Schumacher, Fredrick R.; Conti, David V.; Carlson, Christopher S.; Edlund, Christopher K.; Haile, Robert W.; Gallinger, Steven; Zanke, Brent W.; Lemire, Mathieu; Rangrej, Jagadish; Vijayaraghavan, Raakhee; Chan, Andrew T.; Hazra, Aditi; Hunter, David J.; Ma, Jing; Fuchs, Charles S.; Giovannucci, Edward L.; Kraft, Peter; Liu, Yan; Chen, Lin; Jiao, Shuo; Makar, Karen W.; Taverna, Darin; Gruber, Stephen B.; Rennert, Gad; Moreno, Victor; Ulrich, Cornelia M.; Woods, Michael O.; Green, Roger C.; Parfrey, Patrick S.; Prentice, Ross L.; Kooperberg, Charles; Jackson, Rebecca D.; LaCroix, Andrea Z.; Caan, Bette J.; Hayes, Richard B.; Berndt, Sonja I.; Chanock, Stephen J.; Schoen, Robert E.; Chang-Claude, Jenny; Hoffmeister, Michael; Brenner, Hermann; Frank, Bernd; Bézieau, Stéphane; Küry, Sébastien; Slattery, Martha L.; Hopper, John L.; Jenkins, Mark A.; Le Marchand, Loic; Lindor, Noralane M.; Newcomb, Polly A.; Seminara, Daniela; Hudson, Thomas J.; Duggan, David J.; Potter, John D.; Casey, Graham

    2011-01-01

    Colorectal cancer is the second leading cause of cancer death in developed countries. Genome-wide association studies (GWAS) have successfully identified novel susceptibility loci for colorectal cancer. To follow-up on these findings, and try to identify novel colorectal cancer susceptibility loci, we present results for genome-wide association studies (GWAS) of colorectal cancer (2,906 cases, 3,416 controls) that have not previously published main associations. Specifically, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) using log-additive models for each study. In order to improve our power to detect novel colorectal cancer susceptibility loci, we performed a meta-analysis combining the results across studies. We selected the most statistically significant single nucleotide polymorphisms (SNPs) for replication using 10 independent studies (8,161 cases and 9,101 controls). We again used a meta-analysis to summarize results for the replication studies alone, and for a combined analysis of GWAS and replication studies. We measured 10 SNPs previously identified in colorectal cancer susceptibility loci and found eight to be associated with colorectal cancer (p-value range: 0.02 to 1.8 × 10−8). When we excluded studies that have previously published on these SNPs, five SNPs remained significant at p<0.05 in the combined analysis. No novel susceptibility loci were significant in the replication study after adjustment for multiple testing, and none reached genome-wide significance from a combined analysis of GWAS and replication. We observed marginally significant evidence for a second independent SNP in the BMP2 region at chromosomal location 20p12 (rs4813802; replication p-value 0.03; combined p-value 7.3 × 10−5). In a region on 5p33.15, which includes the coding regions of the TERT-CLPTM1L genes and has been identified in GWAS to be associated with susceptibility to at least seven other cancers, we observed a marginally significant

  8. A genome-wide scan of selective sweeps in two broiler chicken lines divergently selected for abdominal fat content

    PubMed Central

    2012-01-01

    Background Genomic regions controlling abdominal fatness (AF) were studied in the Northeast Agricultural University broiler line divergently selected for AF. In this study, the chicken 60KSNP chip and extended haplotype homozygosity (EHH) test were used to detect genome-wide signatures of AF. Results A total of 5357 and 5593 core regions were detected in the lean and fat lines, and 51 and 57 reached a significant level (P<0.01), respectively. A number of genes in the significant core regions, including RB1, BBS7, MAOA, MAOB, EHBP1, LRP2BP, LRP1B, MYO7A, MYO9A and PRPSAP1, were detected. These genes may be important for AF deposition in chickens. Conclusions We provide a genome-wide map of selection signatures in the chicken genome, and make a contribution to the better understanding the mechanisms of selection for AF content in chickens. The selection for low AF in commercial breeding using this information will accelerate the breeding progress. PMID:23241142

  9. Genetic Variation and Population Substructure in Outbred CD-1 Mice: Implications for Genome-Wide Association Studies

    PubMed Central

    Aldinger, Kimberly A.; Sokoloff, Greta; Rosenberg, David M.; Palmer, Abraham A.; Millen, Kathleen J.

    2009-01-01

    Outbred laboratory mouse populations are widely used in biomedical research. Since little is known about the degree of genetic variation present in these populations, they are not widely used for genetic studies. Commercially available outbred CD-1 mice are drawn from an extremely large breeding population that has accumulated many recombination events, which is desirable for genome-wide association studies. We therefore examined the degree of genome-wide variation within CD-1 mice to investigate their suitability for genetic studies. The CD-1 mouse genome displays patterns of linkage disequilibrium and heterogeneity similar to wild-caught mice. Population substructure and phenotypic differences were observed among CD-1 mice obtained from different breeding facilities. Differences in genetic variation among CD-1 mice from distinct facilities were similar to genetic differences detected between closely related human populations, consistent with a founder effect. This first large-scale genetic analysis of the outbred CD-1 mouse strain provides important considerations for the design and analysis of genetic studies in CD-1 mice. PMID:19266100

  10. Echocardiographic measurements in the Irish wolfhound: reference values for the breed.

    PubMed

    Vollmar, A C

    1999-01-01

    Out of 400 Irish wolfhounds cardiologically examined, echocardiographic measurements of 262 normal dogs were analyzed to obtain reference values for the breed. Based on regression analysis, several echocardiographic parameters showed significant linear correlation with body weight and with age, but coefficients of determination were low. Therefore, due to a high individual variability of echocardiographic measurements in adult Irish wolfhounds, the predictive value of body weight for echocardiographic measurements was clinically not relevant. Sex had no influence on echocardiographic values. For the estimation of myocardial function, end-systolic volume index (ESVI) (mean, 29.0 ml/m2 +/- standard deviation [SD], 5.9 ml/m2) was determined for the group of 262 normal dogs. PMID:10416769

  11. Determination of non-market values to inform conservation strategies for the threatened Alistana-Sanabresa cattle breed.

    PubMed

    Martin-Collado, D; Diaz, C; Drucker, A G; Carabaño, M J; Zander, K K

    2014-08-01

    Livestock breed-related public good functions are often used to justify support for endangered breed conservation despite the fact that little is known about such non-market values. We show how stated preference techniques can be used to assess the non-market values that people place on livestock breeds. Through the application of a case study choice experiment survey in Zamora province, Spain, the total economic value (TEV) of the threatened Alistana-Sanabresa (AS) cattle breed was investigated. An analysis of the relative importance of the non-market components of its TEV and an assessment of the socio-economic variables that influence people's valuation of such components is used to inform conservation strategy design. Overall, the findings reveal that the AS breed had significant non-market values associated with it and that the value that respondents placed on each specific public good function also varied significantly. Functions related with indirect use cultural and existence values were much more highly valued than landscape maintenance values. These high cultural and existence values (totalling over 80% of TEV) suggest that an AS in situ conservation strategy will be required to secure such values. As part of such a strategy, incentive mechanisms will be needed to permit farmers to capture some of these public good values and thus be able to afford to maintain breed population numbers at socially desirable levels. One such mechanism could be related to the development of breed-related agritourism initiatives, with a view to enhancing private good values and providing an important addition to continued direct support. Where linked with cultural dimensions, niche product market development, including through improving AS breed-related product quality and brand recognition may also have a role to play as part of such an overall conservation and use strategy. We conclude that livestock breed conservation strategies with the highest potential to maximise

  12. Assessment of expected breeding values for fertility traits of Murrah buffaloes under subtropical climate

    PubMed Central

    Dash, Soumya; Chakravarty, A. K.; Singh, Avtar; Shivahre, Pushp Raj; Upadhyay, Arpan; Sah, Vaishali; Singh, K. Mahesh

    2015-01-01

    Aim: The aim of the present study was to assess the influence of temperature and humidity prevalent under subtropical climate on the breeding values for fertility traits viz. service period (SP), pregnancy rate (PR) and conception rate (CR) of Murrah buffaloes in National Dairy Research Institute (NDRI) herd. Materials and Methods: Fertility data on 1379 records of 581 Murrah buffaloes spread over four lactations and climatic parameters viz. dry bulb temperature and relative humidity (RH) spanned over 20 years (1993-2012) were collected from NDRI and Central Soil and Salinity Research Institute, Karnal, India. Monthly average temperature humidity index (THI) values were estimated. Threshold THI value affecting fertility traits was identified by fixed least-squares model analysis. Three zones of non-heat stress, heat stress and critical heat stress zones were developed in a year. The genetic parameters heritability (h2) and repeatability (r) of each fertility trait were estimated. Genetic evaluation of Murrah buffaloes was performed in each zone with respect to their expected breeding values (EBV) for fertility traits. Results: Effect of THI was found significant (p<0.001) on all fertility traits with threshold THI value identified as 75. Based on THI values, a year was classified into three zones: Non heat stress zone(THI 56.71-73.21), HSZ (THI 75.39-81.60) and critical HSZ (THI 80.27-81.60). The EBVfor SP, PR, CR were estimated as 138.57 days, 0.362 and 69.02% in non-HSZ while in HSZ EBV were found as 139.62 days, 0.358 and 68.81%, respectively. EBV for SP was increased to 140.92 days and for PR and CR, it was declined to 0.357 and 68.71% in critical HSZ. Conclusion: The negative effect of THI was observed on EBV of fertility traits under the non-HSZ and critical HSZ Thus, the influence of THI should be adjusted before estimating the breeding values for fertility traits in Murrah buffaloes. PMID:27047091

  13. Genome wide association of white blood cell types during vaccination

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Infectious disease of livestock continues to be a cause of substantial economic loss and adverse welfare. Breeding for disease resistant livestock could improve both the economic burden and animal welfare. We aim to identify key genes and pathways that control variation in immune response; knowled...

  14. Development of genome-wide SNP assays for rice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    With the introduction of new sequencing technologies, single nucleotide polymorphisms (SNPs) are rapidly replacing simple sequence repeats (SSRs) as the DNA marker of choice for applications in plant breeding and genetics because they are more abundant, stable, amenable to automation, efficient, and...

  15. A Genome Wide Association Study Links Glutamate Receptor Pathway to Sporadic Creutzfeldt-Jakob Disease Risk

    PubMed Central

    Sanchez-Juan, Pascual; Bishop, Matthew T.; Kovacs, Gabor G.; Calero, Miguel; Aulchenko, Yurii S.; Ladogana, Anna; Boyd, Alison; Lewis, Victoria; Ponto, Claudia; Calero, Olga; Poleggi, Anna; Carracedo, Ángel; van der Lee, Sven J.; Ströbel, Thomas; Rivadeneira, Fernando; Hofman, Albert; Haïk, Stéphane; Combarros, Onofre; Berciano, José; Uitterlinden, Andre G.; Collins, Steven J.; Budka, Herbert; Brandel, Jean-Philippe; Laplanche, Jean Louis; Pocchiari, Maurizio; Zerr, Inga; Knight, Richard S. G.; Will, Robert G.; van Duijn, Cornelia M.

    2015-01-01

    We performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJD) patients and 1939 controls from the United Kingdom, Germany and The Netherlands. The findings were replicated in an independent sample of 1109 sCJD and 2264 controls provided by a multinational consortium. From the initial GWA analysis we selected 23 SNPs for further genotyping in 1109 sCJD cases from seven different countries. Five SNPs were significantly associated with sCJD after correction for multiple testing. Subsequently these five SNPs were genotyped in 2264 controls. The pooled analysis, including 1543 sCJD cases and 4203 controls, yielded two genome wide significant results: rs6107516 (p-value=7.62x10-9) a variant tagging the prion protein gene (PRNP); and rs6951643 (p-value=1.66x10-8) tagging the Glutamate Receptor Metabotropic 8 gene (GRM8). Next we analysed the data stratifying by country of origin combining samples from the pooled analysis with genotypes from the 1000 Genomes Project and imputed genotypes from the Rotterdam Study (Total n=12967). The meta-analysis of the results showed that rs6107516 (p-value=3.00x10-8) and rs6951643 (p-value=3.91x10-5) remained as the two most significantly associated SNPs. Rs6951643 is located in an intronic region of GRM8, a gene that was additionally tagged by a cluster of 12 SNPs within our top100 ranked results. GRM8 encodes for mGluR8, a protein which belongs to the metabotropic glutamate receptor family, recently shown to be involved in the transduction of cellular signals triggered by the prion protein. Pathway enrichment analyses performed with both Ingenuity Pathway Analysis and ALIGATOR postulates glutamate receptor signalling as one of the main pathways associated with sCJD. In summary, we have detected GRM8 as a novel, non-PRNP, genome-wide significant marker associated with heightened disease risk, providing additional evidence supporting a role of glutamate receptors in sCJD pathogenesis. PMID:25918841

  16. A genome wide association study links glutamate receptor pathway to sporadic Creutzfeldt-Jakob disease risk.

    PubMed

    Sanchez-Juan, Pascual; Bishop, Matthew T; Kovacs, Gabor G; Calero, Miguel; Aulchenko, Yurii S; Ladogana, Anna; Boyd, Alison; Lewis, Victoria; Ponto, Claudia; Calero, Olga; Poleggi, Anna; Carracedo, Ángel; van der Lee, Sven J; Ströbel, Thomas; Rivadeneira, Fernando; Hofman, Albert; Haïk, Stéphane; Combarros, Onofre; Berciano, José; Uitterlinden, Andre G; Collins, Steven J; Budka, Herbert; Brandel, Jean-Philippe; Laplanche, Jean Louis; Pocchiari, Maurizio; Zerr, Inga; Knight, Richard S G; Will, Robert G; van Duijn, Cornelia M

    2014-01-01

    We performed a genome-wide association (GWA) study in 434 sporadic Creutzfeldt-Jakob disease (sCJD) patients and 1939 controls from the United Kingdom, Germany and The Netherlands. The findings were replicated in an independent sample of 1109 sCJD and 2264 controls provided by a multinational consortium. From the initial GWA analysis we selected 23 SNPs for further genotyping in 1109 sCJD cases from seven different countries. Five SNPs were significantly associated with sCJD after correction for multiple testing. Subsequently these five SNPs were genotyped in 2264 controls. The pooled analysis, including 1543 sCJD cases and 4203 controls, yielded two genome wide significant results: rs6107516 (p-value=7.62x10-9) a variant tagging the prion protein gene (PRNP); and rs6951643 (p-value=1.66x10-8) tagging the Glutamate Receptor Metabotropic 8 gene (GRM8). Next we analysed the data stratifying by country of origin combining samples from the pooled analysis with genotypes from the 1000 Genomes Project and imputed genotypes from the Rotterdam Study (Total n=12967). The meta-analysis of the results showed that rs6107516 (p-value=3.00x10-8) and rs6951643 (p-value=3.91x10-5) remained as the two most significantly associated SNPs. Rs6951643 is located in an intronic region of GRM8, a gene that was additionally tagged by a cluster of 12 SNPs within our top100 ranked results. GRM8 encodes for mGluR8, a protein which belongs to the metabotropic glutamate receptor family, recently shown to be involved in the transduction of cellular signals triggered by the prion protein. Pathway enrichment analyses performed with both Ingenuity Pathway Analysis and ALIGATOR postulates glutamate receptor signalling as one of the main pathways associated with sCJD. In summary, we have detected GRM8 as a novel, non-PRNP, genome-wide significant marker associated with heightened disease risk, providing additional evidence supporting a role of glutamate receptors in sCJD pathogenesis. PMID:25918841

  17. Breeding objectives for pigs in Kenya. II: economic values incorporating risks in different smallholder production systems.

    PubMed

    Mbuthia, Jackson Mwenda; Rewe, Thomas Odiwuor; Kahi, Alexander Kigunzu

    2015-02-01

    This study estimated economic values for production traits (dressing percentage (DP), %; live weight for growers (LWg), kg; live weight for sows (LWs), kg) and functional traits (feed intake for growers (FEEDg), feed intake for sow (FEEDs), preweaning survival rate (PrSR), %; postweaning survival (PoSR), %; sow survival rate (SoSR), %, total number of piglets born (TNB) and farrowing interval (FI), days) under different smallholder pig production systems in Kenya. Economic values were estimated considering two production circumstances: fixed-herd and fixed-feed. Under the fixed-herd scenario, economic values were estimated assuming a situation where the herd cannot be increased due to other constraints apart from feed resources. The fixed-feed input scenario assumed that the herd size is restricted by limitation of feed resources available. In addition to the tradition profit model, a risk-rated bio-economic model was used to derive risk-rated economic values. This model accounted for imperfect knowledge concerning risk attitude of farmers and variance of input and output prices. Positive economic values obtained for traits DP, LWg, LWs, PoSR, PrSR, SoSR and TNB indicate that targeting them in improvement would positively impact profitability in pig breeding programmes. Under the fixed-feed basis, the risk-rated economic values for DP, LWg, LWs and SoSR were similar to those obtained under the fixed-herd situation. Accounting for risks in the EVs did not yield errors greater than ±50 % in all the production systems and basis of evaluation meaning there would be relatively little effect on the real genetic gain of a selection index. Therefore, both traditional and risk-rated models can be satisfactorily used to predict profitability in pig breeding programmes. PMID:25433647

  18. Genome-Wide Prediction Methods in Highly Diverse and Heterozygous Species: Proof-of-Concept through Simulation in Grapevine

    PubMed Central

    Fodor, Agota; Segura, Vincent; Denis, Marie; Neuenschwander, Samuel; Fournier-Level, Alexandre; Chatelet, Philippe; Homa, Félix Abdel Aziz; Lacombe, Thierry; This, Patrice; Le Cunff, Loic

    2014-01-01

    Nowadays, genome-wide association studies (GWAS) and genomic selection (GS) methods which use genome-wide marker data for phenotype prediction are of much potential interest in plant breeding. However, to our knowledge, no studies have been performed yet on the predictive ability of these methods for structured traits when using training populations with high levels of genetic diversity. Such an example of a highly heterozygous, perennial species is grapevine. The present study compares the accuracy of models based on GWAS or GS alone, or in combination, for predicting simple or complex traits, linked or not with population structure. In order to explore the relevance of these methods in this context, we performed simulations using approx 90,000 SNPs on a population of 3,000 individuals structured into three groups and corresponding to published diversity grapevine data. To estimate the parameters of the prediction models, we defined four training populations of 1,000 individuals, corresponding to these three groups and a core collection. Finally, to estimate the accuracy of the models, we also simulated four breeding populations of 200 individuals. Although prediction accuracy was low when breeding populations were too distant from the training populations, high accuracy levels were obtained using the sole core-collection as training population. The highest prediction accuracy was obtained (up to 0.9) using the combined GWAS-GS model. We thus recommend using the combined prediction model and a core-collection as training population for grapevine breeding or for other important economic crops with the same characteristics. PMID:25365338

  19. An enhanced version of Cochran-Armitage trend test for genome-wide association studies.

    PubMed

    Ghodsi, Mansi; Amiri, Saeid; Hassani, Hossein; Ghodsi, Zara

    2016-09-01

    Genome-wide association studies the evaluation of association between candidate gene and disease status is widely carried out using Cochran-Armitage trend test. However, only a small number of research papers have evaluated the distribution of p-values for the Cochran-Armitage trend test. In this paper, an enhanced version of Cochran-Armitage trend test based on bootstrap approach is introduced. The achieved results confirm that the distribution of p-values of the proposed approach fits better to the uniform distribution, and it is thus concluded that the proposed method, which needs less assumptions in comparison with the conventional method, can be successfully used to test the genetic association. PMID:27617223

  20. A Genome-Wide Association Study in Large White and Landrace Pig Populations for Number Piglets Born Alive

    PubMed Central

    Bergfelder-Drüing, Sarah; Grosse-Brinkhaus, Christine; Lind, Bianca; Erbe, Malena; Schellander, Karl; Simianer, Henner; Tholen, Ernst

    2015-01-01

    The number of piglets born alive (NBA) per litter is one of the most important traits in pig breeding due to its influence on production efficiency. It is difficult to improve NBA because the heritability of the trait is low and it is governed by a high number of loci with low to moderate effects. To clarify the biological and genetic background of NBA, genome-wide association studies (GWAS) were performed using 4,012 Large White and Landrace pigs from herdbook and commercial breeding companies in Germany (3), Austria (1) and Switzerland (1). The animals were genotyped with the Illumina PorcineSNP60 BeadChip. Because of population stratifications within and between breeds, clusters were formed using the genetic distances between the populations. Five clusters for each breed were formed and analysed by GWAS approaches. In total, 17 different significant markers affecting NBA were found in regions with known effects on female reproduction. No overlapping significant chromosome areas or QTL between Large White and Landrace breed were detected. PMID:25781935

  1. A genome-wide association study in large white and landrace pig populations for number piglets born alive.

    PubMed

    Bergfelder-Drüing, Sarah; Grosse-Brinkhaus, Christine; Lind, Bianca; Erbe, Malena; Schellander, Karl; Simianer, Henner; Tholen, Ernst

    2015-01-01

    The number of piglets born alive (NBA) per litter is one of the most important traits in pig breeding due to its influence on production efficiency. It is difficult to improve NBA because the heritability of the trait is low and it is governed by a high number of loci with low to moderate effects. To clarify the biological and genetic background of NBA, genome-wide association studies (GWAS) were performed using 4,012 Large White and Landrace pigs from herdbook and commercial breeding companies in Germany (3), Austria (1) and Switzerland (1). The animals were genotyped with the Illumina PorcineSNP60 BeadChip. Because of population stratifications within and between breeds, clusters were formed using the genetic distances between the populations. Five clusters for each breed were formed and analysed by GWAS approaches. In total, 17 different significant markers affecting NBA were found in regions with known effects on female reproduction. No overlapping significant chromosome areas or QTL between Large White and Landrace breed were detected. PMID:25781935

  2. Genome-Wide Genetic Diversity and Differentially Selected Regions among Suffolk, Rambouillet, Columbia, Polypay, and Targhee Sheep

    PubMed Central

    Zhang, Lifan; Mousel, Michelle R.; Wu, Xiaolin; Michal, Jennifer J.; Zhou, Xiang; Ding, Bo; Dodson, Michael V.; El-Halawany, Nermin K.; Lewis, Gregory S.; Jiang, Zhihua

    2013-01-01

    Sheep are among the major economically important livestock species worldwide because the animals produce milk, wool, skin, and meat. In the present study, the Illumina OvineSNP50 BeadChip was used to investigate genetic diversity and genome selection among Suffolk, Rambouillet, Columbia, Polypay, and Targhee sheep breeds from the United States. After quality-control filtering of SNPs (single nucleotide polymorphisms), we used 48,026 SNPs, including 46,850 SNPs on autosomes that were in Hardy-Weinberg equilibrium and 1,176 SNPs on chromosome × for analysis. Phylogenetic analysis based on all 46,850 SNPs clearly separated Suffolk from Rambouillet, Columbia, Polypay, and Targhee, which was not surprising as Rambouillet contributed to the synthesis of the later three breeds. Based on pair-wise estimates of FST, significant genetic differentiation appeared between Suffolk and Rambouillet (FST = 0.1621), while Rambouillet and Targhee had the closest relationship (FST = 0.0681). A scan of the genome revealed 45 and 41 differentially selected regions (DSRs) between Suffolk and Rambouillet and among Rambouillet-related breed populations, respectively. Our data indicated that regions 13 and 24 between Suffolk and Rambouillet might be good candidates for evaluating breed differences. Furthermore, ovine genome v3.1 assembly was used as reference to link functionally known homologous genes to economically important traits covered by these differentially selected regions. In brief, our present study provides a comprehensive genome-wide view on within- and between-breed genetic differentiation, biodiversity, and evolution among Suffolk, Rambouillet, Columbia, Polypay, and Targhee sheep breeds. These results may provide new guidance for the synthesis of new breeds with different breeding objectives. PMID:23762451

  3. Genome-wide examination of myoblast cell cycle withdrawal duringdifferentiation

    SciTech Connect

    Shen, Xun; Collier, John Michael; Hlaing, Myint; Zhang, Leanne; Delshad, Elizabeth H.; Bristow, James; Bernstein, Harold S.

    2002-12-02

    Skeletal and cardiac myocytes cease division within weeks of birth. Although skeletal muscle retains limited capacity for regeneration through recruitment of satellite cells, resident populations of adult myocardial stem cells have not been identified. Because cell cycle withdrawal accompanies myocyte differentiation, we hypothesized that C2C12 cells, a mouse myoblast cell line previously used to characterize myocyte differentiation, also would provide a model for studying cell cycle withdrawal during differentiation. C2C12 cells were differentiated in culture medium containing horse serum and harvested at various time points to characterize the expression profiles of known cell cycle and myogenic regulatory factors by immunoblot analysis. BrdU incorporation decreased dramatically in confluent cultures 48 hr after addition of horse serum, as cells started to form myotubes. This finding was preceded by up-regulation of MyoD, followed by myogenin, and activation of Bcl-2. Cyclin D1 was expressed in proliferating cultures and became undetectable in cultures containing 40 percent fused myotubes, as levels of p21(WAF1/Cip1) increased and alpha-actin became detectable. Because C2C12 myoblasts withdraw from the cell cycle during myocyte differentiation following a course that recapitulates this process in vivo, we performed a genome-wide screen to identify other gene products involved in this process. Using microarrays containing approximately 10,000 minimally redundant mouse sequences that map to the UniGene database of the National Center for Biotechnology Information, we compared gene expression profiles between proliferating, differentiating, and differentiated C2C12 cells and verified candidate genes demonstrating differential expression by RT-PCR. Cluster analysis of differentially expressed genes revealed groups of gene products involved in cell cycle withdrawal, muscle differentiation, and apoptosis. In addition, we identified several genes, including DDAH2 and Ly

  4. Improved Statistics for Genome-Wide Interaction Analysis

    PubMed Central

    Ueki, Masao; Cordell, Heather J.

