Genetic Determinants of Parkinson's Disease: Can They Help to Stratify the Patients Based on the Underlying Molecular Defect?

PubMed Central

Redenšek, Sara; Trošt, Maja; Dolžan, Vita

2017-01-01

Parkinson's disease (PD) is a sporadic progressive neurodegenerative brain disorder with a relatively strong genetic background. We have reviewed the current literature about the genetic factors that could be indicative of pathophysiological pathways of PD and their applications in everyday clinical practice. Information on novel risk genes is coming from several genome-wide association studies (GWASs) and their meta-analyses. GWASs that have been performed so far enabled the identification of 24 loci as PD risk factors. These loci take part in numerous cellular processes that may contribute to PD pathology: protein aggregation, protein, and membrane trafficking, lysosomal autophagy, immune response, synaptic function, endocytosis, inflammation, and metabolic pathways are among the most important ones. The identified single nucleotide polymorphisms are usually located in the non-coding regions and their functionality remains to be determined, although they presumably influence gene expression. It is important to be aware of a very low contribution of a single genetic risk factor to PD development; therefore, novel prognostic indices need to account for the cumulative nature of genetic risk factors. A better understanding of PD pathophysiology and its genetic background will help to elucidate the underlying pathological processes. Such knowledge may help physicians to recognize subjects with the highest risk for the development of PD, and provide an opportunity for the identification of novel potential targets for neuroprotective treatment. Moreover, it may enable stratification of the PD patients according to their genetic fingerprint to properly personalize their treatment as well as supportive measures. PMID:28239348

Improved performance of epidemiologic and genetic risk models for rheumatoid arthritis serologic phenotypes using family history.

PubMed

Sparks, Jeffrey A; Chen, Chia-Yen; Jiang, Xia; Askling, Johan; Hiraki, Linda T; Malspeis, Susan; Klareskog, Lars; Alfredsson, Lars; Costenbader, Karen H; Karlson, Elizabeth W

2015-08-01

To develop and validate rheumatoid arthritis (RA) risk models based on family history, epidemiologic factors and known genetic risk factors. We developed and validated models for RA based on known RA risk factors, among women in two cohorts: the Nurses' Health Study (NHS, 381 RA cases and 410 controls) and the Epidemiological Investigation of RA (EIRA, 1244 RA cases and 971 controls). Model discrimination was evaluated using the area under the receiver operating characteristic curve (AUC) in logistic regression models for the study population and for those with positive family history. The joint effect of family history with genetics, smoking and body mass index (BMI) was evaluated using logistic regression models to estimate ORs for RA. The complete model including family history, epidemiologic risk factors and genetics demonstrated AUCs of 0.74 for seropositive RA in NHS and 0.77 for anti-citrullinated protein antibody (ACPA)-positive RA in EIRA. Among women with positive family history, discrimination was excellent for complete models for seropositive RA in NHS (AUC 0.82) and ACPA-positive RA in EIRA (AUC 0.83). Positive family history, high genetic susceptibility, smoking and increased BMI had an OR of 21.73 for ACPA-positive RA. We developed models for seropositive and seronegative RA phenotypes based on family history, epidemiological and genetic factors. Among those with positive family history, models using epidemiologic and genetic factors were highly discriminatory for seropositive and seronegative RA. Assessing epidemiological and genetic factors among those with positive family history may identify individuals suitable for RA prevention strategies. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Current and future role of genetic screening in gynecologic malignancies.

PubMed

Ring, Kari L; Garcia, Christine; Thomas, Martha H; Modesitt, Susan C

2017-11-01

The world of hereditary cancers has seen exponential growth in recent years. While hereditary breast and ovarian cancer and Lynch syndrome account for the majority of mutations encountered by gynecologists, newly identified deleterious genetic mutations continue to be unearthed with their associated risks of malignancies. However, these advances in genetic cancer predispositions then force practitioners and their patients to confront the uncertainties of these less commonly identified mutations and the fact that there is limited evidence to guide them in expected cancer risk and appropriate risk-reduction strategies. Given the speed of information, it is imperative to involve cancer genetics experts when counseling these patients. In addition, coordination of screening and care in conjunction with specialty high-risk clinics, if available, allows for patients to have centralized management for multiple cancer risks under the guidance of physicians with experience counseling these patients. The objective of this review is to present the current literature regarding genetic mutations associated with gynecologic malignancies as well to propose screening and risk-reduction options for these high-risk patients. Copyright © 2017 Elsevier Inc. All rights reserved.

Genetics of the Framingham Heart Study Population

PubMed Central

Govindaraju, Diddahally R.; Cupples, L. Adrienne; Kannel, William B.; O’Donnell, Christopher J.; Atwood, Larry D.; D’Agostino, Ralph B.; Fox, Caroline S.; Larson, Marty; Levy, Daniel; Morabito, Joanne; Vasan, Ramachandran S.; Splansky, Greta Lee; Wolf, Philip A.; Benjamin, Emelia J.

2010-01-01

This article provides an introduction to the Framingham Heart Study (FHS) and the genetic research related to cardiovascular diseases conducted in this unique population1. It briefly describes the origins of the study, the risk factors that contribute to heart disease and the approaches taken to discover the genetic basis of some of these risk factors. The genetic architecture of several biological risk factors has been explained using family studies, segregation analysis, heritability, phenotypic and genetic correlations. Many quantitative trait loci underlying cardiovascular diseases have been discovered using different molecular markers. Additionally, results from genome-wide association studies using 100,000 markers, and the prospects of using 550,000 markers for association studies are presented. Finally, the use of this unique sample in genotype and environment interaction is described. PMID:19010253

[The forecast of illicit drug use in adolescents with addictive behavior: personality traits and the level of genetic risk of substance dependence.

PubMed

Yakovlev, A N; Brodyansky, V M; Schurina, A V; Romashkin, R A; Kibitov, A O

2016-01-01

To clarify the psychological mechanism underlying the genetic risk of substance addiction at the first stage of drug use by adolescents. Genetic risk was evaluated by genotyping of 5 polymorphisms of the dopaminergic system genes (dopamine receptor D2 and D4 genes and tyrosine hydroxylase gene). Psychological testing was performed using the Russian version of Temperament and Character Inventory (TCI-125). Seventy-five adolescents, aged 14-17 years, (girls 32%), who misused alcohol, including 22 adolescents using drugs, were examined. The level of genetic risk was directly correlated with the probability of drug use by boys, for girls the correlation was not confirmed. The increase of the level of genetic risk for boys was correlated with the increase on the scale «Self-directedness» of TCI-125 that may reflect a probable tendency to replacement of negative information, feeling of illusory wellbeing. The findings clarify the direction of measures for the prevention of drug use.

Genetic Risk Score for Essential Hypertension and Risk of Preeclampsia.

PubMed

Smith, Caitlin J; Saftlas, Audrey F; Spracklen, Cassandra N; Triche, Elizabeth W; Bjonnes, Andrew; Keating, Brendan; Saxena, Richa; Breheny, Patrick J; Dewan, Andrew T; Robinson, Jennifer G; Hoh, Josephine; Ryckman, Kelli K

2016-01-01

Preeclampsia is a hypertensive complication of pregnancy characterized by novel onset of hypertension after 20 weeks gestation, accompanied by proteinuria. Epidemiological evidence suggests that genetic susceptibility exists for preeclampsia; however, whether preeclampsia is the result of underlying genetic risk for essential hypertension has yet to be investigated. Based on the hypertensive state that is characteristic of preeclampsia, we aimed to determine if established genetic risk scores (GRSs) for hypertension and blood pressure are associated with preeclampsia. Subjects consisted of 162 preeclamptic cases and 108 normotensive pregnant controls, all of Iowa residence. Subjects' DNA was extracted from buccal swab samples and genotyped on the Affymetrix Genome-wide Human SNP Array 6.0 (Affymetrix, Santa Clara, CA). Missing genotypes were imputed using MaCH and Minimac software. GRSs were calculated for hypertension, systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) using established genetic risk loci for each outcome. Regression analyses were performed to determine the association between GRS and risk of preeclampsia. These analyses were replicated in an independent US population of 516 cases and 1,097 controls of European ancestry. GRSs for hypertension, SBP, DBP, and MAP were not significantly associated with risk for preeclampsia (P > 0.189). The results of the replication analysis also yielded nonsignificant associations. GRSs for hypertension and blood pressure are not associated with preeclampsia, suggesting that an underlying predisposition to essential hypertension is not on the causal pathway of preeclampsia. © American Journal of Hypertension, Ltd 2015. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Post-GWAS in Psychiatric Genetics: A Developmental Perspective on the "Other" Next Steps.

PubMed

Dick, Danielle M; Barr, Peter B; Cho, Seung Bin; Cooke, Megan E; Kuo, Sally I-Chun; Lewis, Tenesha J; Neale, Zoe; Salvatore, Jessica E; Savage, Jeanne; Su, Jinni

2018-03-01

As psychiatric genetics enters an era where gene identification is finally yielding robust, replicable genetic associations and polygenic risk scores, it is important to consider next steps and delineate how that knowledge will be applied to ultimately ameliorate suffering associated with substance use and psychiatric disorders. Much of the post-genome-wide association study discussion has focused on the potential of genetic information to elucidate the underlying biology and use this information for the development of more effective pharmaceutical treatments. In this review we focus on additional areas of research that should follow gene identification. By taking genetic findings into longitudinal, developmental studies, we can map the pathways by which genetic risk manifests across development, elucidating the early behavioral manifestations of risk, and studying how various environments and interventions moderate that risk across developmental stages. The delineation of risk across development will advance our understanding of mechanism, sex differences and risk and resilience processes in different racial/ethnic groups. Here, we review how the extant twin study literature can be used to guide these efforts. Together, these new lines of research will enable us to develop more informed, tailored prevention and intervention efforts. © 2017 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Genetic Counselors' Experiences Regarding Communication of Reproductive Risks with Autosomal Recessive Conditions found on Cancer Panels.

PubMed

Mets, Sarah; Tryon, Rebecca; Veach, Patricia McCarthy; Zierhut, Heather A

2016-04-01

The development of hereditary cancer genetic testing panels has altered genetic counseling practice. Mutations within certain genes on cancer panels pose not only a cancer risk, but also a reproductive risk for autosomal recessive conditions such as Fanconi anemia, constitutional mismatch repair deficiency syndrome, and ataxia telangiectasia. This study aimed to determine if genetic counselors discuss reproductive risks for autosomal recessive conditions associated with genes included on cancer panels, and if so, under what circumstances these risks are discussed. An on-line survey was emailed through the NSGC list-serv. The survey assessed 189 cancer genetic counselors' experiences discussing reproductive risks with patients at risk to carry a mutation or variant of uncertain significance (VUS) in a gene associated with both an autosomal dominant cancer risk and an autosomal recessive syndrome. Over half (n = 82, 55 %) reported having discussed reproductive risks; the remainder (n = 66, 45 %) had not. Genetic counselors who reported discussing reproductive risks primarily did so when patients had a positive result and were of reproductive age. Reasons for not discussing these risks included when a patient had completed childbearing or when a VUS was identified. Most counselors discussed reproductive risk after obtaining results and not during the informed consent process. There is inconsistency as to if and when the discussion of reproductive risks is taking place. The wide variation in responses suggests a need to develop professional guidelines for when and how discussions of reproductive risk for autosomal recessive conditions identified through cancer panels should occur with patients.

Serotonin Transporter Gene-Linked Polymorphic Region (5-HTTLPR) Influences Decision Making under Ambiguity and Risk in a Large Chinese Sample

PubMed Central

He, Qinghua; Xue, Gui; Chen, Chuansheng; Lu, Zhonglin; Dong, Qi; Lei, Xuemei; Ding, Ni; Li, Jin; Li, He; Chen, Chunhui; Li, Jun; Moyzis, Robert K.; Bechara, Antoine

2010-01-01

Risky decision-making is a complex process that involves weighing the probabilities of alternative options that can be desirable, undesirable, or neutral. Individuals vary greatly in how they make decisions either under ambiguity and/or under risk. Such individual differences may have genetic bases. Based on previous studies on the genetic basis of decision making, two decision making tasks [i.e., Iowa Gambling Task (IGT) and Loss Aversion Task (LAT)] were used to test the effect of 5-HTTLPR polymorphism on decision making under ambiguity and under risk in a large Han Chinese sample (572 college students, 312 females). Basic intelligence and memory tests were also included to control for the influence of basic cognitive abilities on decision making. We found that 5-HTTLPR polymorphism significantly influenced performance in both IGT and LAT. After controlling for intellectual and memory abilities, subjects homozygous for s allele had lower IGT scores than l carriers in the first 40 trials of the IGT task. They also exhibited higher loss aversion than l carriers in the LAT task. Moreover, the effects of 5-HTTLPR were stronger for males than for females. These results extend the literature on the important role of emotion in decision under ambiguity and risk, and provide additional lights on how decision-making is influenced by culture as well as sex differences. Combining our results with existing literature, we propose that these effects might be mediated by a neural circuitry that comprises the amygdala, ventromedial prefrontal cortex, and insular cortex. Understanding the genetic factors affecting decision in healthy subjects may allow us better identify at-risk individuals, and target better the development of new potential treatments for specific disorders such as schizophrenia, addiction, and depression. PMID:20659488

White matter hyperintensities and vascular risk factors in monozygotic twins.

PubMed

Ten Kate, Mara; Sudre, Carole H; den Braber, Anouk; Konijnenberg, Elles; Nivard, Michel G; Cardoso, M Jorge; Scheltens, Philip; Ourselin, Sébastien; Boomsma, Dorret I; Barkhof, Frederik; Visser, Pieter Jelle

2018-06-01

Cerebral white matter hyperintensities (WMHs) have been associated with vascular risk factors, both of which are under genetic influence. We examined in a monozygotic twin sample whether the association between vascular risk and WMHs is influenced by overlapping genetic factors. We included 195 cognitively normal monozygotic twins (age = 70 ± 7 years), including 94 complete pairs. Regional WMH load was estimated using an automated algorithm. Vascular risk was summarized with the Framingham score. The within-twin pair correlation for total WMHs was 0.76 and for Framingham score was 0.77. Within participants, Framingham score was associated with total and periventricular WMHs (r = 0.32). Framingham score in 1 twin was also associated with total WMHs in the co-twin (r = 0.26). Up to 83% of the relation between both traits could be explained by shared genetic effects. In conclusion, monozygotic twins have highly similar vascular risk and WMH burden, confirming a genetic background for these traits. The association between both traits is largely driven by overlapping genetic factors. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Genetic research: who is at risk for alcoholism.

PubMed

Foroud, Tatiana; Edenberg, Howard J; Crabbe, John C

2010-01-01

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) was founded 40 years ago to help elucidate the biological underpinnings of alcohol dependence, including the potential contribution of genetic factors. Twin, adoption, and family studies conclusively demonstrated that genetic factors account for 50 to 60 percent of the variance in risk for developing alcoholism. Case-control studies and linkage analyses have helped identify DNA variants that contribute to increased risk, and the NIAAA-sponsored Collaborative Studies on Genetics of Alcoholism (COGA) has the expressed goal of identifying contributing genes using state-of-the-art genetic technologies. These efforts have ascertained several genes that may contribute to an increased risk of alcoholism, including certain variants encoding alcohol-metabolizing enzymes and neurotransmitter receptors. Genome-wide association studies allowing the analysis of millions of genetic markers located throughout the genome will enable discovery of further candidate genes. In addition to these human studies, genetic animal models of alcohol's effects and alcohol use have greatly advanced our understanding of the genetic basis of alcoholism, resulting in the identification of quantitative trait loci and allowing for targeted manipulation of candidate genes. Novel research approaches-for example, into epigenetic mechanisms of gene regulation-also are under way and undoubtedly will further clarify the genetic basis of alcoholism.

Genetic Association and Risk Scores in a Chronic Obstructive Pulmonary Disease Meta-analysis of 16,707 Subjects.

PubMed

Busch, Robert; Hobbs, Brian D; Zhou, Jin; Castaldi, Peter J; McGeachie, Michael J; Hardin, Megan E; Hawrylkiewicz, Iwona; Sliwinski, Pawel; Yim, Jae-Joon; Kim, Woo Jin; Kim, Deog K; Agusti, Alvar; Make, Barry J; Crapo, James D; Calverley, Peter M; Donner, Claudio F; Lomas, David A; Wouters, Emiel F; Vestbo, Jørgen; Tal-Singer, Ruth; Bakke, Per; Gulsvik, Amund; Litonjua, Augusto A; Sparrow, David; Paré, Peter D; Levy, Robert D; Rennard, Stephen I; Beaty, Terri H; Hokanson, John; Silverman, Edwin K; Cho, Michael H

2017-07-01

The heritability of chronic obstructive pulmonary disease (COPD) cannot be fully explained by recognized genetic risk factors identified as achieving genome-wide significance. In addition, the combined contribution of genetic variation to COPD risk has not been fully explored. We sought to determine: (1) whether studies of variants from previous studies of COPD or lung function in a larger sample could identify additional associated variants, particularly for severe COPD; and (2) the impact of genetic risk scores on COPD. We genotyped 3,346 single-nucleotide polymorphisms (SNPs) in 2,588 cases (1,803 severe COPD) and 1,782 control subjects from four cohorts, and performed association testing with COPD, combining these results with existing genotyping data from 6,633 cases (3,497 severe COPD) and 5,704 control subjects. In addition, we developed genetic risk scores from SNPs associated with lung function and COPD and tested their discriminatory power for COPD-related measures. We identified significant associations between SNPs near PPIC (P = 1.28 × 10 -8 ) and PPP4R4/SERPINA1 (P = 1.01 × 10 -8 ) and severe COPD; the latter association may be driven by recognized variants in SERPINA1. Genetic risk scores based on SNPs previously associated with COPD and lung function had a modest ability to discriminate COPD (area under the curve, ∼0.6), and accounted for a mean 0.9-1.9% lower forced expiratory volume in 1 second percent predicted for each additional risk allele. In a large genetic association analysis, we identified associations with severe COPD near PPIC and SERPINA1. A risk score based on combining genetic variants had modest, but significant, effects on risk of COPD and lung function.

A Model of Compound Heterozygous, Loss-of-Function Alleles Is Broadly Consistent with Observations from Complex-Disease GWAS Datasets

PubMed Central

Sanjak, Jaleal S.; Long, Anthony D.; Thornton, Kevin R.

2017-01-01

The genetic component of complex disease risk in humans remains largely unexplained. A corollary is that the allelic spectrum of genetic variants contributing to complex disease risk is unknown. Theoretical models that relate population genetic processes to the maintenance of genetic variation for quantitative traits may suggest profitable avenues for future experimental design. Here we use forward simulation to model a genomic region evolving under a balance between recurrent deleterious mutation and Gaussian stabilizing selection. We consider multiple genetic and demographic models, and several different methods for identifying genomic regions harboring variants associated with complex disease risk. We demonstrate that the model of gene action, relating genotype to phenotype, has a qualitative effect on several relevant aspects of the population genetic architecture of a complex trait. In particular, the genetic model impacts genetic variance component partitioning across the allele frequency spectrum and the power of statistical tests. Models with partial recessivity closely match the minor allele frequency distribution of significant hits from empirical genome-wide association studies without requiring homozygous effect sizes to be small. We highlight a particular gene-based model of incomplete recessivity that is appealing from first principles. Under that model, deleterious mutations in a genomic region partially fail to complement one another. This model of gene-based recessivity predicts the empirically observed inconsistency between twin and SNP based estimated of dominance heritability. Furthermore, this model predicts considerable levels of unexplained variance associated with intralocus epistasis. Our results suggest a need for improved statistical tools for region based genetic association and heritability estimation. PMID:28103232

The impact of Alzheimer disease genetics on expert and advanced gerontological nursing practice.

PubMed

Schutte, D L

1998-11-01

Alzheimer disease (AD), a progressive neurodegenerative disorder, is the most common cause of dementia in the United States, affecting as many as 4 million people. Extensive research is under way to identify environmental and genetic risk factors for this complex disease. Currently, four genes are associated with an increased risk for AD: the amyloid precursor protein gene on chromosome 21, the Presenilin I gene on chromosome 14, the Presenilin II gene on chromosome 1, and the apolipoprotein E gene on chromosome 19. Expert and advanced practice gerontological nurses are faced with new challenges as a result of these gene discoveries. Gerontological nurses should assess for relevant environmental and genetic risk factors; obtain comprehensive family health histories recorded as pedigrees; integrate genetic information into diagnosis, intervention, and evaluation strategies; initiate and coordinate referrals to genetic specialists; and provide ongoing emotional and decision-making support for patients and families experiencing AD.

Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression.

PubMed

Wray, Naomi R; Ripke, Stephan; Mattheisen, Manuel; Trzaskowski, Maciej; Byrne, Enda M; Abdellaoui, Abdel; Adams, Mark J; Agerbo, Esben; Air, Tracy M; Andlauer, Till M F; Bacanu, Silviu-Alin; Bækvad-Hansen, Marie; Beekman, Aartjan F T; Bigdeli, Tim B; Binder, Elisabeth B; Blackwood, Douglas R H; Bryois, Julien; Buttenschøn, Henriette N; Bybjerg-Grauholm, Jonas; Cai, Na; Castelao, Enrique; Christensen, Jane Hvarregaard; Clarke, Toni-Kim; Coleman, Jonathan I R; Colodro-Conde, Lucía; Couvy-Duchesne, Baptiste; Craddock, Nick; Crawford, Gregory E; Crowley, Cheynna A; Dashti, Hassan S; Davies, Gail; Deary, Ian J; Degenhardt, Franziska; Derks, Eske M; Direk, Nese; Dolan, Conor V; Dunn, Erin C; Eley, Thalia C; Eriksson, Nicholas; Escott-Price, Valentina; Kiadeh, Farnush Hassan Farhadi; Finucane, Hilary K; Forstner, Andreas J; Frank, Josef; Gaspar, Héléna A; Gill, Michael; Giusti-Rodríguez, Paola; Goes, Fernando S; Gordon, Scott D; Grove, Jakob; Hall, Lynsey S; Hannon, Eilis; Hansen, Christine Søholm; Hansen, Thomas F; Herms, Stefan; Hickie, Ian B; Hoffmann, Per; Homuth, Georg; Horn, Carsten; Hottenga, Jouke-Jan; Hougaard, David M; Hu, Ming; Hyde, Craig L; Ising, Marcus; Jansen, Rick; Jin, Fulai; Jorgenson, Eric; Knowles, James A; Kohane, Isaac S; Kraft, Julia; Kretzschmar, Warren W; Krogh, Jesper; Kutalik, Zoltán; Lane, Jacqueline M; Li, Yihan; Li, Yun; Lind, Penelope A; Liu, Xiaoxiao; Lu, Leina; MacIntyre, Donald J; MacKinnon, Dean F; Maier, Robert M; Maier, Wolfgang; Marchini, Jonathan; Mbarek, Hamdi; McGrath, Patrick; McGuffin, Peter; Medland, Sarah E; Mehta, Divya; Middeldorp, Christel M; Mihailov, Evelin; Milaneschi, Yuri; Milani, Lili; Mill, Jonathan; Mondimore, Francis M; Montgomery, Grant W; Mostafavi, Sara; Mullins, Niamh; Nauck, Matthias; Ng, Bernard; Nivard, Michel G; Nyholt, Dale R; O'Reilly, Paul F; Oskarsson, Hogni; Owen, Michael J; Painter, Jodie N; Pedersen, Carsten Bøcker; Pedersen, Marianne Giørtz; Peterson, Roseann E; Pettersson, Erik; Peyrot, Wouter J; Pistis, Giorgio; Posthuma, Danielle; Purcell, Shaun M; Quiroz, Jorge A; Qvist, Per; Rice, John P; Riley, Brien P; Rivera, Margarita; Saeed Mirza, Saira; Saxena, Richa; Schoevers, Robert; Schulte, Eva C; Shen, Ling; Shi, Jianxin; Shyn, Stanley I; Sigurdsson, Engilbert; Sinnamon, Grant B C; Smit, Johannes H; Smith, Daniel J; Stefansson, Hreinn; Steinberg, Stacy; Stockmeier, Craig A; Streit, Fabian; Strohmaier, Jana; Tansey, Katherine E; Teismann, Henning; Teumer, Alexander; Thompson, Wesley; Thomson, Pippa A; Thorgeirsson, Thorgeir E; Tian, Chao; Traylor, Matthew; Treutlein, Jens; Trubetskoy, Vassily; Uitterlinden, André G; Umbricht, Daniel; Van der Auwera, Sandra; van Hemert, Albert M; Viktorin, Alexander; Visscher, Peter M; Wang, Yunpeng; Webb, Bradley T; Weinsheimer, Shantel Marie; Wellmann, Jürgen; Willemsen, Gonneke; Witt, Stephanie H; Wu, Yang; Xi, Hualin S; Yang, Jian; Zhang, Futao; Arolt, Volker; Baune, Bernhard T; Berger, Klaus; Boomsma, Dorret I; Cichon, Sven; Dannlowski, Udo; de Geus, E C J; DePaulo, J Raymond; Domenici, Enrico; Domschke, Katharina; Esko, Tõnu; Grabe, Hans J; Hamilton, Steven P; Hayward, Caroline; Heath, Andrew C; Hinds, David A; Kendler, Kenneth S; Kloiber, Stefan; Lewis, Glyn; Li, Qingqin S; Lucae, Susanne; Madden, Pamela F A; Magnusson, Patrik K; Martin, Nicholas G; McIntosh, Andrew M; Metspalu, Andres; Mors, Ole; Mortensen, Preben Bo; Müller-Myhsok, Bertram; Nordentoft, Merete; Nöthen, Markus M; O'Donovan, Michael C; Paciga, Sara A; Pedersen, Nancy L; Penninx, Brenda W J H; Perlis, Roy H; Porteous, David J; Potash, James B; Preisig, Martin; Rietschel, Marcella; Schaefer, Catherine; Schulze, Thomas G; Smoller, Jordan W; Stefansson, Kari; Tiemeier, Henning; Uher, Rudolf; Völzke, Henry; Weissman, Myrna M; Werge, Thomas; Winslow, Ashley R; Lewis, Cathryn M; Levinson, Douglas F; Breen, Gerome; Børglum, Anders D; Sullivan, Patrick F

2018-05-01

Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype.

When to Consider Risk-Reducing Mastectomy in BRCA1/BRCA2 Mutation Carriers with Advanced Stage Ovarian Cancer: a Case Study Illustrating the Genetic Counseling Challenges.

PubMed

Speight, Beverley; Tischkowitz, Marc

2017-12-01

Germline mutations in BRCA1/BRCA2 significantly increase the risk of breast and ovarian cancer in women. This case report describes a BRCA1 germline mutation identified in a woman with stage IV epithelial ovarian cancer and the provision of genetic counseling about BRCA1-associated breast cancer risk in the three years following diagnosis. The report centers on the patient's enquiry about risk-reducing breast surgery. We focus on the challenges for health professionals and patients in understanding and balancing the risks and benefits of major prophylactic surgery in the context of a potentially life-limiting cancer diagnosis. Breast cancer risk management in BRCA1/BRCA2 carriers with advanced ovarian cancer is an under-explored area of genetic counseling research. This article includes a case report, a review of the relevant literature and considers some implications for practice.

Predicting type 2 diabetes using genetic and environmental risk factors in a multi-ethnic Malaysian cohort.

PubMed

Abdullah, N; Abdul Murad, N A; Mohd Haniff, E A; Syafruddin, S E; Attia, J; Oldmeadow, C; Kamaruddin, M A; Abd Jalal, N; Ismail, N; Ishak, M; Jamal, R; Scott, R J; Holliday, E G

2017-08-01

Malaysia has a high and rising prevalence of type 2 diabetes (T2D). While environmental (non-genetic) risk factors for the disease are well established, the role of genetic variations and gene-environment interactions remain understudied in this population. This study aimed to estimate the relative contributions of environmental and genetic risk factors to T2D in Malaysia and also to assess evidence for gene-environment interactions that may explain additional risk variation. This was a case-control study including 1604 Malays, 1654 Chinese and 1728 Indians from the Malaysian Cohort Project. The proportion of T2D risk variance explained by known genetic and environmental factors was assessed by fitting multivariable logistic regression models and evaluating McFadden's pseudo R 2 and the area under the receiver-operating characteristic curve (AUC). Models with and without the genetic risk score (GRS) were compared using the log likelihood ratio Chi-squared test and AUCs. Multiplicative interaction between genetic and environmental risk factors was assessed via logistic regression within and across ancestral groups. Interactions were assessed for the GRS and its 62 constituent variants. The models including environmental risk factors only had pseudo R 2 values of 16.5-28.3% and AUC of 0.75-0.83. Incorporating a genetic score aggregating 62 T2D-associated risk variants significantly increased the model fit (likelihood ratio P-value of 2.50 × 10 -4 -4.83 × 10 -12 ) and increased the pseudo R 2 by about 1-2% and AUC by 1-3%. None of the gene-environment interactions reached significance after multiple testing adjustment, either for the GRS or individual variants. For individual variants, 33 out of 310 tested associations showed nominal statistical significance with 0.001 < P < 0.05. This study suggests that known genetic risk variants contribute a significant but small amount to overall T2D risk variation in Malaysian population groups. If gene-environment interactions involving common genetic variants exist, they are likely of small effect, requiring substantially larger samples for detection. Copyright © 2017 The Royal Society for Public Health. All rights reserved.

Convergent synaptic and circuit substrates underlying autism genetic risks.

PubMed

McGee, Aaron; Li, Guohui; Lu, Zhongming; Qiu, Shenfeng

2014-02-01

There has been a surge of diagnosis of autism spectrum disorders (ASD) over the past decade. While large, high powered genome screening studies of children with ASD have identified numerous genetic risk factors, research efforts to understanding how each of these risk factors contributes to the development autism has met with limited success. Revealing the mechanisms by which these genetic risk factors affect brain development and predispose a child to autism requires mechanistic understanding of the neurobiological changes underlying this devastating group of developmental disorders at multifaceted molecular, cellular and system levels. It has been increasingly clear that the normal trajectory of neurodevelopment is compromised in autism, in multiple domains as much as aberrant neuronal production, growth, functional maturation, patterned connectivity, and balanced excitation and inhibition of brain networks. Many autism risk factors identified in humans have been now reconstituted in experimental mouse models to allow mechanistic interrogation of the biological role of the risk gene. Studies utilizing these mouse models have revealed that underlying the enormous heterogeneity of perturbed cellular events, mechanisms directing synaptic and circuit assembly may provide a unifying explanation for the pathophysiological changes and behavioral endophenotypes seen in autism, although synaptic perturbations are far from being the only alterations relevant for ASD. In this review, we discuss synaptic and circuit abnormalities obtained from several prevalent mouse models, particularly those reflecting syndromic forms of ASD that are caused by single gene perturbations. These compiled results reveal that ASD risk genes contribute to proper signaling of the developing gene networks that maintain synaptic and circuit homeostasis, which is fundamental to normal brain development.

QUANTITATIVE CANCER RISK ASSESSMENT METHODOLOGY USING SHORT-TERM GENETIC BIOASSAYS: THE COMPARATIVE POTENCY METHOD

EPA Science Inventory

Quantitative risk assessment is fraught with many uncertainties. The validity of the assumptions underlying the methods employed are often difficult to test or validate. Cancer risk assessment has generally employed either human epidemiological data from relatively high occupatio...

Estimating the risks of cancer mortality and genetic defects resulting from exposures to low levels of ionizing radiation

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

Buhl, T.E.; Hansen, W.R.

1984-05-01

Estimators for calculating the risk of cancer and genetic disorders induced by exposure to ionizing radiation have been recommended by the US National Academy of Sciences Committee on the Biological Effects of Ionizing Radiations, the UN Scientific Committee on the Effects of Atomic Radiation, and the International Committee on Radiological Protection. These groups have also considered the risks of somatic effects other than cancer. The US National Council on Radiation Protection and Measurements has discussed risk estimate procedures for radiation-induced health effects. The recommendations of these national and international advisory committees are summarized and compared in this report. Based onmore » this review, two procedures for risk estimation are presented for use in radiological assessments performed by the US Department of Energy under the National Environmental Policy Act of 1969 (NEPA). In the first procedure, age- and sex-averaged risk estimators calculated with US average demographic statistics would be used with estimates of radiation dose to calculate the projected risk of cancer and genetic disorders that would result from the operation being reviewed under NEPA. If more site-specific risk estimators are needed, and the demographic information is available, a second procedure is described that would involve direct calculation of the risk estimators using recommended risk-rate factors. The computer program REPCAL has been written to perform this calculation and is described in this report. 25 references, 16 tables.« less

Nature Versus Nurture: Does Proteostasis Imbalance Underlie the Genetic, Environmental, and Age-Related Risk Factors for Alzheimer's Disease?