    2012-01-01

    Recently, Wu and colleagues [1] proposed two novel statistics for genome-wide interaction analysis using case/control or case-only data. In computer simulations, their proposed case/control statistic outperformed competing approaches, including the fast-epistasis option in PLINK and logistic regression analysis under the correct model; however, reasons for its superior performance were not fully explored. Here we investigate the theoretical properties and performance of Wu et al.'s proposed statistics and explain why, in some circumstances, they outperform competing approaches. Unfortunately, we find minor errors in the formulae for their statistics, resulting in tests that have higher than nominal type 1 error. We also find minor errors in PLINK's fast-epistasis and case-only statistics, although theory and simulations suggest that these errors have only negligible effect on type 1 error. We propose adjusted versions of all four statistics that, both theoretically and in computer simulations, maintain correct type 1 error rates under the null hypothesis. We also investigate statistics based on correlation coefficients that maintain similar control of type 1 error. Although designed to test specifically for interaction, we show that some of these previously-proposed statistics can, in fact, be sensitive to main effects at one or both loci, particularly in the presence of linkage disequilibrium. We propose two new “joint effects” statistics that, provided the disease is rare, are sensitive only to genuine interaction effects. In computer simulations we find, in most situations considered, that highest power is achieved by analysis under the correct genetic model. Such an analysis is unachievable in practice, as we do not know this model. However, generally high power over a wide range of scenarios is exhibited by our joint effects and adjusted Wu statistics. We recommend use of these alternative or adjusted statistics and urge caution when using Wu et al

  5. Genome-wide association study of sleep in Drosophila melanogaster

    PubMed Central

    2013-01-01

    Background Sleep is a highly conserved behavior, yet its duration and pattern vary extensively among species and between individuals within species. The genetic basis of natural variation in sleep remains unknown. Results We used the Drosophila Genetic Reference Panel (DGRP) to perform a genome-wide association (GWA) study of sleep in D. melanogaster. We identified candidate single nucleotide polymorphisms (SNPs) associated with differences in the mean as well as the environmental sensitivity of sleep traits; these SNPs typically had sex-specific or sex-biased effects, and were generally located in non-coding regions. The majority of SNPs (80.3%) affecting sleep were at low frequency and had moderately large effects. Additive models incorporating multiple SNPs explained as much as 55% of the genetic variance for sleep in males and females. Many of these loci are known to interact physically and/or genetically, enabling us to place them in candidate genetic networks. We confirmed the role of seven novel loci on sleep using insertional mutagenesis and RNA interference. Conclusions We identified many SNPs in novel loci that are potentially associated with natural variation in sleep, as well as SNPs within genes previously known to affect Drosophila sleep. Several of the candidate genes have human homologues that were identified in studies of human sleep, suggesting that genes affecting variation in sleep are conserved across species. Our discovery of genetic variants that influence environmental sensitivity to sleep may have a wider application to all GWA studies, because individuals with highly plastic genotypes will not have consistent phenotypes. PMID:23617951

  6. Probabilistic Protein Function Prediction from Heterogeneous Genome-Wide Data

    PubMed Central

    Nariai, Naoki; Kolaczyk, Eric D.; Kasif, Simon

    2007-01-01

    Dramatic improvements in high throughput sequencing technologies have led to a staggering growth in the number of predicted genes. However, a large fraction of these newly discovered genes do not have a functional assignment. Fortunately, a variety of novel high-throughput genome-wide functional screening technologies provide important clues that shed light on gene function. The integration of heterogeneous data to predict protein function has been shown to improve the accuracy of automated gene annotation systems. In this paper, we propose and evaluate a probabilistic approach for protein function prediction that integrates protein-protein interaction (PPI) data, gene expression data, protein motif information, mutant phenotype data, and protein localization data. First, functional linkage graphs are constructed from PPI data and gene expression data, in which an edge between nodes (proteins) represents evidence for functional similarity. The assumption here is that graph neighbors are more likely to share protein function, compared to proteins that are not neighbors. The functional linkage graph model is then used in concert with protein domain, mutant phenotype and protein localization data to produce a functional prediction. Our method is applied to the functional prediction of Saccharomyces cerevisiae genes, using Gene Ontology (GO) terms as the basis of our annotation. In a cross validation study we show that the integrated model increases recall by 18%, compared to using PPI data alone at the 50% precision. We also show that the integrated predictor is significantly better than each individual predictor. However, the observed improvement vs. PPI depends on both the new source of data and the functional category to be predicted. Surprisingly, in some contexts integration hurts overall prediction accuracy. Lastly, we provide a comprehensive assignment of putative GO terms to 463 proteins that currently have no assigned function. PMID:17396164

  7. Genome-wide activities of Polycomb complexes control pervasive transcription.

    PubMed

    Lee, Hun-Goo; Kahn, Tatyana G; Simcox, Amanda; Schwartz, Yuri B; Pirrotta, Vincenzo

    2015-08-01

    Polycomb group (PcG) complexes PRC1 and PRC2 are well known for silencing specific developmental genes. PRC2 is a methyltransferase targeting histone H3K27 and producing H3K27me3, essential for stable silencing. Less well known but quantitatively much more important is the genome-wide role of PRC2 that dimethylates ∼70% of total H3K27. We show that H3K27me2 occurs in inverse proportion to transcriptional activity in most non-PcG target genes and intergenic regions and is governed by opposing roaming activities of PRC2 and complexes containing the H3K27 demethylase UTX. Surprisingly, loss of H3K27me2 results in global transcriptional derepression proportionally greatest in silent or weakly transcribed intergenic and genic regions and accompanied by an increase of H3K27ac and H3K4me1. H3K27me2 therefore sets a threshold that prevents random, unscheduled transcription all over the genome and even limits the activity of highly transcribed genes. PRC1-type complexes also have global roles. Unexpectedly, we find a pervasive distribution of histone H2A ubiquitylated at lysine 118 (H2AK118ub) outside of canonical PcG target regions, dependent on the RING/Sce subunit of PRC1-type complexes. We show, however, that H2AK118ub does not mediate the global PRC2 activity or the global repression and is predominantly produced by a new complex involving L(3)73Ah, a homolog of mammalian PCGF3. PMID:25986499

  8. Genome-wide signatures of convergent evolution in echolocating mammals

    PubMed Central

    Parker, Joe; Tsagkogeorga, Georgia; Cotton, James A.; Liu, Yuan; Provero, Paolo; Stupka, Elia; Rossiter, Stephen J.

    2013-01-01

    Evolution is typically thought to proceed through divergence of genes, proteins, and ultimately phenotypes1-3. However, similar traits might also evolve convergently in unrelated taxa due to similar selection pressures4,5. Adaptive phenotypic convergence is widespread in nature, and recent results from a handful of genes have suggested that this phenomenon is powerful enough to also drive recurrent evolution at the sequence level6-9. Where homoplasious substitutions do occur these have long been considered the result of neutral processes. However, recent studies have demonstrated that adaptive convergent sequence evolution can be detected in vertebrates using statistical methods that model parallel evolution9,10 although the extent to which sequence convergence between genera occurs across genomes is unknown. Here we analyse genomic sequence data in mammals that have independently evolved echolocation and show for the first time that convergence is not a rare process restricted to a handful of loci but is instead widespread, continuously distributed and commonly driven by natural selection acting on a small number of sites per locus. Systematic analyses of convergent sequence evolution in 805,053 amino acids within 2,326 orthologous coding gene sequences compared across 22 mammals (including four new bat genomes) revealed signatures consistent with convergence in nearly 200 loci. Strong and significant support for convergence among bats and the dolphin was seen in numerous genes linked to hearing or deafness, consistent with an involvement in echolocation. Surprisingly we also found convergence in many genes linked to vision: the convergent signal of many sensory genes was robustly correlated with the strength of natural selection. This first attempt to detect genome-wide convergent sequence evolution across divergent taxa reveals the phenomenon to be much more pervasive than previously recognised. PMID:24005325

  9. Genome-wide signatures of convergent evolution in echolocating mammals.

    PubMed

    Parker, Joe; Tsagkogeorga, Georgia; Cotton, James A; Liu, Yuan; Provero, Paolo; Stupka, Elia; Rossiter, Stephen J

    2013-10-10

    Evolution is typically thought to proceed through divergence of genes, proteins and ultimately phenotypes. However, similar traits might also evolve convergently in unrelated taxa owing to similar selection pressures. Adaptive phenotypic convergence is widespread in nature, and recent results from several genes have suggested that this phenomenon is powerful enough to also drive recurrent evolution at the sequence level. Where homoplasious substitutions do occur these have long been considered the result of neutral processes. However, recent studies have demonstrated that adaptive convergent sequence evolution can be detected in vertebrates using statistical methods that model parallel evolution, although the extent to which sequence convergence between genera occurs across genomes is unknown. Here we analyse genomic sequence data in mammals that have independently evolved echolocation and show that convergence is not a rare process restricted to several loci but is instead widespread, continuously distributed and commonly driven by natural selection acting on a small number of sites per locus. Systematic analyses of convergent sequence evolution in 805,053 amino acids within 2,326 orthologous coding gene sequences compared across 22 mammals (including four newly sequenced bat genomes) revealed signatures consistent with convergence in nearly 200 loci. Strong and significant support for convergence among bats and the bottlenose dolphin was seen in numerous genes linked to hearing or deafness, consistent with an involvement in echolocation. Unexpectedly, we also found convergence in many genes linked to vision: the convergent signal of many sensory genes was robustly correlated with the strength of natural selection. This first attempt to detect genome-wide convergent sequence evolution across divergent taxa reveals the phenomenon to be much more pervasive than previously recognized. PMID:24005325

  10. Genome-wide characteristics of de novo mutations in autism

    PubMed Central

    Yuen, Ryan K C; Merico, Daniele; Cao, Hongzhi; Pellecchia, Giovanna; Alipanahi, Babak; Thiruvahindrapuram, Bhooma; Tong, Xin; Sun, Yuhui; Cao, Dandan; Zhang, Tao; Wu, Xueli; Jin, Xin; Zhou, Ze; Liu, Xiaomin; Nalpathamkalam, Thomas; Walker, Susan; Howe, Jennifer L.; Wang, Zhuozhi; MacDonald, Jeffrey R.; Chan, Ada; D’Abate, Lia; Deneault, Eric; Siu, Michelle T.; Tammimies, Kristiina; Uddin, Mohammed; Zarrei, Mehdi; Wang, Mingbang; Li, Yingrui; Wang, Jun; Wang, Jian; Yang, Huanming; Bookman, Matt; Bingham, Jonathan; Gross, Samuel S.; Loy, Dion; Pletcher, Mathew; Marshall, Christian R.; Anagnostou, Evdokia; Zwaigenbaum, Lonnie; Weksberg, Rosanna; Fernandez, Bridget A; Roberts, Wendy; Szatmari, Peter; Glazer, David; Frey, Brendan J.; Ring, Robert H.; Xu, Xun; Scherer, Stephen W.

    2016-01-01

    De novo mutations (DNMs) are important in Autism Spectrum Disorder (ASD), but so far analyses have mainly been on the ~1.5% of the genome encoding genes. Here, we performed whole genome sequencing (WGS) of 200 ASD parent-child trios and characterized germline and somatic DNMs. We confirmed that the majority of germline DNMs (75.6%) originated from the father, and these increased significantly with paternal age only (p=4.2×10−10). However, when clustered DNMs (those within 20kb) were found in ASD, not only did they mostly originate from the mother (p=7.7×10−13), but they could also be found adjacent to de novo copy number variations (CNVs) where the mutation rate was significantly elevated (p=2.4×10−24). By comparing DNMs detected in controls, we found a significant enrichment of predicted damaging DNMs in ASD cases (p=8.0×10−9; OR=1.84), of which 15.6% (p=4.3×10−3) and 22.5% (p=7.0×10−5) were in the non-coding or genic non-coding, respectively. The non-coding elements most enriched for DNM were untranslated regions of genes, boundaries involved in exon-skipping and DNase I hypersensitive regions. Using microarrays and a novel outlier detection test, we also found aberrant methylation profiles in 2/185 (1.1%) of ASD cases. These same individuals carried independently identified DNMs in the ASD risk- and epigenetic- genes DNMT3A and ADNP. Our data begins to characterize different genome-wide DNMs, and highlight the contribution of non-coding variants, to the etiology of ASD. PMID:27525107

  11. Multicentric Genome-Wide Association Study for Primary Spontaneous Pneumothorax.

    PubMed

    Sousa, Inês; Abrantes, Patrícia; Francisco, Vânia; Teixeira, Gilberto; Monteiro, Marta; Neves, João; Norte, Ana; Robalo Cordeiro, Carlos; Moura E Sá, João; Reis, Ernestina; Santos, Patrícia; Oliveira, Manuela; Sousa, Susana; Fradinho, Marta; Malheiro, Filipa; Negrão, Luís; Feijó, Salvato; Oliveira, Sofia A

    2016-01-01

    Despite elevated incidence and recurrence rates for Primary Spontaneous Pneumothorax (PSP), little is known about its etiology, and the genetics of idiopathic PSP remains unexplored. To identify genetic variants contributing to sporadic PSP risk, we conducted the first PSP genome-wide association study. Two replicate pools of 92 Portuguese PSP cases and of 129 age- and sex-matched controls were allelotyped in triplicate on the Affymetrix Human SNP Array 6.0 arrays. Markers passing quality control were ranked by relative allele score difference between cases and controls (|RASdiff|), by a novel cluster method and by a combined Z-test. 101 single nucleotide polymorphisms (SNPs) were selected using these three approaches for technical validation by individual genotyping in the discovery dataset. 87 out of 94 successfully tested SNPs were nominally associated in the discovery dataset. Replication of the 87 technically validated SNPs was then carried out in an independent replication dataset of 100 Portuguese cases and 425 controls. The intergenic rs4733649 SNP in chromosome 8 (between LINC00824 and LINC00977) was associated with PSP in the discovery (P = 4.07E-03, ORC[95% CI] = 1.88[1.22-2.89]), replication (P = 1.50E-02, ORC[95% CI] = 1.50[1.08-2.09]) and combined datasets (P = 8.61E-05, ORC[95% CI] = 1.65[1.29-2.13]). This study identified for the first time one genetic risk factor for sporadic PSP, but future studies are warranted to further confirm this finding in other populations and uncover its functional role in PSP pathogenesis. PMID:27203581

  12. Genome-Wide Architecture of Disease Resistance Genes in Lettuce.

    PubMed

    Christopoulou, Marilena; Wo, Sebastian Reyes-Chin; Kozik, Alex; McHale, Leah K; Truco, Maria-Jose; Wroblewski, Tadeusz; Michelmore, Richard W

    2015-12-01

    Genome-wide motif searches identified 1134 genes in the lettuce reference genome of cv. Salinas that are potentially involved in pathogen recognition, of which 385 were predicted to encode nucleotide binding-leucine rich repeat receptor (NLR) proteins. Using a maximum-likelihood approach, we grouped the NLRs into 25 multigene families and 17 singletons. Forty-one percent of these NLR-encoding genes belong to three families, the largest being RGC16 with 62 genes in cv. Salinas. The majority of NLR-encoding genes are located in five major resistance clusters (MRCs) on chromosomes 1, 2, 3, 4, and 8 and cosegregate with multiple disease resistance phenotypes. Most MRCs contain primarily members of a single NLR gene family but a few are more complex. MRC2 spans 73 Mb and contains 61 NLRs of six different gene families that cosegregate with nine disease resistance phenotypes. MRC3, which is 25 Mb, contains 22 RGC21 genes and colocates with Dm13. A library of 33 transgenic RNA interference tester stocks was generated for functional analysis of NLR-encoding genes that cosegregated with disease resistance phenotypes in each of the MRCs. Members of four NLR-encoding families, RGC1, RGC2, RGC21, and RGC12 were shown to be required for 16 disease resistance phenotypes in lettuce. The general composition of MRCs is conserved across different genotypes; however, the specific repertoire of NLR-encoding genes varied particularly of the rapidly evolving Type I genes. These tester stocks are valuable resources for future analyses of additional resistance phenotypes. PMID:26449254

  13. Identification of Neural Outgrowth Genes using Genome-Wide RNAi

    PubMed Central

    Sepp, Katharine J.; Hong, Pengyu; Lizarraga, Sofia B.; Liu, Judy S.; Mejia, Luis A.; Walsh, Christopher A.; Perrimon, Norbert

    2008-01-01

    While genetic screens have identified many genes essential for neurite outgrowth, they have been limited in their ability to identify neural genes that also have earlier critical roles in the gastrula, or neural genes for which maternally contributed RNA compensates for gene mutations in the zygote. To address this, we developed methods to screen the Drosophila genome using RNA-interference (RNAi) on primary neural cells and present the results of the first full-genome RNAi screen in neurons. We used live-cell imaging and quantitative image analysis to characterize the morphological phenotypes of fluorescently labelled primary neurons and glia in response to RNAi-mediated gene knockdown. From the full genome screen, we focused our analysis on 104 evolutionarily conserved genes that when downregulated by RNAi, have morphological defects such as reduced axon extension, excessive branching, loss of fasciculation, and blebbing. To assist in the phenotypic analysis of the large data sets, we generated image analysis algorithms that could assess the statistical significance of the mutant phenotypes. The algorithms were essential for the analysis of the thousands of images generated by the screening process and will become a valuable tool for future genome-wide screens in primary neurons. Our analysis revealed unexpected, essential roles in neurite outgrowth for genes representing a wide range of functional categories including signalling molecules, enzymes, channels, receptors, and cytoskeletal proteins. We also found that genes known to be involved in protein and vesicle trafficking showed similar RNAi phenotypes. We confirmed phenotypes of the protein trafficking genes Sec61alpha and Ran GTPase using Drosophila embryo and mouse embryonic cerebral cortical neurons, respectively. Collectively, our results showed that RNAi phenotypes in primary neural culture can parallel in vivo phenotypes, and the screening technique can be used to identify many new genes that have

  14. Genome-wide survey for biologically functional pseudogenes.

    PubMed

    Svensson, Orjan; Arvestad, Lars; Lagergren, Jens

    2006-05-01

    According to current estimates there exist about 20,000 pseudogenes in a mammalian genome. The vast majority of these are disabled and nonfunctional copies of protein-coding genes which, therefore, evolve neutrally. Recent findings that a Makorin1 pseudogene, residing on mouse Chromosome 5, is, indeed, in vivo vital and also evolutionarily preserved, encouraged us to conduct a genome-wide survey for other functional pseudogenes in human, mouse, and chimpanzee. We identify to our knowledge the first examples of conserved pseudogenes common to human and mouse, originating from one duplication predating the human-mouse species split and having evolved as pseudogenes since the species split. Functionality is one possible way to explain the apparently contradictory properties of such pseudogene pairs, i.e., high conservation and ancient origin. The hypothesis of functionality is tested by comparing expression evidence and synteny of the candidates with proper test sets. The tests suggest potential biological function. Our candidate set includes a small set of long-lived pseudogenes whose unknown potential function is retained since before the human-mouse species split, and also a larger group of primate-specific ones found from human-chimpanzee searches. Two processed sequences are notable, their conservation since the human-mouse split being as high as most protein-coding genes; one is derived from the protein Ataxin 7-like 3 (ATX7NL3), and one from the Spinocerebellar ataxia type 1 protein (ATX1). Our approach is comparative and can be applied to any pair of species. It is implemented by a semi-automated pipeline based on cross-species BLAST comparisons and maximum-likelihood phylogeny estimations. To separate pseudogenes from protein-coding genes, we use standard methods, utilizing in-frame disablements, as well as a probabilistic filter based on Ka/Ks ratios. PMID:16680195

  15. Mosaic paternal genome-wide uniparental isodisomy with down syndrome.

    PubMed

    Darcy, Diana; Atwal, Paldeep Singh; Angell, Cathy; Gadi, Inder; Wallerstein, Robert

    2015-10-01

    We report on a 6-month-old girl with two apparent cell lines; one with trisomy 21, and the other with paternal genome-wide uniparental isodisomy (GWUPiD), identified using single nucleotide polymorphism (SNP) based microarray and microsatellite analysis of polymorphic loci. The patient has Beckwith-Wiedemann syndrome (BWS) due to paternal uniparental disomy (UPD) at chromosome location 11p15 (UPD 11p15), which was confirmed through methylation analysis. Hyperinsulinemic hypoglycemia is present, which is associated with paternal UPD 11p15.5; and she likely has medullary nephrocalcinosis, which is associated with paternal UPD 20, although this was not biochemically confirmed. Angelman syndrome (AS) analysis was negative but this testing is not completely informative; she has no specific features of AS. Clinical features of this patient include: dysmorphic features consistent with trisomy 21, tetralogy of Fallot, hemihypertrophy, swirled skin hyperpigmentation, hepatoblastoma, and Wilms tumor. Her karyotype is 47,XX,+21[19]/46,XX[4], and microarray results suggest that the cell line with trisomy 21 is biparentally inherited and represents 40-50% of the genomic material in the tested specimen. The difference in the level of cytogenetically detected mosaicism versus the level of mosaicism observed via microarray analysis is likely caused by differences in the test methodologies. While a handful of cases of mosaic paternal GWUPiD have been reported, this patient is the only reported case that also involves trisomy 21. Other GWUPiD patients have presented with features associated with multiple imprinted regions, as does our patient. PMID:26219535

  16. Genome-wide metabolic (re-) annotation of Kluyveromyces lactis

    PubMed Central

    2012-01-01

    Background Even before having its genome sequence published in 2004, Kluyveromyces lactis had long been considered a model organism for studies in genetics and physiology. Research on Kluyveromyces lactis is quite advanced and this yeast species is one of the few with which it is possible to perform formal genetic analysis. Nevertheless, until now, no complete metabolic functional annotation has been performed to the proteins encoded in the Kluyveromyces lactis genome. Results In this work, a new metabolic genome-wide functional re-annotation of the proteins encoded in the Kluyveromyces lactis genome was performed, resulting in the annotation of 1759 genes with metabolic functions, and the development of a methodology supported by merlin (software developed in-house). The new annotation includes novelties, such as the assignment of transporter superfamily numbers to genes identified as transporter proteins. Thus, the genes annotated with metabolic functions could be exclusively enzymatic (1410 genes), transporter proteins encoding genes (301 genes) or have both metabolic activities (48 genes). The new annotation produced by this work largely surpassed the Kluyveromyces lactis currently available annotations. A comparison with KEGG’s annotation revealed a match with 844 (~90%) of the genes annotated by KEGG, while adding 850 new gene annotations. Moreover, there are 32 genes with annotations different from KEGG. Conclusions The methodology developed throughout this work can be used to re-annotate any yeast or, with a little tweak of the reference organism, the proteins encoded in any sequenced genome. The new annotation provided by this study offers basic knowledge which might be useful for the scientific community working on this model yeast, because new functions have been identified for the so-called metabolic genes. Furthermore, it served as the basis for the reconstruction of a compartmentalized, genome-scale metabolic model of Kluyveromyces lactis, which is

  17. Genome-wide analyses of human perisylvian cerebral cortical patterning

    PubMed Central

    Abrahams, B. S.; Tentler, D.; Perederiy, J. V.; Oldham, M. C.; Coppola, G.; Geschwind, D. H.

    2007-01-01

    Despite the well established role of the frontal and posterior perisylvian cortices in many facets of human-cognitive specializations, including language, little is known about the developmental patterning of these regions in the human brain. We performed a genome-wide analysis of human cerebral patterning during midgestation, a critical epoch in cortical regionalization. A total of 345 genes were identified as differentially expressed between superior temporal gyrus (STG) and the remaining cerebral cortex. Gene ontology categories representing transcription factors were enriched in STG, whereas cell-adhesion and extracellular matrix molecules were enriched in the other cortical regions. Quantitative RT-PCR or in situ hybridization was performed to validate differential expression in a subset of 32 genes, most of which were confirmed. LIM domain-binding 1 (LDB1), which we show to be enriched in the STG, is a recently identified interactor of LIM domain only 4 (LMO4), a gene known to be involved in the asymmetric pattering of the perisylvian region in the developing human brain. Protocadherin 17 (PCDH17), a neuronal cell adhesion molecule, was highly enriched in focal regions of the human prefrontal cortex. Contactin associated protein-like 2 (CNTNAP2), in which mutations are known to cause autism, epilepsy, and language delay, showed a remarkable pattern of anterior-enriched cortical expression in human that was not observed in mouse or rat. These data highlight the importance of expression analysis of human brain and the utility of cross-species comparisons of gene expression. Genes identified here provide a foundation for understanding molecular aspects of human-cognitive specializations and the disorders that disrupt them. PMID:17978184

  18. Genome-Wide Approaches for RNA Structure Probing.

    PubMed

    Silverman, Ian M; Berkowitz, Nathan D; Gosai, Sager J; Gregory, Brian D

    2016-01-01

    RNA molecules of all types fold into complex secondary and tertiary structures that are important for their function and regulation. Structural and catalytic RNAs such as ribosomal RNA (rRNA) and transfer RNA (tRNA) are central players in protein synthesis, and only function through their proper folding into intricate three-dimensional structures. Studies of messenger RNA (mRNA) regulation have also revealed that structural elements embedded within these RNA species are important for the proper regulation of their total level in the transcriptome. More recently, the discovery of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) has shed light on the importance of RNA structure to genome, transcriptome, and proteome regulation. Due to the relatively small number, high conservation, and importance of structural and catalytic RNAs to all life, much early work in RNA structure analysis mapped out a detailed view of these molecules. Computational and physical methods were used in concert with enzymatic and chemical structure probing to create high-resolution models of these fundamental biological molecules. However, the recent expansion in our knowledge of the importance of RNA structure to coding and regulatory RNAs has left the field in need of faster and scalable methods for high-throughput structural analysis. To address this, nuclease and chemical RNA structure probing methodologies have been adapted for genome-wide analysis. These methods have been deployed to globally characterize thousands of RNA structures in a single experiment. Here, we review these experimental methodologies for high-throughput RNA structure determination and discuss the insights gained from each approach. PMID:27256381

  19. Genome-Wide Association Study of Proneness to Anger

    PubMed Central

    Mick, Eric; McGough, James; Deutsch, Curtis K.; Frazier, Jean A.; Kennedy, David; Goldberg, Robert J.