PubMed

Kikis, Elise A

2017-08-22

Aging is a risk factor for a number of "age-related diseases", including Alzheimer's disease (AD). AD affects more than a third of all people over the age of 85, and is the leading cause of dementia worldwide. Symptoms include forgetfulness, memory loss, and cognitive decline, ultimately resulting in the need for full-time care. While there is no cure for AD, pharmacological approaches to alleviate symptoms and target underlying causes of the disease have been developed, albeit with limited success. This review presents the age-related, genetic, and environmental risk factors for AD and proposes a hypothesis for the mechanistic link between genetics and the environment. In short, much is known about the genetics of early-onset familial AD (EO-FAD) and the central role played by the Aβ peptide and protein misfolding, but late-onset AD (LOAD) is not thought to have direct genetic causes. Nonetheless, genetic risk factors such as isoforms of the protein ApoE have been identified. Additional findings suggest that air pollution caused by the combustion of fossil fuels may be an important environmental risk factor for AD. A hypothesis suggesting that poor air quality might act by disrupting protein folding homeostasis (proteostasis) is presented.

Hereditary melanoma and predictive genetic testing: why not?

PubMed

Riedijk, S R; de Snoo, F A; van Dijk, S; Bergman, W; van Haeringen, A; Silberg, S; van Elderen, T M T; Tibben, A

2005-09-01

Since p16-Leiden presymptomatic testing for hereditary melanoma has become available in the Netherlands, the benefits and risks of offering such testing are evaluated. The current paper investigated why the non-participants were reluctant to participate in genetic testing. Sixty six eligible individuals, who were knowledgeable about the test but had not participated in genetic testing by January 2003, completed a self-report questionnaire assessing motivation, anxiety, family dynamics, risk knowledge and causal attributions. Non-participants reported anxiety levels below clinical significance. A principal components analysis on reasons for non-participation distinguished two underlying motives: emotional and rational motivation. Rational motivation for non-participation was associated with more accurate risk knowledge, the inclination to preselect mutation carriers within the family and lower scores on anxiety. Emotional motivation for non-participation was associated with disease misperceptions, hesitation to communicate unfavourable test results within the family and higher scores on anxiety. Rational and emotional motivation for non-participation in the genetic test for hereditary melanoma was found. Emotionally motivated individuals may be reluctant to disseminate genetic risk information. Rationally motivated individuals were better informed than emotionally motivated individuals. It is suggested that a leaflet is added to the invitation letter to enhance informed decision-making about genetic testing.

[Genetic factors in myocardial infarction].

PubMed

Hara, Masahiko; Sakata, Yasuhiko; Sato, Hiroshi

2013-02-01

One of the main mechanisms of acute myocardial infarction (AMI) is plaque rupture or erosion followed by intraluminal thrombus formation and occlusion of the coronary arteries. Thus far, many underlying conditions or environmental factors, such as hypertension, diabetes, dyslipidemia, smoking or obesity, as well as a family history of coronary artery diseases have been identified as risks for the onset of AMI. These risks suggest that AMI occurs due to interactions between underlying conditions and multiple genetic susceptibilities. For this reason, many target gene-disease association studies have been performed with the recent introduction of genome-wide association studies (GWAS) that have further revealed new genetic susceptibilities for AMI. GWAS is a way to examine many common genetic variants in different individuals to see if any variant is associated with a trait in a case-control fashion, and typically focuses on associations between single-nucleotide polymorphisms (SNP) and traits. SNP on chromosome 9p21 is one of the robust susceptibility variants for AMI which has been identified by many GWAS. In this review, we overview the methodology of GWAS, introduce genetic variants identified by GWAS as those with susceptibility for AMI, and describe the foresight of using GWAS to investigate genetic susceptibility to AMI.

Basal cell carcinoma of the skin (part 1): epidemiology, pathology and genetic syndromes.

PubMed

Correia de Sá, Tiago Ribeiro; Silva, Roberto; Lopes, José Manuel

2015-11-01

Basal cell carcinoma (BCC) is the most common skin cancer worldwide with increasing incidence, but difficult to assess due to the current under registration practice. Despite the low mortality rate, BCC is a cause of great morbidity and an economic burden to health services. There are several risk factors that increase the risk of BCC and partly explain its incidence. Low-penetrance susceptibility alleles, as well as genetic alterations in signaling pathways, namely SHH pathway, also contribute to the carcinogenesis. BCC associate with several genetic syndromes, of which basal cell nevus syndrome is the most common.

Exertional rhabdomyolysis: physiological response or manifestation of an underlying myopathy?

PubMed Central

Scalco, Renata S; Snoeck, Marc; Quinlivan, Ros; Treves, Susan; Laforét, Pascal; Jungbluth, Heinz; Voermans, Nicol C

2016-01-01

Exertional rhabdomyolysis is characterised by muscle breakdown associated with strenuous exercise or normal exercise under extreme circumstances. Key features are severe muscle pain and sudden transient elevation of serum creatine kinase (CK) levels with or without associated myoglobinuria. Mild cases may remain unnoticed or undiagnosed. Exertional rhabdomyolysis is well described among athletes and military personnel, but may occur in anybody exposed to unaccustomed exercise. In contrast, exertional rhabdomyolysis may be the first manifestation of a genetic muscle disease that lowers the exercise threshold for developing muscle breakdown. Repeated episodes of exertional rhabdomyolysis should raise the suspicion of such an underlying disorder, in particular in individuals in whom the severity of the rhabdomyolysis episodes exceeds the expected response to the exercise performed. The present review aims to provide a practical guideline for the acute management and postepisode counselling of patients with exertional rhabdomyolysis, with a particular emphasis on when to suspect an underlying genetic disorder. The pathophysiology and its clinical features are reviewed, emphasising four main stepwise approaches: (1) the clinical significance of an acute episode, (2) risks of renal impairment, (3) clinical indicators of an underlying genetic disorders and (4) when and how to recommence sport activity following an acute episode of rhabdomyolysis. Genetic backgrounds that appear to be associated with both enhanced athletic performance and increased rhabdomyolysis risk are briefly reviewed. PMID:27900193

Genetically determined height and coronary artery disease.

PubMed

Nelson, Christopher P; Hamby, Stephen E; Saleheen, Danish; Hopewell, Jenna C; Zeng, Lingyao; Assimes, Themistocles L; Kanoni, Stavroula; Willenborg, Christina; Burgess, Stephen; Amouyel, Phillipe; Anand, Sonia; Blankenberg, Stefan; Boehm, Bernhard O; Clarke, Robert J; Collins, Rory; Dedoussis, George; Farrall, Martin; Franks, Paul W; Groop, Leif; Hall, Alistair S; Hamsten, Anders; Hengstenberg, Christian; Hovingh, G Kees; Ingelsson, Erik; Kathiresan, Sekar; Kee, Frank; König, Inke R; Kooner, Jaspal; Lehtimäki, Terho; März, Winifred; McPherson, Ruth; Metspalu, Andres; Nieminen, Markku S; O'Donnell, Christopher J; Palmer, Colin N A; Peters, Annette; Perola, Markus; Reilly, Muredach P; Ripatti, Samuli; Roberts, Robert; Salomaa, Veikko; Shah, Svati H; Schreiber, Stefan; Siegbahn, Agneta; Thorsteinsdottir, Unnur; Veronesi, Giovani; Wareham, Nicholas; Willer, Cristen J; Zalloua, Pierre A; Erdmann, Jeanette; Deloukas, Panos; Watkins, Hugh; Schunkert, Heribert; Danesh, John; Thompson, John R; Samani, Nilesh J

2015-04-23

The nature and underlying mechanisms of an inverse association between adult height and the risk of coronary artery disease (CAD) are unclear. We used a genetic approach to investigate the association between height and CAD, using 180 height-associated genetic variants. We tested the association between a change in genetically determined height of 1 SD (6.5 cm) with the risk of CAD in 65,066 cases and 128,383 controls. Using individual-level genotype data from 18,249 persons, we also examined the risk of CAD associated with the presence of various numbers of height-associated alleles. To identify putative mechanisms, we analyzed whether genetically determined height was associated with known cardiovascular risk factors and performed a pathway analysis of the height-associated genes. We observed a relative increase of 13.5% (95% confidence interval [CI], 5.4 to 22.1; P<0.001) in the risk of CAD per 1-SD decrease in genetically determined height. There was a graded relationship between the presence of an increased number of height-raising variants and a reduced risk of CAD (odds ratio for height quartile 4 versus quartile 1, 0.74; 95% CI, 0.68 to 0.84; P<0.001). Of the 12 risk factors that we studied, we observed significant associations only with levels of low-density lipoprotein cholesterol and triglycerides (accounting for approximately 30% of the association). We identified several overlapping pathways involving genes associated with both development and atherosclerosis. There is a primary association between a genetically determined shorter height and an increased risk of CAD, a link that is partly explained by the association between shorter height and an adverse lipid profile. Shared biologic processes that determine achieved height and the development of atherosclerosis may explain some of the association. (Funded by the British Heart Foundation and others.).

Shared additive genetic influences on DSM-IV criteria for alcohol dependence in subjects of European ancestry.

PubMed

Palmer, Rohan H C; McGeary, John E; Heath, Andrew C; Keller, Matthew C; Brick, Leslie A; Knopik, Valerie S

2015-12-01

Genetic studies of alcohol dependence (AD) have identified several candidate loci and genes, but most observed effects are small and difficult to reproduce. A plausible explanation for inconsistent findings may be a violation of the assumption that genetic factors contributing to each of the seven DSM-IV criteria point to a single underlying dimension of risk. Given that recent twin studies suggest that the genetic architecture of AD is complex and probably involves multiple discrete genetic factors, the current study employed common single nucleotide polymorphisms in two multivariate genetic models to examine the assumption that the genetic risk underlying DSM-IV AD is unitary. AD symptoms and genome-wide single nucleotide polymorphism (SNP) data from 2596 individuals of European descent from the Study of Addiction: Genetics and Environment were analyzed using genomic-relatedness-matrix restricted maximum likelihood. DSM-IV AD symptom covariance was described using two multivariate genetic factor models. Common SNPs explained 30% (standard error=0.136, P=0.012) of the variance in AD diagnosis. Additive genetic effects varied across AD symptoms. The common pathway model approach suggested that symptoms could be described by a single latent variable that had a SNP heritability of 31% (0.130, P=0.008). Similarly, the exploratory genetic factor model approach suggested that the genetic variance/covariance across symptoms could be represented by a single genetic factor that accounted for at least 60% of the genetic variance in any one symptom. Additive genetic effects on DSM-IV alcohol dependence criteria overlap. The assumption of common genetic effects across alcohol dependence symptoms appears to be a valid assumption. © 2015 Society for the Study of Addiction.

Association between genetic polymorphisms of interleukins and cerebral infarction risk: a meta-analysis

PubMed Central

Wang, Jiantao; Fan, Niannian; Deng, Yili; Zhu, Jie; Mei, Jing; Chen, Yao; Yang, Heng

2016-01-01

Interleukins (ILs) are the most typical inflammatory and immunoregulatory cytokines. Evidences have shown that polymorphisms in ILs are associated with cerebral infarction risk. However, the results remain inconclusive. The present study was to evaluate the role of ILs polymorphisms in cerebral infarction susceptibility. Relevant case-control studies published between January 2000 and December 2015 were searched and retrieved from the electronic databases of Web of Science, PubMed, Embase and the Chinese Biomedical Database. The odds ratio (OR) with its 95% confidence interval (CI) were employed to calculate the strength of association. A total of 55 articles including 12619 cerebral infarction patients and 14436 controls were screened out. Four ILs (IL-1, IL-6, IL-10 and IL-18) contained nine single nucleotide polymorphisms (SNPs; IL-1α −899C/T, IL-1β −511C/T and IL-1β +3953C/T; IL-6 −174G/C and −572C/G; IL-10 −819C/T and −1082A/G; IL-18 −607C/A and −137G/C). Our result showed that IL-1α −899C/T and IL-18 −607C/A (under all the genetic models), and IL-6 −572C/G (under the allelic model, heterogeneity model and dominant model) were associated with increased the risk of cerebral infarction (P<0.05). Subgroup analysis by ethnicity showed that IL-6 −174G/C polymorphism (under all the five models) and IL-10 −1082A/G polymorphism (under the allelic model and heterologous model) were significantly associated with increased the cerebral infarction risk in Asians. Other genetic polymorphisms were not related with cerebral infarction susceptibility under any genetic models. In conclusion, IL-1α −899C/T, IL-6 −572C/G and IL-18 −607C/A might be risk factors for cerebral infarction development. Further studies with well-designed and large sample size are still required. PMID:27679860

Association between stressful life events and psychotic experiences in adolescence: evidence for gene-environment correlations.

PubMed

Shakoor, Sania; Zavos, Helena M S; Haworth, Claire M A; McGuire, Phillip; Cardno, Alastair G; Freeman, Daniel; Ronald, Angelica

2016-06-01

Stressful life events (SLEs) are associated with psychotic experiences. SLEs might act as an environmental risk factor, but may also share a genetic propensity with psychotic experiences. To estimate the extent to which genetic and environmental factors influence the relationship between SLEs and psychotic experiences. Self- and parent reports from a community-based twin sample (4830 16-year-old pairs) were analysed using structural equation model fitting. SLEs correlated with positive psychotic experiences (r = 0.12-0.14, all P<0.001). Modest heritability was shown for psychotic experiences (25-57%) and dependent SLEs (32%). Genetic influences explained the majority of the modest covariation between dependent SLEs and paranoia and cognitive disorganisation (bivariate heritabilities 74-86%). The relationship between SLEs and hallucinations and grandiosity was explained by both genetic and common environmental effects. Further to dependent SLEs being an environmental risk factor, individuals may have an underlying genetic propensity increasing their risk of dependent SLEs and positive psychotic experiences. © The Royal College of Psychiatrists 2016.

Clinical endpoints for developing pharmaceuticals to manage patients with sporadic or genetic risk of colorectal cancer

PubMed Central

Rial, Nathaniel S.; Zell, Jason A.; Cohen, Alfred M.; Gerner, Eugene W.

2013-01-01

To reduce the morbidity and mortality from colorectal cancer, current clinical practice focuses on screening for early detection and polypectomy as a form of secondary prevention, complemented with surgical interventions when appropriate. No pharmaceutical agent is currently approved for use in clinical practice for the management of patients with risk of colorectal cancer. This article will review earlier attempts to develop pharmaceuticals for use in managing patients with sporadic or genetic risk of colorectal cancer. It will also discuss therapeutic endpoints under evaluation in current efforts to develop drugs for treating colorectal cancer risk factors. PMID:22928902

The value of genetic information for diabetes risk prediction - differences according to sex, age, family history and obesity.

PubMed

Mühlenbruch, Kristin; Jeppesen, Charlotte; Joost, Hans-Georg; Boeing, Heiner; Schulze, Matthias B

2013-01-01

Genome-wide association studies have identified numerous single nucleotide polymorphisms associated with type 2 diabetes through the past years. In previous studies, the usefulness of these genetic markers for prediction of diabetes was found to be limited. However, differences may exist between substrata of the population according to the presence of major diabetes risk factors. This study aimed to investigate the added predictive value of genetic information (42 single nucleotide polymorphisms) in subgroups of sex, age, family history of diabetes, and obesity. A case-cohort study (random subcohort N = 1,968; incident cases: N = 578) within the European Prospective Investigation into Cancer and Nutrition Potsdam study was used. Prediction models without and with genetic information were evaluated in terms of the area under the receiver operating characteristic curve and the integrated discrimination improvement. Stratified analyses included subgroups of sex, age (<50 or ≥50 years), family history (positive if either father or mother or a sibling has/had diabetes), and obesity (BMI< or ≥30 kg/m(2)). A genetic risk score did not improve prediction above classic and metabolic markers, but - compared to a non-invasive prediction model - genetic information slightly improved the area under the receiver operating characteristic curve (difference [95%-CI]: 0.007 [0.002-0.011]). Stratified analyses showed stronger improvement in the older age group (0.010 [0.002-0.018]), the group with a positive family history (0.012 [0.000-0.023]) and among obese participants (0.015 [-0.005-0.034]) compared to the younger participants (0.005 [-0.004-0.014]), participants with a negative family history (0.003 [-0.001-0.008]) and non-obese (0.007 [0.000-0.014]), respectively. No difference was found between men and women. There was no incremental value of genetic information compared to standard non-invasive and metabolic markers. Our study suggests that inclusion of genetic variants in diabetes risk prediction might be useful for subgroups with already manifest risk factors such as older age, a positive family history and obesity.

New Insights on the Risk for Cardiovascular Disease in African Americans: The Role of Added Sugars

PubMed Central

Saab, Karim R.; Kendrick, Jessica; Yracheta, Joseph M.; Lanaspa, Miguel A.; Pollard, Maisha

2015-01-01

African Americans are at increased risk for cardiovascular and metabolic diseases, including obesity, high BP, diabetes, CKD, myocardial infarction, and stroke. Here we summarize the current risks and provide an overview of the underlying risk factors that may account for these associations. By reviewing the relationship between cardiovascular and renal diseases and the African-American population during the early 20th century, the historic and recent associations of African heritage with cardiovascular disease, and modern population genetics, it is possible to assemble strong hypotheses for the primary underlying mechanisms driving the increased frequency of disease in African Americans. Our studies suggest that underlying genetic mechanisms may be responsible for the increased frequency of high BP and kidney disease in African Americans, with particular emphasis on the role of APOL1 polymorphisms in causing kidney disease. In contrast, the Western diet, particularly the relatively high intake of fructose-containing sugars and sweetened beverages, appears to be the dominant force driving the increased risk of diabetes, obesity, and downstream complications. Given that intake of added sugars is a remediable risk factor, we recommend clinical trials to examine the reduction of sweetened beverages as a primary means for reducing cardiovascular risk in African Americans. PMID:25090991

Genetic dyslexia risk variant is related to neural connectivity patterns underlying phonological awareness in children.

PubMed

Skeide, Michael A; Kirsten, Holger; Kraft, Indra; Schaadt, Gesa; Müller, Bent; Neef, Nicole; Brauer, Jens; Wilcke, Arndt; Emmrich, Frank; Boltze, Johannes; Friederici, Angela D

2015-09-01

Phonological awareness is the best-validated predictor of reading and spelling skill and therefore highly relevant for developmental dyslexia. Prior imaging genetics studies link several dyslexia risk genes to either brain-functional or brain-structural factors of phonological deficits. However, coherent evidence for genetic associations with both functional and structural neural phenotypes underlying variation in phonological awareness has not yet been provided. Here we demonstrate that rs11100040, a reported modifier of SLC2A3, is related to the functional connectivity of left fronto-temporal phonological processing areas at resting state in a sample of 9- to 12-year-old children. Furthermore, we provide evidence that rs11100040 is related to the fractional anisotropy of the arcuate fasciculus, which forms the structural connection between these areas. This structural connectivity phenotype is associated with phonological awareness, which is in turn associated with the individual retrospective risk scores in an early dyslexia screening as well as to spelling. These results suggest a link between a dyslexia risk genotype and a functional as well as a structural neural phenotype, which is associated with a phonological awareness phenotype. The present study goes beyond previous work by integrating genetic, brain-functional and brain-structural aspects of phonological awareness within a single approach. These combined findings might be another step towards a multimodal biomarker for developmental dyslexia. Copyright © 2015 Elsevier Inc. All rights reserved.

Serotonin transporter gene-linked polymorphic region (5-HTTLPR) influences decision making under ambiguity and risk in a large Chinese sample.

PubMed

He, Qinghua; Xue, Gui; Chen, Chuansheng; Lu, Zhonglin; Dong, Qi; Lei, Xuemei; Ding, Ni; Li, Jin; Li, He; Chen, Chunhui; Li, Jun; Moyzis, Robert K; Bechara, Antoine

2010-11-01

Risky decision making is a complex process that involves weighing the probabilities of alternative options that can be desirable, undesirable, or neutral. Individuals vary greatly in how they make decisions either under ambiguity and/or under risk. Such individual differences may have genetic bases. Based on previous studies on the genetic basis of decision making, two decision making tasks [i.e., the Iowa Gambling Task (IGT) and Loss Aversion Task (LAT)] were used to test the effect of 5-HTTLPR polymorphism on decision making under ambiguity and under risk in a large Han Chinese sample (572 college students, 312 females). Basic intelligence and memory tests were also included to control for the influence of basic cognitive abilities on decision making. We found that 5-HTTLPR polymorphism significantly influenced performance in both IGT and LAT. After controlling for intelligence and memory abilities, subjects homozygous for s allele had lower IGT scores than l carriers in the first 40 trials of the IGT task. They also exhibited higher loss aversion than l carriers in the LAT task. Moreover, the effects of 5-HTTLPR were stronger for males than for females. These results extend the literature on the important role of emotion in decision making under ambiguity and risk, and shed additional lights on how decision making is influenced by culture as well as sex differences. Combining our results with existing literature, we propose that these effects might be mediated by a neural circuitry that comprises the amygdala, ventromedial prefrontal cortex, and insular cortex. Understanding the genetic factors affecting decision making in healthy subjects may allow us to better identify at-risk individuals, and better target the development of new potential treatments for specific disorders such as schizophrenia, addiction, and depression. Copyright © 2010 Elsevier Ltd. All rights reserved.

Genetically Modified Foods: A Brief Overview of the Risk Assessment Process.

PubMed

Finkelstein, Paige E

2016-02-18

Billions of people worldwide are unable to meet their daily micro nutritional needs. Genetically modified (GM) foods, while initially developed to tolerate herbicides and resist disease and insects, have the potential to help alleviate this issue that is currently posing a serious public health concern. However, there is a negative public perception surrounding GM foods, calling for more research regarding the risks that GM foods could pose to the public, specifically on the topics of allergenicity and gene transfer. The risk assessments of GM foods should be performed on a case-by-case basis, by a process outlined by the WHO. The goal of determining food safety is to obtain reasonable certainty that under normal levels of consumption, there will be no harm to people. Current research has shown that GM foods do not cause increased allergenicity or have a meaningful risk of gene transfer to people. GM foods should become publicly accepted products that can bring significant benefit to people at risk of under nutrition.

Imaging genetics in autism spectrum disorders: Linking genetics and brain imaging in the pursuit of the underlying neurobiological mechanisms.

PubMed

Fakhoury, Marc

2018-01-03

Autism spectrum disorders (ASD) include a wide range of heterogeneous neurodevelopmental conditions that affect an individual in several aspects of social communication and behavior. Recent advances in molecular genetic technologies have dramatically increased our understanding of ASD etiology through the identification of several autism risk genes, most of which serve important functions in synaptic plasticity and protein synthesis. However, despite significant progress in this field of research, the characterization of the neurobiological mechanisms by which common genetic risk variants might operate to give rise to ASD symptomatology has proven to be far more difficult than expected. The imaging genetics approach holds great promise for advancing our understanding of ASD etiology by bridging the gap between genetic variations and their resultant biological effects on the brain. This paper provides a conceptual overview of the contribution of genetics in ASD and discusses key findings from the emerging field of imaging genetics. Copyright © 2017 Elsevier Inc. All rights reserved.

COMPLEXO: identifying the missing heritability of breast cancer via next generation collaboration.

PubMed

Southey, Melissa C; Park, Daniel J; Nguyen-Dumont, Tu; Campbell, Ian; Thompson, Ella; Trainer, Alison H; Chenevix-Trench, Georgia; Simard, Jacques; Dumont, Martine; Soucy, Penny; Thomassen, Mads; Jønson, Lars; Pedersen, Inge S; Hansen, Thomas Vo; Nevanlinna, Heli; Khan, Sofia; Sinilnikova, Olga; Mazoyer, Sylvie; Lesueur, Fabienne; Damiola, Francesca; Schmutzler, Rita; Meindl, Alfons; Hahnen, Eric; Dufault, Michael R; Chris Chan, Tl; Kwong, Ava; Barkardóttir, Rosa; Radice, Paolo; Peterlongo, Paolo; Devilee, Peter; Hilbers, Florentine; Benitez, Javier; Kvist, Anders; Törngren, Therese; Easton, Douglas; Hunter, David; Lindstrom, Sara; Kraft, Peter; Zheng, Wei; Gao, Yu-Tang; Long, Jirong; Ramus, Susan; Feng, Bing-Jian; Weitzel, Jeffrey N; Nathanson, Katherine; Offit, Kenneth; Joseph, Vijai; Robson, Mark; Schrader, Kasmintan; Wang, San; Kim, Yeong C; Lynch, Henry; Snyder, Carrie; Tavtigian, Sean; Neuhausen, Susan; Couch, Fergus J; Goldgar, David E

2013-06-21

Linkage analysis, positional cloning, candidate gene mutation scanning and genome-wide association study approaches have all contributed significantly to our understanding of the underlying genetic architecture of breast cancer. Taken together, these approaches have identified genetic variation that explains approximately 30% of the overall familial risk of breast cancer, implying that more, and likely rarer, genetic susceptibility alleles remain to be discovered.

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

Hattemer-Frey, H.A.; Brandt, E.J.; Travis, C.C.

Commercial genetic engineering is advancing into areas that require the small-scale introduction of genetically engineered microorganisms (GEMs) to better quantify variables that affect microorganism distribution and survival and to document potential long-term consequences. A recombinant DNA marker system, the lacZY marker, developed by the Monsanto Agricultural Co., enables the distribution and fate of marked fluorescent pseudomonad organisms to be monitored under actual field conditions. Critical evaluation of GEMs under field conditions is imperative if plant-beneficial effects are to be correlated with organism release. This paper evaluates the effectiveness of this marker system and its ability to facilitate the assessment ofmore » risks associated with deliberate environmental introductions of genetically engineered microorganisms. Results of prerelease contained growth chamber and field experiments demonstrated that: (1) the scientific risk assessment methodology adopted by Monsanto and approved by the U.S. Environmental Protection Agency was appropriate and comprehensive; (2) the deliberate introduction of a GEM did not pose unacceptable or unforeseen risks to human health or the environment; (3) the lacZY marker is an effective environmental tracking tool; and (4) regulatory oversight should reflect the expected risk and not be excessively burdensome for all GEMs.« less

Uptake of Predictive Genetic Testing and Cardiac Evaluation for Children at Risk for an Inherited Arrhythmia or Cardiomyopathy.

PubMed

Christian, Susan; Atallah, Joseph; Clegg, Robin; Giuffre, Michael; Huculak, Cathleen; Dzwiniel, Tara; Parboosingh, Jillian; Taylor, Sherryl; Somerville, Martin

2018-02-01

Predictive genetic testing in minors should be considered when clinical intervention is available. Children who carry a pathogenic variant for an inherited arrhythmia or cardiomyopathy require regular cardiac screening and may be prescribed medication and/or be told to modify their physical activity. Medical genetics and pediatric cardiology charts were reviewed to identify factors associated with uptake of genetic testing and cardiac evaluation for children at risk for long QT syndrome, hypertrophic cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy. The data collected included genetic diagnosis, clinical symptoms in the carrier parent, number of children under 18 years of age, age of children, family history of sudden cardiac arrest/death, uptake of cardiac evaluation and if evaluated, phenotype for each child. We identified 97 at risk children from 58 families found to carry a pathogenic variant for one of these conditions. Sixty six percent of the families pursued genetic testing and 73% underwent cardiac screening when it was recommended. Declining predictive genetic testing was significantly associated with genetic specialist recommendation (p < 0.001) and having an asymptomatic carrier father (p = 0.006). Cardiac evaluation was significantly associated with uptake of genetic testing (p = 0.007). This study provides a greater understanding of factors associated with uptake of genetic testing and cardiac evaluation in children at risk of an inherited arrhythmia or cardiomyopathy. It also identifies a need to educate families about the importance of cardiac evaluation even in the absence of genetic testing.

Predicting stroke through genetic risk functions: the CHARGE Risk Score Project.

PubMed

Ibrahim-Verbaas, Carla A; Fornage, Myriam; Bis, Joshua C; Choi, Seung Hoan; Psaty, Bruce M; Meigs, James B; Rao, Madhu; Nalls, Mike; Fontes, Joao D; O'Donnell, Christopher J; Kathiresan, Sekar; Ehret, Georg B; Fox, Caroline S; Malik, Rainer; Dichgans, Martin; Schmidt, Helena; Lahti, Jari; Heckbert, Susan R; Lumley, Thomas; Rice, Kenneth; Rotter, Jerome I; Taylor, Kent D; Folsom, Aaron R; Boerwinkle, Eric; Rosamond, Wayne D; Shahar, Eyal; Gottesman, Rebecca F; Koudstaal, Peter J; Amin, Najaf; Wieberdink, Renske G; Dehghan, Abbas; Hofman, Albert; Uitterlinden, André G; Destefano, Anita L; Debette, Stephanie; Xue, Luting; Beiser, Alexa; Wolf, Philip A; Decarli, Charles; Ikram, M Arfan; Seshadri, Sudha; Mosley, Thomas H; Longstreth, W T; van Duijn, Cornelia M; Launer, Lenore J

2014-02-01

Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors. The study includes 4 population-based cohorts with 2047 first incident strokes from 22,720 initially stroke-free European origin participants aged ≥55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphisms implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with area under the curve statistics comparing the GRS with age and sex, Framingham Stroke Risk Score models, and reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case-control study of ischemic stroke. In the meta-analysis, adding the GRS to the Framingham Stroke Risk Score, age and sex model resulted in a significant improvement in discrimination (all stroke: Δjoint area under the curve=0.016, P=2.3×10(-6); ischemic stroke: Δjoint area under the curve=0.021, P=3.7×10(-7)), although the overall area under the curve remained low. In all the studies, there was a highly significantly improved net reclassification index (P<10(-4)). The single-nucleotide polymorphisms associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared with the classical epidemiological risk factors for stroke.

A Longitudinal Twin Study on the Association between ADHD Symptoms and Reading

ERIC Educational Resources Information Center

Greven, Corina U.; Rijsdijk, Fruhling V.; Asherson, Philip; Plomin, Robert

2012-01-01

Background: Attention deficit hyperactivity disorder (ADHD) and reading disability commonly co-occur because of shared genetic risk factors. However, the stability and change of these genetic influences and the predictive relationships underlying this association longitudinally remain unclear. Methods: ADHD symptoms and reading were assessed as…

Physical distance, genetic relationship, age, and leprosy classification are independent risk factors for leprosy in contacts of patients with leprosy.

PubMed

Moet, F Johannes; Pahan, David; Schuring, Ron P; Oskam, Linda; Richardus, Jan H

2006-02-01

Close contacts of patients with leprosy have a higher risk of developing leprosy. Several risk factors have been identified, including genetic relationship and physical distance. Their independent contributions to the risk of developing leprosy, however, have never been sufficiently quantified. Logistic-regression analysis was performed on intake data from a prospective cohort study of 1037 patients newly diagnosed as having leprosy and their 21,870 contacts. Higher age showed an increased risk, with a bimodal distribution. Contacts of patients with paucibacillary (PB) leprosy with 2-5 lesions (PB2-5) and those with multibacillary (MB) leprosy had a higher risk than did contacts of patients with single-lesion PB leprosy. The core household group had a higher risk than other contacts living under the same roof and next-door neighbors, who again had a higher risk than neighbors of neighbors. A close genetic relationship indicated an increased risk when blood-related children, parents, and siblings were pooled together. Age of the contact, the disease classification of the index patient, and physical and genetic distance were independently associated with the risk of a contact acquiring leprosy. Contact surveys in leprosy should be not only focused on household contacts but also extended to neighbors and consanguineous relatives, especially when the patient has PB2-5 or MB leprosy.

Association between genetic risk scoring for schizophrenia and bipolar disorder with regional subcortical volumes.

PubMed

Caseras, X; Tansey, K E; Foley, S; Linden, D

2015-12-08

Previous research has shown coincident abnormal regional brain volume in patients with schizophrenia (SCZ) and bipolar disorder (BD) compared with controls. Whether these abnormalities are genetically driven or explained by secondary effects of the disorder or environmental factors is unknown. We aimed to investigate the association between genetic risk scoring (GRS) for SCZ and BD with volume of brain areas previously shown to be different between these clinical groups and healthy controls. We obtained subcortical brain volume measures and GRS for SCZ and BD from a sample of 274 healthy volunteers (71.4% females, mean age 24.7 (s.d. 6.9)). Volume of the globus pallidus was associated with the shared GRS between SCZ and BD, and also with the independent GRS for each of these disorders. Volume of the amygdala was associated with the non-shared GRS between SCZ and BD, and with the independent GRS for BD. Our results for volume of the globus pallidus support the idea of SCZ and BD sharing a common underlying neurobiological abnormality associated with a common genetic risk for both these disorders. Results for volume of the amygdala, though, would suggest the existence of a distinct mechanism only associated with genetic risk for BD. Finally, the lack of association between genetic risk and volume of most subcortical structures suggests that the volumetric differences reported in patient-control comparisons may not be genetically driven, but a consequence of the disorder or co-occurring environmental factors.