    2014-01-01

    Background Community samples suggest that approximately 1 in 20 children and adults exhibit clinically significant anger, hostility, and aggression. Individuals with dysregulated emotional control have a greater lifetime burden of psychiatric morbidity, severe impairment in role functioning, and premature mortality due to cardiovascular disease. Methods With publically available data secured from dbGaP, we conducted a genome-wide association study of proneness to anger using the Spielberger State-Trait Anger Scale in the Atherosclerosis Risk in Communities (ARIC) study (n = 8,747). Results Subjects were, on average, 54 (range 45–64) years old at baseline enrollment, 47% (n = 4,117) were male, and all were of European descent by self-report. The mean Angry Temperament and Angry Reaction scores were 5.8±1.8 and 7.6±2.2. We observed a nominally significant finding (p = 2.9E-08, λ = 1.027 - corrected pgc = 2.2E-07, λ = 1.0015) on chromosome 6q21 in the gene coding for the non-receptor protein-tyrosine kinase, Fyn. Conclusions Fyn interacts with NDMA receptors and inositol-1,4,5-trisphosphate (IP3)-gated channels to regulate calcium influx and intracellular release in the post-synaptic density. These results suggest that signaling pathways regulating intracellular calcium homeostasis, which are relevant to memory, learning, and neuronal survival, may in part underlie the expression of Angry Temperament. PMID:24489884

  20. Bioinformatics challenges for genome-wide association studies

    PubMed Central

    Moore, Jason H.; Asselbergs, Folkert W.; Williams, Scott M.

    2010-01-01

    Motivation: The sequencing of the human genome has made it possible to identify an informative set of >1 million single nucleotide polymorphisms (SNPs) across the genome that can be used to carry out genome-wide association studies (GWASs). The availability of massive amounts of GWAS data has necessitated the development of new biostatistical methods for quality control, imputation and analysis issues including multiple testing. This work has been successful and has enabled the discovery of new associations that have been replicated in multiple studies. However, it is now recognized that most SNPs discovered via GWAS have small effects on disease susceptibility and thus may not be suitable for improving health care through genetic testing. One likely explanation for the mixed results of GWAS is that the current biostatistical analysis paradigm is by design agnostic or unbiased in that it ignores all prior knowledge about disease pathobiology. Further, the linear modeling framework that is employed in GWAS often considers only one SNP at a time thus ignoring their genomic and environmental context. There is now a shift away from the biostatistical approach toward a more holistic approach that recognizes the complexity of the genotype–phenotype relationship that is characterized by significant heterogeneity and gene–gene and gene–environment interaction. We argue here that bioinformatics has an important role to play in addressing the complexity of the underlying genetic basis of common human diseases. The goal of this review is to identify and discuss those GWAS challenges that will require computational methods. Contact: jason.h.moore@dartmouth.edu PMID:20053841

  1. Genome-Wide Architecture of Disease Resistance Genes in Lettuce

    PubMed Central

    Christopoulou, Marilena; Wo, Sebastian Reyes-Chin; Kozik, Alex; McHale, Leah K.; Truco, Maria-Jose; Wroblewski, Tadeusz; Michelmore, Richard W.

    2015-01-01

    Genome-wide motif searches identified 1134 genes in the lettuce reference genome of cv. Salinas that are potentially involved in pathogen recognition, of which 385 were predicted to encode nucleotide binding-leucine rich repeat receptor (NLR) proteins. Using a maximum-likelihood approach, we grouped the NLRs into 25 multigene families and 17 singletons. Forty-one percent of these NLR-encoding genes belong to three families, the largest being RGC16 with 62 genes in cv. Salinas. The majority of NLR-encoding genes are located in five major resistance clusters (MRCs) on chromosomes 1, 2, 3, 4, and 8 and cosegregate with multiple disease resistance phenotypes. Most MRCs contain primarily members of a single NLR gene family but a few are more complex. MRC2 spans 73 Mb and contains 61 NLRs of six different gene families that cosegregate with nine disease resistance phenotypes. MRC3, which is 25 Mb, contains 22 RGC21 genes and colocates with Dm13. A library of 33 transgenic RNA interference tester stocks was generated for functional analysis of NLR-encoding genes that cosegregated with disease resistance phenotypes in each of the MRCs. Members of four NLR-encoding families, RGC1, RGC2, RGC21, and RGC12 were shown to be required for 16 disease resistance phenotypes in lettuce. The general composition of MRCs is conserved across different genotypes; however, the specific repertoire of NLR-encoding genes varied particularly of the rapidly evolving Type I genes. These tester stocks are valuable resources for future analyses of additional resistance phenotypes. PMID:26449254

  2. Multicentric Genome-Wide Association Study for Primary Spontaneous Pneumothorax

    PubMed Central

    Abrantes, Patrícia; Francisco, Vânia; Teixeira, Gilberto; Monteiro, Marta; Neves, João; Norte, Ana; Robalo Cordeiro, Carlos; Moura e Sá, João; Reis, Ernestina; Santos, Patrícia; Oliveira, Manuela; Sousa, Susana; Fradinho, Marta; Malheiro, Filipa; Negrão, Luís

    2016-01-01

    Despite elevated incidence and recurrence rates for Primary Spontaneous Pneumothorax (PSP), little is known about its etiology, and the genetics of idiopathic PSP remains unexplored. To identify genetic variants contributing to sporadic PSP risk, we conducted the first PSP genome-wide association study. Two replicate pools of 92 Portuguese PSP cases and of 129 age- and sex-matched controls were allelotyped in triplicate on the Affymetrix Human SNP Array 6.0 arrays. Markers passing quality control were ranked by relative allele score difference between cases and controls (|RASdiff|), by a novel cluster method and by a combined Z-test. 101 single nucleotide polymorphisms (SNPs) were selected using these three approaches for technical validation by individual genotyping in the discovery dataset. 87 out of 94 successfully tested SNPs were nominally associated in the discovery dataset. Replication of the 87 technically validated SNPs was then carried out in an independent replication dataset of 100 Portuguese cases and 425 controls. The intergenic rs4733649 SNP in chromosome 8 (between LINC00824 and LINC00977) was associated with PSP in the discovery (P = 4.07E-03, ORC[95% CI] = 1.88[1.22–2.89]), replication (P = 1.50E-02, ORC[95% CI] = 1.50[1.08–2.09]) and combined datasets (P = 8.61E-05, ORC[95% CI] = 1.65[1.29–2.13]). This study identified for the first time one genetic risk factor for sporadic PSP, but future studies are warranted to further confirm this finding in other populations and uncover its functional role in PSP pathogenesis. PMID:27203581

  3. Genome-wide profiling of Populus small RNAs

    PubMed Central

    2009-01-01

    Background Short RNAs, and in particular microRNAs, are important regulators of gene expression both within defined regulatory pathways and at the epigenetic scale. We investigated the short RNA (sRNA) population (18-24 nt) of the transcriptome of green leaves from the sequenced Populus trichocarpa using a concatenation strategy in combination with 454 sequencing. Results The most abundant size class of sRNAs were 24 nt. Long Terminal Repeats were particularly associated with 24 nt sRNAs. Additionally, some repetitive elements were associated with 22 nt sRNAs. We identified an sRNA hot-spot on chromosome 19, overlapping a region containing both the proposed sex-determining locus and a major cluster of NBS-LRR genes. A number of phased siRNA loci were identified, a subset of which are predicted to target PPR and NBS-LRR disease resistance genes, classes of genes that have been significantly expanded in Populus. Additional loci enriched for sRNA production were identified and characterised. We identified 15 novel predicted microRNAs (miRNAs), including miRNA*sequences, and identified a novel locus that may encode a dual miRNA or a miRNA and short interfering RNAs (siRNAs). Conclusions The short RNA population of P. trichocarpa is at least as complex as that of Arabidopsis thaliana. We provide a first genome-wide view of short RNA production for P. trichocarpa and identify new, non-conserved miRNAs. PMID:20021695

  4. Genome-Wide Identification and Expression Analysis of WRKY Gene Family in Capsicum annuum L.

    PubMed Central

    Diao, Wei-Ping; Snyder, John C.; Wang, Shu-Bin; Liu, Jin-Bing; Pan, Bao-Gui; Guo, Guang-Jun; Wei, Ge

    2016-01-01

    The WRKY family of transcription factors is one of the most important families of plant transcriptional regulators with members regulating multiple biological processes, especially in regulating defense against biotic and abiotic stresses. However, little information is available about WRKYs in pepper (Capsicum annuum L.). The recent release of completely assembled genome sequences of pepper allowed us to perform a genome-wide investigation for pepper WRKY proteins. In the present study, a total of 71 WRKY genes were identified in the pepper genome. According to structural features of their encoded proteins, the pepper WRKY genes (CaWRKY) were classified into three main groups, with the second group further divided into five subgroups. Genome mapping analysis revealed that CaWRKY were enriched on four chromosomes, especially on chromosome 1, and 15.5% of the family members were tandemly duplicated genes. A phylogenetic tree was constructed depending on WRKY domain' sequences derived from pepper and Arabidopsis. The expression of 21 selected CaWRKY genes in response to seven different biotic and abiotic stresses (salt, heat shock, drought, Phytophtora capsici, SA, MeJA, and ABA) was evaluated by quantitative RT-PCR; Some CaWRKYs were highly expressed and up-regulated by stress treatment. Our results will provide a platform for functional identification and molecular breeding studies of WRKY genes in pepper. PMID:26941768

  5. Genome-Wide Association Mapping for Kernel and Malting Quality Traits Using Historical European Barley Records

    PubMed Central

    Röder, Marion S.; van Eeuwijk, Fred

    2014-01-01

    Malting quality is an important trait in breeding barley (Hordeum vulgare L.). It requires elaborate, expensive phenotyping, which involves micro-malting experiments. Although there is abundant historical information available for different cultivars in different years and trials, that historical information is not often used in genetic analyses. This study aimed to exploit historical records to assist in identifying genomic regions that affect malting and kernel quality traits in barley. This genome-wide association study utilized information on grain yield and 18 quality traits accumulated over 25 years on 174 European spring and winter barley cultivars combined with diversity array technology markers. Marker-trait associations were tested with a mixed linear model. This model took into account the genetic relatedness between cultivars based on principal components scores obtained from marker information. We detected 140 marker-trait associations. Some of these associations confirmed previously known quantitative trait loci for malting quality (on chromosomes 1H, 2H, and 5H). Other associations were reported for the first time in this study. The genetic correlations between traits are discussed in relation to the chromosomal regions associated with the different traits. This approach is expected to be particularly useful when designing strategies for multiple trait improvements. PMID:25372869

  6. Genome-wide association mapping of heritable temperament variation in the Tennessee Walking Horse.

    PubMed

    Staiger, E A; Albright, J D; Brooks, S A

    2016-06-01

    Temperament is a key criterion in the selection of horses for both leisure and competitive riding to ensure optimal performance and safety. The Tennessee Walking Horse (TWH) is described as a calm, docile breed and is often used as a trail, show and pleasure horse. However, among horse owners and caretakers, there are anecdotes supporting familial and disciplinal typical behaviors and personalities. To investigate the contribution of genetics to temperament, we collected a behavior questionnaire, brief training history and identifying information for 276 TWH, as well as blood or hair samples for DNA. Factor analysis was conducted on the 20-item questionnaire for the set of 216 horses that met inclusion thresholds. Factor analysis identified four temperament factors in TWH: 'anxious', 'tractable', 'agonistic' and 'gregarious'. These four factors account for 64% of the total trait variance. DNA from 113 TWHs were selected and genotyped using the Equine SNP70 bead chip for three separate genome-wide association studies (GWAs) using the factor 1-anxious, factor 2-tractable and factor 3-agonistic scores as the phenotype. Quantitative association analysis identified significant candidate loci for each factor that warrant further investigation. PMID:26991152

  7. Genome-Wide Association Study and Pathway-Level Analysis of Tocochromanol Levels in Maize Grain

    PubMed Central

    Lipka, Alexander E.; Gore, Michael A.; Magallanes-Lundback, Maria; Mesberg, Alex; Lin, Haining; Tiede, Tyler; Chen, Charles; Buell, C. Robin; Buckler, Edward S.; Rocheford, Torbert; DellaPenna, Dean

    2013-01-01

    Tocopherols and tocotrienols, collectively known as tocochromanols, are the major lipid-soluble antioxidants in maize (Zea mays L.) grain. Given that individual tocochromanols differ in their degree of vitamin E activity, variation for tocochromanol composition and content in grain from among diverse maize inbred lines has important nutritional and health implications for enhancing the vitamin E and antioxidant contents of maize-derived foods through plant breeding. Toward this end, we conducted a genome-wide association study of six tocochromanol compounds and 14 of their sums, ratios, and proportions with a 281 maize inbred association panel that was genotyped for 591,822 SNP markers. In addition to providing further insight into the association between ZmVTE4 (γ-tocopherol methyltransferase) haplotypes and α-tocopherol content, we also detected a novel association between ZmVTE1 (tocopherol cyclase) and tocotrienol composition. In a pathway-level analysis, we assessed the genetic contribution of 60 a priori candidate genes encoding the core tocochromanol pathway (VTE genes) and reactions for pathways supplying the isoprenoid tail and aromatic head group of tocochromanols. This analysis identified two additional genes, ZmHGGT1 (homogentisate geranylgeranyltransferase) and one prephenate dehydratase parolog (of four in the genome) that also modestly contribute to tocotrienol variation in the panel. Collectively, our results provide the most favorable ZmVTE4 haplotype and suggest three new gene targets for increasing vitamin E and antioxidant levels through marker-assisted selection. PMID:23733887

  8. Genome-wide association study uncovers four QTL predisposing to supernumerary teats in cattle.

    PubMed

    Pausch, Hubert; Jung, Simone; Edel, Christian; Emmerling, Reiner; Krogmeier, Dieter; Götz, Kay-Uwe; Fries, Ruedi

    2012-12-01

    Supernumerary teats (hyperthelia, SNTs) are a common abnormality of the bovine udder with a medium to high heritability and a postulated oligogenic or polygenic inheritance pattern. SNTs not only negatively affect machine milking ability but also act as a reservoir for bacteria. A genome-wide association study was carried out to identify genes involved in the development of SNTs in the dual-purpose Fleckvieh breed. A total of 2467 progeny-tested bulls were genotyped at 43 698 single nucleotide polymorphisms, and daughter yield deviations (DYDs) for 'udder clearness' (UC) were used as high-heritability phenotypes. Massive structuring of the study population was accounted for by principal components analysis-based and mixed model-based approaches. Four loci on BTA5, BTA6, BTA11 and BTA17 were significantly associated with the UC DYD. Three associated regions contain genes of the highly conserved Wnt signalling pathway. The four QTL together account for 10.7% of the variance of the UC DYD, whereas the major fraction of the DYD variance is attributable to chromosomes with no identified QTL. Our results support both an oligogenic and a polygenic inheritance pattern of SNTs in cattle. The identified candidate genes permit insights into the genetic architecture of teat malformations in cattle and provide clues to unravel the molecular mechanisms of mammary gland alterations in cattle and other species. PMID:22497297

  9. Genome-wide interaction study of smoking and bladder cancer risk

    PubMed Central

    Figueroa, Jonine D.; Han, Summer S.; Garcia-Closas, Montserrat; Baris, Dalsu; Jacobs, Eric J.; Kogevinas, Manolis; Schwenn, Molly; Malats, Nuria; Johnson, Alison; Purdue, Mark P.; Caporaso, Neil; Landi, Maria Teresa; Prokunina-Olsson, Ludmila; Wang, Zhaoming; Hutchinson, Amy; Burdette, Laurie; Wheeler, William; Vineis, Paolo; Siddiq, Afshan; Cortessis, Victoria K.; Kooperberg, Charles; Cussenot, Olivier; Benhamou, Simone; Prescott, Jennifer; Porru, Stefano; Bueno-de-Mesquita, H.Bas; Trichopoulos, Dimitrios; Ljungberg, Börje; Clavel-Chapelon, Françoise; Weiderpass, Elisabete; Krogh, Vittorio; Dorronsoro, Miren; Travis, Ruth; Tjønneland, Anne; Brenan, Paul; Chang-Claude, Jenny; Riboli, Elio; Conti, David; Gago-Dominguez, Manuela; Stern, Mariana C.; Pike, Malcolm C.; Van Den Berg, David; Yuan, Jian-Min; Hohensee, Chancellor; Rodabough, Rebecca; Cancel-Tassin, Geraldine; Roupret, Morgan; Comperat, Eva; Chen, Constance; De Vivo, Immaculata; Giovannucci, Edward; Hunter, David J.; Kraft, Peter; Lindstrom, Sara; Carta, Angela; Pavanello, Sofia; Arici, Cecilia; Mastrangelo, Giuseppe; Karagas, Margaret R.; Schned, Alan; Armenti, Karla R.; Hosain, G.M.Monawar; Haiman, Chris A.; Fraumeni, Joseph F.; Chanock, Stephen J.; Chatterjee, Nilanjan; Rothman, Nathaniel; Silverman, Debra T.

    2014-01-01

    Bladder cancer is a complex disease with known environmental and genetic risk factors. We performed a genome-wide interaction study (GWAS) of smoking and bladder cancer risk based on primary scan data from 3002 cases and 4411 controls from the National Cancer Institute Bladder Cancer GWAS. Alternative methods were used to evaluate both additive and multiplicative interactions between individual single nucleotide polymorphisms (SNPs) and smoking exposure. SNPs with interaction P values < 5 × 10− 5 were evaluated further in an independent dataset of 2422 bladder cancer cases and 5751 controls. We identified 10 SNPs that showed association in a consistent manner with the initial dataset and in the combined dataset, providing evidence of interaction with tobacco use. Further, two of these novel SNPs showed strong evidence of association with bladder cancer in tobacco use subgroups that approached genome-wide significance. Specifically, rs1711973 (FOXF2) on 6p25.3 was a susceptibility SNP for never smokers [combined odds ratio (OR) = 1.34, 95% confidence interval (CI) = 1.20–1.50, P value = 5.18 × 10− 7]; and rs12216499 (RSPH3-TAGAP-EZR) on 6q25.3 was a susceptibility SNP for ever smokers (combined OR = 0.75, 95% CI = 0.67–0.84, P value = 6.35 × 10− 7). In our analysis of smoking and bladder cancer, the tests for multiplicative interaction seemed to more commonly identify susceptibility loci with associations in never smokers, whereas the additive interaction analysis identified more loci with associations among smokers—including the known smoking and NAT2 acetylation interaction. Our findings provide additional evidence of gene–environment interactions for tobacco and bladder cancer. PMID:24662972

  10. Genome-Wide Association Analysis to Identify Loci for Milk Yield in Gyr Breed

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A genome scan was conducted to identify QTL affecting milk yield in a Brazilian Gyr population of progeny test bulls (N=319). Data used in this study was derived from traditional genetic evaluation records computed by the Embrapa Dairy Cattleand released in May/2009 (http://www.cnpgl.embrapa.br/nova...

  11. Identification of genome-wide selection signatures in the Limousin beef cattle breed.

    PubMed

    Gurgul, A; Szmatoła, T; Ropka-Molik, K; Jasielczuk, I; Pawlina, K; Semik, E; Bugno-Poniewierska, M

    2016-08-01

    The study is aimed at identifying selection footprints within the genome of Limousin cattle. With the use of Extended Haplotype Homozygosity test, supplemented with correction for variation in recombination rates across the genome, we created map of selection footprints and detected 173 significant (p < 0.01) core haplotypes being potentially under positive selection. Within these regions, a number of candidate genes associated inter alia with skeletal muscle growth (GDF15, BMP7, BMP4 and TGFB3) or postmortem proteolysis and meat maturation (CAPN1 and CAPN5) were annotated. Noticeable clusters of selection footprints were detected on chromosomes 1, 4, 8 and 14, which are known to carry several quantitative trait loci for growth traits and meat quality. The study provides information about the genes and metabolic pathways potentially modified under the influence of directional selection, aimed at improving beef production characteristics in Limousin cattle. PMID:26611546

  12. GENOME-WIDE ASSOCIATION ANALYSIS IDENTIFIES LOCI FOR PRODUCTIVE TRAITS IN JERSEY BREED

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A major objective of genomic research in dairy cattle at present is to identify, map, and characterize individual quantitative trait loci (QTL) that affects production traits. A genome scan was conducted in the US Jersey population to identify QTL affecting milk, fat and protein production. Data use...

  13. Genome-Wide Association Study of Entropion Eyelid in Multiple Breeds of Sheep

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Entropion is an inversion of the eyelid margin causing lashes or external hairs to rub against the ocular surface. If uncorrected, discomfort, ocular damage, increased eye infection rates, and potential blindness can occur. Entropion affects many mammalian species, can be expressed in both upper and...

  14. Genome-Wide Association Study Identifies a Novel Canine Glaucoma Locus

    PubMed Central

    Ahonen, Saija J.; Pietilä, Elina; Mellersh, Cathryn S.; Tiira, Katriina; Hansen, Liz; Johnson, Gary S.; Lohi, Hannes

    2013-01-01

    Glaucoma is an optic neuropathy and one of the leading causes of blindness. Its hereditary forms are classified into primary closed-angle (PCAG), primary open-angle (POAG) and primary congenital glaucoma (PCG). Although many loci have been mapped in human, only a few genes have been identified that are associated with the development of glaucoma and the genetic basis of the disease remains poorly understood. Glaucoma has also been described in many dog breeds, including Dandie Dinmont Terriers (DDT) in which it is a late-onset (>7 years) disease. We designed clinical and genetic studies to better define the clinical features of glaucoma in the DDT and to identify the genetic cause. Clinical diagnosis was based on ophthalmic examinations of the affected dogs and 18 additionally investigated unaffected DDTs. We collected DNA from over 400 DTTs and a genome wide association study was performed in a cohort of 23 affected and 23 controls, followed by a fine mapping, a replication study and candidate gene sequencing. The clinical study suggested that ocular abnormalities including abnormal iridocorneal angles and pectinate ligament dysplasia are common (50% and 72%, respectively) in the breed and the disease resembles human PCAG. The genetic study identified a novel 9.5 Mb locus on canine chromosome 8 including the 1.6 Mb best associated region (p = 1.63×10−10, OR = 32 for homozygosity). Mutation screening in five candidate genes did not reveal any causative variants. This study indicates that although ocular abnormalities are common in DDTs, the genetic risk for glaucoma is conferred by a novel locus on CFA8. The canine locus shares synteny to a region in human chromosome 14q, which harbors several loci associated with POAG and PCG. Our study reveals a new locus for canine glaucoma and ongoing molecular studies will likely help to understand the genetic etiology of the disease. PMID:23951034

  15. Agronomic and Seed Quality Traits Dissected by Genome-Wide Association Mapping in Brassica napus.

    PubMed

    Körber, Niklas; Bus, Anja; Li, Jinquan; Parkin, Isobel A P; Wittkop, Benjamin; Snowdon, Rod J; Stich, Benjamin

    2016-01-01

    In Brassica napus breeding, traits related to commercial success are of highest importance for plant breeders. However, such traits can only be assessed in an advanced developmental stage. Molecular markers genetically linked to such traits have the potential to accelerate the breeding process of B. napus by marker-assisted selection. Therefore, the objectives of this study were to identify (i) genome regions associated with the examined agronomic and seed quality traits, (ii) the interrelationship of population structure and the detected associations, and (iii) candidate genes for the revealed associations. The diversity set used in this study consisted of 405 B. napus inbred lines which were genotyped using a 6K single nucleotide polymorphism (SNP) array and phenotyped for agronomic and seed quality traits in field trials. In a genome-wide association study, we detected a total of 112 associations between SNPs and the seed quality traits as well as 46 SNP-trait associations for the agronomic traits with a P < 1.28e-05 (Bonferroni correction of α = 0.05) for the inbreds of the spring and winter trial. For the seed quality traits, a single SNP-sulfur concentration in seeds (SUL) association explained up to 67.3% of the phenotypic variance, whereas for the agronomic traits, a single SNP-blossom color (BLC) association explained up to 30.2% of the phenotypic variance. In a basic local alignment search tool (BLAST) search within a distance of 2.5 Mbp around these SNP-trait associations, 62 hits of potential candidate genes with a BLAST-score of ≥100 and a sequence identity of ≥70% to A. thaliana or B. rapa could be found for the agronomic SNP-trait associations and 187 hits of potential candidate genes for the seed quality SNP-trait associations. PMID:27066036

  16. Genome-Wide Scans for Delineation of Candidate Genes Regulating Seed-Protein Content in Chickpea.

    PubMed

    Upadhyaya, Hari D; Bajaj, Deepak; Narnoliya, Laxmi; Das, Shouvik; Kumar, Vinod; Gowda, C L L; Sharma, Shivali; Tyagi, Akhilesh K; Parida, Swarup K

    2016-01-01

    Identification of potential genes/alleles governing complex seed-protein content (SPC) is essential in marker-assisted breeding for quality trait improvement of chickpea. Henceforth, the present study utilized an integrated genomics-assisted breeding strategy encompassing trait association analysis, selective genotyping in traditional bi-parental mapping population and differential expression profiling for the first-time to understand the complex genetic architecture of quantitative SPC trait in chickpea. For GWAS (genome-wide association study), high-throughput genotyping information of 16376 genome-based SNPs (single nucleotide polymorphism) discovered from a structured population of 336 sequenced desi and kabuli accessions [with 150-200 kb LD (linkage disequilibrium) decay] was utilized. This led to identification of seven most effective genomic loci (genes) associated [10-20% with 41% combined PVE (phenotypic variation explained)] with SPC trait in chickpea. Regardless of the diverse desi and kabuli genetic backgrounds, a comparable level of association potential of the identified seven genomic loci with SPC trait was observed. Five SPC-associated genes were validated successfully in parental accessions and homozygous individuals of an intra-specific desi RIL (recombinant inbred line) mapping population (ICC 12299 × ICC 4958) by selective genotyping. The seed-specific expression, including differential up-regulation (>four fold) of six SPC-associated genes particularly in accessions, parents and homozygous individuals of the aforementioned mapping population with a high level of contrasting SPC (21-22%) was evident. Collectively, the integrated genomic approach delineated diverse naturally occurring novel functional SNP allelic variants in six potential candidate genes regulating SPC trait in chickpea. Of these, a non-synonymous SNP allele-carrying zinc finger transcription factor gene exhibiting strong association with SPC trait was found to be the most

  17. Agronomic and Seed Quality Traits Dissected by Genome-Wide Association Mapping in Brassica napus

    PubMed Central

    Körber, Niklas; Bus, Anja; Li, Jinquan; Parkin, Isobel A. P.; Wittkop, Benjamin; Snowdon, Rod J.; Stich, Benjamin

    2016-01-01

    In Brassica napus breeding, traits related to commercial success are of highest importance for plant breeders. However, such traits can only be assessed in an advanced developmental stage. Molecular markers genetically linked to such traits have the potential to accelerate the breeding process of B. napus by marker-assisted selection. Therefore, the objectives of this study were to identify (i) genome regions associated with the examined agronomic and seed quality traits, (ii) the interrelationship of population structure and the detected associations, and (iii) candidate genes for the revealed associations. The diversity set used in this study consisted of 405 B. napus inbred lines which were genotyped using a 6K single nucleotide polymorphism (SNP) array and phenotyped for agronomic and seed quality traits in field trials. In a genome-wide association study, we detected a total of 112 associations between SNPs and the seed quality traits as well as 46 SNP-trait associations for the agronomic traits with a P < 1.28e-05 (Bonferroni correction of α = 0.05) for the inbreds of the spring and winter trial. For the seed quality traits, a single SNP-sulfur concentration in seeds (SUL) association explained up to 67.3% of the phenotypic variance, whereas for the agronomic traits, a single SNP-blossom color (BLC) association explained up to 30.2% of the phenotypic variance. In a basic local alignment search tool (BLAST) search within a distance of 2.5 Mbp around these SNP-trait associations, 62 hits of potential candidate genes with a BLAST-score of ≥100 and a sequence identity of ≥70% to A. thaliana or B. rapa could be found for the agronomic SNP-trait associations and 187 hits of potential candidate genes for the seed quality SNP-trait associations. PMID:27066036

  18. Genome-Wide Scans for Delineation of Candidate Genes Regulating Seed-Protein Content in Chickpea

    PubMed Central

    Upadhyaya, Hari D.; Bajaj, Deepak; Narnoliya, Laxmi; Das, Shouvik; Kumar, Vinod; Gowda, C. L. L.; Sharma, Shivali; Tyagi, Akhilesh K.; Parida, Swarup K.

    2016-01-01

    Identification of potential genes/alleles governing complex seed-protein content (SPC) is essential in marker-assisted breeding for quality trait improvement of chickpea. Henceforth, the present study utilized an integrated genomics-assisted breeding strategy encompassing trait association analysis, selective genotyping in traditional bi-parental mapping population and differential expression profiling for the first-time to understand the complex genetic architecture of quantitative SPC trait in chickpea. For GWAS (genome-wide association study), high-throughput genotyping information of 16376 genome-based SNPs (single nucleotide polymorphism) discovered from a structured population of 336 sequenced desi and kabuli accessions [with 150–200 kb LD (linkage disequilibrium) decay] was utilized. This led to identification of seven most effective genomic loci (genes) associated [10–20% with 41% combined PVE (phenotypic variation explained)] with SPC trait in chickpea. Regardless of the diverse desi and kabuli genetic backgrounds, a comparable level of association potential of the identified seven genomic loci with SPC trait was observed. Five SPC-associated genes were validated successfully in parental accessions and homozygous individuals of an intra-specific desi RIL (recombinant inbred line) mapping population (ICC 12299 × ICC 4958) by selective genotyping. The seed-specific expression, including differential up-regulation (>four fold) of six SPC-associated genes particularly in accessions, parents and homozygous individuals of the aforementioned mapping population with a high level of contrasting SPC (21–22%) was evident. Collectively, the integrated genomic approach delineated diverse naturally occurring novel functional SNP allelic variants in six potential candidate genes regulating SPC trait in chickpea. Of these, a non-synonymous SNP allele-carrying zinc finger transcription factor gene exhibiting strong association with SPC trait was found to be the most

  19. Prediction of a time-to-event trait using genome wide SNP data

    PubMed Central

    2013-01-01

    Background A popular objective of many high-throughput genome projects is to discover various genomic markers associated with traits and develop statistical models to predict traits of future patients based on marker values. Results In this paper, we present a prediction method for time-to-event traits using genome-wide single-nucleotide polymorphisms (SNPs). We also propose a MaxTest associating between a time-to-event trait and a SNP accounting for its possible genetic models. The proposed MaxTest can help screen out nonprognostic SNPs and identify genetic models of prognostic SNPs. The performance of the proposed method is evaluated through simulations. Conclusions In conjunction with the MaxTest, the proposed method provides more parsimonious prediction models but includes more prognostic SNPs than some naive prediction methods. The proposed method is demonstrated with real GWAS data. PMID:23418752

  20. Stories and Challenges of Genome Wide Association Studies in Livestock — A Review

    PubMed Central

    Sharma, Aditi; Lee, Jun Seop; Dang, Chang Gwon; Sudrajad, Pita; Kim, Hyeong Cheol; Yeon, Seong Heum; Kang, Hee Seol; Lee, Seung-Hwan

    2015-01-01

    Undoubtedly livestock is one of the major contributors to the economy of any country. The economic value of livestock includes meat, dairy products, fiber, fertilizer etc. Understanding and identifying the associations of quantitative trait loci (QTL) with the economically important traits is believed to substantially benefit the livestock industry. The past two decades have seen a flurry of interest in mapping the QTL associated with traits of economic importance on the genome. With the availability of single nucleotide polymorphism chip of various densities it is possible to identify regions, QTL and genes on the genome that explain the association and its effect on the phenotype under consideration. Remarkable advancement has been seen in genome wide association studies (GWAS) since its inception till the present day. In this review we describe the progress and challenges of GWAS in various livestock species. PMID:26194229

  1. Genome-wide association study of colorectal cancer identifies six new susceptibility loci

    PubMed Central

    Schumacher, Fredrick R.; Schmit, Stephanie L.; Jiao, Shuo; Edlund, Christopher K.; Wang, Hansong; Zhang, Ben; Hsu, Li; Huang, Shu-Chen; Fischer, Christopher P.; Harju, John F.; Idos, Gregory E.; Lejbkowicz, Flavio; Manion, Frank J.; McDonnell, Kevin; McNeil, Caroline E.; Melas, Marilena; Rennert, Hedy S.; Shi, Wei; Thomas, Duncan C.; Van Den Berg, David J.; Hutter, Carolyn M.; Aragaki, Aaron K.; Butterbach, Katja; Caan, Bette J.; Carlson, Christopher S.; Chanock, Stephen J.; Curtis, Keith R.; Fuchs, Charles S.; Gala, Manish; Giovannucci, Edward L.; Gogarten, Stephanie M.; Hayes, Richard B.; Henderson, Brian; Hunter, David J.; Jackson, Rebecca D.; Kolonel, Laurence N.; Kooperberg, Charles; Küry, Sébastien; LaCroix, Andrea; Laurie, Cathy C.; Laurie, Cecelia A.; Lemire, Mathieu; Levine, David; Ma, Jing; Makar, Karen W.; Qu, Conghui; Taverna, Darin; Ulrich, Cornelia M.; Wu, Kana; Kono, Suminori; West, Dee W.; Berndt, Sonja I.; Bezieau, Stéphane; Brenner, Hermann; Campbell, Peter T.; Chan, Andrew T.; Chang-Claude, Jenny; Coetzee, Gerhard A.; Conti, David V.; Duggan, David; Figueiredo, Jane C.; Fortini, Barbara K.; Gallinger, Steven J.; Gauderman, W. James; Giles, Graham; Green, Roger; Haile, Robert; Harrison, Tabitha A.; Hoffmeister, Michael; Hopper, John L.; Hudson, Thomas J.; Jacobs, Eric; Iwasaki, Motoki; Jee, Sun Ha; Jenkins, Mark; Jia, Wei-Hua; Joshi, Amit; Li, Li; Lindor, Noralene M.; Matsuo, Keitaro; Moreno, Victor; Mukherjee, Bhramar; Newcomb, Polly A.; Potter, John D.; Raskin, Leon; Rennert, Gad; Rosse, Stephanie; Severi, Gianluca; Schoen, Robert E.; Seminara, Daniela; Shu, Xiao-Ou; Slattery, Martha L.; Tsugane, Shoichiro; White, Emily; Xiang, Yong-Bing; Zanke, Brent W.; Zheng, Wei; Le Marchand, Loic; Casey, Graham; Gruber, Stephen B.; Peters, Ulrike

    2016-01-01

    Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P<5.0E-08. These findings provide additional insight into the underlying biological mechanisms of colorectal cancer and demonstrate the scientific value of large consortia-based genetic epidemiology studies. PMID:26151821

  2. A human genome-wide loss-of-function screen identifies effective chikungunya antiviral drugs

    PubMed Central

    Karlas, Alexander; Berre, Stefano; Couderc, Thérèse; Varjak, Margus; Braun, Peter; Meyer, Michael; Gangneux, Nicolas; Karo-Astover, Liis; Weege, Friderike; Raftery, Martin; Schönrich, Günther; Klemm, Uwe; Wurzlbauer, Anne; Bracher, Franz; Merits, Andres; Meyer, Thomas F.; Lecuit, Marc

    2016-01-01

    Chikungunya virus (CHIKV) is a globally spreading alphavirus against which there is no commercially available vaccine or therapy. Here we use a genome-wide siRNA screen to identify 156 proviral and 41 antiviral host factors affecting CHIKV replication. We analyse the cellular pathways in which human proviral genes are involved and identify druggable targets. Twenty-one small-molecule inhibitors, some of which are FDA approved, targeting six proviral factors or pathways, have high antiviral activity in vitro, with low toxicity. Three identified inhibitors have prophylactic antiviral effects in mouse models of chikungunya infection. Two of them, the calmodulin inhibitor pimozide and the fatty acid synthesis inhibitor TOFA, have a therapeutic effect in vivo when combined. These results demonstrate the value of loss-of-function screening and pathway analysis for the rational identification of small molecules with therapeutic potential and pave the way for the development of new, host-directed, antiviral agents. PMID:27177310

  3. Genome-wide association study of colorectal cancer identifies six new susceptibility loci.

    PubMed

    Schumacher, Fredrick R; Schmit, Stephanie L; Jiao, Shuo; Edlund, Christopher K; Wang, Hansong; Zhang, Ben; Hsu, Li; Huang, Shu-Chen; Fischer, Christopher P; Harju, John F; Idos, Gregory E; Lejbkowicz, Flavio; Manion, Frank J; McDonnell, Kevin; McNeil, Caroline E; Melas, Marilena; Rennert, Hedy S; Shi, Wei; Thomas, Duncan C; Van Den Berg, David J; Hutter, Carolyn M; Aragaki, Aaron K; Butterbach, Katja; Caan, Bette J; Carlson, Christopher S; Chanock, Stephen J; Curtis, Keith R; Fuchs, Charles S; Gala, Manish; Giovannucc, Edward L; Giocannucci, Edward L; Gogarten, Stephanie M; Hayes, Richard B; Henderson, Brian; Hunter, David J; Jackson, Rebecca D; Kolonel, Laurence N; Kooperberg, Charles; Küry, Sébastien; Kury, Sebastian; LaCroix, Andrea; Laurie, Cathy C; Laurie, Cecelia A; Lemire, Mathieu; Lemire, Mathiew; Levine, David; Ma, Jing; Makar, Karen W; Qu, Conghui; Taverna, Darin; Ulrich, Cornelia M; Wu, Kana; Kono, Suminori; West, Dee W; Berndt, Sonja I; Bezieau, Stéphane; Brenner, Hermann; Campbell, Peter T; Chan, Andrew T; Chang-Claude, Jenny; Coetzee, Gerhard A; Conti, David V; Duggan, David; Figueiredo, Jane C; Fortini, Barbara K; Gallinger, Steven J; Gauderman, W James; Giles, Graham; Green, Roger; Haile, Robert; Harrison, Tabitha A; Hoffmeister, Michael; Hopper, John L; Hudson, Thomas J; Jacobs, Eric; Iwasaki, Motoki; Jee, Sun Ha; Jenkins, Mark; Jia, Wei-Hua; Joshi, Amit; Li, Li; Lindor, Noralene M; Matsuo, Keitaro; Moreno, Victor; Mukherjee, Bhramar; Newcomb, Polly A; Potter, John D; Raskin, Leon; Rennert, Gad; Rosse, Stephanie; Severi, Gianluca; Schoen, Robert E; Seminara, Daniela; Shu, Xiao-Ou; Slattery, Martha L; Tsugane, Shoichiro; White, Emily; Xiang, Yong-Bing; Zanke, Brent W; Zheng, Wei; Le Marchand, Loic; Casey, Graham; Gruber, Stephen B; Peters, Ulrike

    2015-01-01

    Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P<5.0E-08. These findings provide additional insight into the underlying biological mechanisms of colorectal cancer and demonstrate the scientific value of large consortia-based genetic epidemiology studies. PMID:26151821

  4. Stories and Challenges of Genome Wide Association Studies in Livestock - A Review.

    PubMed

    Sharma, Aditi; Lee, Jun Seop; Dang, Chang Gwon; Sudrajad, Pita; Kim, Hyeong Cheol; Yeon, Seong Heum; Kang, Hee Seol; Lee, Seung-Hwan

    2015-10-01

    Undoubtedly livestock is one of the major contributors to the economy of any country. The economic value of livestock includes meat, dairy products, fiber, fertilizer etc. Understanding and identifying the associations of quantitative trait loci (QTL) with the economically important traits is believed to substantially benefit the livestock industry. The past two decades have seen a flurry of interest in mapping the QTL associated with traits of economic importance on the genome. With the availability of single nucleotide polymorphism chip of various densities it is possible to identify regions, QTL and genes on the genome that explain the association and its effect on the phenotype under consideration. Remarkable advancement has been seen in genome wide association studies (GWAS) since its inception till the present day. In this review we describe the progress and challenges of GWAS in various livestock species. PMID:26194229

  5. Methodological Issues in Multistage Genome-wide Association Studies

    PubMed Central

    Thomas, Duncan C.; Casey, Graham; Conti, David V.; Haile, Robert W.; Lewinger, Juan Pablo; Stram, Daniel O.

    2010-01-01

    Because of the high cost of commercial genotyping chip technologies, many investigations have used a two-stage design for genome-wide association studies, using part of the sample for an initial discovery of “promising” SNPs at a less stringent significance level and the remainder in a joint analysis of just these SNPs using custom genotyping. Typical cost savings of about 50% are possible with this design to obtain comparable levels of overall type I error and power by using about half the sample for stage I and carrying about 0.1% of SNPs forward to the second stage, the optimal design depending primarily upon the ratio of costs per genotype for stages I and II. However, with the rapidly declining costs of the commercial panels, the generally low observed ORs of current studies, and many studies aiming to test multiple hypotheses and multiple endpoints, many investigators are abandoning the two-stage design in favor of simply genotyping all available subjects using a standard high-density panel. Concern is sometimes raised about the absence of a “replication” panel in this approach, as required by some high-profile journals, but it must be appreciated that the two-stage design is not a discovery/replication design but simply a more efficient design for discovery using a joint analysis of the data from both stages. Once a subset of highly-significant associations has been discovered, a truly independent “exact replication” study is needed in a similar population of the same promising SNPs using similar methods. This can then be followed by (1) “generalizability” studies to assess the full scope of replicated associations across different races, different endpoints, different interactions, etc.; (2) fine-mapping or re-sequencing to try to identify the causal variant; and (3) experimental studies of the biological function of these genes. Multistage sampling designs may be more useful at this stage, say for selecting subsets of subjects for deep re

  6. Genome-wide association study of colorectal cancer in Hispanics.

    PubMed

    Schmit, Stephanie L; Schumacher, Fredrick R; Edlund, Christopher K; Conti, David V; Ihenacho, Ugonna; Wan, Peggy; Van Den Berg, David; Casey, Graham; Fortini, Barbara K; Lenz, Heinz-Josef; Tusié-Luna, Teresa; Aguilar-Salinas, Carlos A; Moreno-Macías, Hortensia; Huerta-Chagoya, Alicia; Ordóñez-Sánchez, María Luisa; Rodríguez-Guillén, Rosario; Cruz-Bautista, Ivette; Rodríguez-Torres, Maribel; Muñóz-Hernández, Linda Liliana; Arellano-Campos, Olimpia; Gómez, Donají; Alvirde, Ulices; González-Villalpando, Clicerio; González-Villalpando, María Elena; Le Marchand, Loic; Haiman, Christopher A; Figueiredo, Jane C

    2016-06-01

    Genome-wide association studies (GWAS) have identified 58 susceptibility alleles across 37 regions associated with the risk of colorectal cancer (CRC) with P < 5×10(-8) Most studies have been conducted in non-Hispanic whites and East Asians; however, the generalizability of these findings and the potential for ethnic-specific risk variation in Hispanic and Latino (HL) individuals have been largely understudied. We describe the first GWAS of common genetic variation contributing to CRC risk in HL (1611 CRC cases and 4330 controls). We also examine known susceptibility alleles and implement imputation-based fine-mapping to identify potential ethnicity-specific association signals in known risk regions. We discovered 17 variants across 4 independent regions that merit further investigation due to suggestive CRC associations (P < 1×10(-6)) at 1p34.3 (rs7528276; Odds Ratio (OR) = 1.86 [95% confidence interval (CI): 1.47-2.36); P = 2.5×10(-7)], 2q23.3 (rs1367374; OR = 1.37 (95% CI: 1.21-1.55); P = 4.0×10(-7)), 14q24.2 (rs143046984; OR = 1.65 (95% CI: 1.36-2.01); P = 4.1×10(-7)) and 16q12.2 [rs142319636; OR = 1.69 (95% CI: 1.37-2.08); P=7.8×10(-7)]. Among the 57 previously published CRC susceptibility alleles with minor allele frequency ≥1%, 76.5% of SNPs had a consistent direction of effect and 19 (33.3%) were nominally statistically significant (P < 0.05). Further, rs185423955 and rs60892987 were identified as novel secondary susceptibility variants at 3q26.2 (P = 5.3×10(-5)) and 11q12.2 (P = 6.8×10(-5)), respectively. Our findings demonstrate the importance of fine mapping in HL. These results are informative for variant prioritization in functional studies and future risk prediction modeling in minority populations. PMID:27207650

  7. Genome-wide association study of colorectal cancer in Hispanics

    PubMed Central

    Schmit, Stephanie L.; Schumacher, Fredrick R.; Edlund, Christopher K.; Conti, David V.; Ihenacho, Ugonna; Wan, Peggy; Van Den Berg, David; Casey, Graham; Fortini, Barbara K.; Lenz, Heinz-Josef; Tusié-Luna, Teresa; Aguilar-Salinas, Carlos A.; Moreno-Macías, Hortensia; Huerta-Chagoya, Alicia; Ordóñez-Sánchez, María Luisa; Rodríguez-Guillén, Rosario; Cruz-Bautista, Ivette; Rodríguez-Torres, Maribel; Muñóz-Hernández, Linda Liliana; Arellano-Campos, Olimpia; Gómez, Donají; Alvirde, Ulices; González-Villalpando, Clicerio; González-Villalpando, María Elena; Le Marchand, Loic; Haiman, Christopher A.; Figueiredo, Jane C.

    2016-01-01

    Genome-wide association studies (GWAS) have identified 58 susceptibility alleles across 37 regions associated with the risk of colorectal cancer (CRC) with P < 5×10−8. Most studies have been conducted in non-Hispanic whites and East Asians; however, the generalizability of these findings and the potential for ethnic-specific risk variation in Hispanic and Latino (HL) individuals have been largely understudied. We describe the first GWAS of common genetic variation contributing to CRC risk in HL (1611 CRC cases and 4330 controls). We also examine known susceptibility alleles and implement imputation-based fine-mapping to identify potential ethnicity-specific association signals in known risk regions. We discovered 17 variants across 4 independent regions that merit further investigation due to suggestive CRC associations (P < 1×10−6) at 1p34.3 (rs7528276; Odds Ratio (OR) = 1.86 [95% confidence interval (CI): 1.47–2.36); P = 2.5×10−7], 2q23.3 (rs1367374; OR = 1.37 (95% CI: 1.21–1.55); P = 4.0×10−7), 14q24.2 (rs143046984; OR = 1.65 (95% CI: 1.36–2.01); P = 4.1×10−7) and 16q12.2 [rs142319636; OR = 1.69 (95% CI: 1.37–2.08); P=7.8×10−7]. Among the 57 previously published CRC susceptibility alleles with minor allele frequency ≥1%, 76.5% of SNPs had a consistent direction of effect and 19 (33.3%) were nominally statistically significant (P < 0.05). Further, rs185423955 and rs60892987 were identified as novel secondary susceptibility variants at 3q26.2 (P = 5.3×10–5) and 11q12.2 (P = 6.8×10−5), respectively. Our findings demonstrate the importance of fine mapping in HL. These results are informative for variant prioritization in functional studies and future risk prediction modeling in minority populations. PMID:27207650

  8. A Genome-wide Pleiotropy Scan for Prostate Cancer Risk

    PubMed Central

    Panagiotou, Orestis A; Travis, Ruth C; Campa, Daniele; Berndt, Sonja I.; Lindstrom, Sara; Kraft, Peter; Schumacher, Fredrick R.; Siddiq, Afshan; Papatheodorou, Stefania I.; Stanford, Janet L.; Albanes, Demetrius; Virtamo, Jarmo; Weinstein, Stephanie J.; Diver, W. Ryan; Gapstur, Susan M.; Stevens, Victoria L.; Boeing, Heiner; Bueno-de-Mesquita, H. Bas; Gurrea, Aurelio Barricarte; Kaaks, Rudolf; Khaw, Kay-Tee; Krogh, Vittorio; Overvad, Kim; Riboli, Elio; Trichopoulos, Dimitrios; Giovannucci, Edward; Stampfer, Meir; Haiman, Christopher; Henderson, Brian; Le Marchand, Loic; Gaziano, J. Michael; Hunter, DavidJ.; Koutros, Stella; Yeager, Meredith; Hoover, Robert N.; Chanock, Stephen J.; Wacholder, Sholom; Key, Timothy J.; Tsilidis, Konstantinos K

    2014-01-01

    Background No single-nucleotide polymorphisms (SNPs) specific for aggressive prostate cancer have been identified in genome-wide association studies (GWAS). Objective To test if SNPs associated with other traits may also affect the risk of aggressive prostate cancer. Design, setting, and participants SNPs implicated in any phenotype other than prostate cancer (p ≤ 10−7) were identified through the catalog of published GWAS and tested in 2891 aggressive prostate cancer cases and 4592 controls from the Breast and Prostate Cancer Cohort Consortium (BPC3). The 40 most significant SNPs were followed up in 4872 aggressive prostate cancer cases and 24 534 controls from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. Outcome measurements and statistical analysis Odds ratios (ORs) and 95% confidence intervals (CIs) for aggressive prostate cancer were estimated. Results and limitations A total of 4666 SNPs were evaluated by the BPC3. Two signals were seen in regions already reported for prostate cancer risk. rs7014346 at 8q24.21 was marginally associated with aggressive prostate cancer in the BPC3 trial (p = 1.6 × 10-6), whereas after meta-analysis by PRACTICAL the summary OR was 1.21 (95%CI 1.16–1.27; p = 3.22 × 10−18). rs9900242 at 17q24.3 was also marginally associated with aggressive disease in the meta-analysis (OR 0.90, 95% CI 0.86–0.94; p = 2.5 × 10−6). Neither of these SNPs remained statistically significant when conditioning on correlated known prostate cancer SNPs. The meta-analysis by BPC3 and PRACTICAL identified a third promising signal, marked by rs16844874 at 2q34, independent of known prostate cancer loci (OR 1.12,95% CI 1.06–1.19; p = 4.67 × 10−5); it has been shown that SNPs correlated with this signal affect glycine concentrations. The main limitation is the heterogeneity in the definition of aggressive prostate cancer between BPC3 and PRACTICAL. Conclusions We did

  9. Genomic prediction of breeding values in the New Zealand sheep industry using a 50K SNP chip.

    PubMed

    Auvray, B; McEwan, J C; Newman, S-A N; Lee, M; Dodds, K G

    2014-10-01

    The aim of genomic prediction is to predict breeding value from genomic data. We describe the development of genomic prediction equations and accuracies for molecular breeding values (MBV) for industry use, focusing on the methodology used to deal with predictions for the New Zealand sheep population structure. This is made up of a mixture of pure and crossbred animals, but principally Romney based. In particular, we used pedigree-based EBV for 8 traits (weaning weight as a direct effect, weaning weight as a maternal effect, live weight at 8 mo, live weight at 12 mo, greasy fleece weight at 12 mo, lamb fleece weight, adult fleece weight, and number of lambs born) and Illumina OvineSNP50 BeadChip genotypes from 13,420 animals to investigate BLUP with different genomic relationship matrices (GRM) based on SNP markers and to investigate varying sets of older animals (training sets) to predict the MBV of younger animals (validation sets). The GRM tested included modifications to account for allele frequency differences between breeds, rescaling so that the mean GRM is equal to the mean of the traditional pedigree numerator relationship matrix A: , and combining of the GRM with A: using a convex combination with a weight estimated by maximizing a conditional restricted likelihood. We found that these modifications were beneficial and recommend using a breed-adjusted GRM combined with A: . Training data sets with Romney, Coopworth, and Perendale animals all together usually predicted better than using just a pure breed training data set for all traits. But predictions for the breed Perendale were more accurate with a Perendale training set for 3 of the 8 traits. We concluded that using a mixed-breed training set for all combinations of traits and breeds was best but advise that increasing the number of Perendale animals genotyped should be a priority to increase the MBV accuracies obtained for that breed. PMID:25149326

  10. Pharmacogenomics in colorectal cancer: a genome-wide association study to predict toxicity after 5-fluorouracil or FOLFOX administration.