Predicting Risk of Type 2 Diabetes Mellitus with Genetic Risk Models on the Basis of Established Genome-wide Association Markers: A Systematic Review

PubMed Central

Bao, Wei; Hu, Frank B.; Rong, Shuang; Rong, Ying; Bowers, Katherine; Schisterman, Enrique F.; Liu, Liegang; Zhang, Cuilin

2013-01-01

This study aimed to evaluate the predictive performance of genetic risk models based on risk loci identified and/or confirmed in genome-wide association studies for type 2 diabetes mellitus. A systematic literature search was conducted in the PubMed/MEDLINE and EMBASE databases through April 13, 2012, and published data relevant to the prediction of type 2 diabetes based on genome-wide association marker–based risk models (GRMs) were included. Of the 1,234 potentially relevant articles, 21 articles representing 23 studies were eligible for inclusion. The median area under the receiver operating characteristic curve (AUC) among eligible studies was 0.60 (range, 0.55–0.68), which did not differ appreciably by study design, sample size, participants’ race/ethnicity, or the number of genetic markers included in the GRMs. In addition, the AUCs for type 2 diabetes did not improve appreciably with the addition of genetic markers into conventional risk factor–based models (median AUC, 0.79 (range, 0.63–0.91) vs. median AUC, 0.78 (range, 0.63–0.90), respectively). A limited number of included studies used reclassification measures and yielded inconsistent results. In conclusion, GRMs showed a low predictive performance for risk of type 2 diabetes, irrespective of study design, participants’ race/ethnicity, and the number of genetic markers included. Moreover, the addition of genome-wide association markers into conventional risk models produced little improvement in predictive performance. PMID:24008910

Affiliation buffers stress: cumulative genetic risk in oxytocin-vasopressin genes combines with early caregiving to predict PTSD in war-exposed young children.

PubMed

Feldman, R; Vengrober, A; Ebstein, R P

2014-03-11

Research indicates that risk for post-traumatic stress disorder (PTSD) is shaped by the interaction between genetic vulnerability and early caregiving experiences; yet, caregiving has typically been assessed by adult retrospective accounts. Here, we employed a prospective longitudinal design with real-time observations of early caregiving combined with assessment of genetic liability along the axis of vasopressin-oxytocin (OT) gene pathways to test G × E contributions to PTSD. Participants were 232 young Israeli children (1.5-5 years) and their parents, including 148 living in zones of continuous war and 84 controls. A cumulative genetic risk factor was computed for each family member by summing five risk alleles across three genes (OXTR, CD38 and AVPR1a) previously associated with psychopathology, sociality and caregiving. Child PTSD was diagnosed and mother-child interactions were observed in multiple contexts. In middle childhood (7-8 years), child psychopathology was re-evaluated. War exposure increased propensity to develop Axis-I disorder by threefold: 60% of exposed children displayed a psychiatric disorder by middle childhood and 62% of those showed several comorbid disorders. On the other hand, maternal sensitive support reduced risk for psychopathology. G × E effect was found for child genetic risk: in the context of war exposure, greater genetic risk on the vasopressin-OT pathway increased propensity for psychopathology. Among exposed children, chronicity of PTSD from early to middle childhood was related to higher child, maternal and paternal genetic risk, low maternal support and greater initial avoidance symptoms. Child avoidance was predicted by low maternal support and reduced mother-child reciprocity. These findings underscore the saliency of both genetic and behavioral facets of the human affiliation system in shaping vulnerability to PTSD as well as providing an underlying mechanism of post-traumatic resilience.

Affiliation buffers stress: cumulative genetic risk in oxytocin–vasopressin genes combines with early caregiving to predict PTSD in war-exposed young children

PubMed Central

Feldman, R; Vengrober, A; Ebstein, R P

2014-01-01

Research indicates that risk for post-traumatic stress disorder (PTSD) is shaped by the interaction between genetic vulnerability and early caregiving experiences; yet, caregiving has typically been assessed by adult retrospective accounts. Here, we employed a prospective longitudinal design with real-time observations of early caregiving combined with assessment of genetic liability along the axis of vasopressin–oxytocin (OT) gene pathways to test G × E contributions to PTSD. Participants were 232 young Israeli children (1.5–5 years) and their parents, including 148 living in zones of continuous war and 84 controls. A cumulative genetic risk factor was computed for each family member by summing five risk alleles across three genes (OXTR, CD38 and AVPR1a) previously associated with psychopathology, sociality and caregiving. Child PTSD was diagnosed and mother–child interactions were observed in multiple contexts. In middle childhood (7–8 years), child psychopathology was re-evaluated. War exposure increased propensity to develop Axis-I disorder by threefold: 60% of exposed children displayed a psychiatric disorder by middle childhood and 62% of those showed several comorbid disorders. On the other hand, maternal sensitive support reduced risk for psychopathology. G × E effect was found for child genetic risk: in the context of war exposure, greater genetic risk on the vasopressin–OT pathway increased propensity for psychopathology. Among exposed children, chronicity of PTSD from early to middle childhood was related to higher child, maternal and paternal genetic risk, low maternal support and greater initial avoidance symptoms. Child avoidance was predicted by low maternal support and reduced mother–child reciprocity. These findings underscore the saliency of both genetic and behavioral facets of the human affiliation system in shaping vulnerability to PTSD as well as providing an underlying mechanism of post-traumatic resilience. PMID:24618689

Assessing the benefits and risks of translocations in changing environments: a genetic perspective

PubMed Central

Weeks, Andrew R; Sgro, Carla M; Young, Andrew G; Frankham, Richard; Mitchell, Nicki J; Miller, Kim A; Byrne, Margaret; Coates, David J; Eldridge, Mark D B; Sunnucks, Paul; Breed, Martin F; James, Elizabeth A; Hoffmann, Ary A

2011-01-01

Translocations are being increasingly proposed as a way of conserving biodiversity, particularly in the management of threatened and keystone species, with the aims of maintaining biodiversity and ecosystem function under the combined pressures of habitat fragmentation and climate change. Evolutionary genetic considerations should be an important part of translocation strategies, but there is often confusion about concepts and goals. Here, we provide a classification of translocations based on specific genetic goals for both threatened species and ecological restoration, separating targets based on ‘genetic rescue’ of current population fitness from those focused on maintaining adaptive potential. We then provide a framework for assessing the genetic benefits and risks associated with translocations and provide guidelines for managers focused on conserving biodiversity and evolutionary processes. Case studies are developed to illustrate the framework. PMID:22287981

Improved performance of epidemiologic and genetic risk models for rheumatoid arthritis serologic phenotypes using family history

PubMed Central

Sparks, Jeffrey A.; Chen, Chia-Yen; Jiang, Xia; Askling, Johan; Hiraki, Linda T.; Malspeis, Susan; Klareskog, Lars; Alfredsson, Lars; Costenbader, Karen H.; Karlson, Elizabeth W.

2014-01-01

Objective To develop and validate rheumatoid arthritis (RA) risk models based on family history, epidemiologic factors, and known genetic risk factors. Methods We developed and validated models for RA based on known RA risk factors, among women in two cohorts: the Nurses’ Health Study (NHS, 381 RA cases and 410 controls) and the Epidemiological Investigation of RA (EIRA, 1244 RA cases and 971 controls). Model discrimination was evaluated using the area under the receiver operating characteristic curve (AUC) in logistic regression models for the study population and for those with positive family history. The joint effect of family history with genetics, smoking, and body mass index (BMI) was evaluated using logistic regression models to estimate odds ratios (OR) for RA. Results The complete model including family history, epidemiologic risk factors, and genetics demonstrated AUCs of 0.74 for seropositive RA in NHS and 0.77 for anti-citrullinated protein antibody (ACPA)-positive RA in EIRA. Among women with positive family history, discrimination was excellent for complete models for seropositive RA in NHS (AUC 0.82) and ACPA-positive RA in EIRA (AUC 0.83). Positive family history, high genetic susceptibility, smoking, and increased BMI had an OR of 21.73 for ACPA-positive RA. Conclusions We developed models for seropositive and seronegative RA phenotypes based on family history, epidemiologic and genetic factors. Among those with positive family history, models utilizing epidemiologic and genetic factors were highly discriminatory for seropositive and seronegative RA. Assessing epidemiological and genetic factors among those with positive family history may identify individuals suitable for RA prevention strategies. PMID:24685909

Height, height-related SNPs, and risk of non-melanoma skin cancer.

PubMed

Li, Xin; Liang, Liming; Feng, Yen-Chen Anne; De Vivo, Immaculata; Giovannucci, Edward; Tang, Jean Y; Han, Jiali

2017-01-03

Adult height has been associated with risk of several site-specific cancers, including melanoma. However, less attention has been given to non-melanoma skin cancer (NMSC). We prospectively examined the risk of squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) in relation to adult height in the Nurses' Health Study (NHS, n=117 863) and the Health Professionals Follow-up Study (HPFS, n=51 111). We also investigated the relationships between height-related genetic markers and risk of BCC and SCC in the genetic data sets of the NHS and HPFS (3898 BCC cases, and 8530 BCC controls; 527 SCC cases, and 8962 SCC controls). After controlling for potential confounding factors, the hazard ratios were 1.09 (95% CI: 1.02, 1.15) and 1.10 (95% CI: 1.07, 1.13) for the associations between every 10 cm increase in height and risk of SCC and BCC respectively. None of the 687 height-related single-nucleotide polymorphisms (SNPs) was significantly associated with the risk of SCC or BCC, nor were the genetic scores combining independent height-related loci. Our data from two large cohorts provide further evidence that height is associated with an increased risk of NMSC. More studies on height-related genetic loci and early-life exposures may help clarify the underlying mechanisms.

Prediction of individual genetic risk to prostate cancer using a polygenic score.

PubMed

Szulkin, Robert; Whitington, Thomas; Eklund, Martin; Aly, Markus; Eeles, Rosalind A; Easton, Douglas; Kote-Jarai, Z Sofia; Amin Al Olama, Ali; Benlloch, Sara; Muir, Kenneth; Giles, Graham G; Southey, Melissa C; Fitzgerald, Liesel M; Henderson, Brian E; Schumacher, Fredrick; Haiman, Christopher A; Schleutker, Johanna; Wahlfors, Tiina; Tammela, Teuvo L J; Nordestgaard, Børge G; Key, Tim J; Travis, Ruth C; Neal, David E; Donovan, Jenny L; Hamdy, Freddie C; Pharoah, Paul; Pashayan, Nora; Khaw, Kay-Tee; Stanford, Janet L; Thibodeau, Stephen N; McDonnell, Shannon K; Schaid, Daniel J; Maier, Christiane; Vogel, Walther; Luedeke, Manuel; Herkommer, Kathleen; Kibel, Adam S; Cybulski, Cezary; Lubiński, Jan; Kluźniak, Wojciech; Cannon-Albright, Lisa; Brenner, Hermann; Butterbach, Katja; Stegmaier, Christa; Park, Jong Y; Sellers, Thomas; Lin, Hui-Yi; Lim, Hui-Yi; Slavov, Chavdar; Kaneva, Radka; Mitev, Vanio; Batra, Jyotsna; Clements, Judith A; Spurdle, Amanda; Teixeira, Manuel R; Paulo, Paula; Maia, Sofia; Pandha, Hardev; Michael, Agnieszka; Kierzek, Andrzej; Gronberg, Henrik; Wiklund, Fredrik

2015-09-01

Polygenic risk scores comprising established susceptibility variants have shown to be informative classifiers for several complex diseases including prostate cancer. For prostate cancer it is unknown if inclusion of genetic markers that have so far not been associated with prostate cancer risk at a genome-wide significant level will improve disease prediction. We built polygenic risk scores in a large training set comprising over 25,000 individuals. Initially 65 established prostate cancer susceptibility variants were selected. After LD pruning additional variants were prioritized based on their association with prostate cancer. Six-fold cross validation was performed to assess genetic risk scores and optimize the number of additional variants to be included. The final model was evaluated in an independent study population including 1,370 cases and 1,239 controls. The polygenic risk score with 65 established susceptibility variants provided an area under the curve (AUC) of 0.67. Adding an additional 68 novel variants significantly increased the AUC to 0.68 (P = 0.0012) and the net reclassification index with 0.21 (P = 8.5E-08). All novel variants were located in genomic regions established as associated with prostate cancer risk. Inclusion of additional genetic variants from established prostate cancer susceptibility regions improves disease prediction. © 2015 Wiley Periodicals, Inc.

Education and alcohol use: A study of gene-environment interaction in young adulthood.

PubMed

Barr, Peter B; Salvatore, Jessica E; Maes, Hermine; Aliev, Fazil; Latvala, Antti; Viken, Richard; Rose, Richard J; Kaprio, Jaakko; Dick, Danielle M

2016-08-01

The consequences of heavy alcohol use remain a serious public health problem. Consistent evidence has demonstrated that both genetic and social influences contribute to alcohol use. Research on gene-environment interaction (GxE) has also demonstrated that these social and genetic influences do not act independently. Instead, certain environmental contexts may limit or exacerbate an underlying genetic predisposition. However, much of the work on GxE and alcohol use has focused on adolescence and less is known about the important environmental contexts in young adulthood. Using data from the young adult wave of the Finnish Twin Study, FinnTwin12 (N = 3402), we used biometric twin modeling to test whether education moderated genetic risk for alcohol use as assessed by drinking frequency and intoxication frequency. Education is important because it offers greater access to personal resources and helps determine one's position in the broader stratification system. Results from the twin models show that education did not moderate genetic variance components and that genetic risk was constant across levels of education. Instead, education moderated environmental variance so that under conditions of low education, environmental influences explained more of the variation in alcohol use outcomes. The implications and limitations of these results are discussed. Copyright © 2016 Elsevier Ltd. All rights reserved.

Education and Alcohol Use: A Study of Gene-Environment Interaction in Young Adulthood

PubMed Central

Barr, Peter B.; Salvatore, Jessica E.; Maes, Hermine; Aliev, Fazil; Latvala, Antti; Viken, Richard; Rose, Richard J.; Kaprio, Jaakko; Dick, Danielle M.

2016-01-01

The consequences of heavy alcohol use remain a serious public health problem. Consistent evidence has demonstrated that both genetic and social influences contribute to alcohol use. Research on gene-environment interaction (GxE) has also demonstrated that these social and genetic influences do not act independently. Instead, certain environmental contexts may limit or exacerbate an underlying genetic predisposition. However, much of the work on GxE and alcohol use has focused on adolescence and less is known about the important environmental contexts in young adulthood. Using data from the young adult wave of the Finnish Twin Study, FinnTwin12 (N=3,402), we used biometric twin modeling to test whether education moderated genetic risk for alcohol use as assessed by drinking frequency and intoxication frequency. Education is important because it offers greater access to personal resources and helps determine one’s position in the broader stratification system. Results from the twin models show that education did not moderate genetic variance components and that genetic risk was constant across levels of education. Instead, education moderated environmental variance so that under conditions of low education, environmental influences explained more of the variation in alcohol use outcomes. The implications and limitations of these results are discussed. PMID:27367897

Common polygenic variation contributes to risk of schizophrenia that overlaps with bipolar disorder

PubMed Central

2013-01-01

Schizophrenia (SCZ) is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits with heritability estimated at up to 80%1,2. We adopted two analytic approaches to determine the extent to which common genetic variation underlies risk of SCZ using genome-wide association study (GWAS) data from 3,322 European individuals with SCZ and 3,587 controls. First, we implicate the major histocompatibility complex (MHC). Second, we provide molecular genetic evidence for a substantial polygenic component to risk of SCZ involving thousands of common alleles of very small effect. We show that this component also contributes to risk of bipolar disorder (BPD), but not to multiple non-psychiatric diseases. PMID:19571811

Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance.

PubMed

Hernandez, Dena G; Reed, Xylena; Singleton, Andrew B

2016-10-01

Parkinson's disease is a common, progressive neurodegenerative disorder, affecting 3% of those older than 75 years of age. Clinically, Parkinson's disease (PD) is associated with resting tremor, postural instability, rigidity, bradykinesia, and a good response to levodopa therapy. Over the last 15 years, numerous studies have confirmed that genetic factors contribute to the complex pathogenesis of PD. Highly penetrant mutations producing rare, monogenic forms of the disease have been discovered in singular genes such as SNCA, Parkin, DJ-1, PINK 1, LRRK2, and VPS35. Unique variants with incomplete penetrance in LRRK2 and GBA have been shown to be strong risk factors for PD in certain populations. Additionally, over 20 common variants with small effect sizes are now recognized to modulate the risk for PD. Investigating Mendelian forms of PD has provided precious insight into the pathophysiology that underlies the more common idiopathic form of disease; however, no treatment methodologies have developed. Furthermore, for identified common risk alleles, the functional basis underlying risk principally remains unknown. The challenge over the next decade will be to strengthen the findings delivered through genetic discovery by assessing the direct, biological consequences of risk variants in tandem with additional high-content, integrated datasets. This review discusses monogenic risk factors and mechanisms of Mendelian inheritance of Parkinson disease. Highly penetrant mutations in SNCA, Parkin, DJ-1, PINK 1, LRRK2 and VPS35 produce rare, monogenic forms of the disease, while unique variants within LRRK2 and GBA show incomplete penetrance and are strong risk factors for PD. Additionally, over 20 common variants with small effect sizes modulate disease risk. The challenge over the next decade is to strengthen genetic findings by assessing direct, biological consequences of risk variants in tandem with high-content, integrated datasets. This article is part of a special issue on Parkinson disease. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Value of genetic profiling for the prediction of coronary heart disease.

PubMed

van der Net, Jeroen B; Janssens, A Cecile J W; Sijbrands, Eric J G; Steyerberg, Ewout W

2009-07-01

Advances in high-throughput genomics facilitate the identification of novel genetic susceptibility variants for coronary heart disease (CHD). This may improve CHD risk prediction. The aim of the present simulation study was to investigate to what degree CHD risk can be predicted by testing multiple genetic variants (genetic profiling). We simulated genetic profiles for a population of 100,000 individuals with a 10-year CHD incidence of 10%. For each combination of model parameters (number of variants, genotype frequency and odds ratio [OR]), we calculated the area under the receiver operating characteristic curve (AUC) to indicate the discrimination between individuals who will and will not develop CHD. The AUC of genetic profiles could rise to 0.90 when 100 hypothetical variants with ORs of 1.5 and genotype frequencies of 50% were simulated. The AUC of a genetic profile consisting of 10 established variants, with ORs ranging from 1.13 to 1.42, was 0.59. When 2, 5, and 10 times as many identical variants would be identified, the AUCs were 0.63, 0.69, and 0.76. To obtain AUCs similar to those of conventional CHD risk predictors, a considerable number of additional common genetic variants need to be identified with preferably strong effects.

Maternal obesity and tobacco use modify the impact of genetic variants on the occurrence of conotruncal heart defects.

PubMed

Tang, Xinyu; Nick, Todd G; Cleves, Mario A; Erickson, Stephen W; Li, Ming; Li, Jingyun; MacLeod, Stewart L; Hobbs, Charlotte A

2014-01-01

Conotruncal heart defects (CTDs) are among the most severe birth defects worldwide. Studies of CTDs indicate both lifestyle behaviors and genetic variation contribute to the risk of CTDs. Based on a hybrid design using data from 616 case-parental and 1645 control-parental triads recruited for the National Birth Defects Prevention Study between 1997 and 2008, we investigated whether the occurrence of CTDs is associated with interactions between 921 maternal and/or fetal single nucleotide polymorphisms (SNPs) and maternal obesity and tobacco use. The maternal genotypes of the variants in the glutamate-cysteine ligase, catalytic subunit (GCLC) gene and the fetal genotypes of the variants in the glutathione S-transferase alpha 3 (GSTA3) gene were associated with an elevated risk of CTDs among obese mothers. The risk of delivering infants with CTDs among obese mothers carrying AC genotype for a variant in the GCLC gene (rs6458939) was 2.00 times the risk among those carrying CC genotype (95% confidence interval: 1.41, 2.38). The maternal genotypes of several variants in the glutathione-S-transferase (GST) family of genes and the fetal genotypes of the variants in the GCLC gene interacted with tobacco exposures to increase the risk of CTDs. Our study suggests that the genetic basis underlying susceptibility of the developing heart to the adverse effects of maternal obesity and tobacco use involve both maternal and embryonic genetic variants. These results may provide insights into the underlying pathophysiology of CTDs, and ultimately lead to novel prevention strategies.

Mating practices and the dissemination of genetic disorders in domestic animals, based on the example of dog breeding.

PubMed

Leroy, G; Baumung, R

2011-02-01

On the basis of simulations and genealogical data of ten dog breeds, three popular mating practices (popular sire effect, line breeding, close breeding) were investigated along with their effects on the dissemination of genetic disorders. Our results showed that the use of sires in these ten breeds is clearly unbalanced. Depending on the breed, the effective number of sires represented between 33% and 70% of the total number of sires. Mating between close relatives was also found to be quite common, and the percentage of dogs inbred after two generations ranged from 1% to about 8%. A more or less long-term genetic differentiation, linked to line breeding practices, was also emphasized in most breeds. F(IT) index based on gene dropping proved to be efficient in differentiating the effects of the different mating practices, and it ranged from -1.3% to 3.2% when real founders were used to begin a gene dropping process. Simulation results confirmed that the popular sire practice leads to a dissemination of genetic disorders. Under a realistic scenario, regarding the imbalance in the use of sires, the dissemination risk was indeed 4.4 times higher than under random mating conditions. In contrast, line breeding and close breeding practices tend to decrease the risk of the dissemination of genetic disorders. © 2010 The Authors, Animal Genetics © 2010 Stichting International Foundation for Animal Genetics.

BRCA Genetic Counseling Among At-Risk Latinas in New York City: New Beliefs Shape New Generation

PubMed Central

Edwards, Tiffany; Villagra, Cristina; Rodriguez, M. Carina; Thompson, Hayley S.; Jandorf, Lina; Valdimarsdottir, Heiddis B.

2015-01-01

Despite the life-saving information that genetic counseling can provide for women at hereditary breast and/or ovarian cancer (HBOC) risk, Latinas disproportionately underuse such services. Understanding Latinas’ beliefs and attitudes about BRCA genetic counseling may be the key to better health promotion within this underserved, at-risk group. We conducted 12 focus groups (N=54) with at-risk Latina women in New York City, followed by 30 in-depth interviews among a subset of the focus group women. Both were professionally transcribed, translated where applicable and data analysis was completed by two coders trained in qualitative methods. Results revealed personal and community knowledge about BRCA genetic counseling was relatively low, although women felt largely positive about counseling. The main motivator to undergo genetic counseling was concerns about learning family members’ cancer status, while the main barrier was competing demands. Generational differences were apparent, with younger women (approximately <55 years) reporting that they were more interested in educating themselves about counseling and other ways to prevent cancer. Younger women were also less likely to ascribe to traditionally Latino-centered cultural beliefs which could serve as barriers (e.g. machismo, fatalismo, destino) to undergoing genetic counseling. Participants were largely enthusiastic about educational efforts to increase awareness of genetic counseling among Latinos. Revealing the beliefs and attitudes of underserved Latinas may help shape culturally appropriate educational materials and promotion programs to increase BRCA genetic counseling uptake within this under-represented community. PMID:25120034

Evidence for Shared Genetic Risk between ADHD Symptoms and Reduced Mathematics Ability: A Twin Study

ERIC Educational Resources Information Center

Greven, Corina U.; Kovas, Yulia; Willcutt, Erik G.; Petrill, Stephen A.; Plomin, Robert

2013-01-01

Background: Attention-deficit/hyperactivity disorder (ADHD) symptoms and mathematics ability are associated, but little is known about the genetic and environmental influences underlying this association. Methods: Data came from more than 6,000 twelve-year-old twin pairs from the UK population-representative Twins Early Development Study. Parents…

Genetic testing in heritable cardiac arrhythmia syndromes: differentiating pathogenic mutations from background genetic noise.

PubMed

Giudicessi, John R; Ackerman, Michael J

2013-01-01

In this review, we summarize the basic principles governing rare variant interpretation in the heritable cardiac arrhythmia syndromes, focusing on recent advances that have led to disease-specific approaches to the interpretation of positive genetic testing results. Elucidation of the genetic substrates underlying heritable cardiac arrhythmia syndromes has unearthed new arrhythmogenic mechanisms and given rise to a number of clinically meaningful genotype-phenotype correlations. As such, genetic testing for these disorders now carries important diagnostic, prognostic, and therapeutic implications. Recent large-scale systematic studies designed to explore the background genetic 'noise' rate associated with these genetic tests have provided important insights and enhanced how positive genetic testing results are interpreted for these potentially lethal, yet highly treatable, cardiovascular disorders. Clinically available genetic tests for heritable cardiac arrhythmia syndromes allow the identification of potentially at-risk family members and contribute to the risk-stratification and selection of therapeutic interventions in affected individuals. The systematic evaluation of the 'signal-to-noise' ratio associated with these genetic tests has proven critical and essential to assessing the probability that a given variant represents a rare pathogenic mutation or an equally rare, yet innocuous, genetic bystander.

Pervasive sharing of genetic effects in autoimmune disease.

PubMed

Cotsapas, Chris; Voight, Benjamin F; Rossin, Elizabeth; Lage, Kasper; Neale, Benjamin M; Wallace, Chris; Abecasis, Gonçalo R; Barrett, Jeffrey C; Behrens, Timothy; Cho, Judy; De Jager, Philip L; Elder, James T; Graham, Robert R; Gregersen, Peter; Klareskog, Lars; Siminovitch, Katherine A; van Heel, David A; Wijmenga, Cisca; Worthington, Jane; Todd, John A; Hafler, David A; Rich, Stephen S; Daly, Mark J

2011-08-01

Genome-wide association (GWA) studies have identified numerous, replicable, genetic associations between common single nucleotide polymorphisms (SNPs) and risk of common autoimmune and inflammatory (immune-mediated) diseases, some of which are shared between two diseases. Along with epidemiological and clinical evidence, this suggests that some genetic risk factors may be shared across diseases-as is the case with alleles in the Major Histocompatibility Locus. In this work we evaluate the extent of this sharing for 107 immune disease-risk SNPs in seven diseases: celiac disease, Crohn's disease, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes. We have developed a novel statistic for Cross Phenotype Meta-Analysis (CPMA) which detects association of a SNP to multiple, but not necessarily all, phenotypes. With it, we find evidence that 47/107 (44%) immune-mediated disease risk SNPs are associated to multiple-but not all-immune-mediated diseases (SNP-wise P(CPMA)<0.01). We also show that distinct groups of interacting proteins are encoded near SNPs which predispose to the same subsets of diseases; we propose these as the mechanistic basis of shared disease risk. We are thus able to leverage genetic data across diseases to construct biological hypotheses about the underlying mechanism of pathogenesis.

Genetics of Type 2 Diabetes: Insights into the Pathogenesis and Its Clinical Application

PubMed Central

Sun, Xue; Yu, Weihui; Hu, Cheng

2014-01-01

With rapidly increasing prevalence, diabetes has become one of the major causes of mortality worldwide. According to the latest studies, genetic information makes substantial contributions towards the prediction of diabetes risk and individualized antidiabetic treatment. To date, approximately 70 susceptibility genes have been identified as being associated with type 2 diabetes (T2D) at a genome-wide significant level (P < 5 × 10−8). However, all the genetic loci identified so far account for only about 10% of the overall heritability of T2D. In addition, how these novel susceptibility loci correlate with the pathophysiology of the disease remains largely unknown. This review covers the major genetic studies on the risk of T2D based on ethnicity and briefly discusses the potential mechanisms and clinical utility of the genetic information underlying T2D. PMID:24864266

Missing heritability and strategies for finding the underlying causes of complex disease

PubMed Central

Eichler, Evan E.; Flint, Jonathan; Gibson, Greg; Kong, Augustine; Leal, Suzanne M.; Moore, Jason H.; Nadeau, Joseph H.

2010-01-01

Although recent genome-wide studies have provided valuable insights into the genetic basis of human disease, they have explained relatively little of the heritability of most complex traits, and the variants identified through these studies have small effect sizes. This has led to the important and hotly debated issue of where the ‘missing heritability’ of complex diseases might be found. Here, seven leading geneticists offer their opinion about where this heritability is likely to lie, what this could tell us about the underlying genetic architecture of common diseases and how this could inform research strategies for uncovering genetic risk factors. PMID:20479774

Association between stressful life events and psychotic experiences in adolescence: evidence for gene–environment correlations

PubMed Central

Shakoor, Sania; Zavos, Helena M. S.; Haworth, Claire M. A.; McGuire, Phillip; Cardno, Alastair G.; Freeman, Daniel; Ronald, Angelica

2016-01-01

Background Stressful life events (SLEs) are associated with psychotic experiences. SLEs might act as an environmental risk factor, but may also share a genetic propensity with psychotic experiences. Aims To estimate the extent to which genetic and environmental factors influence the relationship between SLEs and psychotic experiences. Method Self- and parent reports from a community-based twin sample (4830 16-year-old pairs) were analysed using structural equation model fitting. Results SLEs correlated with positive psychotic experiences (r = 0.12–0.14, all P<0.001). Modest heritability was shown for psychotic experiences (25–57%) and dependent SLEs (32%). Genetic influences explained the majority of the modest covariation between dependent SLEs and paranoia and cognitive disorganisation (bivariate heritabilities 74–86%). The relationship between SLEs and hallucinations and grandiosity was explained by both genetic and common environmental effects. Conclusions Further to dependent SLEs being an environmental risk factor, individuals may have an underlying genetic propensity increasing their risk of dependent SLEs and positive psychotic experiences. PMID:27056622

Genetic Moderation of Stress Effects on Corticolimbic Circuitry.

PubMed

Bogdan, Ryan; Pagliaccio, David; Baranger, David Aa; Hariri, Ahmad R

2016-01-01

Stress exposure is associated with individual differences in corticolimbic structure and function that often mirror patterns observed in psychopathology. Gene x environment interaction research suggests that genetic variation moderates the impact of stress on risk for psychopathology. On the basis of these findings, imaging genetics, which attempts to link variability in DNA sequence and structure to neural phenotypes, has begun to incorporate measures of the environment. This research paradigm, known as imaging gene x environment interaction (iGxE), is beginning to contribute to our understanding of the neural mechanisms through which genetic variation and stress increase psychopathology risk. Although awaiting replication, evidence suggests that genetic variation within the canonical neuroendocrine stress hormone system, the hypothalamic-pituitary-adrenal axis, contributes to variability in stress-related corticolimbic structure and function, which, in turn, confers risk for psychopathology. For iGxE research to reach its full potential it will have to address many challenges, of which we discuss: (i) small effects, (ii) measuring the environment and neural phenotypes, (iii) the absence of detailed mechanisms, and (iv) incorporating development. By actively addressing these challenges, iGxE research is poised to help identify the neural mechanisms underlying genetic and environmental associations with psychopathology.

Suicidal ideation, depression, and conduct disorder in a sample of adolescent and young adult twins

PubMed Central

Linker, Julie; Gillespie, Nathan A; Maes, Hermine; Eaves, Lindon; Silberg, Judy L.

2012-01-01

Background The co-occurrence of suicidal ideation, depression, and conduct disturbance is likely explained in part by correlated genetic and environmental risk factors. Little is known about the specific nature of these associations. Method Structured interviews on 2814 twins from the Virginia Twin Study of Adolescent Behavioral Development (VTSABD) and young adult follow-up (YAFU) yielded data on symptoms of depression, conduct disorder and adolescent and young adult suicidal ideation. Results Univariate analyses revealed that the familial aggregation for each trait was explained by a combination of additive genetic and shared environmental effects. Suicidal ideation in adolescence was explained in part by genetic influences, but predominantly accounted for by environmental factors. A mixture of genetic and shared environmental influences explained ideation occurring in young adulthood. Multivariate analyses revealed that there are genetic and shared environmental effects common to suicidal ideation, depression, and conduct disorder. The association between adolescent suicidal ideation and CD was attributable to the same genetic and environmental risk factors for depression. Conclusions These findings underscore that prevention and intervention strategies should reflect the different underlying mechanisms involving depression and conduct disorder to assist in identifying adolescents at suicidal risk. PMID:22646517

Suicidal ideation, depression, and conduct disorder in a sample of adolescent and young adult twins.

PubMed

Linker, Julie; Gillespie, Nathan A; Maes, Hermine; Eaves, Lindon; Silberg, Judy L

2012-08-01

The co-occurrence of suicidal ideation, depression, and conduct disturbance is likely explained in part by correlated genetic and environmental risk factors. Little is known about the specific nature of these associations. Structured interviews on 2,814 twins from the Virginia Twin Study of Adolescent Behavioral Development (VTSABD) and Young Adult Follow-Up (YAFU) yielded data on symptoms of depression, conduct disorder, and adolescent and young adult suicidal ideation. Univariate analyses revealed that the familial aggregation for each trait was explained by a combination of additive genetic and shared environmental effects. Suicidal ideation in adolescence was explained in part by genetic influences, but predominantly accounted for by environmental factors. A mixture of genetic and shared environmental influences explained ideation occurring in young adulthood. Multivariate analyses revealed that there are genetic and shared environmental effects common to suicidal ideation, depression, and conduct disorder. The association between adolescent suicidal ideation and CD was attributable to the same genetic and environmental risk factors for depression. These findings underscore that prevention and intervention strategies should reflect the different underlying mechanisms involving depression and conduct disorder to assist in identifying adolescents at suicidal risk. © 2012 The American Association of Suicidology.

Disturbed functional connectivity of cortical activation during semantic discrimination in patients with schizophrenia and subjects at genetic high-risk.

PubMed

Li, Xiaobo; Branch, Craig A; Nierenberg, Jay; Delisi, Lynn E

2010-03-01

Schizophrenia has a strong genetic component that is relevant to the understanding of the pathophysiology of the syndrome. Thus, recent investigations have shifted from studies of diagnosed patients with schizophrenia to examining their unaffected relatives. Previous studies found that during language processing, relatives thought to be at genetic high-risk for the disorder exhibit aberrant functional activation in regions of language processing, specifically in the left inferior frontal gyrus (Broca's area). However, functional connectivity among the regions involved in language pathways is not well understood. In this study, we examined the functional connectivity between a seed located in Broca's area and the remainder of the brain during a visual lexical decision task, in 20 schizophrenia patients, 21 subjects at genetic high risk for the disorder and 21 healthy controls. Both the high-risk subjects and patients showed significantly reduced activation correlations between seed and regions related to visual language processing. Compared to the high-risk subjects, the schizophrenia patients showed even fewer regions that were correlated with the seed regions. These results suggest that there is aberrant functional connectivity within cortical language circuitry in high-risk subjects and patients with schizophrenia. Broca's area, which is one of the important regions for language processing in healthy controls, had a significantly reduced role in the high-risk subjects and patients with schizophrenia. Our findings are consistent with the existence of an underlying biological disturbance that begins in genetically at risk individuals and progresses to a greater extent in those who eventually develop schizophrenia.

Genome-wide association study of bipolar disorder accounting for effect of body mass index identifies a new risk allele in TCF7L2.

PubMed

Winham, S J; Cuellar-Barboza, A B; Oliveros, A; McElroy, S L; Crow, S; Colby, C; Choi, D-S; Chauhan, M; Frye, M; Biernacka, J M

2014-09-01

Bipolar disorder (BD) is associated with higher body mass index (BMI) and increased metabolic comorbidity. Considering the associated phenotypic traits in genetic studies of complex diseases, either by adjusting for covariates or by investigating interactions between genetic variants and covariates, may help to uncover the missing heritability. However, obesity-related traits have not been incorporated in prior genome-wide analyses of BD as covariates or potential interacting factors. To investigate the genetic factors underlying BD while considering BMI, we conducted genome-wide analyses using data from the Genetic Association Information Network BD study. We analyzed 729,454 genotyped single-nucleotide polymorphism (SNP) markers on 388 European-American BD cases and 1020 healthy controls with available data for maximum BMI. We performed genome-wide association analyses of the genetic effects while accounting for the effect of maximum BMI, and also evaluated SNP-BMI interactions. A joint test of main and interaction effects demonstrated significant evidence of association at the genome-wide level with rs12772424 in an intron of TCF7L2 (P=2.85E-8). This SNP exhibited interaction effects, indicating that the bipolar susceptibility risk of this SNP is dependent on BMI. TCF7L2 codes for the transcription factor TCF/LF, part of the Wnt canonical pathway, and is one of the strongest genetic risk variants for type 2 diabetes (T2D). This is consistent with BD pathophysiology, as the Wnt pathway has crucial implications in neurodevelopment, neurogenesis and neuroplasticity, and is involved in the mechanisms of action of BD and depression treatments. We hypothesize that genetic risk for BD is BMI dependent, possibly related to common genetic risk with T2D.

Positive Traits in the Bipolar Spectrum: The Space between Madness and Genius

PubMed Central

Greenwood, Tiffany A.

2017-01-01

Bipolar disorder is a severe, lifelong mood disorder for which little is currently understood of the genetic mechanisms underlying risk. By examining related dimensional phenotypes, we may further our understanding of the disorder. Creativity has a historical connection with the bipolar spectrum and is particularly enhanced among unaffected first-degree relatives and those with bipolar spectrum traits. This suggests that some aspects of the bipolar spectrum may confer advantages, while more severe expressions of symptoms negatively influence creative accomplishment. Creativity is a complex, multidimensional construct with both cognitive and affective components, many of which appear to reflect a shared genetic vulnerability with bipolar disorder. It is suggested that a subset of bipolar risk variants confer advantages as positive traits according to an inverted-U-shaped curve with clinically unaffected allele carriers benefitting from the positive traits and serving to maintain the risk alleles in the population. The association of risk genes with creativity in healthy individuals (e.g., NRG1), as well as an overall sharing of common genetic variation between bipolar patients and creative individuals, provides support for this model. Current findings are summarized from a multidisciplinary perspective to demonstrate the feasibility of research in this area to reveal the mechanisms underlying illness. PMID:28277566

Reconsidering Clinical Staging Model: A Case of Genetic High Risk for Schizophrenia.

PubMed

Lee, Tae Young; Kim, Minah; Kim, Sung Nyun; Kwon, Jun Soo

2017-01-01

The clinical staging model is considered a useful and practical method not only in dealing with the early stage of psychosis overcoming the debate about diagnostic boundaries but also in emerging mood disorder. However, its one limitation is that it cannot discriminate the heterogeneity of individuals at clinical high risk for psychosis, but lumps them all together. Even a healthy offspring of schizophrenia can eventually show clinical symptoms and progress to schizophrenia under the influence of genetic vulnerability and environmental stress even after the peak age of onset of schizophrenia. Therefore, individuals with genetic liability of schizophrenia may require a more intensive intervention than recommended by the staging model based on current clinical status.

Age-Related Macular Degeneration: Genetics and Biology Coming Together

PubMed Central

Fritsche, Lars G.; Fariss, Robert N.; Stambolian, Dwight; Abecasis, Gonçalo R.; Curcio, Christine A.

2014-01-01

Genetic and genomic studies have enhanced our understanding of complex neurodegenerative diseases that exert a devastating impact on individuals and society. One such disease, age-related macular degeneration (AMD), is a major cause of progressive and debilitating visual impairment. Since the pioneering discovery in 2005 of complement factor H (CFH) as a major AMD susceptibility gene, extensive investigations have confirmed 19 additional genetic risk loci, and more are anticipated. In addition to common variants identified by now-conventional genome-wide association studies, targeted genomic sequencing and exome-chip analyses are uncovering rare variant alleles of high impact. Here, we provide a critical review of the ongoing genetic studies and of common and rare risk variants at a total of 20 susceptibility loci, which together explain 40–60% of the disease heritability but provide limited power for diagnostic testing of disease risk. Identification of these susceptibility loci has begun to untangle the complex biological pathways underlying AMD pathophysiology, pointing to new testable paradigms for treatment. PMID:24773320

The Effect of PCDH15 Gene Variations on the Risk of Noise-induced Hearing Loss in a Chinese Population.

PubMed

Xu, Xiang Rong; Wang, Jing Jing; Yang, Qiu Yue; Jiao, Jie; He, Li Hua; Yu, Shan Fa; Gu, Gui Zhen; Chen, Guo Shun; Zhou, Wen Hui; Wu, Hui; Li, Yan Hong; Zhang, Huan Ling; Zhang, Zeng Rui; Jin, Xian Ning

2017-02-01

Noise-induced hearing loss (NIHL) is a complex disease caused by interactions between environmental and genetic factors. This study investigated whether genetic variability in protocadherin related 15 (PCDH15) underlies an increased susceptibility to the development of NIHL in a Chinese population. The results showed that compared with the TT genotype of rs11004085, CT/CC genotypes were associated with an increased risk of NIHL [adjusted odds ratio (OR) = 2.64; 95% confidence interval (CI): 1.14-6.11, P = 0.024]. Additionally, significant interactions between the rs11004085 and rs978842 genetic variations and noise exposure were observed in the high-level exposure groups (P < 0.05). Furthermore, the risk haplotype TAGCC was observed when combined with higher levels of noise exposure (P < 0.05). Thus, our study confirms that genetic variations in PCDH15 modify the susceptibility to NIHL development in humans. Copyright © 2017 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.

Genetic-based prediction of disease traits: prediction is very difficult, especially about the future†

PubMed Central

Schrodi, Steven J.; Mukherjee, Shubhabrata; Shan, Ying; Tromp, Gerard; Sninsky, John J.; Callear, Amy P.; Carter, Tonia C.; Ye, Zhan; Haines, Jonathan L.; Brilliant, Murray H.; Crane, Paul K.; Smelser, Diane T.; Elston, Robert C.; Weeks, Daniel E.

2014-01-01

Translation of results from genetic findings to inform medical practice is a highly anticipated goal of human genetics. The aim of this paper is to review and discuss the role of genetics in medically-relevant prediction. Germline genetics presages disease onset and therefore can contribute prognostic signals that augment laboratory tests and clinical features. As such, the impact of genetic-based predictive models on clinical decisions and therapy choice could be profound. However, given that (i) medical traits result from a complex interplay between genetic and environmental factors, (ii) the underlying genetic architectures for susceptibility to common diseases are not well-understood, and (iii) replicable susceptibility alleles, in combination, account for only a moderate amount of disease heritability, there are substantial challenges to constructing and implementing genetic risk prediction models with high utility. In spite of these challenges, concerted progress has continued in this area with an ongoing accumulation of studies that identify disease predisposing genotypes. Several statistical approaches with the aim of predicting disease have been published. Here we summarize the current state of disease susceptibility mapping and pharmacogenetics efforts for risk prediction, describe methods used to construct and evaluate genetic-based predictive models, and discuss applications. PMID:24917882

Disentangling the heterogeneity of autism spectrum disorder through genetic findings

PubMed Central

Jeste, Shafali S.; Geschwind, Daniel H.

2014-01-01

Autism spectrum disorder (ASD) represents a heterogeneous group of disorders, which presents a substantial challenge to diagnosis and treatment. Over the past decade, considerable progress has been made in the identification of genetic risk factors for ASD that define specific mechanisms and pathways underlying the associated behavioural deficits. In this Review, we discuss how some of the latest advances in the genetics of ASD have facilitated parsing of the phenotypic heterogeneity of this disorder. We argue that only through such advances will we begin to define endophenotypes that can benefit from targeted, hypothesis-driven treatments. We review the latest technologies used to identify and characterize the genetics underlying ASD and then consider three themes—single-gene disorders, the gender bias in ASD, and the genetics of neurological comorbidities—that highlight ways in which we can use genetics to define the many phenotypes within the autism spectrum. We also present current clinical guidelines for genetic testing in ASD and their implications for prognosis and treatment. PMID:24468882

Predictive genetic testing for the identification of high-risk groups: a simulation study on the impact of predictive ability

PubMed Central

2011-01-01

Background Genetic risk models could potentially be useful in identifying high-risk groups for the prevention of complex diseases. We investigated the performance of this risk stratification strategy by examining epidemiological parameters that impact the predictive ability of risk models. Methods We assessed sensitivity, specificity, and positive and negative predictive value for all possible risk thresholds that can define high-risk groups and investigated how these measures depend on the frequency of disease in the population, the frequency of the high-risk group, and the discriminative accuracy of the risk model, as assessed by the area under the receiver-operating characteristic curve (AUC). In a simulation study, we modeled genetic risk scores of 50 genes with equal odds ratios and genotype frequencies, and varied the odds ratios and the disease frequency across scenarios. We also performed a simulation of age-related macular degeneration risk prediction based on published odds ratios and frequencies for six genetic risk variants. Results We show that when the frequency of the high-risk group was lower than the disease frequency, positive predictive value increased with the AUC but sensitivity remained low. When the frequency of the high-risk group was higher than the disease frequency, sensitivity was high but positive predictive value remained low. When both frequencies were equal, both positive predictive value and sensitivity increased with increasing AUC, but higher AUC was needed to maximize both measures. Conclusions The performance of risk stratification is strongly determined by the frequency of the high-risk group relative to the frequency of disease in the population. The identification of high-risk groups with appreciable combinations of sensitivity and positive predictive value requires higher AUC. PMID:21797996

Effect of biodiversity changes in disease risk: exploring disease emergence in a plant-virus system.

PubMed

Pagán, Israel; González-Jara, Pablo; Moreno-Letelier, Alejandra; Rodelo-Urrego, Manuel; Fraile, Aurora; Piñero, Daniel; García-Arenal, Fernando

2012-01-01

The effect of biodiversity on the ability of parasites to infect their host and cause disease (i.e. disease risk) is a major question in pathology, which is central to understand the emergence of infectious diseases, and to develop strategies for their management. Two hypotheses, which can be considered as extremes of a continuum, relate biodiversity to disease risk: One states that biodiversity is positively correlated with disease risk (Amplification Effect), and the second predicts a negative correlation between biodiversity and disease risk (Dilution Effect). Which of them applies better to different host-parasite systems is still a source of debate, due to limited experimental or empirical data. This is especially the case for viral diseases of plants. To address this subject, we have monitored for three years the prevalence of several viruses, and virus-associated symptoms, in populations of wild pepper (chiltepin) under different levels of human management. For each population, we also measured the habitat species diversity, host plant genetic diversity and host plant density. Results indicate that disease and infection risk increased with the level of human management, which was associated with decreased species diversity and host genetic diversity, and with increased host plant density. Importantly, species diversity of the habitat was the primary predictor of disease risk for wild chiltepin populations. This changed in managed populations where host genetic diversity was the primary predictor. Host density was generally a poorer predictor of disease and infection risk. These results support the dilution effect hypothesis, and underline the relevance of different ecological factors in determining disease/infection risk in host plant populations under different levels of anthropic influence. These results are relevant for managing plant diseases and for establishing conservation policies for endangered plant species.

In-silico QTL mapping of postpubertal mammary ductal development in the mouse uncovers potential human breast cancer risk loci

USDA-ARS?s Scientific Manuscript database

Genetic background plays a dominant role in mammary gland development and breast cancer (BrCa). Despite this, the role of genetics is only partially understood. This study used strain-dependent variation in an inbred mouse mapping panel, to identify quantitative trait loci (QTL) underlying structura...

Genetic and environmental influences on the transmission of parental depression to children's depression and conduct disturbance: an extended Children of Twins study.

PubMed

Silberg, Judy L; Maes, Hermine; Eaves, Lindon J

2010-06-01

Despite the increased risk of depression and conduct problems in children of depressed parents, the mechanism by which parental depression affects their children's behavioral and emotional functioning is not well understood. The present study was undertaken to determine whether parental depression represents a genuine environmental risk factor in children's psychopathology, or whether children's depression/conduct can be explained as a secondary consequence of the genetic liability transmitted from parents to their offspring. Children of Twins (COT) data collected on 2,674 adult female and male twins, their spouses, and 2,940 of their children were used to address whether genetic and/or family environmental factors best account for the association between depression in parents and depression and conduct problems in their children. Data collected on juvenile twins from the Virginia Twin Study of Adolescent Behavioral Development (VTSABD) were also included to estimate child-specific genetic and environmental influences apart from those effects arising from the transmission of the parental depression itself. The fit of alternative Children of Twin models were evaluated using the statistical program Mx. The most compelling model for the association between parental and juvenile depression was a model of direct environmental risk. Both family environmental and genetic factors accounted for the association between parental depression and child conduct disturbance. These findings illustrate how a genetically mediated behavior such as parental depression can have both an environmental and genetic impact on children's behavior. We find developmentally specific genetic factors underlying risk to juvenile and adult depression. A shared genetic liability influences both parental depression and juvenile conduct disturbance, implicating child conduct disturbance (CD) as an early indicator of genetic risk for depression in adulthood. In summary, our analyses demonstrate differences in the impact of parental depression on different forms of child psychopathology, and at various stages of development.

Genetic and environmental influences on the transmission of parental depression to children’s depression and conduct disturbance: An extended Children of Twins study

PubMed Central

Silberg, Judy L.; Maes, Hermine; Eaves, Lindon J.

2010-01-01

Background Despite the increased risk of depression and conduct problems in children of depressed parents, the mechanism by which parental depression affects their children’s behavioral and emotional functioning is not well understood. The present study was undertaken to determine whether parental depression represents a genuine environmental risk factor in children’s psychopathology, or whether children’s depression/conduct can be explained as a secondary consequence of the genetic liability transmitted from parents to their offspring. Methods Children of Twins (COT) data collected on 2,674 adult female and male twins, their spouses, and 2,940 of their children were used to address whether genetic and/or family environmental factors best account for the association between depression in parents and depression and conduct problems in their children. Data collected on juvenile twins from the Virginia Twin Study of Adolescent Behavioral Development (VTSABD) were also included to estimate child-specific genetic and environmental influences apart from those effects arising from the transmission of the parental depression itself. The fit of alternative Children of Twin models were evaluated using the statistical program Mx. Results The most compelling model for the association between parental and juvenile depression was a model of direct environmental risk. Both family environmental and genetic factors accounted for the association between parental depression and child conduct disturbance. Conclusions These findings illustrate how a genetically mediated behavior such as parental depression can have both an environmental and genetic impact on children’s behavior. We find developmentally specific genetic factors underlying risk to juvenile and adult depression. A shared genetic liability influence both parental depression and juvenile conduct disturbance, implicating child CD as an early indicator of genetic risk for depression in adulthood. In summary, our analyses demonstrate differences in the impact of parental depression on different forms of child psychopathology, and at various stages of development. PMID:20163497

Familial Hypercholesterolaemia in the Era of Genetic Testing.

PubMed

Hughes, D P; Viljoen, A; Wierzbicki, A S

2016-05-01

Familial hypercholesterolaemia (FH) is a relatively common autosomal dominant genetic condition leading to premature ischaemic vascular disease and mortality if left untreated. Currently, a universal consensus on the diagnostic criteria of FH does not exist but the diagnosis of FH largely relies on the evaluation of low density lipoprotein-cholesterol (LDL-C) levels, a careful documentation of family history, and the identification of clinical features. Diagnosis based purely on lipid levels remains common but there are several limitations to this method of diagnosis both practically and in the proportion of false-negatives and false-positives detected, resulting in substantial under-diagnosis of FH. In some countries, diagnostic algorithms are supplemented with genetic testing of the index case as well as genetic and lipid testing of relatives of the index case. Such "cascade" screening of families following identification of index cases appears to not only improve the rate of diagnosis but is also cost-effective. Currently, we observe a great variation in the excess mortality among patients with FH, which likely reflects a combination of additional genetic and environmental effects on risk overlaid on the risk associated with FH. Current accepted drug therapies for FH include statins and PSCK9 inhibitors. Further work is required to evaluate the cardiovascular disease risk in patients with genetically diagnosed FH and to determine whether a risk-based approach to the treatment of FH is appropriate.

Predictive genetic testing for neurodegenerative conditions: how should conflicting interests within families be managed?

PubMed

Stark, Zornitza; Wallace, Jane; Gillam, Lynn; Burgess, Matthew; Delatycki, Martin B

2016-10-01

Predictive genetic testing for a neurodegenerative condition in one individual in a family may have implications for other family members, in that it can reveal their genetic status. Herein a complex clinical case is explored where the testing wish of one family member was in direct conflict to that of another. The son of a person at 50% risk of an autosomal dominant neurodegenerative condition requested testing to reveal his genetic status. The main reason for the request was if he had the familial mutation, he and his partner planned to utilise preimplantation genetic diagnosis to prevent his offspring having the condition. His at-risk parent was clear that if they found out they had the mutation, they would commit suicide. We assess the potential benefits and harms from acceding to or denying such a request and present an approach to balancing competing rights of individuals within families at risk of late-onset genetic conditions, where family members have irreconcilable differences with respect to predictive testing. We argue that while it may not be possible to completely avoid harm in these situations, it is important to consider the magnitude of risks, and make every effort to limit the potential for adverse outcomes. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Polygenic risk score analysis of pathologically confirmed Alzheimer disease.

PubMed

Escott-Price, Valentina; Myers, Amanda J; Huentelman, Matt; Hardy, John

2017-08-01

Previous estimates of the utility of polygenic risk score analysis for the prediction of Alzheimer disease have given area under the curve (AUC) estimates of <80%. However, these have been based on the genetic analysis of clinical case-control series. Here, we apply the same analytic approaches to a pathological case-control series and show a predictive AUC of 84%. We suggest that this analysis has clinical utility and that there is limited room for further improvement using genetic data. Ann Neurol 2017;82:311-314. © 2017 American Neurological Association.

Height, height-related SNPs, and risk of non-melanoma skin cancer

PubMed Central

Li, Xin; Liang, Liming; Feng, Yen-Chen Anne; De Vivo, Immaculata; Giovannucci, Edward; Tang, Jean Y; Han, Jiali

2017-01-01

Background: Adult height has been associated with risk of several site-specific cancers, including melanoma. However, less attention has been given to non-melanoma skin cancer (NMSC). Methods: We prospectively examined the risk of squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) in relation to adult height in the Nurses' Health Study (NHS, n=117 863) and the Health Professionals Follow-up Study (HPFS, n=51 111). We also investigated the relationships between height-related genetic markers and risk of BCC and SCC in the genetic data sets of the NHS and HPFS (3898 BCC cases, and 8530 BCC controls; 527 SCC cases, and 8962 SCC controls). Results: After controlling for potential confounding factors, the hazard ratios were 1.09 (95% CI: 1.02, 1.15) and 1.10 (95% CI: 1.07, 1.13) for the associations between every 10 cm increase in height and risk of SCC and BCC respectively. None of the 687 height-related single-nucleotide polymorphisms (SNPs) was significantly associated with the risk of SCC or BCC, nor were the genetic scores combining independent height-related loci. Conclusions: Our data from two large cohorts provide further evidence that height is associated with an increased risk of NMSC. More studies on height-related genetic loci and early-life exposures may help clarify the underlying mechanisms. PMID:27846199

Incorporating Known Genetic Variants Does Not Improve the Accuracy of PSA Testing to Identify High Risk Prostate Cancer on Biopsy

PubMed Central

Gilbert, Rebecca; Martin, Richard M.; Evans, David M.; Tilling, Kate; Davey Smith, George; Kemp, John P.; Lane, J. Athene; Hamdy, Freddie C.; Neal, David E.; Donovan, Jenny L.; Metcalfe, Chris

2015-01-01

Introduction Prostate-specific antigen (PSA) testing is a widely accepted screening method for prostate cancer, but with low specificity at thresholds giving good sensitivity. Previous research identified four single nucleotide polymorphisms (SNPs) principally associated with circulating PSA levels rather than with prostate cancer risk (TERT rs2736098, FGFR2 rs10788160, TBX3 rs11067228, KLK3 rs17632542). Removing the genetic contribution to PSA levels may improve the ability of the remaining biologically-determined variation in PSA to discriminate between high and low risk of progression within men with identified prostate cancer. We investigate whether incorporating information on the PSA-SNPs improves the discrimination achieved by a single PSA threshold in men with raised PSA levels. Materials and Methods Men with PSA between 3-10ng/mL and histologically-confirmed prostate cancer were categorised as high or low risk of progression (Low risk: Gleason score≤6 and stage T1-T2a; High risk: Gleason score 7–10 or stage T2C). We used the combined genetic effect of the four PSA-SNPs to calculate a genetically corrected PSA risk score. We calculated the Area under the Curve (AUC) to determine how well genetically corrected PSA risk scores distinguished men at high risk of progression from low risk men. Results The analysis includes 868 men with prostate cancer (Low risk: 684 (78.8%); High risk: 184 (21.2%)). Receiver operating characteristic (ROC) curves indicate that including the 4 PSA-SNPs does not improve the performance of measured PSA as a screening tool for high/low risk prostate cancer (measured PSA level AU C = 59.5% (95% CI: 54.7,64.2) vs additionally including information from the 4 PSA-SNPs AUC = 59.8% (95% CI: 55.2,64.5) (p-value = 0.40)). Conclusion We demonstrate that genetically correcting PSA for the combined genetic effect of four PSA-SNPs, did not improve discrimination between high and low risk prostate cancer in men with raised PSA levels (3-10ng/mL). Replication and gaining more accurate estimates of the effects of the 4 PSA-SNPs and additional variants associated with PSA levels and not prostate cancer could be obtained from subsequent GWAS from larger prospective studies. PMID:26431041

Potential Genetic Risk Factors for Chronic TMD: Genetic Associations from the OPPERA Case Control Study

PubMed Central

Smith, Shad B.; Maixner, Dylan; Greenspan, Joel; Dubner, Ron; Fillingim, Roger; Ohrbach, Richard; Knott, Charles; Slade, Gary; Bair, Eric; Gibson, Dustin G.; Zaykin, Dmitri V.; Weir, Bruce; Maixner, William; Diatchenko, Luda

2011-01-01

Genetic factors play a role in the etiology of persistent pain conditions, putatively by modulating underlying processes such as nociceptive sensitivity, psychological well-being, inflammation, and autonomic response. However, to date, only a few genes have been associated with temporomandibular disorders (TMD). This study evaluated 358 genes involved in pain processes, comparing allelic frequencies between 166 cases with chronic TMD and 1442 controls enrolled in the OPPERA (Orofacial Pain: Prospective Evaluation and Risk Assessment) study cooperative agreement. To enhance statistical power, 182 TMD cases and 170 controls from a similar study were included in the analysis. Genotyping was performed using the Pain Research Panel, an Affymetrix gene chip representing 3295 single nucleotide polymorphisms, including ancestry-informative markers that were used to adjust for population stratification. Adjusted associations between genetic markers and TMD case status were evaluated using logistic regression. The OPPERA findings provided evidence supporting previously-reported associations between TMD and two genes: HTR2A and COMT. Other genes were revealed as potential new genetic risk factors for TMD, including NR3C1, CAMK4, CHRM2, IFRD1, and GRK5. While these findings need to be replicated in independent cohorts, the genes potentially represent important markers of risk for TMD and they identify potential targets for therapeutic intervention. PMID:22074755

Interplay of host genetics and gut microbiota underlying the onset and clinical presentation of inflammatory bowel disease.

PubMed

Imhann, Floris; Vich Vila, Arnau; Bonder, Marc Jan; Fu, Jingyuan; Gevers, Dirk; Visschedijk, Marijn C; Spekhorst, Lieke M; Alberts, Rudi; Franke, Lude; van Dullemen, Hendrik M; Ter Steege, Rinze W F; Huttenhower, Curtis; Dijkstra, Gerard; Xavier, Ramnik J; Festen, Eleonora A M; Wijmenga, Cisca; Zhernakova, Alexandra; Weersma, Rinse K

2018-01-01

Patients with IBD display substantial heterogeneity in clinical characteristics. We hypothesise that individual differences in the complex interaction of the host genome and the gut microbiota can explain the onset and the heterogeneous presentation of IBD. Therefore, we performed a case-control analysis of the gut microbiota, the host genome and the clinical phenotypes of IBD. Stool samples, peripheral blood and extensive phenotype data were collected from 313 patients with IBD and 582 truly healthy controls, selected from a population cohort. The gut microbiota composition was assessed by tag-sequencing the 16S rRNA gene. All participants were genotyped. We composed genetic risk scores from 11 functional genetic variants proven to be associated with IBD in genes that are directly involved in the bacterial handling in the gut: NOD2 , CARD9 , ATG16L1 , IRGM and FUT2 . Strikingly, we observed significant alterations of the gut microbiota of healthy individuals with a high genetic risk for IBD: the IBD genetic risk score was significantly associated with a decrease in the genus Roseburia in healthy controls (false discovery rate 0.017). Moreover, disease location was a major determinant of the gut microbiota: the gut microbiota of patients with colonic Crohn's disease (CD) is different from that of patients with ileal CD, with a decrease in alpha diversity associated to ileal disease (p=3.28×10 -13 ). We show for the first time that genetic risk variants associated with IBD influence the gut microbiota in healthy individuals. Roseburia spp are acetate-to-butyrate converters, and a decrease has already been observed in patients with IBD. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Investigation of Genetic Variation Underlying Central Obesity amongst South Asians.

PubMed

Scott, William R; Zhang, Weihua; Loh, Marie; Tan, Sian-Tsung; Lehne, Benjamin; Afzal, Uzma; Peralta, Juan; Saxena, Richa; Ralhan, Sarju; Wander, Gurpreet S; Bozaoglu, Kiymet; Sanghera, Dharambir K; Elliott, Paul; Scott, James; Chambers, John C; Kooner, Jaspal S

2016-01-01

South Asians are 1/4 of the world's population and have increased susceptibility to central obesity and related cardiometabolic disease. Knowledge of genetic variants affecting risk of central obesity is largely based on genome-wide association studies of common SNPs in Europeans. To evaluate the contribution of DNA sequence variation to the higher levels of central obesity (defined as waist hip ratio adjusted for body mass index, WHR) among South Asians compared to Europeans we carried out: i) a genome-wide association analysis of >6M genetic variants in 10,318 South Asians with focused analysis of population-specific SNPs; ii) an exome-wide association analysis of ~250K SNPs in protein-coding regions in 2,637 South Asians; iii) a comparison of risk allele frequencies and effect sizes of 48 known WHR SNPs in 12,240 South Asians compared to Europeans. In genome-wide analyses, we found no novel associations between common genetic variants and WHR in South Asians at P<5x10-8; variants showing equivocal association with WHR (P<1x10-5) did not replicate at P<0.05 in an independent cohort of South Asians (N = 1,922) or in published, predominantly European meta-analysis data. In the targeted analyses of 122,391 population-specific SNPs we also found no associations with WHR in South Asians at P<0.05 after multiple testing correction. Exome-wide analyses showed no new associations between genetic variants and WHR in South Asians, either individually at P<1.5x10-6 or grouped by gene locus at P<2.5x10-6. At known WHR loci, risk allele frequencies were not higher in South Asians compared to Europeans (P = 0.77), while effect sizes were unexpectedly smaller in South Asians than Europeans (P<5.0x10-8). Our findings argue against an important contribution for population-specific or cosmopolitan genetic variants underlying the increased risk of central obesity in South Asians compared to Europeans.

Investigation of Genetic Variation Underlying Central Obesity amongst South Asians

PubMed Central

Scott, William R.; Zhang, Weihua; Loh, Marie; Tan, Sian-Tsung; Lehne, Benjamin; Afzal, Uzma; Peralta, Juan; Saxena, Richa; Ralhan, Sarju; Wander, Gurpreet S.; Bozaoglu, Kiymet; Sanghera, Dharambir K.; Elliott, Paul; Scott, James; Chambers, John C.; Kooner, Jaspal S.

2016-01-01

South Asians are 1/4 of the world’s population and have increased susceptibility to central obesity and related cardiometabolic disease. Knowledge of genetic variants affecting risk of central obesity is largely based on genome-wide association studies of common SNPs in Europeans. To evaluate the contribution of DNA sequence variation to the higher levels of central obesity (defined as waist hip ratio adjusted for body mass index, WHR) among South Asians compared to Europeans we carried out: i) a genome-wide association analysis of >6M genetic variants in 10,318 South Asians with focused analysis of population-specific SNPs; ii) an exome-wide association analysis of ~250K SNPs in protein-coding regions in 2,637 South Asians; iii) a comparison of risk allele frequencies and effect sizes of 48 known WHR SNPs in 12,240 South Asians compared to Europeans. In genome-wide analyses, we found no novel associations between common genetic variants and WHR in South Asians at P<5x10-8; variants showing equivocal association with WHR (P<1x10-5) did not replicate at P<0.05 in an independent cohort of South Asians (N = 1,922) or in published, predominantly European meta-analysis data. In the targeted analyses of 122,391 population-specific SNPs we also found no associations with WHR in South Asians at P<0.05 after multiple testing correction. Exome-wide analyses showed no new associations between genetic variants and WHR in South Asians, either individually at P<1.5x10-6 or grouped by gene locus at P<2.5x10−6. At known WHR loci, risk allele frequencies were not higher in South Asians compared to Europeans (P = 0.77), while effect sizes were unexpectedly smaller in South Asians than Europeans (P<5.0x10-8). Our findings argue against an important contribution for population-specific or cosmopolitan genetic variants underlying the increased risk of central obesity in South Asians compared to Europeans. PMID:27195708

Molecular mechanisms underlying neurodevelopmental disorders, ADHD and autism.

PubMed

Bădescu, George Mihai; Fîlfan, Mădălina; Sandu, Raluca Elena; Surugiu, Roxana; Ciobanu, Ovidiu; Popa-Wagner, Aurel

2016-01-01

Neurodevelopmental disorders such as attention deficit hyperactivity disorder and autism represent a significant economic burden, which justify vigorous research to uncover its genetics and developmental clinics for a diagnostic workup. The urgency of addressing attention deficit hyperactivity disorder comorbidities is seen in the chilling fact that attention deficit hyperactivity disorder (ADHD), mood disorders, substance use disorders and obesity each increase the risk for mortality. However, data about comorbidity is mainly descriptive, with mechanistic studies limited to genetic epidemiological studies that document shared genetic risk factors among these conditions. Autism and intellectual disability affects 1.5 to 2% of the population in Western countries with many individuals displaying social-emotional agnosia and having difficulty in forming attachments and relationships. Underlying mechanisms include: (i) dysfunctions of neuronal miRNAs; (ii) deletions in the chromosome 21, subtelomeric deletions, duplications and a maternally inherited duplication of the chromosomal region 15q11-q13; (iii) microdeletions in on the long (q) arm of the chromosome in a region designated q21.1 increases the risk of delayed development, intellectual disability, physical abnormalities, and neurological and psychiatric problems associated with autism, schizophrenia, and epilepsy and weak muscle tone (hypotonia); (iv) interstitial duplications encompassing 16p13.11.

77 FR 66851 - Submission for OMB Review; Comment Request The Sister Study: A Prospective Study of the Genetic...

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2012-11-07

... Breast Cancer SUMMARY: Under the provisions of Section 3507(a)(1)(D) of the Paperwork Reduction Act of... Environmental Risk Factors for Breast Cancer. Type of Information Collection Request: Revision. Need and Use of... and environmental risk factors for the development of breast cancer in a high-risk cohort of sisters...