    PubMed

    Fernandez-Rozadilla, C; Cazier, J B; Moreno, V; Crous-Bou, M; Guinó, E; Durán, G; Lamas, M J; López, R; Candamio, S; Gallardo, E; Paré, L; Baiget, M; Páez, D; López-Fernández, L A; Cortejoso, L; García, M I; Bujanda, L; González, D; Gonzalo, V; Rodrigo, L; Reñé, J M; Jover, R; Brea-Fernández, A; Andreu, M; Bessa, X; Llor, X; Xicola, R; Palles, C; Tomlinson, I; Castellví-Bel, S; Castells, A; Ruiz-Ponte, C; Carracedo, A

    2013-06-01

    The development of genotyping technologies has allowed for wider screening for inherited causes of variable outcomes following drug administration. We have performed a genome-wide association study (GWAS) on 221 colorectal cancer (CRC) patients that had been treated with 5-fluorouracil (5-FU), either alone or in combination with oxaliplatin (FOLFOX). A validation set of 791 patients was also studied. Seven SNPs (rs16857540, rs2465403, rs10876844, rs10784749, rs17626122, rs7325568 and rs4243761) showed evidence of association (pooled P-values 0.020, 9.426E-03, 0.010, 0.017, 0.042, 2.302E-04, 2.803E-03) with adverse drug reactions (ADRs). This is the first study to explore the genetic basis of inter-individual variation in toxicity responses to the administration of 5-FU or FOLFOX in CRC patients on a genome-wide scale. PMID:22310351

  11. A genome-wide association scan in admixed Latin Americans identifies loci influencing facial and scalp hair features

    PubMed Central

    Adhikari, Kaustubh; Fontanil, Tania; Cal, Santiago; Mendoza-Revilla, Javier; Fuentes-Guajardo, Macarena; Chacón-Duque, Juan-Camilo; Al-Saadi, Farah; Johansson, Jeanette A.; Quinto-Sanchez, Mirsha; Acuña-Alonzo, Victor; Jaramillo, Claudia; Arias, William; Barquera Lozano, Rodrigo; Macín Pérez, Gastón; Gómez-Valdés, Jorge; Villamil-Ramírez, Hugo; Hunemeier, Tábita; Ramallo, Virginia; Silva de Cerqueira, Caio C.; Hurtado, Malena; Villegas, Valeria; Granja, Vanessa; Gallo, Carla; Poletti, Giovanni; Schuler-Faccini, Lavinia; Salzano, Francisco M.; Bortolini, Maria-Cátira; Canizales-Quinteros, Samuel; Rothhammer, Francisco; Bedoya, Gabriel; Gonzalez-José, Rolando; Headon, Denis; López-Otín, Carlos; Tobin, Desmond J.; Balding, David; Ruiz-Linares, Andrés

    2016-01-01

    We report a genome-wide association scan in over 6,000 Latin Americans for features of scalp hair (shape, colour, greying, balding) and facial hair (beard thickness, monobrow, eyebrow thickness). We found 18 signals of association reaching genome-wide significance (P values 5 × 10−8 to 3 × 10−119), including 10 novel associations. These include novel loci for scalp hair shape and balding, and the first reported loci for hair greying, monobrow, eyebrow and beard thickness. A newly identified locus influencing hair shape includes a Q30R substitution in the Protease Serine S1 family member 53 (PRSS53). We demonstrate that this enzyme is highly expressed in the hair follicle, especially the inner root sheath, and that the Q30R substitution affects enzyme processing and secretion. The genome regions associated with hair features are enriched for signals of selection, consistent with proposals regarding the evolution of human hair. PMID:26926045

  12. A genome-wide association scan in admixed Latin Americans identifies loci influencing facial and scalp hair features.

    PubMed

    Adhikari, Kaustubh; Fontanil, Tania; Cal, Santiago; Mendoza-Revilla, Javier; Fuentes-Guajardo, Macarena; Chacón-Duque, Juan-Camilo; Al-Saadi, Farah; Johansson, Jeanette A; Quinto-Sanchez, Mirsha; Acuña-Alonzo, Victor; Jaramillo, Claudia; Arias, William; Barquera Lozano, Rodrigo; Macín Pérez, Gastón; Gómez-Valdés, Jorge; Villamil-Ramírez, Hugo; Hunemeier, Tábita; Ramallo, Virginia; Silva de Cerqueira, Caio C; Hurtado, Malena; Villegas, Valeria; Granja, Vanessa; Gallo, Carla; Poletti, Giovanni; Schuler-Faccini, Lavinia; Salzano, Francisco M; Bortolini, Maria-Cátira; Canizales-Quinteros, Samuel; Rothhammer, Francisco; Bedoya, Gabriel; Gonzalez-José, Rolando; Headon, Denis; López-Otín, Carlos; Tobin, Desmond J; Balding, David; Ruiz-Linares, Andrés

    2016-01-01

    We report a genome-wide association scan in over 6,000 Latin Americans for features of scalp hair (shape, colour, greying, balding) and facial hair (beard thickness, monobrow, eyebrow thickness). We found 18 signals of association reaching genome-wide significance (P values 5 × 10(-8) to 3 × 10(-119)), including 10 novel associations. These include novel loci for scalp hair shape and balding, and the first reported loci for hair greying, monobrow, eyebrow and beard thickness. A newly identified locus influencing hair shape includes a Q30R substitution in the Protease Serine S1 family member 53 (PRSS53). We demonstrate that this enzyme is highly expressed in the hair follicle, especially the inner root sheath, and that the Q30R substitution affects enzyme processing and secretion. The genome regions associated with hair features are enriched for signals of selection, consistent with proposals regarding the evolution of human hair. PMID:26926045

  13. Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index.

    PubMed

    Felix, Janine F; Bradfield, Jonathan P; Monnereau, Claire; van der Valk, Ralf J P; Stergiakouli, Evie; Chesi, Alessandra; Gaillard, Romy; Feenstra, Bjarke; Thiering, Elisabeth; Kreiner-Møller, Eskil; Mahajan, Anubha; Pitkänen, Niina; Joro, Raimo; Cavadino, Alana; Huikari, Ville; Franks, Steve; Groen-Blokhuis, Maria M; Cousminer, Diana L; Marsh, Julie A; Lehtimäki, Terho; Curtin, John A; Vioque, Jesus; Ahluwalia, Tarunveer S; Myhre, Ronny; Price, Thomas S; Vilor-Tejedor, Natalia; Yengo, Loïc; Grarup, Niels; Ntalla, Ioanna; Ang, Wei; Atalay, Mustafa; Bisgaard, Hans; Blakemore, Alexandra I; Bonnefond, Amelie; Carstensen, Lisbeth; Eriksson, Johan; Flexeder, Claudia; Franke, Lude; Geller, Frank; Geserick, Mandy; Hartikainen, Anna-Liisa; Haworth, Claire M A; Hirschhorn, Joel N; Hofman, Albert; Holm, Jens-Christian; Horikoshi, Momoko; Hottenga, Jouke Jan; Huang, Jinyan; Kadarmideen, Haja N; Kähönen, Mika; Kiess, Wieland; Lakka, Hanna-Maaria; Lakka, Timo A; Lewin, Alexandra M; Liang, Liming; Lyytikäinen, Leo-Pekka; Ma, Baoshan; Magnus, Per; McCormack, Shana E; McMahon, George; Mentch, Frank D; Middeldorp, Christel M; Murray, Clare S; Pahkala, Katja; Pers, Tune H; Pfäffle, Roland; Postma, Dirkje S; Power, Christine; Simpson, Angela; Sengpiel, Verena; Tiesler, Carla M T; Torrent, Maties; Uitterlinden, André G; van Meurs, Joyce B; Vinding, Rebecca; Waage, Johannes; Wardle, Jane; Zeggini, Eleftheria; Zemel, Babette S; Dedoussis, George V; Pedersen, Oluf; Froguel, Philippe; Sunyer, Jordi; Plomin, Robert; Jacobsson, Bo; Hansen, Torben; Gonzalez, Juan R; Custovic, Adnan; Raitakari, Olli T; Pennell, Craig E; Widén, Elisabeth; Boomsma, Dorret I; Koppelman, Gerard H; Sebert, Sylvain; Järvelin, Marjo-Riitta; Hyppönen, Elina; McCarthy, Mark I; Lindi, Virpi; Harri, Niinikoski; Körner, Antje; Bønnelykke, Klaus; Heinrich, Joachim; Melbye, Mads; Rivadeneira, Fernando; Hakonarson, Hakon; Ring, Susan M; Smith, George Davey; Sørensen, Thorkild I A; Timpson, Nicholas J; Grant, Struan F A; Jaddoe, Vincent W V

    2016-01-15

    A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10(-10)) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index. PMID:26604143

  14. A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis

    PubMed Central

    Chiò, Adriano; Schymick, Jennifer C.; Restagno, Gabriella; Scholz, Sonja W.; Lombardo, Federica; Lai, Shiao-Lin; Mora, Gabriele; Fung, Hon-Chung; Britton, Angela; Arepalli, Sampath; Gibbs, J. Raphael; Nalls, Michael; Berger, Stephen; Kwee, Lydia Coulter; Oddone, Eugene Z.; Ding, Jinhui; Crews, Cynthia; Rafferty, Ian; Washecka, Nicole; Hernandez, Dena; Ferrucci, Luigi; Bandinelli, Stefania; Guralnik, Jack; Macciardi, Fabio; Torri, Federica; Lupoli, Sara; Chanock, Stephen J.; Thomas, Gilles; Hunter, David J.; Gieger, Christian; Wichmann, H. Erich; Calvo, Andrea; Mutani, Roberto; Battistini, Stefania; Giannini, Fabio; Caponnetto, Claudia; Mancardi, Giovanni Luigi; La Bella, Vincenzo; Valentino, Francesca; Monsurrò, Maria Rosaria; Tedeschi, Gioacchino; Marinou, Kalliopi; Sabatelli, Mario; Conte, Amelia; Mandrioli, Jessica; Sola, Patrizia; Salvi, Fabrizio; Bartolomei, Ilaria; Siciliano, Gabriele; Carlesi, Cecilia; Orrell, Richard W.; Talbot, Kevin; Simmons, Zachary; Connor, James; Pioro, Erik P.; Dunkley, Travis; Stephan, Dietrich A.; Kasperaviciute, Dalia; Fisher, Elizabeth M.; Jabonka, Sibylle; Sendtner, Michael; Beck, Marcus; Bruijn, Lucie; Rothstein, Jeffrey; Schmidt, Silke; Singleton, Andrew; Hardy, John; Traynor, Bryan J.

    2009-01-01

    The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown, but genetic factors are thought to play a significant role in determining susceptibility to motor neuron degeneration. To identify genetic variants altering risk of ALS, we undertook a two-stage genome-wide association study (GWAS): we followed our initial GWAS of 545 066 SNPs in 553 individuals with ALS and 2338 controls by testing the 7600 most associated SNPs from the first stage in three independent cohorts consisting of 2160 cases and 3008 controls. None of the SNPs selected for replication exceeded the Bonferroni threshold for significance. The two most significantly associated SNPs, rs2708909 and rs2708851 [odds ratio (OR) = 1.17 and 1.18, and P-values = 6.98 × 10−7 and 1.16 × 10−6], were located on chromosome 7p13.3 within a 175 kb linkage disequilibrium block containing the SUNC1, HUS1 and C7orf57 genes. These associations did not achieve genome-wide significance in the original cohort and failed to replicate in an additional independent cohort of 989 US cases and 327 controls (OR = 1.18 and 1.19, P-values = 0.08 and 0.06, respectively). Thus, we chose to cautiously interpret our data as hypothesis-generating requiring additional confirmation, especially as all previously reported loci for ALS have failed to replicate successfully. Indeed, the three loci (FGGY, ITPR2 and DPP6) identified in previous GWAS of sporadic ALS were not significantly associated with disease in our study. Our findings suggest that ALS is more genetically and clinically heterogeneous than previously recognized. Genotype data from our study have been made available online to facilitate such future endeavors. PMID:19193627

  15. A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis.

    PubMed

    Chiò, Adriano; Schymick, Jennifer C; Restagno, Gabriella; Scholz, Sonja W; Lombardo, Federica; Lai, Shiao-Lin; Mora, Gabriele; Fung, Hon-Chung; Britton, Angela; Arepalli, Sampath; Gibbs, J Raphael; Nalls, Michael; Berger, Stephen; Kwee, Lydia Coulter; Oddone, Eugene Z; Ding, Jinhui; Crews, Cynthia; Rafferty, Ian; Washecka, Nicole; Hernandez, Dena; Ferrucci, Luigi; Bandinelli, Stefania; Guralnik, Jack; Macciardi, Fabio; Torri, Federica; Lupoli, Sara; Chanock, Stephen J; Thomas, Gilles; Hunter, David J; Gieger, Christian; Wichmann, H Erich; Calvo, Andrea; Mutani, Roberto; Battistini, Stefania; Giannini, Fabio; Caponnetto, Claudia; Mancardi, Giovanni Luigi; La Bella, Vincenzo; Valentino, Francesca; Monsurrò, Maria Rosaria; Tedeschi, Gioacchino; Marinou, Kalliopi; Sabatelli, Mario; Conte, Amelia; Mandrioli, Jessica; Sola, Patrizia; Salvi, Fabrizio; Bartolomei, Ilaria; Siciliano, Gabriele; Carlesi, Cecilia; Orrell, Richard W; Talbot, Kevin; Simmons, Zachary; Connor, James; Pioro, Erik P; Dunkley, Travis; Stephan, Dietrich A; Kasperaviciute, Dalia; Fisher, Elizabeth M; Jabonka, Sibylle; Sendtner, Michael; Beck, Marcus; Bruijn, Lucie; Rothstein, Jeffrey; Schmidt, Silke; Singleton, Andrew; Hardy, John; Traynor, Bryan J

    2009-04-15

    The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown, but genetic factors are thought to play a significant role in determining susceptibility to motor neuron degeneration. To identify genetic variants altering risk of ALS, we undertook a two-stage genome-wide association study (GWAS): we followed our initial GWAS of 545 066 SNPs in 553 individuals with ALS and 2338 controls by testing the 7600 most associated SNPs from the first stage in three independent cohorts consisting of 2160 cases and 3008 controls. None of the SNPs selected for replication exceeded the Bonferroni threshold for significance. The two most significantly associated SNPs, rs2708909 and rs2708851 [odds ratio (OR) = 1.17 and 1.18, and P-values = 6.98 x 10(-7) and 1.16 x 10(-6)], were located on chromosome 7p13.3 within a 175 kb linkage disequilibrium block containing the SUNC1, HUS1 and C7orf57 genes. These associations did not achieve genome-wide significance in the original cohort and failed to replicate in an additional independent cohort of 989 US cases and 327 controls (OR = 1.18 and 1.19, P-values = 0.08 and 0.06, respectively). Thus, we chose to cautiously interpret our data as hypothesis-generating requiring additional confirmation, especially as all previously reported loci for ALS have failed to replicate successfully. Indeed, the three loci (FGGY, ITPR2 and DPP6) identified in previous GWAS of sporadic ALS were not significantly associated with disease in our study. Our findings suggest that ALS is more genetically and clinically heterogeneous than previously recognized. Genotype data from our study have been made available online to facilitate such future endeavors. PMID:19193627

  16. Genome-Wide Association Study of Lung Function Phenotypes in a Founder Population

    PubMed Central

    Yao, Tsung-Chieh; Du, Gaixin; Han, Lide; Sun, Ying; Hu, Donglei; Yang, James J.; Mathias, Rasika; Roth, Lindsey A.; Rafaels, Nicholas; Thompson, Emma E.; Loisel, Dagan A.; Anderson, Rebecca; Eng, Celeste; Orbegozo, Maitane Arruabarrena; Young, Melody; Klocksieben, James M.; Anderson, Elizabeth; Shanovich, Kathleen; Lester, Lucille A.; Williams, L. Keoki; Barnes, Kathleen C.; Burchard, Esteban G.; Nicolae, Dan L.; Abney, Mark; Ober, Carole

    2014-01-01

    Background Lung function is a long-term predictor of mortality and morbidity. Objective We sought to identify single nucleotide polymorphisms (SNPs) associated with lung function. Methods We performed a genome-wide association study (GWAS) of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC in 1,144 Hutterites aged 6–89 years, who are members of a founder population of European descent. We performed least absolute shrinkage and selection operation (LASSO) regression to select the minimum set of SNPs that best predict FEV1/FVC in the Hutterites and used the GRAIL algorithm to mine the Gene Ontology database for evidence of functional connections between genes near the predictive SNPs. Results Our GWAS identified significant associations between FEV1/FVC and SNPs at the THSD4-UACA-TLE3 locus on chromosome 15q23 (P = 5.7x10−8 ~ 3.4x10−9). Nine SNPs at or near four additional loci had P-values < 10−5 with FEV1/FVC. There were only two SNPs with P-values < 10−5 for FEV1 or FVC. We found nominal levels of significance with SNPs at 9 of the 27 previously reported loci associated with lung function measures. Among a predictive set of 80 SNPs, six loci were identified that had a significant degree of functional connectivity (GRAIL P < 0.05), including three clusters of β-defensin genes, two chemokine genes (CCL18 and CXCL12), and TNFRSF13B. Conclusion This study identifies genome-wide significant associations and replicates results of previous GWAS. Multimarker modeling implicated for the first time common variation in genes involved in anti-microbial immunity in airway mucosa influences lung function. PMID:23932459

  17. White matter lesion progression: A genome-wide search for genetic influences

    PubMed Central

    Hofer, Edith; Cavalieri, Margherita; Bis, Joshua C; DeCarli, Charles; Fornage, Myriam; Sigurdsson, Sigurdur; Srikanth, Velandai; Trompet, Stella; Verhaaren, Benjamin FJ; Wolf, Christiane; Yang, Qiong; Adams, Hieab HH; Amouyel, Philippe; Beiser, Alexa; Buckley, Brendan M; Callisaya, Michele; Chauhan, Ganesh; de Craen, Anton JM; Dufouil, Carole; van Duijn, Cornelia M; Ford, Ian; Freudenberger, Paul; Gottesman, Rebecca F; Gudnason, Vilmundur; Heiss, Gerardo; Hofman, Albert; Lumley, Thomas; Martinez, Oliver; Mazoyer, Bernard; Moran, Chris; Niessen, Wiro J.; Phan, Thanh; Psaty, Bruce M; Satizabal, Claudia L; Sattar, Naveed; Schilling, Sabrina; Shibata, Dean K; Slagboom, P Eline; Smith, Albert; Stott, David J; Taylor, Kent D; Thomson, Russell; Töglhofer, Anna M; Tzourio, Christophe; van Buchem, Mark; Wang, Jing; Westendorp, Rudi GJ; Windham, B Gwen; Vernooij, Meike W; Zijdenbos, Alex; Beare, Richard; Debette, Stéphanie; Ikram, M Arfan; Jukema, J Wouter; Launer, Lenore J; Longstreth, W T; Mosley, Thomas H; Seshadri, Sudha; Schmidt, Helena; Schmidt, Reinhold

    2016-01-01

    Background and Purpose White matter lesion (WML) progression on magnetic resonance imaging (MRI) is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Methods Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in seven cohorts risk models including demographics, vascular risk factors plus single nucleotide polymorphisms (SNPs) that have been shown to be associated cross-sectionally with WML in the current and previous association studies. Results A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no SNPs achieved genome-wide significance (p-value < 5×10−8). Four loci were suggestive (p-value < 1×10−5) of an association with WML progression: 10q24.32 (rs10883817, p=1.46×10−6); 12q13.13 (rs4761974, p=8.71×10−7); 20p12.1 (rs6135309, p=3.69×10−6); and 4p15.31 (rs7664442, p=2.26×10−6). Variants that have been previously related to WML explained only 0.8% to 11.7% more of the variance in WML progression than age, vascular risk factors and baseline WML burden. Conclusions Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, life-style or host-related biological factors. PMID:26451028

  18. Genome-wide association study of toxic metals and trace elements reveals novel associations

    PubMed Central

    Ng, Esther; Lind, P. Monica; Lindgren, Cecilia; Ingelsson, Erik; Mahajan, Anubha; Morris, Andrew; Lind, Lars

    2015-01-01

    The accumulation of toxic metals in the human body is influenced by exposure and mechanisms involved in metabolism, some of which may be under genetic control. This is the first genome-wide association study to investigate variants associated with whole blood levels of a range of toxic metals. Eleven toxic metals and trace elements (aluminium, cadmium, cobalt, copper, chromium, mercury, manganese, molybdenum, nickel, lead and zinc) were assayed in a cohort of 949 individuals using mass spectrometry. DNA samples were genotyped on the Infinium Omni Express bead microarray and imputed up to reference panels from the 1000 Genomes Project. Analyses revealed two regions associated with manganese level at genome-wide significance, mapping to 4q24 and 1q41. The lead single nucleotide polymorphism (SNP) in the 4q24 locus was rs13107325 (P-value = 5.1 × 10−11, β = −0.77), located in an exon of SLC39A8, which encodes a protein involved in manganese and zinc transport. The lead SNP in the 1q41 locus is rs1776029 (P-value = 2.2 × 10−14, β = −0.46). The SNP lies within the intronic region of SLC30A10, another transporter protein. Among other metals, the loci 6q14.1 and 3q26.32 were associated with cadmium and mercury levels (P = 1.4 × 10−10, β = −1.2 and P = 1.8 × 10−9, β = −1.8, respectively). Whole blood measurements of toxic metals are associated with genetic variants in metal transporter genes and others. This is relevant in inferring metabolic pathways of metals and identifying subsets of individuals who may be more susceptible to metal toxicity. PMID:26025379

  19. Genome-Wide Association Study for Autism Spectrum Disorder in Taiwanese Han Population

    PubMed Central

    Kuo, Po-Hsiu; Chuang, Li-Chung; Su, Mei-Hsin; Chen, Chia-Hsiang; Chen, Chien-Hsiun; Wu, Jer-Yuarn; Yen, Chung-Jen; Wu, Yu-Yu; Liu, Shih-Kai; Chou, Miao-Chun; Chou, Wen-Jiun; Chiu, Yen-Nan; Tsai, Wen-Che; Gau, Susan Shur-Fen