Characterizing Genetic Susceptibility to Breast Cancer in Women of African Ancestry.

PubMed

Feng, Ye; Rhie, Suhn Kyong; Huo, Dezheng; Ruiz-Narvaez, Edward A; Haddad, Stephen A; Ambrosone, Christine B; John, Esther M; Bernstein, Leslie; Zheng, Wei; Hu, Jennifer J; Ziegler, Regina G; Nyante, Sarah; Bandera, Elisa V; Ingles, Sue A; Press, Michael F; Deming, Sandra L; Rodriguez-Gil, Jorge L; Zheng, Yonglan; Yao, Song; Han, Yoo-Jeong; Ogundiran, Temidayo O; Rebbeck, Timothy R; Adebamowo, Clement; Ojengbede, Oladosu; Falusi, Adeyinka G; Hennis, Anselm; Nemesure, Barbara; Ambs, Stefan; Blot, William; Cai, Qiuyin; Signorello, Lisa; Nathanson, Katherine L; Lunetta, Kathryn L; Sucheston-Campbell, Lara E; Bensen, Jeannette T; Chanock, Stephen J; Marchand, Loic Le; Olshan, Andrew F; Kolonel, Laurence N; Conti, David V; Coetzee, Gerhard A; Stram, Daniel O; Olopade, Olufunmilayo I; Palmer, Julie R; Haiman, Christopher A

2017-07-01

Background: Genome-wide association studies have identified approximately 100 common genetic variants associated with breast cancer risk, the majority of which were discovered in women of European ancestry. Because of different patterns of linkage disequilibrium, many of these genetic markers may not represent signals in populations of African ancestry. Methods: We tested 74 breast cancer risk variants and conducted fine-mapping of these susceptibility regions in 6,522 breast cancer cases and 7,643 controls of African ancestry from three genetic consortia (AABC, AMBER, and ROOT). Results: Fifty-four of the 74 variants (73%) were found to have ORs that were directionally consistent with those previously reported, of which 12 were nominally statistically significant ( P < 0.05). Through fine-mapping, in six regions ( 3p24, 12p11, 14q13, 16q12/FTO, 16q23, 19p13 ), we observed seven markers that better represent the underlying risk variant for overall breast cancer or breast cancer subtypes, whereas in another two regions ( 11q13, 16q12/TOX3 ), we identified suggestive evidence of signals that are independent of the reported index variant. Overlapping chromatin features and regulatory elements suggest that many of the risk alleles lie in regions with biological functionality. Conclusions: Through fine-mapping of known susceptibility regions, we have revealed alleles that better characterize breast cancer risk in women of African ancestry. Impact: The risk alleles identified represent genetic markers for modeling and stratifying breast cancer risk in women of African ancestry. Cancer Epidemiol Biomarkers Prev; 26(7); 1016-26. ©2017 AACR . ©2017 American Association for Cancer Research.

Type 2 Diabetes Genetic Predisposition, Obesity, and All-Cause Mortality Risk in the U.S.: A Multiethnic Analysis

PubMed Central

Leong, Aaron; Porneala, Bianca; Dupuis, Josée; Florez, Jose C.

2016-01-01

OBJECTIVE Type 2 diabetes (T2D) is associated with increased mortality in ethnically diverse populations, although the extent to which this association is genetically determined is unknown. We sought to determine whether T2D-related genetic variants predicted all-cause mortality, even after accounting for BMI, in the Third National Health and Nutrition Examination Survey. RESEARCH DESIGN AND METHODS We modeled mortality risk using a genetic risk score (GRS) from a weighted sum of risk alleles at 38 T2D-related single nucleotide polymorphisms. In age-, sex-, and BMI-adjusted logistic regression models, accounting for the complex survey design, we tested the association with mortality in 6,501 participants. We repeated the analysis within ethnicities (2,528 non-Hispanic white [NHW], 1,979 non-Hispanic black [NHB], and 1,994 Mexican American [MA]) and within BMI categories (<25, 25–30, and ≥30 kg/m2). Significance was set at P < 0.05. RESULTS Over 17 years, 1,556 participants died. GRS was associated with mortality risk (OR 1.04 [95% CI 1.00–1.07] per T2D-associated risk allele, P = 0.05). Within ethnicities, GRS was positively associated with mortality risk in NHW and NHB, but not in MA (0.95 [0.90–1.01], P = 0.07). The negative trend in MA was largely driven by those with BMI <25 kg/m2 (0.91 [0.82–1.00]). In NHW, the positive association was strongest among those with BMI ≥30 kg/m2 (1.07 [1.02–1.12]). CONCLUSIONS In the U.S., a higher T2D genetic risk was associated with increased mortality risk, especially among obese NHW. The underlying genetic basis for mortality likely involves complex interactions with factors related to ethnicity, T2D, and body weight. PMID:26884474

Systems Level Analysis of Systemic Sclerosis Shows a Network of Immune and Profibrotic Pathways Connected with Genetic Polymorphisms

PubMed Central

Mahoney, J. Matthew; Taroni, Jaclyn; Martyanov, Viktor; Wood, Tammara A.; Greene, Casey S.; Pioli, Patricia A.; Hinchcliff, Monique E.; Whitfield, Michael L.

2015-01-01

Systemic sclerosis (SSc) is a rare systemic autoimmune disease characterized by skin and organ fibrosis. The pathogenesis of SSc and its progression are poorly understood. The SSc intrinsic gene expression subsets (inflammatory, fibroproliferative, normal-like, and limited) are observed in multiple clinical cohorts of patients with SSc. Analysis of longitudinal skin biopsies suggests that a patient's subset assignment is stable over 6–12 months. Genetically, SSc is multi-factorial with many genetic risk loci for SSc generally and for specific clinical manifestations. Here we identify the genes consistently associated with the intrinsic subsets across three independent cohorts, show the relationship between these genes using a gene-gene interaction network, and place the genetic risk loci in the context of the intrinsic subsets. To identify gene expression modules common to three independent datasets from three different clinical centers, we developed a consensus clustering procedure based on mutual information of partitions, an information theory concept, and performed a meta-analysis of these genome-wide gene expression datasets. We created a gene-gene interaction network of the conserved molecular features across the intrinsic subsets and analyzed their connections with SSc-associated genetic polymorphisms. The network is composed of distinct, but interconnected, components related to interferon activation, M2 macrophages, adaptive immunity, extracellular matrix remodeling, and cell proliferation. The network shows extensive connections between the inflammatory- and fibroproliferative-specific genes. The network also shows connections between these subset-specific genes and 30 SSc-associated polymorphic genes including STAT4, BLK, IRF7, NOTCH4, PLAUR, CSK, IRAK1, and several human leukocyte antigen (HLA) genes. Our analyses suggest that the gene expression changes underlying the SSc subsets may be long-lived, but mechanistically interconnected and related to a patients underlying genetic risk. PMID:25569146

Affiliation with substance-using peers: Examining gene-environment correlations among parent monitoring, polygenic risk, and children's impulsivity.

PubMed

Elam, Kit K; Chassin, Laurie; Lemery-Chalfant, Kathryn; Pandika, Danielle; Wang, Frances L; Bountress, Kaitlin; Dick, Danielle; Agrawal, Arpana

2017-07-01

Parental monitoring can buffer the effect of deviant peers on adolescents' substance use by reducing affiliation with substance-using peers. However, children's genetic predispositions may evoke poorer monitoring, contributing to negative child outcomes. We examined evocative genotype-environment correlations underlying children's genetic predisposition for behavioral undercontrol and parental monitoring in early adolescence via children's impulsivity in middle childhood, and the influence of parental monitoring on affiliation with substance-using peers a year and a half later (n = 359). Genetic predisposition for behavioral undercontrol was captured using a polygenic risk score, and a portion of passive rGE was controlled by including parents' polygenic risk scores. Children's polygenic risk predicted poorer parental monitoring via greater children's impulsivity, indicating evocative rGE, controlling for a portion of passive rGE. Poorer parental monitoring predicted greater children's affiliation with substance-using peers a year and a half later. Results are discussed with respect to gene-environment correlations within developmental cascades. © 2017 Wiley Periodicals, Inc.

Interpretation of genetic testing for lynch syndrome in patients with putative familial colorectal cancer.

PubMed

Rybak, Christina; Hall, Michael J

2011-11-01

Colorectal cancer (CRC) risk assessment involves the evaluation of an individual's personal and family history for characteristics of an inherited susceptibility to develop CRC. Lynch syndrome (LS), or hereditary nonpolyposis colorectal cancer, is the most common cause of hereditary CRC, underlying 2% to 3% of patients with newly diagnosed (incident) CRC. Risk assessment for LS is complex, and the interpretation of the many available tests can be challenging even for the genetics specialist. A move toward universal (reflex) LS screening for mismatch repair in all patients with incident CRC supports the importance of improving the awareness and understanding of LS testing, teaching rational testing approaches, and honing interpretive skills among cancer care providers. This article reviews important clinical features of LS genetic evaluation using 3 pedigree-based case examples from the Fox Chase Cancer Center Gastrointestinal Risk Assessment Clinic.

Molecular Mechanisms and Management of a Cutaneous Inflammatory Disorder: Psoriasis

PubMed Central

Cho, Dae Ho; Park, Hyun Jeong

2017-01-01

Psoriasis is a complex chronic inflammatory cutaneous disorder. To date, robust molecular mechanisms of psoriasis have been reported. Among diverse aberrant immunopathogenetic mechanisms, the current model emphasizes the role of Th1 and the IL-23/Th17 axis, skin-resident immune cells and major signal transduction pathways involved in psoriasis. The multiple genetic risk loci for psoriasis have been rapidly revealed with the advent of a novel technology. Moreover, identifying epigenetic modifications could bridge the gap between genetic and environmental risk factors in psoriasis. This review will provide a better understanding of the pathogenesis of psoriasis by unraveling the complicated interplay among immunological abnormalities, genetic risk foci, epigenetic modification and environmental factors of psoriasis. With advances in molecular biology, diverse new targets are under investigation to manage psoriasis. The recent advances in treatment modalities for psoriasis based on targeted molecules are also discussed. PMID:29232931

Insights into Metabolic Mechanisms Underlying Folate-Responsive Neural Tube Defects: A Minireview

PubMed Central

Beaudin, Anna E.; Stover, Patrick J.

2015-01-01

Neural tube defects (NTDs), including anencephaly and spina bifida, arise from the failure of neurulation during early embryonic development. Neural tube defects are common birth defects with a heterogenous and multifactorial etiology with interacting genetic and environmental risk factors. Although the mechanisms resulting in failure of neural tube closure are unknown, up to 70% of NTDs can be prevented by maternal folic acid supplementation. However, the metabolic mechanisms underlying the association between folic acid and NTD pathogenesis have not been identified. This review summarizes our current understanding of the mechanisms by which impairments in folate metabolism might ultimately lead to failure of neural tube closure, with an emphasis on untangling the relative contributions of nutritional deficiency and genetic risk factors to NTD pathogenesis. PMID:19180567

Genetic variant in CXCL13 gene is associated with susceptibility to intrauterine infection of hepatitis B virus

PubMed Central

Wan, Zhihua; Lin, Xiaofang; Li, Tongyang; Zhou, Aifen; Yang, Mei; Hu, Dan; Feng, Li; Peng, Songxu; Fan, Linlin; Tu, Si; Bin Zhang; Du, Yukai

2016-01-01

Intrauterine infection of hepatitis B virus (HBV), which accounts for the majority of mother-to-child transmission, is one of the main reasons for the failure of combined immunoprophylaxis against the transmission. Recent studies have identified that genetic background might influence the susceptibility to intrauterine infection of HBV. We conducted this study to investigate the associations between 10 genetic variants in 9 genes (SLC10A1, HLA-DP, HLA-C, CXCR5, CXCL13, TLR3, TLR4, TLR9 and UBE2L3) of mothers and their neonates and HBV intrauterine infection. A significantly decreased risk of HBV intrauterine transmission were found among mothers who carried the rs355687 CT genotypes in CXCL13 gene compared to those with CC genotypes (OR = 0.25, 95% CI, 0.08–0.82, P = 0.022); and a marginally significantly decreased risk was also observed under the dominant model (OR = 0.34, 95% CI, 0.11–1.01, P = 0.052). Besides, neonatal rs3130542 in HLA-C gene was found to be marginally significantly associated with decreased risk of HBV intrauterine infection under the additive model (OR = 0.55, 95% CI, 0.29–1.04, P = 0.064). However, we found no evidence of associations between the remaining 8 SNPs and risk of HBV intrauterine infection among mothers and their neonates. In conclusion, this study suggested that genetic variant in CXCL13 gene was associated with susceptibility to intrauterine infection of HBV. PMID:27212637

Apocalypse...now? Molecular epidemiology, predictive genetic tests, and social communication of genetic contents.

PubMed

Castiel, L D

1999-01-01

The author analyzes the underlying theoretical aspects in the construction of the molecular watershed of epidemiology and the concept of genetic risk, focusing on issues raised by contemporary reality: new technologies, globalization, proliferation of communications strategies, and the dilution of identity matrices. He discusses problems pertaining to the establishment of such new interdisciplinary fields as molecular epidemiology and molecular genetics. Finally, he analyzes the repercussions of the social communication of genetic content, especially as related to predictive genetic tests and cloning of animals, based on triumphal, deterministic metaphors sustaining beliefs relating to the existence and supremacy of concepts such as 'purity', 'essence', and 'unification' of rational, integrated 'I's/egos'.

Women-specific risk factors for heart failure: A genetic approach.

PubMed

van der Kemp, Jet; van der Schouw, Yvonne T; Asselbergs, Folkert W; Onland-Moret, N Charlotte

2018-03-01

Heart failure is a complex disease, which is presented differently by men and women. Several studies have shown that reproductive factors, such as age at natural menopause, parity and polycystic ovarian syndrome (PCOS), may play a role in the development of heart failure. Shared genetics may provide clues to underlying mechanisms; however, this has never been examined. Therefore, the aim of the current study was to explore whether any reproductive factor is potentially related to heart failure in women, based on genetic similarities. Conducting a systematic literature review, single nucleotide polymorphisms (SNPs) associated with reproductive factors, heart failure and its risk factors were extracted from recent genome-wide association studies. We tested whether there was any overlap between the SNPs and their proxies of reproductive risk factors with those known for heart failure or its risk factors. In total, 520 genetic variants were found that are associated with reproductive factors, namely age at menarche, age at natural menopause, menstrual cycle length, PCOS, preeclampsia, preterm delivery and spontaneous dizygotic twinning. For heart failure and associated phenotypes, 25 variants were found. Genetic variants for reproductive factors did not overlap with those for heart failure. However, age at menarche, gestational diabetes and PCOS were found to be genetically linked to risk factors for heart failure, such as atrial fibrillation, diabetes and smoking. Corresponding implicated genes, such as TNNI3K, ErbB3, MKL2, MTNR1B and PRKD1, may explain the associations between reproductive factors and heart failure. Exact effector mechanisms of these genes remain to be investigated further. Copyright © 2017. Published by Elsevier B.V.

The Effect on Melanoma Risk of Genes Previously Associated With Telomere Length

PubMed Central

Bishop, D. Timothy; Taylor, John C.; Hayward, Nicholas K.; Brossard, Myriam; Cust, Anne E.; Dunning, Alison M.; Lee, Jeffrey E.; Moses, Eric K.; Akslen, Lars A.; Andresen, Per A.; Avril, Marie-Françoise; Azizi, Esther; Scarrà, Giovanna Bianchi; Brown, Kevin M.; Dębniak, Tadeusz; Elder, David E.; Friedman, Eitan; Ghiorzo, Paola; Gillanders, Elizabeth M.; Goldstein, Alisa M.; Gruis, Nelleke A.; Hansson, Johan; Harland, Mark; Helsing, Per; Hočevar, Marko; Höiom, Veronica; Ingvar, Christian; Kanetsky, Peter A.; Landi, Maria Teresa; Lang, Julie; Lathrop, G. Mark; Lubiński, Jan; Mackie, Rona M.; Martin, Nicholas G.; Molven, Anders; Montgomery, Grant W.; Novaković, Srdjan; Olsson, Håkan; Puig, Susana; Puig-Butille, Joan Anton; Radford-Smith, Graham L.; Randerson-Moor, Juliette; van der Stoep, Nienke; van Doorn, Remco; Whiteman, David C.; MacGregor, Stuart; Pooley, Karen A.; Ward, Sarah V.; Mann, Graham J.; Amos, Christopher I.; Pharoah, Paul D. P.; Demenais, Florence; Law, Matthew H.; Newton Bishop, Julia A.; Barrett, Jennifer H.

2014-01-01

Telomere length has been associated with risk of many cancers, but results are inconsistent. Seven single nucleotide polymorphisms (SNPs) previously associated with mean leukocyte telomere length were either genotyped or well-imputed in 11108 case patients and 13933 control patients from Europe, Israel, the United States and Australia, four of the seven SNPs reached a P value under .05 (two-sided). A genetic score that predicts telomere length, derived from these seven SNPs, is strongly associated (P = 8.92x10-9, two-sided) with melanoma risk. This demonstrates that the previously observed association between longer telomere length and increased melanoma risk is not attributable to confounding via shared environmental effects (such as ultraviolet exposure) or reverse causality. We provide the first proof that multiple germline genetic determinants of telomere length influence cancer risk. PMID:25231748

Characterizing the genetic risk for Type 2 diabetes in a Malaysian multi-ethnic cohort.

PubMed

Abdullah, N; Abdul Murad, N A; Attia, J; Oldmeadow, C; Mohd Haniff, E A; Syafruddin, S E; Abd Jalal, N; Ismail, N; Ishak, M; Jamal, R; Scott, R J; Holliday, E G

2015-10-01

To characterize the association with Type 2 diabetes of known Type 2 diabetes risk variants in people in Malaysia of Malay, Chinese and Indian ancestry who participated in the Malaysian Cohort project. We genotyped 1604 people of Malay ancestry (722 cases, 882 controls), 1654 of Chinese ancestry (819 cases, 835 controls) and 1728 of Indian ancestry (851 cases, 877 controls). First, 62 candidate single-nucleotide polymorphisms previously associated with Type 2 diabetes were assessed for association via logistic regression within ancestral groups and then across ancestral groups using a meta-analysis. Second, estimated odds ratios were assessed for excess directional concordance with previously studied populations. Third, a genetic risk score aggregating allele dosage across the candidate single-nucleotide polymorphisms was tested for association within and across ancestral groups. After Bonferroni correction, seven individual single-nucleotide polymorphisms were associated with Type 2 diabetes in the combined Malaysian sample. We observed a highly significant excess in concordance of effect directions between Malaysian and previously studied populations. The genetic risk score was strongly associated with Type 2 diabetes in all Malaysian groups, explaining from 1.0 to 1.7% of total Type 2 diabetes risk variance. This study suggests there is substantial overlap of the genetic risk alleles underlying Type 2 diabetes in Malaysian and other populations. © 2015 The Authors. Diabetic Medicine © 2015 Diabetes UK.

Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study.

PubMed

Cleynen, Isabelle; Boucher, Gabrielle; Jostins, Luke; Schumm, L Philip; Zeissig, Sebastian; Ahmad, Tariq; Andersen, Vibeke; Andrews, Jane M; Annese, Vito; Brand, Stephan; Brant, Steven R; Cho, Judy H; Daly, Mark J; Dubinsky, Marla; Duerr, Richard H; Ferguson, Lynnette R; Franke, Andre; Gearry, Richard B; Goyette, Philippe; Hakonarson, Hakon; Halfvarson, Jonas; Hov, Johannes R; Huang, Hailang; Kennedy, Nicholas A; Kupcinskas, Limas; Lawrance, Ian C; Lee, James C; Satsangi, Jack; Schreiber, Stephan; Théâtre, Emilie; van der Meulen-de Jong, Andrea E; Weersma, Rinse K; Wilson, David C; Parkes, Miles; Vermeire, Severine; Rioux, John D; Mansfield, John; Silverberg, Mark S; Radford-Smith, Graham; McGovern, Dermot P B; Barrett, Jeffrey C; Lees, Charlie W

2016-01-09

Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34,819 patients (19,713 with Crohn's disease, 14,683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype-phenotype associations across 156,154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. After quality control, the primary analysis included 29,838 patients (16,902 with Crohn's disease, 12,597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1·65 × 10(-78)), even after exclusion of NOD2, MHC, and 3p21 (p=9·23 × 10(-18)). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohn's disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6·8 × 10(-4)). Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohn's disease, colonic Crohn's disease, and ulcerative colitis) than by Crohn's disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time. International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list). Copyright © 2016 Cleynen et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.

Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women.

PubMed

Mehta, Divya; Tropf, Felix C; Gratten, Jacob; Bakshi, Andrew; Zhu, Zhihong; Bacanu, Silviu-Alin; Hemani, Gibran; Magnusson, Patrik K E; Barban, Nicola; Esko, Tõnu; Metspalu, Andres; Snieder, Harold; Mowry, Bryan J; Kendler, Kenneth S; Yang, Jian; Visscher, Peter M; McGrath, John J; Mills, Melinda C; Wray, Naomi R; Lee, S Hong; Andreassen, Ole A; Bramon, Elvira; Bruggeman, Richard; Buxbaum, Joseph D; Cairns, Murray J; Cantor, Rita M; Cloninger, C Robert; Cohen, David; Crespo-Facorro, Benedicto; Darvasi, Ariel; DeLisi, Lynn E; Dinan, Timothy; Djurovic, Srdjan; Donohoe, Gary; Drapeau, Elodie; Escott-Price, Valentina; Freimer, Nelson B; Georgieva, Lyudmila; de Haan, Lieuwe; Henskens, Frans A; Joa, Inge; Julià, Antonio; Khrunin, Andrey; Lerer, Bernard; Limborska, Svetlana; Loughland, Carmel M; Macek, Milan; Magnusson, Patrik K E; Marsal, Sara; McCarley, Robert W; McIntosh, Andrew M; McQuillin, Andrew; Melegh, Bela; Michie, Patricia T; Morris, Derek W; Murphy, Kieran C; Myin-Germeys, Inez; Olincy, Ann; Van Os, Jim; Pantelis, Christos; Posthuma, Danielle; Quested, Digby; Schall, Ulrich; Scott, Rodney J; Seidman, Larry J; Toncheva, Draga; Tooney, Paul A; Waddington, John; Weinberger, Daniel R; Weiser, Mark; Wu, Jing Qin

2016-05-01

A recently published study of national data by McGrath et al in 2014 showed increased risk of schizophrenia (SCZ) in offspring associated with both early and delayed parental age, consistent with a U-shaped relationship. However, it remains unclear if the risk to the child is due to psychosocial factors associated with parental age or if those at higher risk for SCZ tend to have children at an earlier or later age. To determine if there is a genetic association between SCZ and age at first birth (AFB) using genetically informative but independently ascertained data sets. This investigation used multiple independent genome-wide association study data sets. The SCZ sample comprised 18 957 SCZ cases and 22 673 controls in a genome-wide association study from the second phase of the Psychiatric Genomics Consortium, and the AFB sample comprised 12 247 genotyped women measured for AFB from the following 4 community cohorts: Estonia (Estonian Genome Center Biobank, University of Tartu), the Netherlands (LifeLines Cohort Study), Sweden (Swedish Twin Registry), and the United Kingdom (TwinsUK). Schizophrenia genetic risk for each woman in the AFB community sample was estimated using genetic effects inferred from the SCZ genome-wide association study. We tested if SCZ genetic risk was a significant predictor of response variables based on published polynomial functions that described the relationship between maternal age and SCZ risk in offspring in Denmark. We substituted AFB for maternal age in these functions, one of which was corrected for the age of the father, and found that the fit was superior for the model without adjustment for the father's age. We observed a U-shaped relationship between SCZ risk and AFB in the community cohorts, consistent with the previously reported relationship between SCZ risk in offspring and maternal age when not adjusted for the age of the father. We confirmed that SCZ risk profile scores significantly predicted the response variables (coefficient of determination R2 = 1.1E-03, P = 4.1E-04), reflecting the published relationship between maternal age and SCZ risk in offspring by McGrath et al in 2014. This study provides evidence for a significant overlap between genetic factors associated with risk of SCZ and genetic factors associated with AFB. It has been reported that SCZ risk associated with increased maternal age is explained by the age of the father and that de novo mutations that occur more frequently in the germline of older men are the underlying causal mechanism. This explanation may need to be revised if, as suggested herein and if replicated in future studies, there is also increased genetic risk of SCZ in older mothers.

When the face says it all: dysmorphology in identifying syndromic causes of epilepsy.

PubMed

Dixit, Abhijit; Suri, Mohnish

2016-04-01

Identifying the underlying cause of epilepsy often helps in choosing the appropriate management, suggests the long-term prognosis and clarifies the risk of the same condition in relatives. Epilepsy has many causes and a small but significant proportion of affected people have an identifiable genetic cause. Here, we discuss the role of genetic testing in adults with epilepsy, focusing on dysmorphic features noticeable on physical examination that might provide a strong clue to a specific genetic syndrome. We give illustrative examples of recognisable facial 'gestalt'. An astute clinician can recognise such clues and significantly shorten the process of making the underlying diagnosis in their patient. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Genetics of coronary artery disease and myocardial infarction

PubMed Central

Dai, Xuming; Wiernek, Szymon; Evans, James P; Runge, Marschall S

2016-01-01

Atherosclerotic coronary artery disease (CAD) comprises a broad spectrum of clinical entities that include asymptomatic subclinical atherosclerosis and its clinical complications, such as angina pectoris, myocardial infarction (MI) and sudden cardiac death. CAD continues to be the leading cause of death in industrialized society. The long-recognized familial clustering of CAD suggests that genetics plays a central role in its development, with the heritability of CAD and MI estimated at approximately 50% to 60%. Understanding the genetic architecture of CAD and MI has proven to be difficult and costly due to the heterogeneity of clinical CAD and the underlying multi-decade complex pathophysiological processes that involve both genetic and environmental interactions. This review describes the clinical heterogeneity of CAD and MI to clarify the disease spectrum in genetic studies, provides a brief overview of the historical understanding and estimation of the heritability of CAD and MI, recounts major gene discoveries of potential causal mutations in familial CAD and MI, summarizes CAD and MI-associated genetic variants identified using candidate gene approaches and genome-wide association studies (GWAS), and summarizes the current status of the construction and validations of genetic risk scores for lifetime risk prediction and guidance for preventive strategies. Potential protective genetic factors against the development of CAD and MI are also discussed. Finally, GWAS have identified multiple genetic factors associated with an increased risk of in-stent restenosis following stent placement for obstructive CAD. This review will also address genetic factors associated with in-stent restenosis, which may ultimately guide clinical decision-making regarding revascularization strategies for patients with CAD and MI. PMID:26839654

Oxytocin Receptor Genetic and Epigenetic Variations: Association with Child Abuse and Adult Psychiatric Symptoms

ERIC Educational Resources Information Center

Smearman, Erica L.; Almli, Lynn M.; Conneely, Karen N.; Brody, Gene H.; Sales, Jessica M.; Bradley, Bekh; Ressler, Kerry J.; Smith, Alicia K.

2016-01-01

Childhood abuse can alter biological systems and increase risk for adult psychopathology. Epigenetic mechanisms, alterations in DNA structure that regulate the gene expression, are a potential mechanism underlying this risk. While abuse associates with methylation of certain genes, particularly those in the stress response system, no study to date…

The Role of Pharmacogenetics in Atrial Fibrillation Therapeutics: Is Personalized Therapy in Sight?

PubMed

Darbar, Dawood

2016-01-01

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia worldwide requiring therapy. Despite recent advances in catheter-based and surgical therapy, antiarrhythmic drugs (AADs) remain the mainstay of treatment for symptomatic AF. However, response in individual patients is highly variable with over half the patients treated with rhythm control therapy experiencing recurrence of AF within a year. Contemporary AADs used to suppress AF are incompletely and unpredictably effective and associated with significant risks of proarrhythmia and noncardiac toxicities. Furthermore, this "one-size" fits all strategy for selecting antiarrhythmics is based largely on minimizing risk of adverse effects rather than on the likelihood of suppressing AF. The limited success of rhythm control therapy is in part due to heterogeneity of the underlying substrate, interindividual differences in disease mechanisms, and our inability to predict response to AADs in individual patients. Genetic studies of AF over the past decade have revealed that susceptibility to and response to therapy for AF is modulated by the underlying genetic substrate. However, the bedside application of these new discoveries to the management of AF patients has thus far been disappointing. This may in part be related to our limited understanding about genetic predictors of drug response in general, the challenges associated with determining efficacy of response to AADs, and lack of randomized genotype-directed clinical trials. Nonetheless, recent studies have shown that common AF susceptibility risk alleles at the chromosome 4q25 locus modulated response to AADs, electrical cardioversion, and ablation therapy. This monograph discusses how genetic approaches to AF have not only provided important insights into underlying mechanisms but also identified AF subtypes that can be better targeted with more mechanism-based "personalized" therapy.

The Role of Pharmacogenetics in Atrial Fibrillation Therapeutics – Is Personalized Therapy in Sight?

PubMed Central

Darbar, Dawood

2015-01-01

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia worldwide requiring therapy. Despite recent advances in catheter-based and surgical therapy, antiarrhythmic drugs (AAD) remain the mainstay of treatment for symptomatic AF. However, response in individual patients is highly variable with over half the patients treated with rhythm control therapy experiencing recurrence of AF within a year. Contemporary AADs used to suppress AF are incompletely and unpredictably effective and associated with significant risks of proarrhythmia and non-cardiac toxicities. Furthermore, this ‘one-size’ fits all strategy for selecting antiarrhythmics is based largely on minimizing risk of adverse effects rather than on the likelihood of suppressing AF. The limited success of rhythm-control therapy is in part due to heterogeneity of the underlying substrate, interindividual differences in disease mechanisms, and our inability to predict response to AADs in individual patients. Genetic studies of AF over the last decade have revealed that susceptibility to and response to therapy for AF is modulated by the underlying genetic substrate. However, the bedside application of these new discoveries to the management of AF patients has thus far been disappointing. This may in part be related to our limited understanding about genetic predictors of drug response in general, the challenges associated with determining efficacy of response to AADs and lack of randomized genotype-directed clinical trials. Nonetheless, recent studies have shown that common AF susceptibility risk alleles at the chromosome 4q25 locus modulated response to AADs, electrical cardioversion and ablation therapy. This monograph discusses how genetic approaches to AF have not only provided important insights into underlying mechanisms but also identified AF sub-types that can be better targeted with more mechanism-based ‘personalized’ therapy. PMID:25970841

Gene-Gene and Gene-Environment Interactions in Ulcerative Colitis

PubMed Central

Wang, Ming-Hsi; Fiocchi, Claudio; Zhu, Xiaofeng; Ripke, Stephan; Kamboh, M. Ilyas; Rebert, Nancy; Duerr, Richard H.; Achkar, Jean-Paul

2014-01-01

Genome-wide association studies (GWAS) have identified at least 133 ulcerative colitis (UC) associated loci. The role of genetic factors in clinical practice is not clearly defined. The relevance of genetic variants to disease pathogenesis is still uncertain because of not characterized gene-gene and gene-environment interactions. We examined the predictive value of combining the 133 UC risk loci with genetic interactions in an ongoing inflammatory bowel disease (IBD) GWAS. The Wellcome Trust Case-Control Consortium (WTCCC) IBD GWAS was used as a replication cohort. We applied logic regression (LR), a novel adaptive regression methodology, to search for high order interactions. Exploratory genotype correlations with UC sub-phenotypes (extent of disease, need of surgery, age of onset, extra-intestinal manifestations and primary sclerosing cholangitis (PSC)) were conducted. The combination of 133 UC loci yielded good UC risk predictability (area under the curve [AUC] of 0.86). A higher cumulative allele score predicted higher UC risk. Through LR, several lines of evidence for genetic interactions were identified and successfully replicated in the WTCCC cohort. The genetic interactions combined with the gene-smoking interaction significantly improved predictability in the model (AUC, from 0.86 to 0.89, P=3.26E-05). Explained UC variance increased from 37% to 42% after adding the interaction terms. A within case analysis found suggested genetic association with PSC. Our study demonstrates that the LR methodology allows the identification and replication of high order genetic interactions in UC GWAS datasets. UC risk can be predicted by a 133 loci and improved by adding gene-gene and gene-environment interactions. PMID:24241240

Polygenic Risk for Schizophrenia Influences Cortical Gyrification in 2 Independent General Populations.

PubMed

Liu, Bing; Zhang, Xiaolong; Cui, Yue; Qin, Wen; Tao, Yan; Li, Jin; Yu, Chunshui; Jiang, Tianzi

2017-05-01

Schizophrenia is highly heritable, whereas the effect of each genetic variant is very weak. Since clinical heterogeneity and complexity of schizophrenia is high, considerable effort has been made to relate genetic variants to underlying neurobiological aspects of schizophrenia (endophenotypes). Given the polygenic nature of schizophrenia, our goal was to form a measure of additive genetic risk and explore its relationship to cortical morphology. Utilizing the data from a recent genome-wide association study that included nearly 37 000 cases of schizophrenia, we computed a polygenic risk score (PGRS) for each subject in 2 independent and healthy general populations. We then investigated the effect of polygenic risk for schizophrenia on cortical gyrification calculated from 3.0T structural imaging data in the discovery dataset (N = 315) and replication dataset (N = 357). We found a consistent effect of the polygenic risk for schizophrenia on cortical gyrification in the inferior parietal lobules in 2 independent general-population samples. A higher PGRS was significantly associated with a lower local gyrification index in the bilateral inferior parietal lobles, where case-control differences have been reported in previous studies on schizophrenia. Our findings strongly support the effectiveness of both PGRSs and endophenotypes in establishing the genetic architecture of psychiatry. Our findings may provide some implications regarding individual differences in the genetic risk for schizophrenia to cortical morphology and brain development. © The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Vascular Health and Genetic Risk Affect Mild Cognitive Impairment Status and 4-Year Stability: Evidence From the Victoria Longitudinal Study

PubMed Central

MacDonald, Stuart W. S.; Vergote, David; Jhamandas, Jack; Westaway, David; Dixon, Roger A.

2016-01-01

Objectives: Mild cognitive impairment (MCI) is a high-risk condition for progression to Alzheimer’s disease (AD). Vascular health is a key mechanism underlying age-related cognitive decline and neurodegeneration. AD-related genetic risk factors may be associated with preclinical cognitive status changes. We examine independent and cross-domain interactive effects of vascular and genetic markers for predicting MCI status and stability. Method: We used cross-sectional and 2-wave longitudinal data from the Victoria Longitudinal Study, including indicators of vascular health (e.g., reported vascular diseases, measured lung capacity and pulse rate) and genetic risk factors—that is, apolipoprotein E (APOE; rs429358 and rs7412; the presence vs absence of ε4) and catechol-O-methyltransferase (COMT; rs4680; met/met vs val/val). We examined associations with objectively classified (a) cognitive status at baseline (not impaired congnitive (NIC) controls vs MCI) and (b) stability or transition of cognitive status across a 4-year interval (stable NIC–NIC vs chronic MCI–MCI or transitional NIC–MCI). Results: Using logistic regression, indicators of vascular health, both independently and interactively with APOE ε4, were associated with risk of MCI at baseline and/or associated with MCI conversion or MCI stability over the retest interval. Discussion: Several vascular health markers of aging predict MCI risk. Interactively, APOE ε4 may intensify the vascular health risk for MCI. PMID:26362601

Management of pregnancy in women with genetic disorders, Part 1: Disorders of the connective tissue, muscle, vascular, and skeletal systems.

PubMed

Chetty, Shilpa Prema; Shaffer, Brian L; Norton, Mary E

2011-11-01

Due to early diagnosis and increasingly effective medical advances, the number of women with various genetic syndromes who are undergoing pregnancy is increasing, and this represents an important issue for providers of obstetric care. Each year more women with genetic disease reach childbearing age. Advances in assisted reproductive technology have enabled pregnancy in a cohort of woman who may experience impaired fertility due to their underlying diagnosis. Management of these women requires coordination of care by healthcare providers from multiple specialties to optimize outcomes. Potentially serious medical issues specific to each diagnosis often exist in the preconception, antepartum, intrapartum, and postpartum periods, all of which must be recognized to allow timely diagnosis and treatment. The fetus may also face issues related to risk for inheritance of the genetic disorder itself, as well as risks related to the chronic disease status of the mother. This article will explore the issues faced by women with various genetic disorders that may affect connective tissue, muscular, vascular, and skeletal systems. Obstetricians & Gynecologists and Family Physicians. After the completing the CME activity, physicians should be better able to classify the cardiovascular manifestations observed in Marfan syndrome and Ehlers-Danlos, evaluate prenatal diagnostic options and limitations for various genetic syndromes, assess the risks to the fetus in women with various genetic syndromes. Determine whether there is a preferred mode of delivery for pregnant patients with various genetic syndromes described in this paper.

On the validity of within-nuclear-family genetic association analysis in samples of extended families.

PubMed

Bureau, Alexandre; Duchesne, Thierry

2015-12-01

Splitting extended families into their component nuclear families to apply a genetic association method designed for nuclear families is a widespread practice in familial genetic studies. Dependence among genotypes and phenotypes of nuclear families from the same extended family arises because of genetic linkage of the tested marker with a risk variant or because of familial specificity of genetic effects due to gene-environment interaction. This raises concerns about the validity of inference conducted under the assumption of independence of the nuclear families. We indeed prove theoretically that, in a conditional logistic regression analysis applicable to disease cases and their genotyped parents, the naive model-based estimator of the variance of the coefficient estimates underestimates the true variance. However, simulations with realistic effect sizes of risk variants and variation of this effect from family to family reveal that the underestimation is negligible. The simulations also show the greater efficiency of the model-based variance estimator compared to a robust empirical estimator. Our recommendation is therefore, to use the model-based estimator of variance for inference on effects of genetic variants.

Determining Risk of Barrett's Esophagus and Esophageal Adenocarcinoma Based on Epidemiologic Factors and Genetic Variants.

PubMed

Dong, Jing; Buas, Matthew F; Gharahkhani, Puya; Kendall, Bradley J; Onstad, Lynn; Zhao, Shanshan; Anderson, Lesley A; Wu, Anna H; Ye, Weimin; Bird, Nigel C; Bernstein, Leslie; Chow, Wong-Ho; Gammon, Marilie D; Liu, Geoffrey; Caldas, Carlos; Pharoah, Paul D; Risch, Harvey A; Iyer, Prasad G; Reid, Brian J; Hardie, Laura J; Lagergren, Jesper; Shaheen, Nicholas J; Corley, Douglas A; Fitzgerald, Rebecca C; Whiteman, David C; Vaughan, Thomas L; Thrift, Aaron P

2018-04-01

We developed comprehensive models to determine risk of Barrett's esophagus (BE) or esophageal adenocarcinoma (EAC) based on genetic and non-genetic factors. We used pooled data from 3288 patients with BE, 2511 patients with EAC, and 2177 individuals without either (controls) from participants in the international Barrett's and EAC consortium as well as the United Kingdom's BE gene study and stomach and esophageal cancer study. We collected data on 23 genetic variants associated with risk for BE or EAC, and constructed a polygenic risk score (PRS) for cases and controls by summing the risk allele counts for the variants weighted by their natural log-transformed effect estimates (odds ratios) extracted from genome-wide association studies. We also collected data on demographic and lifestyle factors (age, sex, smoking, body mass index, use of nonsteroidal anti-inflammatory drugs) and symptoms of gastroesophageal reflux disease (GERD). Risk models with various combinations of non-genetic factors and the PRS were compared for their accuracy in identifying patients with BE or EAC using the area under the receiver operating characteristic curve (AUC) analysis. Individuals in the highest quartile of risk, based on genetic factors (PRS), had a 2-fold higher risk of BE (odds ratio, 2.22; 95% confidence interval, 1.89-2.60) or EAC (odds ratio, 2.46; 95% confidence interval, 2.07-2.92) than individual in the lowest quartile of risk based on PRS. Risk models developed based on only demographic or lifestyle factors or GERD symptoms identified patients with BE or EAC with AUC values ranging from 0.637 to 0.667. Combining data on demographic or lifestyle factors with data on GERD symptoms identified patients with BE with an AUC of 0.793 and patients with EAC with an AUC of 0.745. Including PRSs with these data only minimally increased the AUC values for BE (to 0.799) and EAC (to 0.754). Including the PRSs in the model developed based on non-genetic factors resulted in a net reclassification improvement for BE of 3.0% and for EAC of 5.6%. We used data from 3 large databases of patients from studies of BE or EAC to develop a risk prediction model based on genetic, clinical, and demographic/lifestyle factors. We identified a PRS that increases discrimination and net reclassification of individuals with vs without BE and EAC. However, the absolute magnitude of improvement is not sufficient to justify its clinical use. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

Involvement and Influence of Healthcare Providers, Family Members, and Other Mutation Carriers in the Cancer Risk Management Decision-Making Process of BRCA1 and BRCA2 Mutation Carriers.

PubMed

Puski, Athena; Hovick, Shelly; Senter, Leigha; Toland, Amanda Ewart

2018-03-29

Deciding between increased cancer screening or prophylactic surgery and the timing of such procedures can be a difficult and complex process for women with BRCA mutations. There are gaps in our understanding of involvement of others in the decision-making process for women with BRCA mutations. This study evaluated the management decision-making process of women with BRCA mutations, focusing on the involvement of others. Grounded theory was used to analyze and code risk management decision-making information from interviews with 20 BRCA mutation carriers. Unaffected at-risk participants with a BRCA mutation, those under age 40, and those with no children described having a difficult time making risk management decisions. Physicians were an integral part of the decision-making process by providing decisional support and management recommendations. Family members and other mutation carriers filled similar yet distinct roles by providing experiential information as well as decisional and emotional support for carriers. Participants described genetic counselors as short-term providers of risk information and management recommendations. The study findings suggest that unaffected at-risk women, women under 40, and those who do not have children may benefit from additional support and information during the decision-making process. Genetic counselors are well trained to help women through this process and connect them with resources, and may be under-utilized in long-term follow-up for women with a BRCA mutation.

Association between vascular endothelial growth factor polymorphism and recurrent pregnancy loss: A systematic review and meta-analysis.

PubMed

Sun, Yaling; Chen, Min; Mao, Benyu; Cheng, Xianglin; Zhang, Xianping; Xu, Chuanxin

2017-04-01

Some studies have reported that vascular endothelial growth factor (VEGF) genetic polymorphisms are associated with recurrent pregnancy loss (RPL), but the results are controversial. This study is aimed to quantify the strength of this association. A systematic review of the published literature from Medline, Springer, and China National Knowledge Infra structure (CNKI) databases was conducted and investigations of VEGF genetic polymorphisms in RPL were selected. We estimated the pooled odds ratio (OR) to assess this possible association. Fifteen case-control studies comprising 2702 cases and 2667 controls and including five genetic polymorphisms (rs3025039, rs833061, rs15703060, rs2010963 and rs699947) were eligible for this meta-analysis. The overall analysis suggested that only two genetic polymorphisms (rs1570360, rs3025039) were associated with increased risk of RPL. A significant increased risk between VEGF rs1570360 polymorphism and RPL was only found under the dominant model in Caucasians (OR=1.70, 95% CI 1.02-2.82, P=0.04). Whereas, we found that VEGF rs3025039 polymorphism was significantly associated with RPL both under the dominant and recessive model in East Asians, and their summary odd ratios and 95% CIs were 1.26, 1.04-1.53, P=0.02 and 2.94, 1.80-4.83, P=0, respectively. This meta-analysis showed that only rs1570360 (especially in Caucasians) and rs3025039 (especially in East Asians) may be risk factors for RPL. Copyright © 2017 Elsevier B.V. All rights reserved.

Association of substance use disorders with childhood trauma but not African genetic heritage in an African American cohort.

PubMed

Ducci, Francesca; Roy, Alec; Shen, Pei-Hong; Yuan, Qiaoping; Yuan, Nicole P; Hodgkinson, Colin A; Goldman, Lynn R; Goldman, David

2009-09-01

Genetic variation influences differential vulnerability to addiction within populations. However, it remains unclear whether differences in frequencies of vulnerability alleles contribute to disparities between populations and to what extent ancestry correlates with differential exposure to environmental risk factors, including poverty and trauma. The authors used 186 ancestry-informative markers to measure African ancestry in 407 addicts and 457 comparison subjects self-identified as African Americans. The reference group was 1,051 individuals from the Human Genome Diversity Cell Line Panel, which includes 51 diverse populations representing most worldwide genetic diversity. African Americans varied in degrees of African, European, Middle Eastern, and Central Asian genetic heritage. The overall level of African ancestry was actually smaller among cocaine, opiate, and alcohol addicts (proportion=0.76-0.78) than nonaddicted African American comparison subjects (proportion=0.81). African ancestry was associated with living in impoverished neighborhoods, a factor previously associated with risk. There was no association between African ancestry and exposure to childhood abuse or neglect, a factor that strongly predicted all types of addictions. These results suggest that African genetic heritage does not increase the likelihood of genetic risk for addictions. They highlight the complex interrelation between genetic ancestry and social, economic, and environmental conditions and the strong relation of those factors to addiction. Studies of epidemiological samples characterized for genetic ancestry and social, psychological, demographic, economic, cultural, and historical factors are needed to better disentangle the effects of genetic and environmental factors underlying interpopulation differences in vulnerability to addiction and other health disparities.

Imaging genetics of schizophrenia in the post-GWAS era.

PubMed

Arslan, Ayla

2018-01-03

Imaging genetics is a research methodology studying the effect of genetic variation on brain structure, function, behavior, and risk for psychopathology. Since the early 2000s, imaging genetics has been increasingly used in the research of schizophrenia (SZ). SZ is a severe mental disorder with no precise knowledge of its underlying neurobiology, however, new genetic and neurobiological data generate a climate for new avenues. The accumulating data of genome wide association studies (GWAS) continuously decode SZ risk genes. Global neuroimaging consortia produce collections of brain phenotypes from tens of thousands of people. In this context, imaging genetics will be strategically important both for the validation and discovery of SZ related findings. Thus, the study of GWAS supported risk variants as candidate genes to validate by neuroimaging is one trend. The study of epigenetic differences in relation to variations of brain phenotypes and the study of large scale multivariate analysis of genome wide and brain wide associations are other trends. While these studies hold a big potential for understanding the neurobiology of SZ, the problem of reproducibility appears as a major challenge, which requires standardizations in study designs and compensations of methodological limitations such as sensitivity and specificity. On the other hand, advancements of neuroimaging, optical and electron microscopy along with the use of genetically encoded fluorescent probes and robust statistical approaches will not only catalyze integrative methodologies but also will help better design the imaging genetics studies. In this invited paper, I will discuss the current perspective of imaging genetics and emerging opportunities of SZ research. Copyright © 2017 Elsevier Inc. All rights reserved.

Association of Substance Use Disorders With Childhood Trauma but not African Genetic Heritage in an African American Cohort

PubMed Central

Ducci, Francesca; Roy, Alec; Shen, Pei-Hong; Yuan, Qiaoping; Yuan, Nicole P.; Hodgkinson, Colin A.; Goldman, Lynn R.; Goldman, David

2009-01-01

Objective Genetic variation influences differential vulnerability to addiction within populations. However, it remains unclear whether differences in frequencies of vulnerability alleles contribute to disparities between populations and to what extent ancestry correlates with differential exposure to environmental risk factors, including poverty and trauma. Method The authors used 186 ancestry-informative markers to measure African ancestry in 407 addicts and 457 comparison subjects self-identified as African Americans. The reference group was 1,051 individuals from the Human Genome Diversity Cell Line Panel, which includes 51 diverse populations representing most worldwide genetic diversity. Results African Americans varied in degrees of African, European, Middle Eastern, and Central Asian genetic heritage. The overall level of African ancestry was actually smaller among cocaine, opiate, and alcohol addicts (proportion=0.76–0.78) than nonaddicted African American comparison subjects (proportion=0.81). African ancestry was associated with living in impoverished neighborhoods, a factor previously associated with risk. There was no association between African ancestry and exposure to childhood abuse or neglect, a factor that strongly predicted all types of addictions. Conclusions These results suggest that African genetic heritage does not increase the likelihood of genetic risk for addictions. They highlight the complex interrelation between genetic ancestry and social, economic, and environmental conditions and the strong relation of those factors to addiction. Studies of epidemiological samples characterized for genetic ancestry and social, psychological, demographic, economic, cultural, and historical factors are needed to better disentangle the effects of genetic and environmental factors underlying interpopulation differences in vulnerability to addiction and other health disparities. PMID:19605534

Epigenetics in Developmental Disorder: ADHD and Endophenotypes

PubMed Central

Archer, Trevor; Oscar-Berman, Marlene; Blum, Kenneth

2011-01-01

Heterogeneity in attention-deficit/hyperactivity disorder (ADHD), with complex interactive operations of genetic and environmental factors, is expressed in a variety of disorder manifestations: severity, co-morbidities of symptoms, and the effects of genes on phenotypes. Neurodevelopmental influences of genomic imprinting have set the stage for the structural-physiological variations that modulate the cognitive, affective, and pathophysiological domains of ADHD. The relative contributions of genetic and environmental factors provide rapidly proliferating insights into the developmental trajectory of the condition, both structurally and functionally. Parent-of-origin effects seem to support the notion that genetic risks for disease process debut often interact with the social environment, i.e., the parental environment in infants and young children. The notion of endophenotypes, markers of an underlying liability to the disorder, may facilitate detection of genetic risks relative to a complex clinical disorder. Simple genetic association has proven insufficient to explain the spectrum of ADHD. At a primary level of analysis, the consideration of epigenetic regulation of brain signalling mechanisms, dopamine, serotonin, and noradrenaline is examined. Neurotrophic factors that participate in the neurogenesis, survival, and functional maintenance of brain systems, are involved in neuroplasticity alterations underlying brain disorders, and are implicated in the genetic predisposition to ADHD, but not obviously, nor in a simple or straightforward fashion. In the context of intervention, genetic linkage studies of ADHD pharmacological intervention have demonstrated that associations have fitted the “drug response phenotype,” rather than the disorder diagnosis. Despite conflicting evidence for the existence, or not, of genetic associations between disorder diagnosis and genes regulating the structure and function of neurotransmitters and brain-derived neurotrophic factor (BDNF), associations between symptoms-profiles endophenotypes and single nucleotide polymorphisms appear reassuring. PMID:22224195

An Underlying Common Factor, Influenced by Genetics and Unique Environment, Explains the Covariation Between Major Depressive Disorder, Generalized Anxiety Disorder, and Burnout: A Swedish Twin Study.

PubMed

Mather, Lisa; Blom, Victoria; Bergström, Gunnar; Svedberg, Pia

2016-12-01

Depression and anxiety are highly comorbid due to shared genetic risk factors, but less is known about whether burnout shares these risk factors. We aimed to examine whether the covariation between major depressive disorder (MDD), generalized anxiety disorder (GAD), and burnout is explained by common genetic and/or environmental factors. This cross-sectional study included 25,378 Swedish twins responding to a survey in 2005-2006. Structural equation models were used to analyze whether the trait variances and covariances were due to additive genetics, non-additive genetics, shared environment, and unique environment. Univariate analyses tested sex limitation models and multivariate analysis tested Cholesky, independent pathway, and common pathway models. The phenotypic correlations were 0.71 (0.69-0.74) between MDD and GAD, 0.58 (0.56-0.60) between MDD and burnout, and 0.53 (0.50-0.56) between GAD and burnout. Heritabilities were 45% for MDD, 49% for GAD, and 38% for burnout; no statistically significant sex differences were found. A common pathway model was chosen as the final model. The common factor was influenced by genetics (58%) and unique environment (42%), and explained 77% of the variation in MDD, 69% in GAD, and 44% in burnout. GAD and burnout had additive genetic factors unique to the phenotypes (11% each), while MDD did not. Unique environment explained 23% of the variability in MDD, 20% in GAD, and 45% in burnout. In conclusion, the covariation was explained by an underlying common factor, largely influenced by genetics. Burnout was to a large degree influenced by unique environmental factors not shared with MDD and GAD.

Common genetic risk factors for coronary artery disease: new opportunities for prevention?

PubMed

Hamrefors, Viktor

2017-05-01

Atherosclerotic cardiovascular disease (CVD) is a leading cause of mortality and morbidity worldwide, with coronary artery disease (CAD) being the single leading cause of death. Better control of risk factors, enhanced diagnostic techniques and improved medical therapies have all substantially decreased the mortality of CAD in developed countries. However, CAD and other forms of atherosclerotic CVD are projected to remain the leading cause of death by 2030 and we face a number of challenges if the outcomes of CAD are to be further improved. The fact that a substantial fraction of high-risk subjects do not reach treatment goals for important risk factors is one of these challenges. At the same time, there is also a non-negotiable fraction of 'concealed' high-risk subjects who are not detected by current risk algorithms and diagnostic modalities. In recent years, we have started to rapidly increase our knowledge of the framework of common genetics underlying CAD and atherosclerotic CVD in the population. In conjunction with modern diagnostic and therapeutic options, this new genetic knowledge may provide a valuable tool for further improvements in prevention. This review summarizes the recent findings from the search for common genetic risk factors for CAD. Furthermore, the author discusses how such recent findings could potentially be used in a number of clinical applications within CAD prevention, including in clinical risk stratification, in prediction of drug treatment response and in the search for targets for novel preventive therapies. © 2015 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.

The influence of polygenic risk for bipolar disorder on neural activation assessed using fMRI

PubMed Central

Whalley, H C; Papmeyer, M; Sprooten, E; Romaniuk, L; Blackwood, D H; Glahn, D C; Hall, J; Lawrie, S M; Sussmann, Je; McIntosh, A M

2012-01-01

Genome-wide association studies (GWAS) have demonstrated a significant polygenic contribution to bipolar disorder (BD) where disease risk is determined by the summation of many alleles of small individual magnitude. Modelling polygenic risk scores may be a powerful way of identifying disrupted brain regions whose genetic architecture is related to that of BD. We determined the extent to which common genetic variation underlying risk to BD affected neural activation during an executive processing/language task in individuals at familial risk of BD and healthy controls. Polygenic risk scores were calculated for each individual based on GWAS data from the Psychiatric GWAS Consortium Bipolar Disorder Working Group (PGC-BD) of over 16 000 subjects. The familial group had a significantly higher polygene score than the control group (P=0.04). There were no significant group by polygene interaction effects in terms of association with brain activation. However, we did find that an increasing polygenic risk allele load for BD was associated with increased activation in limbic regions previously implicated in BD, including the anterior cingulate cortex and amygdala, across both groups. The findings suggest that this novel polygenic approach to examine brain-imaging data may be a useful means of identifying genetically mediated traits mechanistically linked to the aetiology of BD. PMID:22760554

Improving coeliac disease risk prediction by testing non-HLA variants additional to HLA variants.

PubMed

Romanos, Jihane; Rosén, Anna; Kumar, Vinod; Trynka, Gosia; Franke, Lude; Szperl, Agata; Gutierrez-Achury, Javier; van Diemen, Cleo C; Kanninga, Roan; Jankipersadsing, Soesma A; Steck, Andrea; Eisenbarth, Georges; van Heel, David A; Cukrowska, Bozena; Bruno, Valentina; Mazzilli, Maria Cristina; Núñez, Concepcion; Bilbao, Jose Ramon; Mearin, M Luisa; Barisani, Donatella; Rewers, Marian; Norris, Jill M; Ivarsson, Anneli; Boezen, H Marieke; Liu, Edwin; Wijmenga, Cisca

2014-03-01

The majority of coeliac disease (CD) patients are not being properly diagnosed and therefore remain untreated, leading to a greater risk of developing CD-associated complications. The major genetic risk heterodimer, HLA-DQ2 and DQ8, is already used clinically to help exclude disease. However, approximately 40% of the population carry these alleles and the majority never develop CD. We explored whether CD risk prediction can be improved by adding non-HLA-susceptible variants to common HLA testing. We developed an average weighted genetic risk score with 10, 26 and 57 single nucleotide polymorphisms (SNP) in 2675 cases and 2815 controls and assessed the improvement in risk prediction provided by the non-HLA SNP. Moreover, we assessed the transferability of the genetic risk model with 26 non-HLA variants to a nested case-control population (n=1709) and a prospective cohort (n=1245) and then tested how well this model predicted CD outcome for 985 independent individuals. Adding 57 non-HLA variants to HLA testing showed a statistically significant improvement compared to scores from models based on HLA only, HLA plus 10 SNP and HLA plus 26 SNP. With 57 non-HLA variants, the area under the receiver operator characteristic curve reached 0.854 compared to 0.823 for HLA only, and 11.1% of individuals were reclassified to a more accurate risk group. We show that the risk model with HLA plus 26 SNP is useful in independent populations. Predicting risk with 57 additional non-HLA variants improved the identification of potential CD patients. This demonstrates a possible role for combined HLA and non-HLA genetic testing in diagnostic work for CD.

Effects of autozygosity and schizophrenia polygenic risk on cognitive and brain developmental trajectories.

PubMed

Córdova-Palomera, Aldo; Kaufmann, Tobias; Bettella, Francesco; Wang, Yunpeng; Doan, Nhat Trung; van der Meer, Dennis; Alnæs, Dag; Rokicki, Jaroslav; Moberget, Torgeir; Sønderby, Ida Elken; Andreassen, Ole A; Westlye, Lars T

2018-04-27

Cognitive and brain development are determined by dynamic interactions between genes and environment across the lifespan. Aside from marker-by-marker analyses of polymorphisms, biologically meaningful features of the whole genome (derived from the combined effect of individual markers) have been postulated to inform on human phenotypes including cognitive traits and their underlying biological substrate. Here, estimates of inbreeding and genetic susceptibility for schizophrenia calculated from genome-wide data-runs of homozygosity (ROH) and schizophrenia polygenic risk score (PGRS)-are analyzed in relation to cognitive abilities (n = 4183) and brain structure (n = 516) in a general-population sample of European-ancestry participants aged 8-22, from the Philadelphia Neurodevelopmental Cohort. The findings suggest that a higher ROH burden and higher schizophrenia PGRS are associated with higher intelligence. Cognition-ROH and cognition-PGRS associations obtained in this cohort may, respectively, evidence that assortative mating influences intelligence, and that individuals with high schizophrenia genetic risk who do not transition to disease status are cognitively resilient. Neuroanatomical data showed that the effects of schizophrenia PGRS on cognition could be modulated by brain structure, although larger imaging datasets are needed to accurately disentangle the underlying neural mechanisms linking IQ with both inbreeding and the genetic burden for schizophrenia.

Neurobiological correlates in forensic assessment: a systematic review.

PubMed

van der Gronde, Toon; Kempes, Maaike; van El, Carla; Rinne, Thomas; Pieters, Toine

2014-01-01

With the increased knowledge of biological risk factors, interest in including this information in forensic assessments is growing. Currently, forensic assessments are predominantly focused on psychosocial factors. A better understanding of the neurobiology of violent criminal behaviour and biological risk factors could improve forensic assessments. To provide an overview of the current evidence about biological risk factors that predispose people to antisocial and violent behaviour, and determine its usefulness in forensic assessment. A systematic literature search was conducted using articles from PsycINFO, Embase and Pubmed published between 2000 and 2013. This review shows that much research on the relationship between genetic predisposition and neurobiological alterations with aggression is performed on psychiatric patients or normal populations. However, the number of studies comparing offenders is limited. There is still a great need to understand how genetic and neurobiological alterations and/or deficits are related to violent behaviour, specifically criminality. Most studies focus on only one of the genetic or neurobiological fields related to antisocial and/or violent behaviour. To reliably correlate the findings of these fields, a standardization of methodology is urgently needed. Findings from the current review suggest that violent aggression, like all forms of human behaviour, both develops under specific genetic and environmental conditions, and requires interplay between these conditions. Violence should be considered as the end product of a chain of life events, during which risks accumulate and potentially reinforce each other, displaying or triggering a specific situation. This systematic review did not find evidence of predispositions or neurobiological alterations that solely explain antisocial or violent behaviour. With better designed studies, more correlation between diverse fields, and more standardisation, it might be possible to elucidate underlying mechanisms. Thus, we advocate maintaining the current case-by-case differentiated approach to evidence-based forensic assessment.

Neurobiological Correlates in Forensic Assessment: A Systematic Review

PubMed Central

van der Gronde, Toon; Kempes, Maaike; van El, Carla; Rinne, Thomas; Pieters, Toine

2014-01-01

Background With the increased knowledge of biological risk factors, interest in including this information in forensic assessments is growing. Currently, forensic assessments are predominantly focused on psychosocial factors. A better understanding of the neurobiology of violent criminal behaviour and biological risk factors could improve forensic assessments. Objective To provide an overview of the current evidence about biological risk factors that predispose people to antisocial and violent behaviour, and determine its usefulness in forensic assessment. Methods A systematic literature search was conducted using articles from PsycINFO, Embase and Pubmed published between 2000 and 2013. Results This review shows that much research on the relationship between genetic predisposition and neurobiological alterations with aggression is performed on psychiatric patients or normal populations. However, the number of studies comparing offenders is limited. There is still a great need to understand how genetic and neurobiological alterations and/or deficits are related to violent behaviour, specifically criminality. Most studies focus on only one of the genetic or neurobiological fields related to antisocial and/or violent behaviour. To reliably correlate the findings of these fields, a standardization of methodology is urgently needed. Conclusion Findings from the current review suggest that violent aggression, like all forms of human behaviour, both develops under specific genetic and environmental conditions, and requires interplay between these conditions. Violence should be considered as the end product of a chain of life events, during which risks accumulate and potentially reinforce each other, displaying or triggering a specific situation. This systematic review did not find evidence of predispositions or neurobiological alterations that solely explain antisocial or violent behaviour. With better designed studies, more correlation between diverse fields, and more standardisation, it might be possible to elucidate underlying mechanisms. Thus, we advocate maintaining the current case-by-case differentiated approach to evidence-based forensic assessment. PMID:25330208

Additive composite ABCG2, SLC2A9 and SLC22A12 scores of high-risk alleles with alcohol use modulate gout risk.

PubMed

Tu, Hung-Pin; Chung, Chia-Min; Min-Shan Ko, Albert; Lee, Su-Shin; Lai, Han-Ming; Lee, Chien-Hung; Huang, Chung-Ming; Liu, Chiu-Shong; Ko, Ying-Chin

2016-09-01

The aim of the present study was to evaluate the contribution of urate transporter genes and alcohol use to the risk of gout/tophi. Eight variants of ABCG2, SLC2A9, SLC22A12, SLC22A11 and SLC17A3 were genotyped in male individuals in a case-control study with 157 gout (33% tophi), 106 asymptomatic hyperuricaemia and 295 control subjects from Taiwan. The multilocus profiles of the genetic risk scores for urate gene variants were used to evaluate the risk of asymptomatic hyperuricaemia, gout and tophi. ABCG2 Q141K (T), SLC2A9 rs1014290 (A) and SLC22A12 rs475688 (C) under an additive model and alcohol use independently predicted the risk of gout (respective odds ratio for each factor=2.48, 2.03, 1.95 and 2.48). The additive composite Q141K, rs1014290 and rs475688 scores of high-risk alleles were associated with gout risk (P<0.0001). We observed the supramultiplicative interaction effect of genetic urate scores and alcohol use on gout and tophi risk (P for interaction=0.0452, 0.0033). The synergistic effect of genetic urate score 5-6 and alcohol use indicates that these combined factors correlate with gout and tophi occurrence.

Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.