    2015-01-01

    Background Autism spectrum disorder (ASD) is a neurodevelopmental disorder with strong genetic components. Several recent genome-wide association (GWA) studies in Caucasian samples have reported a number of gene regions and loci correlated with the risk of ASD—albeit with very little consensus across studies. Methods A two-stage GWA study was employed to identify common genetic variants for ASD in the Taiwanese Han population. The discovery stage included 315 patients with ASD and 1,115 healthy controls, using the Affymetrix SNP array 6.0 platform for genotyping. Several gene regions were then selected for fine-mapping and top markers were examined in extended samples. Single marker, haplotype, gene-based, and pathway analyses were conducted for associations. Results Seven SNPs had p-values ranging from 3.4~9.9*10−6, but none reached the genome-wide significant level. Five of them were mapped to three known genes (OR2M4, STYK1, and MNT) with significant empirical gene-based p-values in OR2M4 (p = 3.4*10−5) and MNT (p = 0.0008). Results of the fine-mapping study showed single-marker associations in the GLIS1 (rs12082358 and rs12080993) and NAALADL2 (rs3914502 and rs2222447) genes, and gene-based associations for the OR2M3-OR2T5 (olfactory receptor genes, p = 0.02), and GLIPR1/KRR1 gene regions (p = 0.015). Pathway analyses revealed important pathways for ASD, such as olfactory and G protein–coupled receptors signaling pathways. Conclusions We reported Taiwanese Han specific susceptibility genes and variants for ASD. However, further replication in other Asian populations is warranted to validate our findings. Investigation in the biological functions of our reported genetic variants might also allow for better understanding on the underlying pathogenesis of autism. PMID:26398136

  20. Genome-Wide Analyses Suggest Mechanisms Involving Early B-Cell Development in Canine IgA Deficiency

    PubMed Central

    Frankowiack, Marcel; Kierczak, Marcin; Bergvall, Kerstin; Axelsson, Erik; Tintle, Linda; Marti, Eliane; Roosje, Petra; Leeb, Tosso; Hedhammar, Åke; Hammarström, Lennart; Lindblad-Toh, Kerstin

    2015-01-01

    Immunoglobulin A deficiency (IgAD) is the most common primary immune deficiency disorder in both humans and dogs, characterized by recurrent mucosal tract infections and a predisposition for allergic and other immune mediated diseases. In several dog breeds, low IgA levels have been observed at a high frequency and with a clinical resemblance to human IgAD. In this study, we used genome-wide association studies (GWAS) to identify genomic regions associated with low IgA levels in dogs as a comparative model for human IgAD. We used a novel percentile groups-approach to establish breed-specific cut-offs and to perform analyses in a close to continuous manner. GWAS performed in four breeds prone to low IgA levels (German shepherd, Golden retriever, Labrador retriever and Shar-Pei) identified 35 genomic loci suggestively associated (p <0.0005) to IgA levels. In German shepherd, three genomic regions (candidate genes include KIRREL3 and SERPINA9) were genome-wide significantly associated (p <0.0002) with IgA levels. A ~20kb long haplotype on CFA28, significantly associated (p = 0.0005) to IgA levels in Shar-Pei, was positioned within the first intron of the gene SLIT1. Both KIRREL3 and SLIT1 are highly expressed in the central nervous system and in bone marrow and are potentially important during B-cell development. SERPINA9 expression is restricted to B-cells and peaks at the time-point when B-cells proliferate into antibody-producing plasma cells. The suggestively associated regions were enriched for genes in Gene Ontology gene sets involving inflammation and early immune cell development. PMID:26225558

  1. Family-Based Genome-Wide Association Scan of Attention-Deficit/Hyperactivity Disorder

    ERIC Educational Resources Information Center

    Mick, Eric; Todorov, Alexandre; Smalley, Susan; Hu, Xiaolan; Loo, Sandra; Todd, Richard D.; Biederman, Joseph; Byrne, Deirdre; Dechairo, Bryan; Guiney, Allan; McCracken, James; McGough, James; Nelson, Stanley F.; Reiersen, Angela M.; Wilens, Timothy E.; Wozniak, Janet; Neale, Benjamin M.; Faraone, Stephen V.

    2010-01-01

    Objective: Genes likely play a substantial role in the etiology of attention-deficit/hyperactivity disorder (ADHD). However, the genetic architecture of the disorder is unknown, and prior genome-wide association studies (GWAS) have not identified a genome-wide significant association. We have conducted a third, independent, multisite GWAS of…

  2. Case-Control Genome-Wide Association Study of Attention-Deficit/Hyperactivity Disorder

    ERIC Educational Resources Information Center

    Neale, Benjamin M.; Medland, Sarah; Ripke, Stephan; Anney, Richard J. L.; Asherson, Philip; Buitelaar, Jan; Franke, Barbara; Gill, Michael; Kent, Lindsey; Holmans, Peter; Middleton, Frank; Thapar, Anita; Lesch, Klaus-Peter; Faraone, Stephen V.; Daly, Mark; Nguyen, Thuy Trang; Schafer, Helmut; Steinhausen, Hans-Christoph; Reif, Andreas; Renner, Tobias J.; Romanos, Marcel; Romanos, Jasmin; Warnke, Andreas; Walitza, Susanne; Freitag, Christine; Meyer, Jobst; Palmason, Haukur; Rothenberger, Aribert; Hawi, Ziarih; Sergeant, Joseph; Roeyers, Herbert; Mick, Eric; Biederman, Joseph

    2010-01-01

    Objective: Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. Thus additional genome-wide association studies (GWAS) are needed. Method: We used case-control analyses of 896 cases…

  3. Meta-Analysis of Genome-Wide Association Studies of Attention-Deficit/Hyperactivity Disorder

    ERIC Educational Resources Information Center

    Neale, Benjamin M.; Medland, Sarah E.; Ripke, Stephan; Asherson, Philip; Franke, Barbara; Lesch, Klaus-Peter; Faraone, Stephen V.; Nguyen, Thuy Trang; Schafer, Helmut; Holmans, Peter; Daly, Mark; Steinhausen, Hans-Christoph; Freitag, Christine; Reif, Andreas; Renner, Tobias J.; Romanos, Marcel; Romanos, Jasmin; Walitza, Susanne; Warnke, Andreas; Meyer, Jobst; Palmason, Haukur; Buitelaar, Jan; Vasquez, Alejandro Arias; Lambregts-Rommelse, Nanda; Gill, Michael; Anney, Richard J. L.; Langely, Kate; O'Donovan, Michael; Williams, Nigel; Owen, Michael; Thapar, Anita; Kent, Lindsey; Sergeant, Joseph; Roeyers, Herbert; Mick, Eric; Biederman, Joseph; Doyle, Alysa; Smalley, Susan; Loo, Sandra; Hakonarson, Hakon; Elia, Josephine; Todorov, Alexandre; Miranda, Ana; Mulas, Fernando; Ebstein, Richard P.; Rothenberger, Aribert; Banaschewski, Tobias; Oades, Robert D.; Sonuga-Barke, Edmund; McGough, James; Nisenbaum, Laura; Middleton, Frank; Hu, Xiaolan; Nelson, Stan

    2010-01-01

    Objective: Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association studies (GWAS) have not yielded significant results, we conducted a meta-analysis of…

  4. Genome-wide screening and identification of antigens for rickettsial vaccine development

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The capacity to identify immunogens for vaccine development by genome-wide screening has been markedly enhanced by the availability of complete microbial genome sequences coupled to rapid proteomic and bioinformatic analysis. Critical to this genome-wide screening is in vivo testing in the context o...

  5. Genome-Wide Association of Lipid-Lowering Response to Statins in Combined Study Populations

    PubMed Central

    Hyde, Craig L.; Chasman, Daniel I.; Smith, Joshua D.; McCarty, Catherine A.; Li, Xiaohui; Wilke, Russell A.; Rieder, Mark J.; Williams, Paul T.; Ridker, Paul M.; Chatterjee, Aurobindo; Rotter, Jerome I.; Nickerson, Deborah A.; Stephens, Matthew; Krauss, Ronald M.

    2010-01-01

    Background Statins effectively lower total and plasma LDL-cholesterol, but the magnitude of decrease varies among individuals. To identify single nucleotide polymorphisms (SNPs) contributing to this variation, we performed a combined analysis of genome-wide association (GWA) results from three trials of statin efficacy. Methods and Principal Findings Bayesian and standard frequentist association analyses were performed on untreated and statin-mediated changes in LDL-cholesterol, total cholesterol, HDL-cholesterol, and triglyceride on a total of 3932 subjects using data from three studies: Cholesterol and Pharmacogenetics (40 mg/day simvastatin, 6 weeks), Pravastatin/Inflammation CRP Evaluation (40 mg/day pravastatin, 24 weeks), and Treating to New Targets (10 mg/day atorvastatin, 8 weeks). Genotype imputation was used to maximize genomic coverage and to combine information across studies. Phenotypes were normalized within each study to account for systematic differences among studies, and fixed-effects combined analysis of the combined sample were performed to detect consistent effects across studies. Two SNP associations were assessed as having posterior probability greater than 50%, indicating that they were more likely than not to be genuinely associated with statin-mediated lipid response. SNP rs8014194, located within the CLMN gene on chromosome 14, was strongly associated with statin-mediated change in total cholesterol with an 84% probability by Bayesian analysis, and a p-value exceeding conventional levels of genome-wide significance by frequentist analysis (P = 1.8×10−8). This SNP was less significantly associated with change in LDL-cholesterol (posterior probability = 0.16, P = 4.0×10−6). Bayesian analysis also assigned a 51% probability that rs4420638, located in APOC1 and near APOE, was associated with change in LDL-cholesterol. Conclusions and Significance Using combined GWA analysis from three clinical trials involving nearly 4

  6. Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-wide Meta-analysis

    PubMed Central

    Peters, Ulrike; Jiao, Shuo; Schumacher, Fredrick R.; Hutter, Carolyn M.; Aragaki, Aaron K.; Baron, John A.; Berndt, Sonja I.; Bézieau, Stéphane; Brenner, Hermann; Butterbach, Katja; Caan, Bette J.; Campbell, Peter T.; Carlson, Christopher S.; Casey, Graham; Chan, Andrew T.; Chang-Claude, Jenny; Chanock, Stephen J.; Chen, Lin S.; Coetzee, Gerhard A.; Coetzee, Simon G.; Conti, David V.; Curtis, Keith R.; Duggan, David; Edwards, Todd; Fuchs, Charles S.; Gallinger, Steven; Giovannucci, Edward L.; Gogarten, Stephanie M.; Gruber, Stephen B.; Haile, Robert W.; Harrison, Tabitha A.; Hayes, Richard B.; Henderson, Brian E.; Hoffmeister, Michael; Hopper, John L.; Hudson, Thomas J.; Hunter, David J.; Jackson, Rebecca D.; Jee, Sun Ha; Jenkins, Mark A.; Jia, Wei-Hua; Kolonel, Laurence N.; Kooperberg, Charles; Küry, Sébastien; Lacroix, Andrea Z.; Laurie, Cathy C.; Laurie, Cecelia A.; Le Marchand, Loic; Lemire, Mathieu; Levine, David; Lindor, Noralane M.; Liu, Yan; Ma, Jing; Makar, Karen W.; Matsuo, Keitaro; Newcomb, Polly A.; Potter, John D.; Prentice, Ross L.; Qu, Conghui; Rohan, Thomas; Rosse, Stephanie A.; Schoen, Robert E.; Seminara, Daniela; Shrubsole, Martha; Shu, Xiao-Ou; Slattery, Martha L.; Taverna, Darin; Thibodeau, Stephen N.; Ulrich, Cornelia M.; White, Emily; Xiang, Yongbing; Zanke, Brent W.; Zeng, Yi-Xin; Zhang, Ben; Zheng, Wei; Hsu, Li

    2013-01-01

    BACKGROUND & AIMS Heritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis. METHODS We conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent. RESULTS Based on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 × 10−8: an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 × 10−8). We also found evidence for 3 additional loci with P values less than 5.0 × 10−7: a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 × 10−8), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 × 10−8), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 × 10−7). CONCLUSIONS In a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to β-catenin). The roles of these genes and their products

  7. Genome-wide association studies identify genetic loci for low von Willebrand factor levels.

    PubMed

    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

    2016-07-01

    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

  8. Promising Loci and Genes for Yolk and Ovary Weight in Chickens Revealed by a Genome-Wide Association Study

    PubMed Central

    Yi, Guoqiang; Yuan, Jingwei; Duan, Zhongyi; Qu, Lujiang; Xu, Guiyun; Wang, Kehua; Yang, Ning

    2015-01-01

    Because it serves as the cytoplasm of the oocyte and provides a large amount of reserves, the egg yolk has biological significance for developing embryos. The ovary and its hierarchy of follicles are the main reproductive organs responsible for yolk deposition in chickens. However, the genetic architecture underlying the yolk and ovarian follicle weights remains elusive. Here, we measured the yolk weight (YW) at 11 age points from onset of egg laying to 72 weeks of age and measured the follicle weight (FW) and ovary weight (OW) at 73 weeks as part of a comprehensive genome-wide association study (GWAS) in 1,534 F2 hens derived from reciprocal crosses between White Leghorn (WL) and Dongxiang chickens (DX). For all ages, YWs exhibited moderate single nucleotide polymorphism (SNP)-based heritability estimates (0.25–0.38), while the estimates for FW (0.16) and OW (0.20) were relatively low. Independent univariate genome-wide screens for each trait identified 12, 3, and 31 novel significant associations with YW, FW, and OW, respectively. A list of candidate genes such as ZAR1, STARD13, ACER1b, ACSBG2, and DHRS12 were identified for having a plausible function in yolk and follicle development. These genes are important to the initiation of embryogenesis, lipid transport, lipoprotein synthesis, lipid droplet promotion, and steroid hormone metabolism, respectively. Our study provides for the first time a genome-wide association (GWA) analysis for follicle and ovary weight. Identification of the promising loci as well as potential candidate genes will greatly advance our understanding of the genetic basis underlying dynamic yolk weight and ovarian follicle development and has practical significance in breeding programs for the alteration of yolk weight at different age points. PMID:26332579

  9. Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS.

    PubMed

    Mattheisen, M; Samuels, J F; Wang, Y; Greenberg, B D; Fyer, A J; McCracken, J T; Geller, D A; Murphy, D L; Knowles, J A; Grados, M A; Riddle, M A; Rasmussen, S A; McLaughlin, N C; Nurmi, E L; Askland, K D; Qin, H-D; Cullen, B A; Piacentini, J; Pauls, D L; Bienvenu, O J; Stewart, S E; Liang, K-Y; Goes, F S; Maher, B; Pulver, A E; Shugart, Y Y; Valle, D; Lange, C; Nestadt, G

    2015-03-01

    Obsessive-compulsive disorder (OCD) is a psychiatric condition characterized by intrusive thoughts and urges and repetitive, intentional behaviors that cause significant distress and impair functioning. The OCD Collaborative Genetics Association Study (OCGAS) is comprised of comprehensively assessed OCD patients with an early age of OCD onset. After application of a stringent quality control protocol, a total of 1065 families (containing 1406 patients with OCD), combined with population-based samples (resulting in a total sample of 5061 individuals), were studied. An integrative analyses pipeline was utilized, involving association testing at single-nucleotide polymorphism (SNP) and gene levels (via a hybrid approach that allowed for combined analyses of the family- and population-based data). The smallest P-value was observed for a marker on chromosome 9 (near PTPRD, P=4.13 × 10(-)(7)). Pre-synaptic PTPRD promotes the differentiation of glutamatergic synapses and interacts with SLITRK3. Together, both proteins selectively regulate the development of inhibitory GABAergic synapses. Although no SNPs were identified as associated with OCD at genome-wide significance level, follow-up analyses of genome-wide association study (GWAS) signals from a previously published OCD study identified significant enrichment (P=0.0176). Secondary analyses of high-confidence interaction partners of DLGAP1 and GRIK2 (both showing evidence for association in our follow-up and the original GWAS study) revealed a trend of association (P=0.075) for a set of genes such as NEUROD6, SV2A, GRIA4, SLC1A2 and PTPRD. Analyses at the gene level revealed association of IQCK and C16orf88 (both P<1 × 10(-)(6), experiment-wide significant), as well as OFCC1 (P=6.29 × 10(-)(5)). The suggestive findings in this study await replication in larger samples. PMID:24821223

  10. A "candidate-interactome" aggregate analysis of genome-wide association data in multiple sclerosis.

    PubMed

    Mechelli, Rosella; Umeton, Renato; Policano, Claudia; Annibali, Viviana; Coarelli, Giulia; Ricigliano, Vito A G; Vittori, Danila; Fornasiero, Arianna; Buscarinu, Maria Chiara; Romano, Silvia; Salvetti, Marco; Ristori, Giovanni

    2013-01-01

    Though difficult, the study of gene-environment interactions in multifactorial diseases is crucial for interpreting the relevance of non-heritable factors and prevents from overlooking genetic associations with small but measurable effects. We propose a "candidate interactome" (i.e. a group of genes whose products are known to physically interact with environmental factors that may be relevant for disease pathogenesis) analysis of genome-wide association data in multiple sclerosis. We looked for statistical enrichment of associations among interactomes that, at the current state of knowledge, may be representative of gene-environment interactions of potential, uncertain or unlikely relevance for multiple sclerosis pathogenesis: Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, HHV8-Kaposi sarcoma, H1N1-influenza, JC virus, human innate immunity interactome for type I interferon, autoimmune regulator, vitamin D receptor, aryl hydrocarbon receptor and a panel of proteins targeted by 70 innate immune-modulating viral open reading frames from 30 viral species. Interactomes were either obtained from the literature or were manually curated. The P values of all single nucleotide polymorphism mapping to a given interactome were obtained from the last genome-wide association study of the International Multiple Sclerosis Genetics Consortium & the Wellcome Trust Case Control Consortium, 2. The interaction between genotype and Epstein Barr virus emerges as relevant for multiple sclerosis etiology. However, in line with recent data on the coexistence of common and unique strategies used by viruses to perturb the human molecular system, also other viruses have a similar potential, though probably less relevant in epidemiological terms. PMID:23696811

  11. Genome-wide association study of comorbid depressive syndrome and alcohol dependence

    PubMed Central

    Edwards, Alexis C.; Aliev, Fazil; Bierut, Laura J.; Bucholz, Kathleen K.; Edenberg, Howard; Hesselbrock, Victor; Kramer, John; Kuperman, Samuel; Nurnberger, John I.; Schuckit, Marc A.; Porjesz, Bernice; Dick, Danielle M.

    2011-01-01

    Objective Depression and alcohol dependence are common psychiatric disorders that often co-occur. Both disorders are genetically influenced, with heritability estimates in the range of 35–60%. In addition, evidence from twin studies suggests that alcohol dependence and depression are genetically correlated. Here we report results from a genome-wide association study (GWAS) of a comorbid phenotype in which cases meet the DSM-IV symptom threshold for major depressive symptomatology and DSM-IV criteria for alcohol dependence. Methods Samples (N=467 cases and N=407 controls) were of European-American descent, and were genotyped using the Illumina Human 1M BeadChip array. Results Although no SNP meets genome-wide significance criteria, we identify ten markers with p-values < 1 × 10−5, seven of which are located in known genes, which have not been previously implicated in either disorder. Genes harboring SNPs yielding p<1 × 10−3 are functionally enriched for a number of gene ontology categories, notably several related to glutamatergic function. Investigation of expression localization using online resources suggests that these genes are expressed across a variety of tissues, including behaviorally relevant brain regions. Genes that have been previously associated with depression, alcohol dependence, or other addiction-related phenotypes – such as CDH13, CSMD2, GRID1, and HTR1B – were implicated by nominally significant SNPs. Finally, the degree of overlap of significant SNPs between a comorbid phenotype and an alcohol dependence-only phenotype is modest. Conclusions These results underscore the complex genomic influences on psychiatric phenotypes, and suggest that a comorbid phenotype is partially influenced by genetic variants that do not affect alcohol dependence alone. PMID:22064162

  12. Genome-wide Association Study of Exercise Behavior in Dutch and American Adults

    PubMed Central

    De Moor, Marleen HM; Liu, Yong-Jun; Boomsma, Dorret I; Li, Jian; Hamilton, James J; Hottenga, Jouke-Jan; Levy, Shawn; Liu, Xiao-Gang; Pei, Yu-Fang; Posthuma, Danielle; Recker, Robert R; Sullivan, Patrick F; Wang, Liang; Willemsen, Gonneke; Yan, Han; De Geus, Eco JC; Deng, Hong-Wen

    2009-01-01

    Introduction The objective of this study was to identify genetic variants that are associated with adult leisure-time exercise behavior using genome-wide association in two independent samples. Methods Exercise behavior was measured in 1,772 unrelated Dutch and 978 unrelated American adults with detailed questions about type, frequency and duration of exercise. Individuals were classified into regular exercisers or non-exercisers using a threshold of 4 METhours (metabolic equivalents*hours per week). Regular exercisers were further divided into 5 categories of METhours, ranging from moderate (>=4 METhours) to highly vigorous (>=40 METhours) exercisers. Genome-wide association analyses with a total of 470,719 SNPs were conducted in both samples independently using regression-based techniques in SNPtest, including sex, age and BMI as covariates. Results SNPs located in SGIP1, DNASE2B, PRSS16, ERCC2 and PAPSS2 were associated with exercise participation (combined p-value between 0.0004 and 4.5*10-6 with the same direction of allelic effects in both samples). Associations of candidate genes based on existing literature were replicated for the LEPR gene in the American sample (rs12405556, p=0.0005) and for the CYP19A1 gene in the Dutch sample (rs2470158, 0.0098). Conclusion Two genes (SGIP1 and LEPR) are expressed in the hypothalamus and involved in the regulation of energy homeostasis. Their effects were independent of BMI, suggesting a direct role of hypothalamic factors in the drive to exercise. PMID:19727025

  13. SYSTEMS BIOLOGY ANALYSES OF GENE EXPRESSION AND GENOME WIDE ASSOCIATION STUDY DATA IN OBSTRUCTIVE SLEEP APNEA

    PubMed Central

    LIU, YU; PATEL, SANJAY; NIBBE, ROD; MAXWELL, SEAN; CHOWDHURY, SALIM A.; KOYUTURK, MEHMET; ZHU, XIAOFENG; LARKIN, EMMA K.; BUXBAUM, SARAH G; PUNJABI, NARESH M.; GHARIB, SINA A.; REDLINE, SUSAN; CHANCE, MARK R.

    2015-01-01

    The precise molecular etiology of obstructive sleep apnea (OSA) is unknown; however recent research indicates that several interconnected aberrant pathways and molecular abnormalities are contributors to OSA. Identifying the genes and pathways associated with OSA can help to expand our understanding of the risk factors for the disease as well as provide new avenues for potential treatment. Towards these goals, we have integrated relevant high dimensional data from various sources, such as genome-wide expression data (microarray), protein-protein interaction (PPI) data and results from genome-wide association studies (GWAS) in order to define sub-network elements that connect some of the known pathways related to the disease as well as define novel regulatory modules related to OSA. Two distinct approaches are applied to identify sub-networks significantly associated with OSA. In the first case we used a biased approach based on sixty genes/proteins with known associations with sleep disorders and/or metabolic disease to seed a search using commercial software to discover networks associated with disease followed by information theoretic (mutual information) scoring of the sub-networks. In the second case we used an unbiased approach and generated an interactome constructed from publicly available gene expression profiles and PPI databases, followed by scoring of the network with p-values from GWAS data derived from OSA patients to uncover sub-networks significant for the disease phenotype. A comparison of the approaches reveals a number of proteins that have been previously known to be associated with OSA or sleep. In addition, our results indicate a novel association of Phosphoinositide 3-kinase, the STAT family of proteins and its related pathways with OSA. PMID:21121029

  14. Genome-wide association study of age at menarche in African-American women

    PubMed Central

    Demerath, Ellen W.; Liu, Ching-Ti; Franceschini, Nora; Chen, Gary; Palmer, Julie R.; Smith, Erin N.; Chen, Christina T.L.; Ambrosone, Christine B.; Arnold, Alice M.; Bandera, Elisa V.; Berenson, Gerald S.; Bernstein, Leslie; Britton, Angela; Cappola, Anne R.; Carlson, Christopher S.; Chanock, Stephen J.; Chen, Wei; Chen, Zhao; Deming, Sandra L.; Elks, Cathy E.; Evans, Michelle K.; Gajdos, Zofia; Henderson, Brian E.; Hu, Jennifer J.; Ingles, Sue; John, Esther M.; Kerr, Kathleen F.; Kolonel, Laurence N.; Le Marchand, Loic; Lu, Xiaoning; Millikan, Robert C.; Musani, Solomon K.; Nock, Nora L.; North, Kari; Nyante, Sarah; Press, Michael F.; Rodriquez-Gil, Jorge L.; Ruiz-Narvaez, Edward A.; Schork, Nicholas J.; Srinivasan, Sathanur R.; Woods, Nancy F.; Zheng, Wei; Ziegler, Regina G.; Zonderman, Alan; Heiss, Gerardo; Gwen Windham, B.; Wellons, Melissa; Murray, Sarah S.; Nalls, Michael; Pastinen, Tomi; Rajkovic, Aleksandar; Hirschhorn, Joel; Adrienne Cupples, L.; Kooperberg, Charles; Murabito, Joanne M.; Haiman, Christopher A.

    2013-01-01

    African-American (AA) women have earlier menarche on average than women of European ancestry (EA), and earlier menarche is a risk factor for obesity and type 2 diabetes among other chronic diseases. Identification of common genetic variants associated with age at menarche has a potential value in pointing to the genetic pathways underlying chronic disease risk, yet comprehensive genome-wide studies of age at menarche are lacking for AA women. In this study, we tested the genome-wide association of self-reported age at menarche with common single-nucleotide polymorphisms (SNPs) in a total of 18 089 AA women in 15 studies using an additive genetic linear regression model, adjusting for year of birth and population stratification, followed by inverse-variance weighted meta-analysis (Stage 1). Top meta-analysis results were then tested in an independent sample of 2850 women (Stage 2). First, while no SNP passed the pre-specified P < 5 × 10−8 threshold for significance in Stage 1, suggestive associations were found for variants near FLRT2 and PIK3R1, and conditional analysis identified two independent SNPs (rs339978 and rs980000) in or near RORA, strengthening the support for this suggestive locus identified in EA women. Secondly, an investigation of SNPs in 42 previously identified menarche loci in EA women demonstrated that 25 (60%) of them contained variants significantly associated with menarche in AA women. The findings provide the first evidence of cross-ethnic generalization of menarche loci identified to date, and suggest a number of novel biological links to menarche timing in AA women. PMID:23599027

  15. Genome-wide association study of age at menarche in African-American women.

    PubMed

    Demerath, Ellen W; Liu, Ching-Ti; Franceschini, Nora; Chen, Gary; Palmer, Julie R; Smith, Erin N; Chen, Christina T L; Ambrosone, Christine B; Arnold, Alice M; Bandera, Elisa V; Berenson, Gerald S; Bernstein, Leslie; Britton, Angela; Cappola, Anne R; Carlson, Christopher S; Chanock, Stephen J; Chen, Wei; Chen, Zhao; Deming, Sandra L; Elks, Cathy E; Evans, Michelle K; Gajdos, Zofia; Henderson, Brian E; Hu, Jennifer J; Ingles, Sue; John, Esther M; Kerr, Kathleen F; Kolonel, Laurence N; Le Marchand, Loic; Lu, Xiaoning; Millikan, Robert C; Musani, Solomon K; Nock, Nora L; North, Kari; Nyante, Sarah; Press, Michael F; Rodriquez-Gil, Jorge L; Ruiz-Narvaez, Edward A; Schork, Nicholas J; Srinivasan, Sathanur R; Woods, Nancy F; Zheng, Wei; Ziegler, Regina G; Zonderman, Alan; Heiss, Gerardo; Gwen Windham, B; Wellons, Melissa; Murray, Sarah S; Nalls, Michael; Pastinen, Tomi; Rajkovic, Aleksandar; Hirschhorn, Joel; Adrienne Cupples, L; Kooperberg, Charles; Murabito, Joanne M; Haiman, Christopher A

    2013-08-15

    African-American (AA) women have earlier menarche on average than women of European ancestry (EA), and earlier menarche is a risk factor for obesity and type 2 diabetes among other chronic diseases. Identification of common genetic variants associated with age at menarche has a potential value in pointing to the genetic pathways underlying chronic disease risk, yet comprehensive genome-wide studies of age at menarche are lacking for AA women. In this study, we tested the genome-wide association of self-reported age at menarche with common single-nucleotide polymorphisms (SNPs) in a total of 18 089 AA women in 15 studies using an additive genetic linear regression model, adjusting for year of birth and population stratification, followed by inverse-variance weighted meta-analysis (Stage 1). Top meta-analysis results were then tested in an independent sample of 2850 women (Stage 2). First, while no SNP passed the pre-specified P < 5 × 10(-8) threshold for significance in Stage 1, suggestive associations were found for variants near FLRT2 and PIK3R1, and conditional analysis identified two independent SNPs (rs339978 and rs980000) in or near RORA, strengthening the support for this suggestive locus identified in EA women. Secondly, an investigation of SNPs in 42 previously identified menarche loci in EA women demonstrated that 25 (60%) of them contained variants significantly associated with menarche in AA women. The findings provide the first evidence of cross-ethnic generalization of menarche loci identified to date, and suggest a number of novel biological links to menarche timing in AA women. PMID:23599027

  16. A GENOME-WIDE ASSOCIATION STUDY OF BRONCHODILATOR RESPONSE IN LATINOS IMPLICATES RARE VARIANTS

    PubMed Central

    Drake, Katherine A.; Torgerson, Dara G.; Gignoux, Christopher R.; Galanter, Joshua M.; Roth, Lindsey A.; Huntsman, Scott; Eng, Celeste; Oh, Sam S.; Yee, Sook Wah; Lin, Lawrence; Bustamante, Carlos D.; Moreno-Estrada, Andrés; Sandoval, Karla; Davis, Adam; Borrell, Luisa N.; Farber, Harold J.; Kumar, Rajesh; Avila, Pedro C.; Brigino-Buenaventura, Emerita; Chapela, Rocio; Ford, Jean G.; LeNoir, Michael A.; Lurmann, Fred; Meade, Kelley; Serebrisky, Denise; Thyne, Shannon; Rodríguez-Cintrón, William; Sen, Saunak; Rodríguez-Santana, José R.; Hernandez, Ryan D.; Giacomini, Kathleen M.; Burchard, Esteban G.

    2013-01-01

    Rationale The primary rescue medication to treat acute asthma exacerbation is short-acting β2- adrenergic receptor (β2AR) agonists (SABAs), however there is variation in how well an individual responds to treatment. Although these differences may be due to environmental factors, there is mounting evidence for a genetic contribution to variability in bronchodilator drug response (BDR). Methods We performed a genome-wide association study (GWAS) for BDR in 1,782 Latino children with asthma using standard linear regression, adjusting for genetic ancestry and ethnicity, and performed replication studies in an additional 531 Latinos. We also performed admixture mapping across the genome by testing for an association between local European, African, and Native American ancestry and BDR, adjusting for genomic ancestry and ethnicity. Results We identified seven genetic variants associated with BDR at a genome-wide significant threshold (p<5×10−8), all of which had frequencies below 5%. Furthermore, we observed an excess of small p-values driven by rare variants (frequency < 5%), and by variants in the proximity of solute carrier (SLC) genes. Admixture mapping identified five significant peaks; fine mapping within these peaks identified two rare variants in SLC22A15 as being associated with increased BDR in Mexicans. Quantitative PCR and immunohistochemistry identified SLC22A15 as being expressed in the lung and bronchial epithelial cells. Conclusion Our results suggest that rare variation contributes to individual differences in response to albuterol in Latinos, notably in solute carrier genes that include membrane transport proteins involved in the transport of endogenous metabolites and xenobiotics. Resequencing in larger, multi-ethnic population samples and additional functional studies are required to further understand the role of rare variation in BDR. PMID:23992748

  17. A genome-wide association scan on estrogen receptor-negative breast cancer

    PubMed Central

    2010-01-01

    Introduction Breast cancer is a heterogeneous disease and may be characterized on the basis of whether estrogen receptors (ER) are expressed in the tumour cells. ER status of breast cancer is important clinically, and is used both as a prognostic indicator and treatment predictor. In this study, we focused on identifying genetic markers associated with ER-negative breast cancer risk. Methods We conducted a genome-wide association analysis of 285,984 single nucleotide polymorphisms (SNPs) genotyped in 617 ER-negative breast cancer cases and 4,583 controls. We also conducted a genome-wide pathway analysis on the discovery dataset using permutation-based tests on pre-defined pathways. The extent of shared polygenic variation between ER-negative and ER-positive breast cancers was assessed by relating risk scores, derived using ER-positive breast cancer samples, to disease state in independent, ER-negative breast cancer cases. Results Association with ER-negative breast cancer was not validated for any of the five most strongly associated SNPs followed up in independent studies (1,011 ER-negative breast cancer cases, 7,604 controls). However, an excess of small P-values for SNPs with known regulatory functions in cancer-related pathways was found (global P = 0.052). We found no evidence to suggest that ER-negative breast cancer shares a polygenic basis to disease with ER-positive breast cancer. Conclusions ER-negative breast cancer is a distinct breast cancer subtype that merits independent analyses. Given the clinical importance of this phenotype and the likelihood that genetic effect sizes are small, greater sample sizes and further studies are required to understand the etiology of ER-negative breast cancers. PMID:21062454

  18. A “Candidate-Interactome” Aggregate Analysis of Genome-Wide Association Data in Multiple Sclerosis

    PubMed Central

    Policano, Claudia; Annibali, Viviana; Coarelli, Giulia; Ricigliano, Vito A. G.; Vittori, Danila; Fornasiero, Arianna; Buscarinu, Maria Chiara; Romano, Silvia; Salvetti, Marco; Ristori, Giovanni

    2013-01-01

    Though difficult, the study of gene-environment interactions in multifactorial diseases is crucial for interpreting the relevance of non-heritable factors and prevents from overlooking genetic associations with small but measurable effects. We propose a “candidate interactome” (i.e. a group of genes whose products are known to physically interact with environmental factors that may be relevant for disease pathogenesis) analysis of genome-wide association data in multiple sclerosis. We looked for statistical enrichment of associations among interactomes that, at the current state of knowledge, may be representative of gene-environment interactions of potential, uncertain or unlikely relevance for multiple sclerosis pathogenesis: Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, HHV8-Kaposi sarcoma, H1N1-influenza, JC virus, human innate immunity interactome for type I interferon, autoimmune regulator, vitamin D receptor, aryl hydrocarbon receptor and a panel of proteins targeted by 70 innate immune-modulating viral open reading frames from 30 viral species. Interactomes were either obtained from the literature or were manually curated. The P values of all single nucleotide polymorphism mapping to a given interactome were obtained from the last genome-wide association study of the International Multiple Sclerosis Genetics Consortium & the Wellcome Trust Case Control Consortium, 2. The interaction between genotype and Epstein Barr virus emerges as relevant for multiple sclerosis etiology. However, in line with recent data on the coexistence of common and unique strategies used by viruses to perturb the human molecular system, also other viruses have a similar potential, though probably less relevant in epidemiological terms. PMID:23696811

  19. Maternal gestational diabetes is associated with genome-wide DNA methylation variation in placenta and cord blood of exposed offspring.

    PubMed

    Finer, Sarah; Mathews, Chris; Lowe, Rob; Smart, Melissa; Hillman, Sara; Foo, Lin; Sinha, Ajay; Williams, David; Rakyan, Vardhman K; Hitman, Graham A

    2015-06-01

    Exposure of a developing foetus to maternal gestational diabetes (GDM) has been shown to programme future risk of diabetes and obesity. Epigenetic variation in foetal tissue may have a mechanistic role in metabolic disease programming through interaction of the pregnancy environment with gene function. We aimed to identify genome-wide DNA methylation variation in cord blood and placenta from offspring born to mothers with and without GDM. Pregnant women of South Asian origin were studied and foetal tissues sampled at term delivery. The Illumina HumanMethylation450 BeadChip was used to assay genome-wide DNA methylation in placenta and cord blood from 27 GDM exposed and 21 unexposed offspring. We identified 1485 cord blood and 1708 placenta methylation variable positions (MVPs) achieving genome-wide significance (adjusted P-value <0.05) with methylation differences of >5%. MVPs were disproportionately located within first exons. A bioinformatic co-methylation algorithm was used to detect consistent directionality of methylation in 1000 bp window around each MVP was observed at 74% of placenta and 59% of cord blood MVPs. KEGG pathway analysis showed enrichment of pathways involved in endocytosis, MAPK signalling and extracellular triggers to intracellular metabolic processes. Replication studies should integrate genomics and transcriptomics with longitudinal sampling to elucidate stability, determine causality for translation into biomarker and prevention studies. PMID:25634562

  20. Detection of genetic variants affecting cattle behaviour and their impact on milk production: a genome-wide association study.

    PubMed

    Friedrich, Juliane; Brand, Bodo; Ponsuksili, Siriluck; Graunke, Katharina L; Langbein, Jan; Knaust, Jacqueline; Kühn, Christa; Schwerin, Manfred

    2016-02-01

    Behaviour traits of cattle have been reported to affect important production traits, such as meat quality and milk performance as well as reproduction and health. Genetic predisposition is, together with environmental stimuli, undoubtedly involved in the development of behaviour phenotypes. Underlying molecular mechanisms affecting behaviour in general and behaviour and productions traits in particular still have to be studied in detail. Therefore, we performed a genome-wide association study in an F2 Charolais × German Holstein cross-breed population to identify genetic variants that affect behaviour-related traits assessed in an open-field and novel-object test and analysed their putative impact on milk performance. Of 37,201 tested single nucleotide polymorphism (SNPs), four showed a genome-wide and 37 a chromosome-wide significant association with behaviour traits assessed in both tests. Nine of the SNPs that were associated with behaviour traits likewise showed a nominal significant association with milk performance traits. On chromosomes 14 and 29, six SNPs were identified to be associated with exploratory behaviour and inactivity during the novel-object test as well as with milk yield traits. Least squares means for behaviour and milk performance traits for these SNPs revealed that genotypes associated with higher inactivity and less exploratory behaviour promote higher milk yields. Whether these results are due to molecular mechanisms simultaneously affecting behaviour and milk performance or due to a behaviour predisposition, which causes indirect effects on milk performance by influencing individual reactivity, needs further investigation. PMID:26515756

  1. Genome-Wide Analysis of Seed Acid Detergent Lignin (ADL) and Hull Content in Rapeseed (Brassica napus L.).

    PubMed

    Wang, Jia; Jian, Hongju; Wei, Lijuan; Qu, Cunmin; Xu, Xinfu; Lu, Kun; Qian, Wei; Li, Jiana; Li, Maoteng; Liu, Liezhao

    2015-01-01

    A stable yellow-seeded variety is the breeding goal for obtaining the ideal rapeseed (Brassica napus L.) plant, and the amount of acid detergent lignin (ADL) in the seeds and the hull content (HC) are often used as yellow-seeded rapeseed screening indices. In this study, a genome-wide association analysis of 520 accessions was performed using the Q + K model with a total of 31,839 single-nucleotide polymorphism (SNP) sites. As a result, three significant associations on the B. napus chromosomes A05, A09, and C05 were detected for seed ADL content. The peak SNPs were within 9.27, 14.22, and 20.86 kb of the key genes BnaA.PAL4, BnaA.CAD2/BnaA.CAD3, and BnaC.CCR1, respectively. Further analyses were performed on the major locus of A05, which was also detected in the seed HC examination. A comparison of our genome-wide association study (GWAS) results and previous linkage mappings revealed a common chromosomal region on A09, which indicates that GWAS can be used as a powerful complementary strategy for dissecting complex traits in B. napus. Genomic selection (GS) utilizing the significant SNP markers based on the GWAS results exhibited increased predictive ability, indicating that the predictive ability of a given model can be substantially improved by using GWAS and GS. PMID:26673885

  2. Genome-Wide Analysis of Seed Acid Detergent Lignin (ADL) and Hull Content in Rapeseed (Brassica napus L.)

    PubMed Central

    Wei, Lijuan; Qu, Cunmin; Xu, Xinfu; Lu, Kun; Qian, Wei; Li, Jiana; Li, Maoteng; Liu, Liezhao

    2015-01-01

    A stable yellow-seeded variety is the breeding goal for obtaining the ideal rapeseed (Brassica napus L.) plant, and the amount of acid detergent lignin (ADL) in the seeds and the hull content (HC) are often used as yellow-seeded rapeseed screening indices. In this study, a genome-wide association analysis of 520 accessions was performed using the Q + K model with a total of 31,839 single-nucleotide polymorphism (SNP) sites. As a result, three significant associations on the B. napus chromosomes A05, A09, and C05 were detected for seed ADL content. The peak SNPs were within 9.27, 14.22, and 20.86 kb of the key genes BnaA.PAL4, BnaA.CAD2/BnaA.CAD3, and BnaC.CCR1, respectively. Further analyses were performed on the major locus of A05, which was also detected in the seed HC examination. A comparison of our genome-wide association study (GWAS) results and previous linkage mappings revealed a common chromosomal region on A09, which indicates that GWAS can be used as a powerful complementary strategy for dissecting complex traits in B. napus. Genomic selection (GS) utilizing the significant SNP markers based on the GWAS results exhibited increased predictive ability, indicating that the predictive ability of a given model can be substantially improved by using GWAS and GS. PMID:26673885

  3. Genome-Wide Association Study Singles Out SCD and LEPR as the Two Main Loci Influencing Intramuscular Fat Content and Fatty Acid Composition in Duroc Pigs

    PubMed Central

    Ros-Freixedes, Roger; Gol, Sofia; Pena, Ramona N.; Tor, Marc; Ibáñez-Escriche, Noelia; Dekkers, Jack C. M.; Estany, Joan

    2016-01-01

    Intramuscular fat (IMF) content and fatty acid composition affect the organoleptic quality and nutritional value of pork. A genome-wide association study was performed on 138 Duroc pigs genotyped with a 60k SNP chip to detect biologically relevant genomic variants influencing fat content and composition. Despite the limited sample size, the genome-wide association study was powerful enough to detect the association between fatty acid composition and a known haplotypic variant in SCD (SSC14) and to reveal an association of IMF and fatty acid composition in the LEPR region (SSC6). The association of LEPR was later validated with an independent set of 853 pigs using a candidate quantitative trait nucleotide. The SCD gene is responsible for the biosynthesis of oleic acid (C18:1) from stearic acid. This locus affected the stearic to oleic desaturation index (C18:1/C18:0), C18:1, and saturated (SFA) and monounsaturated (MUFA) fatty acids content. These effects were consistently detected in gluteus medius, longissimus dorsi, and subcutaneous fat. The association of LEPR with fatty acid composition was detected only in muscle and was, at least in part, a consequence of its effect on IMF content, with increased IMF resulting in more SFA, less polyunsaturated fatty acids (PUFA), and greater SFA/PUFA ratio. Marker substitution effects estimated with a subset of 65 animals were used to predict the genomic estimated breeding values of 70 animals born 7 years later. Although predictions with the whole SNP chip information were in relatively high correlation with observed SFA, MUFA, and C18:1/C18:0 (0.48–0.60), IMF content and composition were in general better predicted by using only SNPs at the SCD and LEPR loci, in which case the correlation between predicted and observed values was in the range of 0.36 to 0.54 for all traits. Results indicate that markers in the SCD and LEPR genes can be useful to select for optimum fatty acid profiles of pork. PMID:27023885

  4. Genome-wide association study of tick resistance in South African Nguni cattle.

    PubMed

    Mapholi, N O; Maiwashe, A; Matika, O; Riggio, V; Bishop, S C; MacNeil, M D; Banga, C; Taylor, J F; Dzama, K

    2016-04-01

    Ticks and tick-borne diseases are among the main causes of economic loss in the South African cattle industry through high morbidity and mortality rates. Concerns of the general public regarding chemical residues may tarnish their perceptions of food safety and environmental health when the husbandry of cattle includes frequent use of acaricides to manage ticks. The primary objective of this study was to identify single nucleotide polymorphism (SNP) markers associated with host resistance to ticks in South African Nguni cattle. Tick count data were collected monthly from 586 Nguni cattle reared in four herds under natural grazing conditions over a period of two years. The counts were recorded for six species of ticks attached in eight anatomical locations on the animals and were summed by species and anatomical location. This gave rise to 63 measured phenotypes or traits, with results for 12 of these traits being reported here. Tick count (x) data were transformed using log10(x+1) and the resulting values were examined for normality. DNA was extracted from hair and blood samples and was genotyped using the Illumina BovineSNP50 assay. After quality control (call rate >90%, minor allele frequency >0.02), 40,436 SNPs were retained for analysis. Genetic parameters were estimated and association analysis for tick resistance was carried out using two approaches: a genome-wide association (GWA) analysis using the GenABEL package and a regional heritability mapping (RHM) analysis. The Bonferroni genome-wide (P<0.05) corrected significance threshold was 1.24×10(-6), with 2.47×10(-5) as the suggestive significance threshold (P<0.10) (i.e., one false positive per genome scan) in the GWA analysis. Likelihood ratio test (LRT) thresholds for genome-wide and suggestive significance were 13.5 and 9.15 for the RHM analysis. Six ixodid tick species were identified, with Amblyomma hebraeum (the vector for Heartwater disease) being the dominant species. Heritability estimates (h(2

  5. Association of adiponectin and adiponectin receptor genes with sow productivity estimated breeding values.

    PubMed

    Jafarikia, Moshen; Méthot, Steve; Maignel, Laurence; Fortin, Frédéric; Wyss, Stefanie; Sullivan, Brian; Palin, Marie-France

    2015-09-01

    Our objectives were to estimate frequencies of previously identified single nucleotide polymorphisms (SNPs) in adiponectin (ADIPOQ) and its receptors (ADIPOR1 and ADIPOR2) in a population of Duroc, Landrace and Yorkshire pigs and evaluate the effect of these alleles on sow productivity estimated breeding values (EBVs). Eight SNPs were genotyped on 446 pigs in the ADIPOQ (c.178G>A, c.*300A>G, c.*1094_1095insC and c.*1779A>C), ADIPOR1 (c.*129A>C) and ADIPOR2 (c.*112G>A, c.*295G>C and c.*1455G>A) genes. Association analyses were performed with sow productivity EBVs based on litter records collected in Canadian breeding farms. There were significant associations between ADIPOQ c.178G>A and c.*1094_1095insC SNPs and studied traits. However, none of these associations remained significant after applying a Bonferroni correction. The ADIPOR2 c.*112G>A SNP was associated with the total number of piglets born (TNB, P < 0.001) and litter weight at weaning (LWW, P < 0.001) EBVs. Associations were also observed between the ADIPOR2 [A;C;G] haplotype and TNB and LWW (P < 0.001). Our results demonstrate that a selection in favor of the c.*112G allele or against the [A;C;G] haplotype may have the potential to increase LWW EBVs. However, the c.*112G allele is also associated with lower TNB EBVs. Some of the alleles of the genes studied showed substantial variability and in general, the results corroborated previously reported findings for an independent sow population. However, careful cost-benefits analyses should be performed before using these markers in selection program as an improvement in TNB may translate into lighter LWW, with its associated negative impact on production traits such as growth performances. PMID:26210991

  6. Multibreed genome wide association can improve precision of mapping causative variants underlying milk production in dairy cattle

    PubMed Central

    2014-01-01

    Background Genome wide association studies (GWAS) in most cattle breeds result in large genomic intervals of significant associations making it difficult to identify causal mutations. This is due to the extensive, low-level linkage disequilibrium within a cattle breed. As there is less linkage disequilibrium across breeds, multibreed GWAS may improve precision of causal variant mapping. Here we test this hypothesis in a Holstein and Jersey cattle data set with 17,925 individuals with records for production and functional traits and 632,003 SNP markers. Results By using a cross validation strategy within the Holstein and Jersey data sets, we were able to identify and confirm a large number of QTL. As expected, the precision of mapping these QTL within the breeds was limited. In the multibreed analysis, we found that many loci were not segregating in both breeds. This was partly an artefact of power of the experiments, with the number of QTL shared between the breeds generally increasing with trait heritability. False discovery rates suggest that the multibreed analysis was less powerful than between breed analyses, in terms of how much genetic variance was explained by the detected QTL. However, the multibreed analysis could more accurately pinpoint the location of the well-described mutations affecting milk production such as DGAT1. Further, the significant SNP in the multibreed analysis were significantly enriched in genes regions, to a considerably greater extent than was observed in the single breed analyses. In addition, we have refined QTL on BTA5 and BTA19 to very small intervals and identified a small number of potential candidate genes in these, as well as in a number of other regions. Conclusion Where QTL are segregating across breed, multibreed GWAS can refine these to reasonably small genomic intervals. However, such QTL appear to represent only a fraction of the genetic variation. Our results suggest a significant proportion of QTL affecting milk

  7. Genome-wide Association Study of Porcine Hematological Parameters in a Large White × Minzhu F2 Resource Population

    PubMed Central

    Luo, Weizhen; Chen, Shaokang; Cheng, Duxue; Wang, Ligang; Li, Yong; Ma, Xiaojun; Song, Xin; Liu, Xin; Li, Wen; Liang, Jing; Yan, Hua; Zhao, Kebin; Wang, Chuduan; Wang, Lixian; Zhang, Longchao

    2012-01-01

    Hematological traits, which are important indicators of immune function in animals, have been commonly examined as biomarkers of disease and disease severity in humans and animals. Genome-wide significant quantitative trait loci (QTLs) provide important information for use in breeding programs of animals such as pigs. QTLs for hematological parameters (hematological traits) have been detected in pig chromosomes, although these are often mapped by linkage analysis to large intervals making identification of the underlying mutation problematic. Single nucleotide polymorphisms (SNPs) are the common form of genetic variation among individuals and are thought to account for the majority of inherited traits. In this study, a genome-wide association study (GWAS) was performed to detect regions of association with hematological traits in a three-generation resource population produced by intercrossing Large White boars and Minzhu sows during the period from 2007 to 2011. Illumina PorcineSNP60 BeadChip technology was used to genotype each animal and seven hematological parameters were measured (hematocrit (HCT), hemoglobin (HGB), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), red blood cell count (RBC) and red blood cell volume distribution width (RDW)). Data were analyzed in a three step Genome-wide Rapid Association using the Mixed Model and Regression-Genomic Control (GRAMMAR-GC) method. A total of 62 genome-wide significant and three chromosome-wide significant SNPs associated with hematological parameters were detected in this GWAS. Seven and five SNPs were associated with HCT and HGB, respectively. These SNPs were all located within the region of 34.6-36.5 Mb on SSC7. Four SNPs within the region of 43.7-47.0 Mb and fifty-five SNPs within the region of 42.2-73.8 Mb on SSC8 showed significant association with MCH and MCV, respectively. At chromosome-wide significant level, one SNP at 29.2 Mb on SSC1