PubMed

Malik, Rainer; Chauhan, Ganesh; Traylor, Matthew; Sargurupremraj, Muralidharan; Okada, Yukinori; Mishra, Aniket; Rutten-Jacobs, Loes; Giese, Anne-Katrin; van der Laan, Sander W; Gretarsdottir, Solveig; Anderson, Christopher D; Chong, Michael; Adams, Hieab H H; Ago, Tetsuro; Almgren, Peter; Amouyel, Philippe; Ay, Hakan; Bartz, Traci M; Benavente, Oscar R; Bevan, Steve; Boncoraglio, Giorgio B; Brown, Robert D; Butterworth, Adam S; Carrera, Caty; Carty, Cara L; Chasman, Daniel I; Chen, Wei-Min; Cole, John W; Correa, Adolfo; Cotlarciuc, Ioana; Cruchaga, Carlos; Danesh, John; de Bakker, Paul I W; DeStefano, Anita L; den Hoed, Marcel; Duan, Qing; Engelter, Stefan T; Falcone, Guido J; Gottesman, Rebecca F; Grewal, Raji P; Gudnason, Vilmundur; Gustafsson, Stefan; Haessler, Jeffrey; Harris, Tamara B; Hassan, Ahamad; Havulinna, Aki S; Heckbert, Susan R; Holliday, Elizabeth G; Howard, George; Hsu, Fang-Chi; Hyacinth, Hyacinth I; Ikram, M Arfan; Ingelsson, Erik; Irvin, Marguerite R; Jian, Xueqiu; Jiménez-Conde, Jordi; Johnson, Julie A; Jukema, J Wouter; Kanai, Masahiro; Keene, Keith L; Kissela, Brett M; Kleindorfer, Dawn O; Kooperberg, Charles; Kubo, Michiaki; Lange, Leslie A; Langefeld, Carl D; Langenberg, Claudia; Launer, Lenore J; Lee, Jin-Moo; Lemmens, Robin; Leys, Didier; Lewis, Cathryn M; Lin, Wei-Yu; Lindgren, Arne G; Lorentzen, Erik; Magnusson, Patrik K; Maguire, Jane; Manichaikul, Ani; McArdle, Patrick F; Meschia, James F; Mitchell, Braxton D; Mosley, Thomas H; Nalls, Michael A; Ninomiya, Toshiharu; O'Donnell, Martin J; Psaty, Bruce M; Pulit, Sara L; Rannikmäe, Kristiina; Reiner, Alexander P; Rexrode, Kathryn M; Rice, Kenneth; Rich, Stephen S; Ridker, Paul M; Rost, Natalia S; Rothwell, Peter M; Rotter, Jerome I; Rundek, Tatjana; Sacco, Ralph L; Sakaue, Saori; Sale, Michele M; Salomaa, Veikko; Sapkota, Bishwa R; Schmidt, Reinhold; Schmidt, Carsten O; Schminke, Ulf; Sharma, Pankaj; Slowik, Agnieszka; Sudlow, Cathie L M; Tanislav, Christian; Tatlisumak, Turgut; Taylor, Kent D; Thijs, Vincent N S; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Tiedt, Steffen; Trompet, Stella; Tzourio, Christophe; van Duijn, Cornelia M; Walters, Matthew; Wareham, Nicholas J; Wassertheil-Smoller, Sylvia; Wilson, James G; Wiggins, Kerri L; Yang, Qiong; Yusuf, Salim; Bis, Joshua C; Pastinen, Tomi; Ruusalepp, Arno; Schadt, Eric E; Koplev, Simon; Björkegren, Johan L M; Codoni, Veronica; Civelek, Mete; Smith, Nicholas L; Trégouët, David A; Christophersen, Ingrid E; Roselli, Carolina; Lubitz, Steven A; Ellinor, Patrick T; Tai, E Shyong; Kooner, Jaspal S; Kato, Norihiro; He, Jiang; van der Harst, Pim; Elliott, Paul; Chambers, John C; Takeuchi, Fumihiko; Johnson, Andrew D; Sanghera, Dharambir K; Melander, Olle; Jern, Christina; Strbian, Daniel; Fernandez-Cadenas, Israel; Longstreth, W T; Rolfs, Arndt; Hata, Jun; Woo, Daniel; Rosand, Jonathan; Pare, Guillaume; Hopewell, Jemma C; Saleheen, Danish; Stefansson, Kari; Worrall, Bradford B; Kittner, Steven J; Seshadri, Sudha; Fornage, Myriam; Markus, Hugh S; Howson, Joanna M M; Kamatani, Yoichiro; Debette, Stephanie; Dichgans, Martin; Malik, Rainer; Chauhan, Ganesh; Traylor, Matthew; Sargurupremraj, Muralidharan; Okada, Yukinori; Mishra, Aniket; Rutten-Jacobs, Loes; Giese, Anne-Katrin; van der Laan, Sander W; Gretarsdottir, Solveig; Anderson, Christopher D; Chong, Michael; Adams, Hieab H H; Ago, Tetsuro; Almgren, Peter; Amouyel, Philippe; Ay, Hakan; Bartz, Traci M; Benavente, Oscar R; Bevan, Steve; Boncoraglio, Giorgio B; Brown, Robert D; Butterworth, Adam S; Carrera, Caty; Carty, Cara L; Chasman, Daniel I; Chen, Wei-Min; Cole, John W; Correa, Adolfo; Cotlarciuc, Ioana; Cruchaga, Carlos; Danesh, John; de Bakker, Paul I W; DeStefano, Anita L; Hoed, Marcel den; Duan, Qing; Engelter, Stefan T; Falcone, Guido J; Gottesman, Rebecca F; Grewal, Raji P; Gudnason, Vilmundur; Gustafsson, Stefan; Haessler, Jeffrey; Harris, Tamara B; Hassan, Ahamad; Havulinna, Aki S; Heckbert, Susan R; Holliday, Elizabeth G; Howard, George; Hsu, Fang-Chi; Hyacinth, Hyacinth I; Ikram, M Arfan; Ingelsson, Erik; Irvin, Marguerite R; Jian, Xueqiu; Jiménez-Conde, Jordi; Johnson, Julie A; Jukema, J Wouter; Kanai, Masahiro; Keene, Keith L; Kissela, Brett M; Kleindorfer, Dawn O; Kooperberg, Charles; Kubo, Michiaki; Lange, Leslie A; Langefeld, Carl D; Langenberg, Claudia; Launer, Lenore J; Lee, Jin-Moo; Lemmens, Robin; Leys, Didier; Lewis, Cathryn M; Lin, Wei-Yu; Lindgren, Arne G; Lorentzen, Erik; Magnusson, Patrik K; Maguire, Jane; Manichaikul, Ani; McArdle, Patrick F; Meschia, James F; Mitchell, Braxton D; Mosley, Thomas H; Nalls, Michael A; Ninomiya, Toshiharu; O'Donnell, Martin J; Psaty, Bruce M; Pulit, Sara L; Rannikmäe, Kristiina; Reiner, Alexander P; Rexrode, Kathryn M; Rice, Kenneth; Rich, Stephen S; Ridker, Paul M; Rost, Natalia S; Rothwell, Peter M; Rotter, Jerome I; Rundek, Tatjana; Sacco, Ralph L; Sakaue, Saori; Sale, Michele M; Salomaa, Veikko; Sapkota, Bishwa R; Schmidt, Reinhold; Schmidt, Carsten O; Schminke, Ulf; Sharma, Pankaj; Slowik, Agnieszka; Sudlow, Cathie L M; Tanislav, Christian; Tatlisumak, Turgut; Taylor, Kent D; Thijs, Vincent N S; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Tiedt, Steffen; Trompet, Stella; Tzourio, Christophe; van Duijn, Cornelia M; Walters, Matthew; Wareham, Nicholas J; Wassertheil-Smoller, Sylvia; Wilson, James G; Wiggins, Kerri L; Yang, Qiong; Yusuf, Salim; Amin, Najaf; Aparicio, Hugo S; Arnett, Donna K; Attia, John; Beiser, Alexa S; Berr, Claudine; Buring, Julie E; Bustamante, Mariana; Caso, Valeria; Cheng, Yu-Ching; Choi, Seung Hoan; Chowhan, Ayesha; Cullell, Natalia; Dartigues, Jean-François; Delavaran, Hossein; Delgado, Pilar; Dörr, Marcus; Engström, Gunnar; Ford, Ian; Gurpreet, Wander S; Hamsten, Anders; Heitsch, Laura; Hozawa, Atsushi; Ibanez, Laura; Ilinca, Andreea; Ingelsson, Martin; Iwasaki, Motoki; Jackson, Rebecca D; Jood, Katarina; Jousilahti, Pekka; Kaffashian, Sara; Kalra, Lalit; Kamouchi, Masahiro; Kitazono, Takanari; Kjartansson, Olafur; Kloss, Manja; Koudstaal, Peter J; Krupinski, Jerzy; Labovitz, Daniel L; Laurie, Cathy C; Levi, Christopher R; Li, Linxin; Lind, Lars; Lindgren, Cecilia M; Lioutas, Vasileios; Liu, Yong Mei; Lopez, Oscar L; Makoto, Hirata; Martinez-Majander, Nicolas; Matsuda, Koichi; Minegishi, Naoko; Montaner, Joan; Morris, Andrew P; Muiño, Elena; Müller-Nurasyid, Martina; Norrving, Bo; Ogishima, Soichi; Parati, Eugenio A; Peddareddygari, Leema Reddy; Pedersen, Nancy L; Pera, Joanna; Perola, Markus; Pezzini, Alessandro; Pileggi, Silvana; Rabionet, Raquel; Riba-Llena, Iolanda; Ribasés, Marta; Romero, Jose R; Roquer, Jaume; Rudd, Anthony G; Sarin, Antti-Pekka; Sarju, Ralhan; Sarnowski, Chloe; Sasaki, Makoto; Satizabal, Claudia L; Satoh, Mamoru; Sattar, Naveed; Sawada, Norie; Sibolt, Gerli; Sigurdsson, Ásgeir; Smith, Albert; Sobue, Kenji; Soriano-Tárraga, Carolina; Stanne, Tara; Stine, O Colin; Stott, David J; Strauch, Konstantin; Takai, Takako; Tanaka, Hideo; Tanno, Kozo; Teumer, Alexander; Tomppo, Liisa; Torres-Aguila, Nuria P; Touze, Emmanuel; Tsugane, Shoichiro; Uitterlinden, Andre G; Valdimarsson, Einar M; van der Lee, Sven J; Völzke, Henry; Wakai, Kenji; Weir, David; Williams, Stephen R; Wolfe, Charles D A; Wong, Quenna; Xu, Huichun; Yamaji, Taiki; Sanghera, Dharambir K; Melander, Olle; Jern, Christina; Strbian, Daniel; Fernandez-Cadenas, Israel; Longstreth, W T; Rolfs, Arndt; Hata, Jun; Woo, Daniel; Rosand, Jonathan; Pare, Guillaume; Hopewell, Jemma C; Saleheen, Danish; Stefansson, Kari; Worrall, Bradford B; Kittner, Steven J; Seshadri, Sudha; Fornage, Myriam; Markus, Hugh S; Howson, Joanna M M; Kamatani, Yoichiro; Debette, Stephanie; Dichgans, Martin

2018-04-01

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes

PubMed Central

Malik, Rainer; Chauhan, Ganesh; Traylor, Matthew; Sargurupremraj, Muralidharan; Okada, Yukinori; Mishra, Aniket; Rutten-Jacobs, Loes; Giese, Anne-Katrin; van der Laan, Sander W.; Gretarsdottir, Solveig; Anderson, Christopher D.; Chong, Michael; Adams, Hieab H. H.; Ago, Tetsuro; Almgren, Peter; Amouyel, Philippe; Ay, Hakan; Bartz, Traci M.; Benavente, Oscar R.; Bevan, Steve; Boncoraglio, Giorgio B.; Brown, Robert D.; Butterworth, Adam S.; Carrera, Caty; Carty, Cara L.; Chasman, Daniel I.; Chen, Wei-Min; Cole, John W.; Correa, Adolfo; Cotlarciuc, Ioana; Cruchaga, Carlos; Danesh, John; de Bakker, Paul I. W.; DeStefano, Anita L.; den Hoed, Marcel; Duan, Qing; Engelter, Stefan T.; Falcone, Guido J.; Gottesman, Rebecca F.; Grewal, Raji P.; Gudnason, Vilmundur; Gustafsson, Stefan; Haessler, Jeffrey; Harris, Tamara B.; Hassan, Ahamad; Havulinna, Aki S.; Heckbert, Susan R.; Holliday, Elizabeth G.; Howard, George; Hsu, Fang-Chi; Hyacinth, Hyacinth I.; Ikram, M. Arfan; ingelsson, Erik; Irvin, Marguerite R.; Jian, Xueqiu; Jimenez-Conde, Jordi; Johnson, Julie A.; Jukema, J. Wouter; Kanai, Masahiro; Keene, Keith L.; Kissela, Brett M.; Kleindorfer, Dawn O.; Kooperberg, Charles; Kubo, Michiaki; Lange, Leslie A.; Langefeld, Carl D.; Langenberg, Claudia; Launer, Lenore J.; Lee, Jin-Moo; Lemmens, Robin; Leys, Didier; Lewis, Cathryn M.; Lin, Wei-Yu; Lindgren, Arne G.; Lorentzen, Erik; Magnusson, Patrik K.; Maguire, Jane; Manichaikul, Ani; McArdle, Patrick F.; Meschia, James F.; Mitchell, Braxton D.; Mosley, Thomas H.; Nalls, Michael A.; Ninomiya, Toshiharu; O’Donnell, Martin J.; Psaty, Bruce M.; Pulit, Sara L.; Rannikmäe, Kristiina; Reiner, Alexander P.; Rexrode, Kathryn M.; Rice, Kenneth; Rich, Stephen S.; Ridker, Paul M.; Rost, Natalia S.; Rothwell, Peter M.; Rotter, Jerome I.; Rundek, Tatjana; Sacco, Ralph L.; Sakaue, Saori; Sale, Michele M.; Salomaa, Veikko; Sapkota, Bishwa R.; Schmidt, Reinhold; Schmidt, Carsten O.; Schminke, Ulf; Sharma, Pankaj; Slowik, Agnieszka; Sudlow, Cathie L. M.; Tanislav, Christian; Tatlisumak, Turgut; Taylor, Kent D.; Thijs, Vincent N. S.; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Tiedt, Steffen; Trompet, Stella; Tzourio, Christophe; van Duijn, Cornelia M.; Walters, Matthew; Wareham, Nicholas J.; Wassertheil-Smoller, Sylvia; Wilson, James G.; Wiggins, Kerri L.; Yang, Qiong; Yusuf, Salim; Bis, Joshua C.; Pastinen, Tomi; Ruusalepp, Arno; Schadt, Eric E.; Koplev, Simon; Björkegren, Johan L. M.; Codoni, Veronica; Civelek, Mete; Smith, Nicholas L.; Tregouet, David A.; Christophersen, Ingrid E.; Roselli, Carolina; Lubitz, Steven A.; Ellinor, Patrick T.; Tai, E. Shyong; Kooner, Jaspal S.; Kato, Norihiro; He, Jiang; van der Harst, Pim; Elliott, Paul; Chambers, John C.; Takeuchi, Fumihiko; Johnson, Andrew D.; Sanghera, Dharambir K.; Melander, Olle; Jern, Christina; Strbian, Daniel; Fernandez-Cadenas, Israel; Longstreth, W. T.; Rolfs, Arndt; Hata, Jun; Woo, Daniel; Rosand, Jonathan; Pare, Guillaume; Hopewell, Jemma C.; Saleheen, Danish; Stefansson, Kari; Worrall, Bradford B.; Kittner, Steven J.; Seshadri, Sudha; Fornage, Myriam; Markus, Hugh S.; Howson, Joanna M. M.; Kamatani, Yoichiro; Debette, Stephanie; Dichgans, Martin

2018-01-01

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy. PMID:29531354

Schizophrenia-associated methylomic variation: molecular signatures of disease and polygenic risk burden across multiple brain regions.

PubMed

Viana, Joana; Hannon, Eilis; Dempster, Emma; Pidsley, Ruth; Macdonald, Ruby; Knox, Olivia; Spiers, Helen; Troakes, Claire; Al-Saraj, Safa; Turecki, Gustavo; Schalkwyk, Leonard C; Mill, Jonathan

2017-01-01

Genetic association studies provide evidence for a substantial polygenic component to schizophrenia, although the neurobiological mechanisms underlying the disorder remain largely undefined. Building on recent studies supporting a role for developmentally regulated epigenetic variation in the molecular aetiology of schizophrenia, this study aimed to identify epigenetic variation associated with both a diagnosis of schizophrenia and elevated polygenic risk burden for the disease across multiple brain regions. Genome-wide DNA methylation was quantified in 262 post-mortem brain samples, representing tissue from four brain regions (prefrontal cortex, striatum, hippocampus and cerebellum) from 41 schizophrenia patients and 47 controls. We identified multiple disease-associated and polygenic risk score-associated differentially methylated positions and regions, which are not enriched in genomic regions identified in genetic studies of schizophrenia and do not reflect direct genetic effects on DNA methylation. Our study represents the first analysis of epigenetic variation associated with schizophrenia across multiple brain regions and highlights the utility of polygenic risk scores for identifying molecular pathways associated with aetiological variation in complex disease. © The Author 2016. Published by Oxford University Press.

Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation.

PubMed

Gusev, Alexander; Shi, Huwenbo; Kichaev, Gleb; Pomerantz, Mark; Li, Fugen; Long, Henry W; Ingles, Sue A; Kittles, Rick A; Strom, Sara S; Rybicki, Benjamin A; Nemesure, Barbara; Isaacs, William B; Zheng, Wei; Pettaway, Curtis A; Yeboah, Edward D; Tettey, Yao; Biritwum, Richard B; Adjei, Andrew A; Tay, Evelyn; Truelove, Ann; Niwa, Shelley; Chokkalingam, Anand P; John, Esther M; Murphy, Adam B; Signorello, Lisa B; Carpten, John; Leske, M Cristina; Wu, Suh-Yuh; Hennis, Anslem J M; Neslund-Dudas, Christine; Hsing, Ann W; Chu, Lisa; Goodman, Phyllis J; Klein, Eric A; Witte, John S; Casey, Graham; Kaggwa, Sam; Cook, Michael B; Stram, Daniel O; Blot, William J; Eeles, Rosalind A; Easton, Douglas; Kote-Jarai, Zsofia; Al Olama, Ali Amin; Benlloch, Sara; Muir, Kenneth; Giles, Graham G; Southey, Melissa C; Fitzgerald, Liesel M; Gronberg, Henrik; Wiklund, Fredrik; Aly, Markus; Henderson, Brian E; Schleutker, Johanna; Wahlfors, Tiina; Tammela, Teuvo L J; Nordestgaard, Børge G; Key, Tim J; Travis, Ruth C; Neal, David E; Donovan, Jenny L; Hamdy, Freddie C; Pharoah, Paul; Pashayan, Nora; Khaw, Kay-Tee; Stanford, Janet L; Thibodeau, Stephen N; McDonnell, Shannon K; Schaid, Daniel J; Maier, Christiane; Vogel, Walther; Luedeke, Manuel; Herkommer, Kathleen; Kibel, Adam S; Cybulski, Cezary; Wokolorczyk, Dominika; Kluzniak, Wojciech; Cannon-Albright, Lisa; Teerlink, Craig; Brenner, Hermann; Dieffenbach, Aida K; Arndt, Volker; Park, Jong Y; Sellers, Thomas A; Lin, Hui-Yi; Slavov, Chavdar; Kaneva, Radka; Mitev, Vanio; Batra, Jyotsna; Spurdle, Amanda; Clements, Judith A; Teixeira, Manuel R; Pandha, Hardev; Michael, Agnieszka; Paulo, Paula; Maia, Sofia; Kierzek, Andrzej; Conti, David V; Albanes, Demetrius; Berg, Christine; Berndt, Sonja I; Campa, Daniele; Crawford, E David; Diver, W Ryan; Gapstur, Susan M; Gaziano, J Michael; Giovannucci, Edward; Hoover, Robert; Hunter, David J; Johansson, Mattias; Kraft, Peter; Le Marchand, Loic; Lindström, Sara; Navarro, Carmen; Overvad, Kim; Riboli, Elio; Siddiq, Afshan; Stevens, Victoria L; Trichopoulos, Dimitrios; Vineis, Paolo; Yeager, Meredith; Trynka, Gosia; Raychaudhuri, Soumya; Schumacher, Frederick R; Price, Alkes L; Freedman, Matthew L; Haiman, Christopher A; Pasaniuc, Bogdan

2016-04-07

Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.

Overview of the Genetics of Alcohol Use Disorder

PubMed Central

Tawa, Elisabeth A.; Hall, Samuel D.; Lohoff, Falk W.

2016-01-01

Aims Alcohol Use Disorder (AUD) is a chronic psychiatric illness characterized by harmful drinking patterns leading to negative emotional, physical, and social ramifications. While the underlying pathophysiology of AUD is poorly understood, there is substantial evidence for a genetic component; however, identification of universal genetic risk variants for AUD has been difficult. Recent efforts in the search for AUD susceptibility genes will be reviewed in this article. Methods In this review, we provide an overview of genetic studies on AUD, including twin studies, linkage studies, candidate gene studies, and genome-wide association studies (GWAS). Results Several potential genetic susceptibility factors for AUD have been identified, but the genes of alcohol metabolism, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), have been found to be protective against the development of AUD. GWAS have also identified a heterogeneous list of SNPs associated with AUD and alcohol-related phenotypes, emphasizing the complexity and heterogeneity of the disorder. In addition, many of these findings have small effect sizes when compared to alcohol metabolism genes, and biological relevance is often unknown. Conclusions Although studies spanning multiple approaches have suggested a genetic basis for AUD, identification of the genetic risk variants has been challenging. Some promising results are emerging from GWAS studies; however, larger sample sizes are needed to improve GWAS results and resolution. As the field of genetics is rapidly developing, whole genome sequencing could soon become the new standard of interrogation of the genes and neurobiological pathways which contribute to the complex phenotype of AUD. Short summary This review examines the genetic underpinnings of Alcohol Use Disorder (AUD), with an emphasis on GWAS approaches for identifying genetic risk variants. The most promising results associated with AUD and alcohol-related phenotypes have included SNPs of the alcohol metabolism genes ADH and ALDH. PMID:27445363

Valuations of genetic test information for treatable conditions: the case of colorectal cancer screening.

PubMed

Kilambi, Vikram; Johnson, F Reed; González, Juan Marcos; Mohamed, Ateesha F

2014-12-01

The value of the information that genetic testing services provide can be questioned for insurance-based health systems. The results of genetic tests oftentimes may not lead to well-defined clinical interventions; however, Lynch syndrome, a genetic mutation for which carriers are at an increased risk for colorectal cancer, can be identified through genetic testing, and meaningful health interventions are available via increased colonoscopic surveillance. Valuations of test information for such conditions ought to account for the full impact of interventions and contingent outcomes. To conduct a discrete-choice experiment to elicit individuals' preferences for genetic test information. A Web-enabled discrete-choice experiment survey was administered to a representative sample of US residents aged 50 years and older. In addition to specifying expenditures on colonoscopies, respondents were asked to make a series of nine selections between two hypothetical genetic tests or a no-test option under the premise that a relative had Lynch syndrome. The hypothetical genetic tests were defined by the probability of developing colorectal cancer, the probability of a false-negative test result, privacy of the result, and out-of-pocket cost. A model specification identifying necessary interactions was derived from assumptions of risk behavior and the decision context and was estimated using random-parameters logit. A total of 650 respondents were contacted, and 385 completed the survey. The monetary equivalent of test information was approximately $1800. Expenditures on colonoscopies to reduce mortality risks affected valuations. Respondents with lower income or who reported being employed significantly valued genetic tests more. Genetic testing may confer benefits through the impact of subsequent interventions on private individuals. Copyright © 2014. Published by Elsevier Inc.

Chronic Pancreatitis.

PubMed

Stram, Michelle; Liu, Shu; Singhi, Aatur D

2016-12-01

Chronic pancreatitis is a debilitating condition often associated with severe abdominal pain and exocrine and endocrine dysfunction. The underlying cause is multifactorial and involves complex interaction of environmental, genetic, and/or other risk factors. The pathology is dependent on the underlying pathogenesis of the disease. This review describes the clinical, gross, and microscopic findings of the main subtypes of chronic pancreatitis: alcoholic chronic pancreatitis, obstructive chronic pancreatitis, paraduodenal ("groove") pancreatitis, pancreatic divisum, autoimmune pancreatitis, and genetic factors associated with chronic pancreatitis. As pancreatic ductal adenocarcinoma may be confused with chronic pancreatitis, the main distinguishing features between these 2 diseases are discussed. Copyright © 2016 Elsevier Inc. All rights reserved.

Eating disorder-specific risk factors moderate the relationship between negative urgency and binge eating: A behavioral genetic investigation.

PubMed

Racine, Sarah E; VanHuysse, Jessica L; Keel, Pamela K; Burt, S Alexandra; Neale, Michael C; Boker, Steven; Klump, Kelly L

2017-07-01

Theoretical models of binge eating and eating disorders include both transdiagnostic and eating disorder-specific risk factors. Negative urgency (i.e., the tendency to act impulsively when distressed) is a critical transdiagnostic risk factor for binge eating, but limited research has examined interactions between negative urgency and disorder-specific variables. Investigating these interactions can help identify the circumstances under which negative urgency is most strongly associated with binge eating. We examined whether prominent risk factors (i.e., appearance pressures, thin-ideal internalization, body dissatisfaction, dietary restraint) specified in well-established etiologic models of eating disorders moderate negative urgency-binge eating associations. Further, we investigated whether phenotypic moderation effects were due to genetic and/or environmental associations between negative urgency and binge eating. Participants were 988 female twins aged 11-25 years from the Michigan State University Twin Registry. Appearance pressures, thin-ideal internalization, and body dissatisfaction, but not dietary restraint, significantly moderated negative urgency-binge eating associations, with high levels of these risk factors and high negative urgency associated with the greatest binge eating. Twin moderation models revealed that genetic, but not environmental, sharing between negative urgency and binge eating was enhanced at higher levels of these eating disorder-specific variables. Future longitudinal research should investigate whether eating disorder risk factors shape genetic influences on negative urgency into manifesting as binge eating. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

GENES AS INSTRUMENTS FOR STUDYING RISK BEHAVIOR EFFECTS: AN APPLICATION TO MATERNAL SMOKING AND OROFACIAL CLEFTS

PubMed Central

Jugessur, Astanand; Murray, Jeffrey C.; Moreno, Lina; Wilcox, Allen; Lie, Rolv T.

2011-01-01

This study uses instrumental variable (IV) models with genetic instruments to assess the effects of maternal smoking on the child’s risk of orofacial clefts (OFC), a common birth defect. The study uses genotypic variants in neurotransmitter and detoxification genes relateded to smoking as instruments for cigarette smoking before and during pregnancy. Conditional maximum likelihood and two-stage IV probit models are used to estimate the IV model. The data are from a population-level sample of affected and unaffected children in Norway. The selected genetic instruments generally fit the IV assumptions but may be considered “weak” in predicting cigarette smoking. We find that smoking before and during pregnancy increases OFC risk substantially under the IV model (by about 4–5 times at the sample average smoking rate). This effect is greater than that found with classical analytic models. This may be because the usual models are not able to consider self-selection into smoking based on unobserved confounders, or it may to some degree reflect limitations of the instruments. Inference based on weak-instrument robust confidence bounds is consistent with standard inference. Genetic instruments may provide a valuable approach to estimate the “causal” effects of risk behaviors with genetic-predisposing factors (such as smoking) on health and socioeconomic outcomes. PMID:22102793

Discriminatory power of common genetic variants in personalized breast cancer diagnosis

NASA Astrophysics Data System (ADS)

Wu, Yirong; Abbey, Craig K.; Liu, Jie; Ong, Irene; Peissig, Peggy; Onitilo, Adedayo A.; Fan, Jun; Yuan, Ming; Burnside, Elizabeth S.

2016-03-01

Technology advances in genome-wide association studies (GWAS) has engendered optimism that we have entered a new age of precision medicine, in which the risk of breast cancer can be predicted on the basis of a person's genetic variants. The goal of this study is to evaluate the discriminatory power of common genetic variants in breast cancer risk estimation. We conducted a retrospective case-control study drawing from an existing personalized medicine data repository. We collected variables that predict breast cancer risk: 153 high-frequency/low-penetrance genetic variants, reflecting the state-of-the-art GWAS on breast cancer, mammography descriptors and BI-RADS assessment categories in the Breast Imaging Reporting and Data System (BI-RADS) lexicon. We trained and tested naïve Bayes models by using these predictive variables. We generated ROC curves and used the area under the ROC curve (AUC) to quantify predictive performance. We found that genetic variants achieved comparable predictive performance to BI-RADS assessment categories in terms of AUC (0.650 vs. 0.659, p-value = 0.742), but significantly lower predictive performance than the combination of BI-RADS assessment categories and mammography descriptors (0.650 vs. 0.751, p-value < 0.001). A better understanding of relative predictive capability of genetic variants and mammography data may benefit clinicians and patients to make appropriate decisions about breast cancer screening, prevention, and treatment in the era of precision medicine.

Late-onset Alzheimer disease genetic variants in posterior cortical atrophy and posterior AD.

PubMed

Carrasquillo, Minerva M; Khan, Qurat ul Ain; Murray, Melissa E; Krishnan, Siddharth; Aakre, Jeremiah; Pankratz, V Shane; Nguyen, Thuy; Ma, Li; Bisceglio, Gina; Petersen, Ronald C; Younkin, Steven G; Dickson, Dennis W; Boeve, Bradley F; Graff-Radford, Neill R; Ertekin-Taner, Nilüfer

2014-04-22

To investigate association of genetic risk factors for late-onset Alzheimer disease (LOAD) with risk of posterior cortical atrophy (PCA), a syndrome of visual impairment with predominant Alzheimer disease (AD) pathology in posterior cortical regions, and with risk of "posterior AD" neuropathology. We assessed 81 participants with PCA diagnosed clinically and 54 with neuropathologic diagnosis of posterior AD vs 2,523 controls for association with 11 significant single nucleotide polymorphisms (SNPs) from published LOAD risk genome-wide association studies. There was highly significant association with APOE ε4 and increased risk of PCA (p = 0.0003, odds ratio [OR] = 3.17) and posterior AD (p = 1.11 × 10(-17), OR = 6.43). No other locus was significant after corrections for multiple testing, although rs11136000 near CLU (p = 0.019, OR = 0.60) and rs744373 near BIN1 (p = 0.025, OR = 1. 63) associated nominally significantly with posterior AD, and rs3851179 at the PICALM locus had significant association with PCA (p = 0.0003, OR = 2.84). ABCA7 locus SNP rs3764650, which was also tested under the recessive model because of Hardy-Weinberg disequilibrium, also had nominally significant association with PCA risk. The direction of association at APOE, CLU, and BIN1 loci was the same for participants with PCA and posterior AD. The effects for all SNPs, except rs3851179, were consistent with those for LOAD risk. We identified a significant effect for APOE and nominate CLU, BIN1, and ABCA7 as additional risk loci for PCA and posterior AD. Our findings suggest that at least some of the genetic risk factors for LOAD are shared with these atypical conditions and provide effect-size estimates for their future genetic studies.

Likelihood ratio-based integrated personal risk assessment of type 2 diabetes.

PubMed

Sato, Noriko; Htun, Nay Chi; Daimon, Makoto; Tamiya, Gen; Kato, Takeo; Kubota, Isao; Ueno, Yoshiyuki; Yamashita, Hidetoshi; Fukao, Akira; Kayama, Takamasa; Muramatsu, Masaaki

2014-01-01

To facilitate personalized health care for multifactorial diseases, risks of genetic and clinical/environmental factors should be assessed together for each individual in an integrated fashion. This approach is possible with the likelihood ratio (LR)-based risk assessment system, as this system can incorporate manifold tests. We examined the usefulness of this system for assessing type 2 diabetes (T2D). Our system employed 29 genetic susceptibility variants, body mass index (BMI), and hypertension as risk factors whose LRs can be estimated from openly available T2D association data for the Japanese population. The pretest probability was set at a sex- and age-appropriate population average of diabetes prevalence. The classification performance of our LR-based risk assessment was compared to that of a non-invasive screening test for diabetes called TOPICS (with score based on age, sex, family history, smoking, BMI, and hypertension) using receiver operating characteristic analysis with a community cohort (n = 1263). The area under the receiver operating characteristic curve (AUC) for the LR-based assessment and TOPICS was 0.707 (95% CI 0.665-0.750) and 0.719 (0.675-0.762), respectively. These AUCs were much higher than that of a genetic risk score constructed using the same genetic susceptibility variants, 0.624 (0.574-0.674). The use of ethnically matched LRs is necessary for proper personal risk assessment. In conclusion, although LR-based integrated risk assessment for T2D still requires additional tests that evaluate other factors, such as risks involved in missing heritability, our results indicate the potential usability of LR-based assessment system and stress the importance of stratified epidemiological investigations in personalized medicine.

Imaging-Genetics in Dyslexia: Connecting risk genetic variants to brain neuroimaging and ultimately to reading impairments

PubMed Central

Eicher, John D.; Gruen, Jeffrey R.

2013-01-01

Dyslexia is a common pediatric disorder that affects 5-17% of schoolchildren in the United States. It is marked by unexpected difficulties in fluent reading despite adequate intelligence, opportunity, and instruction. Classically, neuropsychologists have studied dyslexia using a variety of neurocognitive batteries to gain insight into the specific deficits and impairments in affected children. Since dyslexia is a complex genetic trait with high heritability, analyses conditioned on performance on these neurocognitive batteries have been used to try to identify associated genes. This has led to some successes in identifying contributing genes, although much of the heritability remains unexplained. Additionally, the lack of relevant human brain tissue for analysis and the challenges of modeling a uniquely human trait in animals are barriers to advancing our knowledge of the underlying pathophysiology. In vivo imaging technologies, however, present new opportunities to examine dyslexia and reading skills in a clearly relevant context in human subjects. Recent investigations have started to integrate these imaging data with genetic data in attempts to gain a more complete and complex understanding of reading processes. In addition to bridging the gap from genetic risk variant to a discernible neuroimaging phenotype and ultimately to the clinical impairments in reading performance, the use of neuroimaging phenotypes will reveal novel risk genes and variants. In this article, we briefly discuss the genetic and imaging investigations and take an in-depth look at the recent imaging-genetics investigations of dyslexia. PMID:23916419

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

2015-07-07

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.

Genetic Variation in Complement Component 2 of the Classical Complement Pathway is Associated with Increased Mortality and Infection: A Study of 627 Trauma Patients

PubMed Central

Morris, John A.; Francois, Cedric; Olson, Paul K.; Cotton, Bryan A.; Summar, Marshall; Jenkins, Judith M.; Norris, Patrick R.; Moore, Jason H.; Williams, Anna E.; McNew, Brent S.; Canter, Jeffrey A.