  8. Genome-Wide Association Study Identifies Phospholipase C zeta 1 (PLCz1) as a Stallion Fertility Locus in Hanoverian Warmblood Horses

    PubMed Central

    Schrimpf, Rahel; Dierks, Claudia; Martinsson, Gunilla; Sieme, Harald; Distl, Ottmar

    2014-01-01

    A consistently high level of stallion fertility plays an economically important role in modern horse breeding. We performed a genome-wide association study for estimated breeding values of the paternal component of the pregnancy rate per estrus cycle (EBV-PAT) in Hanoverian stallions. A total of 228 Hanoverian stallions were genotyped using the Equine SNP50 Beadchip. The most significant association was found on horse chromosome 6 for a single nucleotide polymorphism (SNP) within phospholipase C zeta 1 (PLCz1). In the close neighbourhood to PLCz1 is located CAPZA3 (capping protein (actin filament) muscle Z-line, alpha 3). The gene PLCz1 encodes a protein essential for spermatogenesis and oocyte activation through sperm induced Ca2+-oscillation during fertilization. We derived equine gene models for PLCz1 and CAPZA3 based on cDNA and genomic DNA sequences. The equine PLCz1 had four different transcripts of which two contained a premature termination codon. Sequencing all exons and their flanking sequences using genomic DNA samples from 19 Hanoverian stallions revealed 47 polymorphisms within PLCz1 and one SNP within CAPZA3. Validation of these 48 polymorphisms in 237 Hanoverian stallions identified three intronic SNPs within PLCz1 as significantly associated with EBV-PAT. Bioinformatic analysis suggested regulatory effects for these SNPs via transcription factor binding sites or microRNAs. In conclusion, non-coding polymorphisms within PLCz1 were identified as conferring stallion fertility and PLCz1 as candidate locus for male fertility in Hanoverian warmblood. CAPZA3 could be eliminated as candidate gene for fertility in Hanoverian stallions. PMID:25354211

  9. Prediction of breeding values for tenderness of market animals from measurements on bulls.

    PubMed

    Barkhouse, K L; Van Vleck, L D; Cundiff, L V; Koohmaraie, M; Lunstra, D D; Crouse, J D

    1996-11-01

    Data were tenderness measures on steaks from 237 bulls (Group II) slaughtered after producing freezable semen and on 1,431 related steers and heifers (market animals, Group I) from Angus, Hereford, Pinzgauer, Brahman, and Sahiwal crosses from the Germ Plasm Evaluation project at the U.S. Meat Animal Research Center. Tenderness was assessed through Warner-Bratzler Shear Force (SF), taste panel tenderness (TPT), marbling score (MS), and myofibrillar fragmentation index (MFI). For all traits, as fraction Bos indicus inheritance increased, implied tenderness decreased. Heritability estimates were generally not significantly different from zero. Genetic correlations generally indicated favorable associations among the traits. The range in predicted breeding values of bulls for market animal tenderness was small and from -.34 to .32 kg for market animal shear force. Because of low estimates of heritability for SF or TPT, results from this experiment indicate that selection based on tenderness of steaks sampled from intact or late castrate males slaughtered following collection of freezable quality semen would not be very effective in improving average tenderness of steaks from steers of heifer progeny. If a mean of heritability estimates reported in the literature of .27 for shear value was assumed for market steer and heifer progeny instead of .02 as found in the present study, then selection based on estimates of shear force in young bulls would be relatively more effective in improving shear force of market progeny. PMID:8923175

  10. Value of standardised exercise tests and blood biochemistry in the selection and training of breeding stallions.

    PubMed

    Sloet van Oldruitenborgh-Oosterbaan, M M; Wensing, T; Barneveld, A; Breukink, H J

    1991-10-19

    Stallions selected by the Royal Dutch Warmblood Society were submitted to a standardised lungeing test at the beginning and at the end of a 100-day test of performance and ability. The heart rate, haematology and biochemistry values obtained in the first lungeing test showed no significant differences between the 15 stallions which were rejected by the Royal Dutch Warmblood Society during the first month of the 100-day test, the 15 stallions rejected during the last month and the 11 stallions which were approved for registration in the studbook. The 26 stallions submitted to the second lungeing test had significantly lower heart rates and blood lactate concentrations than in the first test. The standardised lungeing test had no value in predicting the rejection or approval of the stallions, and the fitness of a stallion at the beginning of the 100-day test did not influence its chance of being approved as a breeding stallion. The differences between the results of the first and the second tests suggest that the fitness of the stallions improved during the 100-day test. PMID:1759338

  11. Genome Wide Association Study for Drought, Aflatoxin Resistance, and Important Agronomic Traits of Maize Hybrids in the Sub-Tropics

    PubMed Central

    Farfan, Ivan D. Barrero; De La Fuente, Gerald N.; Murray, Seth C.; Isakeit, Thomas; Huang, Pei-Cheng; Warburton, Marilyn; Williams, Paul; Windham, Gary L.; Kolomiets, Mike

    2015-01-01

    The primary maize (Zea mays L.) production areas are in temperate regions throughout the world and this is where most maize breeding is focused. Important but lower yielding maize growing regions such as the sub-tropics experience unique challenges, the greatest of which are drought stress and aflatoxin contamination. Here we used a diversity panel consisting of 346 maize inbred lines originating in temperate, sub-tropical and tropical areas testcrossed to stiff-stalk line Tx714 to investigate these traits. Testcross hybrids were evaluated under irrigated and non-irrigated trials for yield, plant height, ear height, days to anthesis, days to silking and other agronomic traits. Irrigated trials were also inoculated with Aspergillus flavus and evaluated for aflatoxin content. Diverse maize testcrosses out-yielded commercial checks in most trials, which indicated the potential for genetic diversity to improve sub-tropical breeding programs. To identify genomic regions associated with yield, aflatoxin resistance and other important agronomic traits, a genome wide association analysis was performed. Using 60,000 SNPs, this study found 10 quantitative trait variants for grain yield, plant and ear height, and flowering time after stringent multiple test corrections, and after fitting different models. Three of these variants explained 5–10% of the variation in grain yield under both water conditions. Multiple identified SNPs co-localized with previously reported QTL, which narrows the possible location of causal polymorphisms. Novel significant SNPs were also identified. This study demonstrated the potential to use genome wide association studies to identify major variants of quantitative and complex traits such as yield under drought that are still segregating between elite inbred lines. PMID:25714370

  12. Genome wide association study for drought, aflatoxin resistance, and important agronomic traits of maize hybrids in the sub-tropics.

    PubMed

    Farfan, Ivan D Barrero; De La Fuente, Gerald N; Murray, Seth C; Isakeit, Thomas; Huang, Pei-Cheng; Warburton, Marilyn; Williams, Paul; Windham, Gary L; Kolomiets, Mike

    2015-01-01

    The primary maize (Zea mays L.) production areas are in temperate regions throughout the world and this is where most maize breeding is focused. Important but lower yielding maize growing regions such as the sub-tropics experience unique challenges, the greatest of which are drought stress and aflatoxin contamination. Here we used a diversity panel consisting of 346 maize inbred lines originating in temperate, sub-tropical and tropical areas testcrossed to stiff-stalk line Tx714 to investigate these traits. Testcross hybrids were evaluated under irrigated and non-irrigated trials for yield, plant height, ear height, days to anthesis, days to silking and other agronomic traits. Irrigated trials were also inoculated with Aspergillus flavus and evaluated for aflatoxin content. Diverse maize testcrosses out-yielded commercial checks in most trials, which indicated the potential for genetic diversity to improve sub-tropical breeding programs. To identify genomic regions associated with yield, aflatoxin resistance and other important agronomic traits, a genome wide association analysis was performed. Using 60,000 SNPs, this study found 10 quantitative trait variants for grain yield, plant and ear height, and flowering time after stringent multiple test corrections, and after fitting different models. Three of these variants explained 5-10% of the variation in grain yield under both water conditions. Multiple identified SNPs co-localized with previously reported QTL, which narrows the possible location of causal polymorphisms. Novel significant SNPs were also identified. This study demonstrated the potential to use genome wide association studies to identify major variants of quantitative and complex traits such as yield under drought that are still segregating between elite inbred lines. PMID:25714370

  13. Genome-Wide Association Study Identifies Candidate Genes for Starch Content Regulation in Maize Kernels.

    PubMed

    Liu, Na; Xue, Yadong; Guo, Zhanyong; Li, Weihua; Tang, Jihua

    2016-01-01

    Kernel starch content is an important trait in maize (Zea mays L.) as it accounts for 65-75% of the dry kernel weight and positively correlates with seed yield. A number of starch synthesis-related genes have been identified in maize in recent years. However, many loci underlying variation in starch content among maize inbred lines still remain to be identified. The current study is a genome-wide association study that used a set of 263 maize inbred lines. In this panel, the average kernel starch content was 66.99%, ranging from 60.60 to 71.58% over the three study years. These inbred lines were genotyped with the SNP50 BeadChip maize array, which is comprised of 56,110 evenly spaced, random SNPs. Population structure was controlled by a mixed linear model (MLM) as implemented in the software package TASSEL. After the statistical analyses, four SNPs were identified as significantly associated with starch content (P ≤ 0.0001), among which one each are located on chromosomes 1 and 5 and two are on chromosome 2. Furthermore, 77 candidate genes associated with starch synthesis were found within the 100-kb intervals containing these four QTLs, and four highly associated genes were within 20-kb intervals of the associated SNPs. Among the four genes, Glucose-1-phosphate adenylyltransferase (APS1; Gene ID GRMZM2G163437) is known as an important regulator of kernel starch content. The identified SNPs, QTLs, and candidate genes may not only be readily used for germplasm improvement by marker-assisted selection in breeding, but can also elucidate the genetic basis of starch content. Further studies on these identified candidate genes may help determine the molecular mechanisms regulating kernel starch content in maize and other important cereal crops. PMID:27512395

  14. Genome-Wide Association Study Identifies Candidate Genes for Starch Content Regulation in Maize Kernels

    PubMed Central

    Liu, Na; Xue, Yadong; Guo, Zhanyong; Li, Weihua; Tang, Jihua

    2016-01-01

    Kernel starch content is an important trait in maize (Zea mays L.) as it accounts for 65–75% of the dry kernel weight and positively correlates with seed yield. A number of starch synthesis-related genes have been identified in maize in recent years. However, many loci underlying variation in starch content among maize inbred lines still remain to be identified. The current study is a genome-wide association study that used a set of 263 maize inbred lines. In this panel, the average kernel starch content was 66.99%, ranging from 60.60 to 71.58% over the three study years. These inbred lines were genotyped with the SNP50 BeadChip maize array, which is comprised of 56,110 evenly spaced, random SNPs. Population structure was controlled by a mixed linear model (MLM) as implemented in the software package TASSEL. After the statistical analyses, four SNPs were identified as significantly associated with starch content (P ≤ 0.0001), among which one each are located on chromosomes 1 and 5 and two are on chromosome 2. Furthermore, 77 candidate genes associated with starch synthesis were found within the 100-kb intervals containing these four QTLs, and four highly associated genes were within 20-kb intervals of the associated SNPs. Among the four genes, Glucose-1-phosphate adenylyltransferase (APS1; Gene ID GRMZM2G163437) is known as an important regulator of kernel starch content. The identified SNPs, QTLs, and candidate genes may not only be readily used for germplasm improvement by marker-assisted selection in breeding, but can also elucidate the genetic basis of starch content. Further studies on these identified candidate genes may help determine the molecular mechanisms regulating kernel starch content in maize and other important cereal crops. PMID:27512395

  15. Genome-wide association study for behavior, type traits, and muscular development in Charolais beef cattle.

    PubMed

    Vallée, A; Daures, J; van Arendonk, J A M; Bovenhuis, H

    2016-06-01

    Behavior, type traits, and muscular development are of interest for beef cattle breeding. Genome-wide association studies (GWAS) enable the identification of candidate genes, which enables gene-based selection and provides insight in the genetic architecture of these traits. The objective of the current study was to perform a GWAS for 3 behavior traits, 12 type traits, and muscular development in Charolais cattle. Behavior traits, including aggressiveness at parturition, aggressiveness during gestation period, and maternal care, were scored by farmers. Type traits, including udder conformation, teat, feet and legs, and locomotion, were scored by trained classifiers. Data used in the GWAS consisted of 3,274 cows with phenotypic records and genotyping information for 44,930 SNP. When SNP had a false discovery rate (FDR) smaller than 0.05, they were referred to as significant. When SNP had a FDR between 0.05 and 0.20, they were referred to as suggestive. Four significant and 12 suggestive regions were detected for aggressiveness during gestation, maternal care, udder balance, teat thinness, teat length, foot angle, foot depth, and locomotion. These 4 significant and 12 suggestive regions were not supported by other significant SNP in close proximity. No SNP with major effects were detected for behavior and type traits, and SNP associations for these traits were spread across the genome, suggesting that behavior and type traits were influenced by many genes, each explaining a small part of genetic variance. The GWAS identified 1 region on chromosome 2 significantly associated with muscular development, which included the myostatin gene (), which is known to affect muscularity. No other regions associated with muscular development were found. Results showed that the myostatin region associated with muscular development had pleiotropic effects on udder volume, teat thinness, rear leg, and leg angle. PMID:27285908

  16. Genome-Wide Analysis of miRNA targets in Brachypodium and Biomass Energy Crops

    SciTech Connect

    Green, Pamela J.

    2015-08-11

    MicroRNAs (miRNAs) contribute to the control of numerous biological processes through the regulation of specific target mRNAs. Although the identities of these targets are essential to elucidate miRNA function, the targets are much more difficult to identify than the small RNAs themselves. Before this work, we pioneered the genome-wide identification of the targets of Arabidopsis miRNAs using an approach called PARE (German et al., Nature Biotech. 2008; Nature Protocols, 2009). Under this project, we applied PARE to Brachypodium distachyon (Brachypodium), a model plant in the Poaceae family, which includes the major food grain and bioenergy crops. Through in-depth global analysis and examination of specific examples, this research greatly expanded our knowledge of miRNAs and target RNAs of Brachypodium. New regulation in response to environmental stress or tissue type was found, and many new miRNAs were discovered. More than 260 targets of new and known miRNAs with PARE sequences at the precise sites of miRNA-guided cleavage were identified and characterized. Combining PARE data with the small RNA data also identified the miRNAs responsible for initiating approximately 500 phased loci, including one of the novel miRNAs. PARE analysis also revealed that differentially expressed miRNAs in the same family guide specific target RNA cleavage in a correspondingly tissue-preferential manner. The project included generation of small RNA and PARE resources for bioenergy crops, to facilitate ongoing discovery of conserved miRNA-target RNA regulation. By associating specific miRNA-target RNA pairs with known physiological functions, the research provides insights about gene regulation in different tissues and in response to environmental stress. This, and release of new PARE and small RNA data sets should contribute basic knowledge to enhance breeding and may suggest new strategies for improvement of biomass energy crops.

  17. Genome-Wide Scan for Adaptive Divergence and Association with Population-Specific Covariates.

    PubMed

    Gautier, Mathieu

    2015-12-01

    In population genomics studies, accounting for the neutral covariance structure across population allele frequencies is critical to improve the robustness of genome-wide scan approaches. Elaborating on the BayEnv model, this study investigates several modeling extensions (i) to improve the estimation accuracy of the population covariance matrix and all the related measures, (ii) to identify significantly overly differentiated SNPs based on a calibration procedure of the XtX statistics, and (iii) to consider alternative covariate models for analyses of association with population-specific covariables. In particular, the auxiliary variable model allows one to deal with multiple testing issues and, providing the relative marker positions are available, to capture some linkage disequilibrium information. A comprehensive simulation study was carried out to evaluate the performances of these different models. Also, when compared in terms of power, robustness, and computational efficiency to five other state-of-the-art genome-scan methods (BayEnv2, BayScEnv, BayScan, flk, and lfmm), the proposed approaches proved highly effective. For illustration purposes, genotyping data on 18 French cattle breeds were analyzed, leading to the identification of 13 strong signatures of selection. Among these, four (surrounding the KITLG, KIT, EDN3, and ALB genes) contained SNPs strongly associated with the piebald coloration pattern while a fifth (surrounding PLAG1) could be associated to morphological differences across the populations. Finally, analysis of Pool-Seq data from 12 populations of Littorina saxatilis living in two different ecotypes illustrates how the proposed framework might help in addressing relevant ecological issues in nonmodel species. Overall, the proposed methods define a robust Bayesian framework to characterize adaptive genetic differentiation across populations. The BayPass program implementing the different models is available at http://www1.montpellier

  18. Sympatric speciation revealed by genome-wide divergence in the blind mole rat Spalax.

    PubMed

    Li, Kexin; Hong, Wei; Jiao, Hengwu; Wang, Guo-Dong; Rodriguez, Karl A; Buffenstein, Rochelle; Zhao, Yang; Nevo, Eviatar; Zhao, Huabin

    2015-09-22

    Sympatric speciation (SS), i.e., speciation within a freely breeding population or in contiguous populations, was first proposed by Darwin [Darwin C (1859) On the Origins of Species by Means of Natural Selection] and is still controversial despite theoretical support [Gavrilets S (2004) Fitness Landscapes and the Origin of Species (MPB-41)] and mounting empirical evidence. Speciation of subterranean mammals generally, including the genus Spalax, was considered hitherto allopatric, whereby new species arise primarily through geographic isolation. Here we show in Spalax a case of genome-wide divergence analysis in mammals, demonstrating that SS in continuous populations, with gene flow, encompasses multiple widespread genomic adaptive complexes, associated with the sharply divergent ecologies. The two abutting soil populations of S. galili in northern Israel habituate the ancestral Senonian chalk population and abutting derivative Plio-Pleistocene basalt population. Population divergence originated ∼0.2-0.4 Mya based on both nuclear and mitochondrial genome analyses. Population structure analysis displayed two distinctly divergent clusters of chalk and basalt populations. Natural selection has acted on 300+ genes across the genome, diverging Spalax chalk and basalt soil populations. Gene ontology enrichment analysis highlights strong but differential soil population adaptive complexes: in basalt, sensory perception, musculature, metabolism, and energetics, and in chalk, nutrition and neurogenetics are outstanding. Population differentiation of chemoreceptor genes suggests intersoil population's mate and habitat choice substantiating SS. Importantly, distinctions in protein degradation may also contribute to SS. Natural selection and natural genetic engineering [Shapiro JA (2011) Evolution: A View From the 21st Century] overrule gene flow, evolving divergent ecological adaptive complexes. Sharp ecological divergences abound in nature; therefore, SS appears to be an

  19. A genome-wide linkage analysis for reproductive traits in F2 Large White × Meishan cross gilts

    PubMed Central

    Hernandez, S C; Finlayson, H A; Ashworth, C J; Haley, C S; Archibald, A L

    2014-01-01

    Female reproductive performance traits in pigs have low heritabilities thus limiting improvement through traditional selective breeding programmes. However, there is substantial genetic variation found between pig breeds with the Chinese Meishan being one of the most prolific pig breeds known. In this study, three cohorts of Large White × Meishan F2 cross-bred pigs were analysed to identify quantitative trait loci (QTL) with effects on reproductive traits, including ovulation rate, teat number, litter size, total born alive and prenatal survival. A total of 307 individuals were genotyped for 174 genetic markers across the genome. The genome-wide analysis of the trait-recorded F2 gilts in their first parity/litter revealed one QTL for teat number significant at the genome level and a total of 12 QTL, which are significant at the chromosome-wide level, for: litter size (three QTL), total born alive (two QTL), ovulation rate (four QTL), prenatal survival (one QTL) and teat number (two QTL). Further support for eight of these QTL is provided by results from other studies. Four of these 12 QTL were mapped for the first time in this study: on SSC15 for ovulation rate and on SSC18 for teat number, ovulation rate and litter size. PMID:24456574

  20. A genome-wide association study identifies a genomic region for the polycerate phenotype in sheep (Ovis aries)

    PubMed Central

    Ren, Xue; Yang, Guang-Li; Peng, Wei-Feng; Zhao, Yong-Xin; Zhang, Min; Chen, Ze-Hui; Wu, Fu-An; Kantanen, Juha; Shen, Min; Li, Meng-Hua

    2016-01-01

    Horns are a cranial appendage found exclusively in Bovidae, and play important roles in accessing resources and mates. In sheep (Ovies aries), horns vary from polled to six-horned, and human have been selecting polled animals in farming and breeding. Here, we conducted a genome-wide association study on 24 two-horned versus 22 four-horned phenotypes in a native Chinese breed of Sishui Fur sheep. Together with linkage disequilibrium (LD) analyses and haplotype-based association tests, we identified a genomic region comprising 132.0–133.1 Mb on chromosome 2 that contained the top 10 SNPs (including 4 significant SNPs) and 5 most significant haplotypes associated with the polycerate phenotype. In humans and mice, this genomic region contains the HOXD gene cluster and adjacent functional genes EVX2 and KIAA1715, which have a close association with the formation of limbs and genital buds. Our results provide new insights into the genetic basis underlying variable numbers of horns and represent a new resource for use in sheep genetics and breeding. PMID:26883901

  1. Genome-wide association of coagulation properties, curd firmness modeling, protein percentage, and acidity in milk from Brown Swiss cows.

    PubMed

    Dadousis, C; Biffani, S; Cipolat-Gotet, C; Nicolazzi, E L; Rossoni, A; Santus, E; Bittante, G; Cecchinato, A

    2016-05-01

    Cheese production is increasing in many countries, and a desire toward genetic selection for milk coagulation properties in dairy cattle breeding exists. However, measurements of individual cheesemaking properties are hampered by high costs and labor, whereas traditional single-point milk coagulation properties (MCP) are sometimes criticized. Nevertheless, new modeling of the entire curd firmness and syneresis process (CFt equation) offers new insight into the cheesemaking process. Moreover, identification of genomic regions regulating milk cheesemaking properties might enhance direct selection of individuals in breeding programs based on cheese ability rather than related milk components. Therefore, the objective of this study was to perform genome-wide association studies to identify genomic regions linked to traditional MCP and new CFt parameters, milk acidity (pH), and milk protein percentage. Milk and DNA samples from 1,043 Italian Brown Swiss cows were used. Milk pH and 3 MCP traits were grouped together to represent the MCP set. Four CFt equation parameters, 2 derived traits, and protein percentage were considered as the second group of traits (CFt set). Animals were genotyped with the Illumina SNP50 BeadChip v.2 (Illumina Inc., San Diego, CA). Multitrait animal models were used to estimate variance components. For genome-wide association studies, the genome-wide association using mixed model and regression-genomic control approach was used. In total, 106 significant marker traits associations and 66 single nucleotide polymorphisms were identified on 12 chromosomes (1, 6, 9, 11, 13, 15, 16, 19, 20, 23, 26, and 28). Sharp peaks were detected at 84 to 88 Mbp on Bos taurus autosome (BTA) 6, with a peak at 87.4 Mbp in the region harboring the casein genes. Evidence of quantitative trait loci at 82.6 and 88.4 Mbp on the same chromosome was found. All chromosomes but BTA6, BTA11, and BTA28 were associated with only one trait. Only BTA6 was in common between MCP

  2. Genome-wide analysis reveals artificial selection on coat colour and reproductive traits in Chinese domestic pigs.

    PubMed

    Wang, Chao; Wang, Hongyang; Zhang, Yu; Tang, Zhonglin; Li, Kui; Liu, Bang

    2015-03-01

    Pigs from Asia and Europe were independently domesticated from c. 9000 years ago. During this period, strong artificial selection has led to dramatic phenotypic changes in domestic pigs. However, the genetic basis underlying these morphological and behavioural adaptations is relatively unknown, particularly for indigenous Chinese pigs. Here, we performed a genome-wide analysis to screen 196 regions with selective sweep signals in Tongcheng pigs, which are a typical indigenous Chinese breed. Genes located in these regions have been found to be involved in lipid metabolism, melanocyte differentiation, neural development and other biological processes, which coincide with the evolutionary phenotypic changes in this breed. A synonymous substitution, c.669T>C, in ESR1, which colocalizes with a major quantitative trait locus for litter size, shows extreme differences in allele frequency between Tongcheng pigs and wild boars. Notably, the variant C allele in this locus exhibits high allele frequency in most Chinese populations, suggesting a consequence of positive selection. Five genes (PRM1, PRM2, TNP2, GPR149 and JMJD1C) related to reproductive traits were found to have high haplotype similarity in Chinese breeds. Two selected genes, MITF and EDNRB, are implied to shape the two-end black colour trait in Tongcheng pig. Subsequent SNP microarray studies of five Chinese white-spotted breeds displayed a concordant signature at both loci, suggesting that these two genes are responsible for colour variations in Chinese breeds. Utilizing massively parallel sequencing, we characterized the candidate sites that adapt to artificial and environmental selections during the Chinese pig domestication. This study provides fundamental proof for further research on the evolutionary adaptation of Chinese pigs. PMID:25132237

  3. [Genome-wide association study on complex diseases: study design and genetic markers].