2009-01-01

Trauma is a disease of inflammation. Complement Component 2 (C2) is a protease involved in activation of complement through the classical pathway and has been implicated in a variety of chronic inflammatory diseases. We hypothesized that genetic variation in C2 (E318D) identifies a high-risk subgroup of trauma patients reflecting increased mortality and infection (Ventilator associated pneumonia: VAP). Consequently, genetic variation in C2 may stratify patient risk and illuminate underlying mechanisms for therapeutic intervention. Methods DNA samples from 702 trauma patients were genotyped for C2 E318D and linked with covariates (age: mean 42.8 years, gender: 74% male, ethnicity: 80% Caucasian, mechanism: 84% blunt, ISS: mean 25.0, admission lactate: mean 3.13 mEq/L) and outcomes: mortality 9.9% and VAP: 18.5%. VAP was defined by quantitative bronchoalveolar lavage (>104). Multivariate regression determined the relationship of genotype and covariates to risk of death and VAP. However, patients with ISS ≥ 45 were excluded from the multivariate analysis, as magnitude of injury overwhelms genetics and covariates in determining outcome. Results 52 patients (8.3%) had the high-risk heterozygous genotype, associated with a significant increase in mortality and VAP. Conclusion In 702 trauma patients, 8.3% had a high-risk genetic variation in C2 associated with increased mortality (OR=2.65) and infection (OR=2.00). This variation: 1) Identifies a previously unknown high risk group for infection and mortality; 2) Can be determined on admission; 3) May provide opportunity for early therapeutic intervention; and 4) Requires validation in a distinct cohort of patients. PMID:19430225

Associations Between Fetal Growth and Self-Perceived Health Throughout Adulthood: A Co-twin Control Study.

PubMed

Mosing, Miriam A; Cnattingius, Sven; Gatz, Margaret; Neiderhiser, Jenae M; Pedersen, Nancy L

2016-05-01

The literature shows evidence for long-lasting effects of low birth weight (LBW) on many health outcomes, but little is known about effects on self-perceived health. Findings are mixed and studies are small, mostly focusing on LBW effects on health outcomes before adulthood. Further, as LBW and most health conditions including self-perceived health are partly heritable, associations between birth weight (BW) and adverse health outcomes may also be due to shared genetic as well as other (pre- and postnatal) unmeasured environmental influences. We explored LBW effects on self-perceived health in early and later adulthood using a very large and genetically informative sample of more than 50,000 Swedish twins. In addition, analyses within twin pairs (the co-twin control design) were used to examine potential associations between BW and the offspring's risk for poor self-perceived health independent of shared environmental or genetic factors, evidence which is critical for the understanding of underlying mechanisms. Results showed that lower BW was significantly associated with poorer self-perceived health during adulthood, although the effect size was small. Co-twin control analyses suggested that this increased risk may be due to shared underlying liability (environmental or genetic) rather than a direct effect of BW, but findings were not conclusive.

Improving the value of costly genetic reference laboratory testing with active utilization management.

PubMed

Dickerson, Jane A; Cole, Bonnie; Conta, Jessie H; Wellner, Monica; Wallace, Stephanie E; Jack, Rhona M; Rutledge, Joe; Astion, Michael L

2014-01-01

Tests that are performed outside of the ordering institution, send-out tests, represent an area of risk to patients because of complexity associated with sending tests out. Risks related to send-out tests include increased number of handoffs, ordering the wrong or unnecessary test, specimen delays, data entry errors, preventable delays in reporting and acknowledging results, and excess financial liability. Many of the most expensive and most misunderstood tests are send-out genetic tests. To design and develop an active utilization management program to reduce the risk to patients and improve value of genetic send-out tests. Send-out test requests that met defined criteria were reviewed by a rotating team of doctoral-level consultants and a genetic counselor in a pediatric tertiary care center. Two hundred fifty-one cases were reviewed during an 8-month period. After review, nearly one-quarter of genetic test requests were modified in the downward direction, saving a total of 2% of the entire send-out bill and 19% of the test requests under management. Ultimately, these savings were passed on to patients. Implementing an active utilization strategy for expensive send-out tests can be achieved with minimal technical resources and results in improved value of testing to patients.

The Genetics of Autism: Key Issues, Recent Findings and Clinical Implications

PubMed Central

El-Fishawy, Paul; State, Matthew W.

2010-01-01

Autism spectrum disorders (ASD’S) are highly heritable. Consequently, gene discovery promises to help illuminate the pathophysiology of these syndromes, yielding important opportunities for the development of novel treatments and a more nuanced understanding of the natural history of these disorders. Although the underlying genetic architecture of ASD’s is not yet known, the literature demonstrates that it is not, writ large, a monogenic disorder with Mendelian inheritance, but rather a group of complex genetic syndromes with risk deriving from genetic variations in multiple genes. The widely accepted “Common Disease-Common Variant” hypothesis predicts that the risk alleles in ASD’s and other complex disorders will be common in the general population. However, recent evidence from gene discovery efforts in a wide range of diseases raises important questions regarding the overall applicability of the theory and the extent of its usefulness in explaining individual genetic liability. In contrast, considerable evidence points to the importance of rare alleles both with regard to their value in providing a foothold into the molecular mechanisms of ASD and their overall contribution to the population-wide risk. This chapter reviews the origins of the common versus rare variant debate, highlights recent findings in the field, and addresses the clinical implications of both common and rare variant discoveries. PMID:20159341

Integrating genome-wide association studies and gene expression data highlights dysregulated multiple sclerosis risk pathways.

PubMed

Liu, Guiyou; Zhang, Fang; Jiang, Yongshuai; Hu, Yang; Gong, Zhongying; Liu, Shoufeng; Chen, Xiuju; Jiang, Qinghua; Hao, Junwei

2017-02-01

Much effort has been expended on identifying the genetic determinants of multiple sclerosis (MS). Existing large-scale genome-wide association study (GWAS) datasets provide strong support for using pathway and network-based analysis methods to investigate the mechanisms underlying MS. However, no shared genetic pathways have been identified to date. We hypothesize that shared genetic pathways may indeed exist in different MS-GWAS datasets. Here, we report results from a three-stage analysis of GWAS and expression datasets. In stage 1, we conducted multiple pathway analyses of two MS-GWAS datasets. In stage 2, we performed a candidate pathway analysis of the large-scale MS-GWAS dataset. In stage 3, we performed a pathway analysis using the dysregulated MS gene list from seven human MS case-control expression datasets. In stage 1, we identified 15 shared pathways. In stage 2, we successfully replicated 14 of these 15 significant pathways. In stage 3, we found that dysregulated MS genes were significantly enriched in 10 of 15 MS risk pathways identified in stages 1 and 2. We report shared genetic pathways in different MS-GWAS datasets and highlight some new MS risk pathways. Our findings provide new insights on the genetic determinants of MS.

Gene × Environment Interactions in Autism Spectrum Disorders: Role of Epigenetic Mechanisms

PubMed Central

Tordjman, Sylvie; Somogyi, Eszter; Coulon, Nathalie; Kermarrec, Solenn; Cohen, David; Bronsard, Guillaume; Bonnot, Olivier; Weismann-Arcache, Catherine; Botbol, Michel; Lauth, Bertrand; Ginchat, Vincent; Roubertoux, Pierre; Barburoth, Marianne; Kovess, Viviane; Geoffray, Marie-Maude; Xavier, Jean

2014-01-01

Several studies support currently the hypothesis that autism etiology is based on a polygenic and epistatic model. However, despite advances in epidemiological, molecular and clinical genetics, the genetic risk factors remain difficult to identify, with the exception of a few chromosomal disorders and several single gene disorders associated with an increased risk for autism. Furthermore, several studies suggest a role of environmental factors in autism spectrum disorders (ASD). First, arguments for a genetic contribution to autism, based on updated family and twin studies, are examined. Second, a review of possible prenatal, perinatal, and postnatal environmental risk factors for ASD are presented. Then, the hypotheses are discussed concerning the underlying mechanisms related to a role of environmental factors in the development of ASD in association with genetic factors. In particular, epigenetics as a candidate biological mechanism for gene × environment interactions is considered and the possible role of epigenetic mechanisms reported in genetic disorders associated with ASD is discussed. Furthermore, the example of in utero exposure to valproate provides a good illustration of epigenetic mechanisms involved in ASD and innovative therapeutic strategies. Epigenetic remodeling by environmental factors opens new perspectives for a better understanding, prevention, and early therapeutic intervention of ASD. PMID:25136320

Evidence that hippocampal-parahippocampal dysfunction is related to genetic risk for schizophrenia.

PubMed

Di Giorgio, A; Gelao, B; Caforio, G; Romano, R; Andriola, I; D'Ambrosio, E; Papazacharias, A; Elifani, F; Bianco, L Lo; Taurisano, P; Fazio, L; Popolizio, T; Blasi, G; Bertolino, A

2013-08-01

Abnormalities in hippocampal-parahippocampal (H-PH) function are prominent features of schizophrenia and have been associated with deficits in episodic memory. However, it remains unclear whether these abnormalities represent a phenotype related to genetic risk for schizophrenia or whether they are related to disease state. We investigated H-PH-mediated behavior and physiology, using blood oxygenation level-dependent functional magnetic resonance imaging (BOLD fMRI), during episodic memory in a sample of patients with schizophrenia, clinically unaffected siblings and healthy subjects. Patients with schizophrenia and unaffected siblings displayed abnormalities in episodic memory performance. During an fMRI memory encoding task, both patients and siblings demonstrated a similar pattern of reduced H-PH engagement compared with healthy subjects. Our findings suggest that the pathophysiological mechanism underlying the inability of patients with schizophrenia to properly engage the H-PH during episodic memory is related to genetic risk for the disorder. Therefore, H-PH dysfunction can be assumed as a schizophrenia susceptibility-related phenotype.

The threshold vs LNT showdown: Dose rate findings exposed flaws in the LNT model part 2. How a mistake led BEIR I to adopt LNT

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

Calabrese, Edward J., E-mail: edwardc@schoolph.uma

This paper reveals that nearly 25 years after the used Russell's dose-rate data to support the adoption of the linear-no-threshold (LNT) dose response model for genetic and cancer risk assessment, Russell acknowledged a significant under-reporting of the mutation rate of the historical control group. This error, which was unknown to BEIR I, had profound implications, leading it to incorrectly adopt the LNT model, which was a decision that profoundly changed the course of risk assessment for radiation and chemicals to the present. -- Highlights: • The BEAR I Genetics Panel made an error in denying dose rate for mutation. •more » The BEIR I Genetics Subcommittee attempted to correct this dose rate error. • The control group used for risk assessment by BEIR I is now known to be in error. • Correcting this error contradicts the LNT, supporting a threshold model.« less

Vascular Health and Genetic Risk Affect Mild Cognitive Impairment Status and 4-Year Stability: Evidence From the Victoria Longitudinal Study.

PubMed

DeCarlo, Correne A; MacDonald, Stuart W S; Vergote, David; Jhamandas, Jack; Westaway, David; Dixon, Roger A

2016-11-01

Mild cognitive impairment (MCI) is a high-risk condition for progression to Alzheimer's disease (AD). Vascular health is a key mechanism underlying age-related cognitive decline and neurodegeneration. AD-related genetic risk factors may be associated with preclinical cognitive status changes. We examine independent and cross-domain interactive effects of vascular and genetic markers for predicting MCI status and stability. We used cross-sectional and 2-wave longitudinal data from the Victoria Longitudinal Study, including indicators of vascular health (e.g., reported vascular diseases, measured lung capacity and pulse rate) and genetic risk factors-that is, apolipoprotein E (APOE; rs429358 and rs7412; the presence vs absence of ε4) and catechol-O-methyltransferase (COMT; rs4680; met/met vs val/val). We examined associations with objectively classified (a) cognitive status at baseline (not impaired congnitive (NIC) controls vs MCI) and (b) stability or transition of cognitive status across a 4-year interval (stable NIC-NIC vs chronic MCI-MCI or transitional NIC-MCI). Using logistic regression, indicators of vascular health, both independently and interactively with APOE ε4, were associated with risk of MCI at baseline and/or associated with MCI conversion or MCI stability over the retest interval. Several vascular health markers of aging predict MCI risk. Interactively, APOE ε4 may intensify the vascular health risk for MCI. © The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Genetics of Addiction: Future Focus on Gene × Environment Interaction?

PubMed

Vink, Jacqueline M

2016-09-01

The heritability of substance use is moderate to high. Successful efforts to find genetic variants associated with substance use (smoking, alcohol, cannabis) have been undertaken by large consortia. However, the proportion of phenotypic variance explained by the identified genetic variants is small. Interestingly, there is overlap between the genetic variants that influence different substances. Moreover, there are sets of "substance-specific" genes and sets of genes contributing to a "vulnerability for addictive behavior" in general. It is important to recognize that genes alone do not determine addiction phenotypes: Environmental factors such as parental monitoring, peer pressure, or socioeconomic status also play an important role. Despite a rich epidemiologic literature focused on the social determinants of substance use, few studies have examined the moderation of genetic influences like gene-environment (G × E) interactions. Understanding this balance may hold the key to understanding the individual differences in substance use, abuse, and addictive behavior. Recommendations for future research are described in this commentary and include increasing the power of G × E studies by using state-of-the-art methods such as polygenic risk scores instead of single genetic variants and taking genetic overlap between substances into account. Future genetic studies should also investigate environmental risk factors for addictive behavior more extensively to unravel the interaction between nature and nurture. Focusing on G × E interactions not only will give insight into the underlying biological mechanism but will also characterize subgroups (based on environmental factors) at high risk for addictive behaviors. With this information, we could bridge the gap between fundamental research and applications for society.

Developmental cognitive genetics: How psychology can inform genetics and vice versa

PubMed Central

Bishop, Dorothy V. M.

2006-01-01

Developmental neuropsychology is concerned with uncovering the underlying basis of developmental disorders such as specific language impairment (SLI), developmental dyslexia, and autistic disorder. Twin and family studies indicate that genetic influences play an important part in the aetiology of all of these disorders, yet progress in identifying genes has been slow. One way forward is to cut loose from conventional clinical criteria for diagnosing disorders and to focus instead on measures of underlying cognitive mechanisms. Psychology can inform genetics by clarifying what the key dimensions are for heritable phenotypes. However, it is not a one-way street. By using genetically informative designs, one can gain insights about causal relationships between different cognitive deficits. For instance, it has been suggested that low-level auditory deficits cause phonological problems in SLI. However, a twin study showed that, although both types of deficit occur in SLI, they have quite different origins, with environmental factors more important for auditory deficit, and genes more important for deficient phonological short-term memory. Another study found that morphosyntactic deficits in SLI are also highly heritable, but have different genetic origins from impairments of phonological short-term memory. A genetic perspective shows that a search for the underlying cause of developmental disorders may be misguided, because they are complex and heterogeneous and are associated with multiple risk factors that only cause serious disability when they occur in combination. PMID:16769616

Prediction of breast cancer risk based on common genetic variants in women of East Asian ancestry.

PubMed

Wen, Wanqing; Shu, Xiao-Ou; Guo, Xingyi; Cai, Qiuyin; Long, Jirong; Bolla, Manjeet K; Michailidou, Kyriaki; Dennis, Joe; Wang, Qin; Gao, Yu-Tang; Zheng, Ying; Dunning, Alison M; García-Closas, Montserrat; Brennan, Paul; Chen, Shou-Tung; Choi, Ji-Yeob; Hartman, Mikael; Ito, Hidemi; Lophatananon, Artitaya; Matsuo, Keitaro; Miao, Hui; Muir, Kenneth; Sangrajrang, Suleeporn; Shen, Chen-Yang; Teo, Soo H; Tseng, Chiu-Chen; Wu, Anna H; Yip, Cheng Har; Simard, Jacques; Pharoah, Paul D P; Hall, Per; Kang, Daehee; Xiang, Yongbing; Easton, Douglas F; Zheng, Wei

2016-12-08

Approximately 100 common breast cancer susceptibility alleles have been identified in genome-wide association studies (GWAS). The utility of these variants in breast cancer risk prediction models has not been evaluated adequately in women of Asian ancestry. We evaluated 88 breast cancer risk variants that were identified previously by GWAS in 11,760 cases and 11,612 controls of Asian ancestry. SNPs confirmed to be associated with breast cancer risk in Asian women were used to construct a polygenic risk score (PRS). The relative and absolute risks of breast cancer by the PRS percentiles were estimated based on the PRS distribution, and were used to stratify women into different levels of breast cancer risk. We confirmed significant associations with breast cancer risk for SNPs in 44 of the 78 previously reported loci at P < 0.05. Compared with women in the middle quintile of the PRS, women in the top 1% group had a 2.70-fold elevated risk of breast cancer (95% CI: 2.15-3.40). The risk prediction model with the PRS had an area under the receiver operating characteristic curve of 0.606. The lifetime risk of breast cancer for Shanghai Chinese women in the lowest and highest 1% of the PRS was 1.35% and 10.06%, respectively. Approximately one-half of GWAS-identified breast cancer risk variants can be directly replicated in East Asian women. Collectively, common genetic variants are important predictors for breast cancer risk. Using common genetic variants for breast cancer could help identify women at high risk of breast cancer.

Evidence for heritability of adult men's sexual interest in youth under age 16 from a population-based extended twin design.

PubMed

Alanko, Katarina; Salo, Benny; Mokros, Andreas; Santtila, Pekka

2013-04-01

Sexual interest in children resembles sexual gender orientation in terms of early onset and stability across the life span. Although a genetic component to sexual interest in children seems possible, no research has addressed this question to date. Prior research showing familial transmission of pedophilia remains inconclusive about shared environmental or genetic factors. Studies from the domains of sexual orientation and sexually problematic behavior among children pointed toward genetic components. Adult men's sexual interest in youthfulness-related cues may be genetically influenced. The aim of the present study was to test whether male sexual interest in children and youth under age 16 involves a heritable component. The main outcome measure was responses in a confidential survey concerning sexual interest, fantasies, or activity pertaining to children under the age of 16 years during the previous 12 months. The present study used an extended family design within behavioral genetic modeling to estimate the contributions of genetic and environmental factors in the occurrence of adult men's sexual interest in children and youth under age 16. Participants were male twins and their male siblings from a population-based Finnish cohort sample aged 21-43 years (N = 3,967). The incidence of sexual interest in children under age was 3%. Twin correlations were higher for monozygotic than for dizygotic twins. Behavioral genetic model fitting indicated that a model including genetic effects as well as nonshared environmental influences (including measurement error), but not common environmental influences, fits the data best. The amount of variance attributable to nonadditive genetic influences (heritability) was estimated at 14.6%. The present study provides the first indication that genetic influences may play a role in shaping sexual interest toward children and adolescents among adult men. Compared with the variance attributable to nonshared environmental effects (plus measurement error), the contribution of any genetic factors seems comparatively weak. Future research should address the possible interplay of genetic with environmental risk factors, such as own sexual victimization in childhood. © 2013 International Society for Sexual Medicine.

Preimplantation genetic diagnosis and rational choice under risk or uncertainty.

PubMed

Zuradzki, Tomasz

2014-11-01

In this paper I present an argument in favour of a parental duty to use preimplantation genetic diagnosis (PGD). I argue that if embryos created in vitro were able to decide for themselves in a rational manner, they would sometimes choose PGD as a method of selection. Couples, therefore, should respect their hypothetical choices on a principle similar to that of patient autonomy. My thesis shows that no matter which moral doctrine couples subscribe to, they ought to conduct the PGD procedure in the situations when it is impossible to implant all of the created embryos and if there is a significant risk for giving birth to a child with a serious condition. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Heritability of DUI convictions: a twin study of driving under the influence of alcohol.

PubMed

Anum, Emmanuel A; Silberg, Judy; Retchin, Sheldon M

2014-02-01

The study was undertaken to assess the relative contributions of genetic and environmental influences on drunk-driving. Driving records of a cohort of male and female twins (N = 17,360) from the Mid-Atlantic Twin Registry were examined. Structural equation models were used to estimate the magnitude of genetic and environmental effects on male and female phenotypes, and test for gender differences. There were significant gender and age effects. Compared with females, males were five times more likely to engage in driving under the influence. Among persons aged 21-49 years, the risk for drunk-driving was eight times that for those aged 50+ years and five times greater than those ≤20 years. In both males and females, aged 21-49 years, a large proportion (57%) of the variance in drunk-driving was due to genetic factors and the remaining 43% due to individual specific environmental influences. Drunk-driving is under significant genetic influence in both males and females. Our findings suggest that a different set of genes influence DUIs in men and women.

Partitioning heritability analysis reveals a shared genetic basis of brain anatomy and schizophrenia

PubMed Central

Lee, Phil H.; Baker, Justin T.; Holmes, Avram J.; Jahanshad, Neda; Ge, Tian; Jung, Jae-Yoon; Cruz, Yanela; Manoach, Dara S.; Hibar, Derrek P.; Faskowitz, Joshua; McMahon, Katie L.; de Zubicaray, Greig I.; Martin, Nicolas H.; Wright, Margaret J.; Öngür, Dost; Buckner, Randy; Roffman, Joshua; Thompson, Paul M.; Smoller, Jordan W.

2016-01-01

Schizophrenia is a devastating neurodevelopmental disorder with a complex genetic etiology. Widespread cortical gray matter loss has been observed in patients and prodromal samples. However, it remains unresolved whether schizophrenia-associated cortical structure variations arise due to disease etiology or secondary to the illness. Here we address this question using a partitioning-based heritability analysis of genome-wide SNP and neuroimaging data from 1,750 healthy individuals. We find that schizophrenia-associated genetic variants explain a significantly enriched proportion of trait heritability in eight brain phenotypes (FDR=10%). In particular, intracranial volume (ICV) and left superior frontal gyrus thickness exhibit significant and robust associations with schizophrenia genetic risk under varying SNP selection conditions. Cross disorder comparison suggests that the neurogenetic architecture of schizophrenia-associated brain regions is, at least in part, shared with other psychiatric disorders. Our study highlights key neuroanatomical correlates of schizophrenia genetic risk in the general population. These may provide fundamental insights into the complex pathophysiology of the illness, and a potential link to neurocognitive deficits shaping the disorder. PMID:27725656

Partitioning heritability analysis reveals a shared genetic basis of brain anatomy and schizophrenia.

PubMed

Lee, P H; Baker, J T; Holmes, A J; Jahanshad, N; Ge, T; Jung, J-Y; Cruz, Y; Manoach, D S; Hibar, D P; Faskowitz, J; McMahon, K L; de Zubicaray, G I; Martin, N H; Wright, M J; Öngür, D; Buckner, R; Roffman, J; Thompson, P M; Smoller, J W

2016-12-01

Schizophrenia is a devastating neurodevelopmental disorder with a complex genetic etiology. Widespread cortical gray matter loss has been observed in patients and prodromal samples. However, it remains unresolved whether schizophrenia-associated cortical structure variations arise due to disease etiology or secondary to the illness. Here we address this question using a partitioning-based heritability analysis of genome-wide single-nucleotide polymorphism (SNP) and neuroimaging data from 1750 healthy individuals. We find that schizophrenia-associated genetic variants explain a significantly enriched proportion of trait heritability in eight brain phenotypes (false discovery rate=10%). In particular, intracranial volume and left superior frontal gyrus thickness exhibit significant and robust associations with schizophrenia genetic risk under varying SNP selection conditions. Cross-disorder comparison suggests that the neurogenetic architecture of schizophrenia-associated brain regions is, at least in part, shared with other psychiatric disorders. Our study highlights key neuroanatomical correlates of schizophrenia genetic risk in the general population. These may provide fundamental insights into the complex pathophysiology of the illness, and a potential link to neurocognitive deficits shaping the disorder.

Insights from human genetic studies of lung and organ fibrosis.

PubMed

Garcia, Christine Kim

2018-01-02

Genetic investigations of fibrotic diseases, including those of late onset, often yield unanticipated insights into disease pathogenesis. This Review focuses on pathways underlying lung fibrosis that are generalizable to other organs. Herein, we discuss genetic variants subdivided into those that shorten telomeres, activate the DNA damage response, change resident protein expression or function, or affect organelle activity. Genetic studies provide a window into the downstream cascade of maladaptive responses and pathways that lead to tissue fibrosis. In addition, these studies reveal interactions between genetic variants, environmental factors, and age that influence the phenotypic spectrum of disease. The discovery of forces counterbalancing inherited risk alleles identifies potential therapeutic targets, thus providing hope for future prevention or reversal of fibrosis.

Parent of origin, mosaicism, and recurrence risk: probabilistic modeling explains the broken symmetry of transmission genetics.

PubMed

Campbell, Ian M; Stewart, Jonathan R; James, Regis A; Lupski, James R; Stankiewicz, Paweł; Olofsson, Peter; Shaw, Chad A

2014-10-02

Most new mutations are observed to arise in fathers, and increasing paternal age positively correlates with the risk of new variants. Interestingly, new mutations in X-linked recessive disease show elevated familial recurrence rates. In male offspring, these mutations must be inherited from mothers. We previously developed a simulation model to consider parental mosaicism as a source of transmitted mutations. In this paper, we extend and formalize the model to provide analytical results and flexible formulas. The results implicate parent of origin and parental mosaicism as central variables in recurrence risk. Consistent with empirical data, our model predicts that more transmitted mutations arise in fathers and that this tendency increases as fathers age. Notably, the lack of expansion later in the male germline determines relatively lower variance in the proportion of mutants, which decreases with paternal age. Subsequently, observation of a transmitted mutation has less impact on the expected risk for future offspring. Conversely, for the female germline, which arrests after clonal expansion in early development, variance in the mutant proportion is higher, and observation of a transmitted mutation dramatically increases the expected risk of recurrence in another pregnancy. Parental somatic mosaicism considerably elevates risk for both parents. These findings have important implications for genetic counseling and for understanding patterns of recurrence in transmission genetics. We provide a convenient online tool and source code implementing our analytical results. These tools permit varying the underlying parameters that influence recurrence risk and could be useful for analyzing risk in diverse family structures. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Human genetics as a tool to identify progranulin regulators.

PubMed

Nicholson, Alexandra M; Finch, NiCole A; Rademakers, Rosa

2011-11-01

Frontotemporal lobar degeneration (FTLD) is a common neurodegenerative disorder that predominantly affects individuals under the age of 65. It is known that the most common pathological subtype is FTLD with TAR DNA-binding protein 43 inclusions (FTLD-TDP). FTLD has a strong genetic component with about 50% of cases having a positive family history. Mutations identified in the progranulin gene (GRN) have been shown to cause FTLD-TDP as a result of progranulin haploinsufficiency. These findings suggest a progranulin-dependent mechanism in this pathological FTLD subtype. Thus, identifying regulators of progranulin levels is essential for new therapies and treatments for FTLD and related disorders. In this review, we discuss the role of genetic studies in identifying progranulin regulators, beginning with the discovery of pathogenic GRN mutations and additional GRN risk variants. We also cover more recent genetic advances, including the detection of variants in the transmembrane protein 106 B gene that increase FTLD-TDP risk presumably by modulating progranulin levels and the identification of a potential progranulin receptor, sortilin. This review highlights the importance of genetic studies in the context of FTLD and further emphasizes the need for future genetic and cell biology research to continue the effort in finding a cure for progranulin-related diseases.

Genetics and Genomics of Coronary Artery Disease.

PubMed

Pjanic, Milos; Miller, Clint L; Wirka, Robert; Kim, Juyong B; DiRenzo, Daniel M; Quertermous, Thomas

2016-10-01

Coronary artery disease (or coronary heart disease), is the leading cause of mortality in many of the developing as well as the developed countries of the world. Cholesterol-enriched plaques in the heart's blood vessels combined with inflammation lead to the lesion expansion, narrowing of blood vessels, reduced blood flow, and may subsequently cause lesion rupture and a heart attack. Even though several environmental risk factors have been established, such as high LDL-cholesterol, diabetes, and high blood pressure, the underlying genetic composition may substantially modify the disease risk; hence, genome composition and gene-environment interactions may be critical for disease progression. Ongoing scientific efforts have seen substantial advancements related to the fields of genetics and genomics, with the major breakthroughs yet to come. As genomics is the most rapidly advancing field in the life sciences, it is important to present a comprehensive overview of current efforts. Here, we present a summary of various genetic and genomics assays and approaches applied to coronary artery disease research.

Conservation genetics of high-arctic Gull species at risk: I. Diversity in the mtDNA control region of circumpolar populations of the Endangered Ivory Gull (Pagophila eburnea).

PubMed

Royston, Stephanie R; Carr, Steven M

2016-11-01

The high-arctic Ivory Gull (Pagophila eburnea) has recently undergone a sharp decline in numbers, and in Canada it is listed as "Endangered" under the Species-At-Risk Act. To test for circumpolar genetic distinctiveness, we examined 264 bp of the mtDNA Control Region Domain I from 127 museum specimens collected during the breeding season from northern Canada, Greenland, and Norway, and during the non-breeding season from adjacent overwintering grounds in Canada, Greenland, and a disjunct area in Alaska adjacent to the Bering Sea. Partition of genetic variance according to various phylogeographic and breeding ground models indicates no strong population structure, except that Alaska birds are consistently differentiated from other locations, and there are significant temporal shifts in haplotype frequencies. The evidence suggests that Ivory Gulls in Canada, Greenland, and Norway are a single genetic entity, in contrast to Alaska birds, which may represent a distinctive Siberian population.

Twins and virtual twins: Do genetic (as well as experiential) factors affect developmental risks?

PubMed

Segal, Nancy L; Tan, Tony Xing; Graham, Jamie L

2015-08-01

Factors underlying developmental delays and psychosocial risks are of interest to international adoption communities. The current study administered a Pre-Adoption Adversity (PAA) Questionnaire to mostly American parents raising (a) adopted Chinese twins or (b) same-age unrelated adopted siblings. A goal was to replicate earlier analyses of pre-adoption adversity/adjustment among adopted preschool-age Chinese girls. A second goal was to conduct genetic analyses of four content areas (Developmental Delays at Adoption, Initial Adaptation to Adoption, Crying/Clinging, and Refusal/Avoidance) derived from the PAA Questionnaire. A key finding was that age at adoption added less than other predictors to adoptees' externalizing and internalizing behaviors. Family factors (e.g., parental education) contributed significantly to behavioral outcomes among the adopted Chinese twins. Genetic effects were indicated for all four content areas, with shared environmental effects evident for Developmental Delays at Adoption and Crying/Clinging. Future investigators should consider incorporating genetically sensitive designs into developmental research programs. Copyright © 2015 Elsevier Inc. All rights reserved.

Heritability of major depressive and comorbid anxiety disorders in multi-generational families at high risk for depression.

PubMed

Guffanti, Guia; Gameroff, Marc J; Warner, Virginia; Talati, Ardesheer; Glatt, Charles E; Wickramaratne, Priya; Weissman, Myrna M

2016-12-01

Family studies have shown that MDD is highly transmittable but have not studied its heritability. Twin studies show heritability of about 40% and do not include anxiety disorders. We assessed heritability of MDD and comorbid anxiety disorders in a multigenerational study of family members at high risk for MDD. In addition, we tested the hypothesis that examined clinical subtypes of MDD defined by early and late age of onset would be under relatively stronger genetic control than broadly defined DSM-IV MDD. The first generation with moderate to severe MDD was recruited from an ambulatory psychiatric treatment setting, and their descendants in the second, third, and fourth generation, were interviewed by clinicians up to six times during a 30-year period. Lifetime rates of MDD and anxiety disorders were collected for 545 participants from 65 multigenerational families. The heritability (h 2 ) of MDD in this high risk sample was estimated at 67%. Anxiety and sequential comorbidity of anxiety disorders and MDD revealed h 2 of 49% and 53%, respectively, and strong positive genetic correlation (rho g  = 0.92, P = 7.3 × 10 -7 ). Early onset MDD did not appear to be under greater genetic control than broadly defined DSM-IV MDD. Individuals who are direct descendants of subjects ascertained for moderate to severe MDD have strong genetic vulnerability to develop anxiety or MDD. Our findings support family based studies as appropriate and useful design to understand the heritability of common disorders such as MDD. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Classification and Reporting of Potentially Proarrhythmic Common Genetic Variation in Long QT Syndrome Genetic Testing.

PubMed

Giudicessi, John R; Roden, Dan M; Wilde, Arthur A M; Ackerman, Michael J

2018-02-06

The acquired and congenital forms of long QT syndrome represent 2 distinct but clinically and genetically intertwined disorders of cardiac repolarization characterized by the shared final common pathway of QT interval prolongation and risk of potentially life-threatening arrhythmias. Over the past 2 decades, our understanding of the spectrum of genetic variation that (1) perturbs the function of cardiac ion channel macromolecular complexes and intracellular calcium-handling proteins, (2) underlies acquired/congenital long QT syndrome susceptibility, and (3) serves as a determinant of QT interval duration in the general population has grown exponentially. In turn, these molecular insights led to the development and increased utilization of clinically impactful genetic testing for congenital long QT syndrome. However, the widespread adoption and potential misinterpretation of the 2015 American College of Medical Genetics and Genomics variant classification and reporting guidelines may have contributed unintentionally to the reduced reporting of common genetic variants, with compelling epidemiological and functional evidence to support a potentially proarrhythmic role in patients with congenital and acquired long QT syndrome. As a result, some genetic testing reports may fail to convey the full extent of a patient's genetic susceptibility for a potentially life-threatening arrhythmia to the ordering healthcare professional. In this white paper, we examine the current classification and reporting (or lack thereof) of potentially proarrhythmic common genetic variants and investigate potential mechanisms to facilitate the reporting of these genetic variants without increasing the risk of diagnostic miscues. © 2018 American Heart Association, Inc.

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

PubMed

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

2014-01-01

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

Genetic Allee effects and their interaction with ecological Allee effects.

PubMed

Wittmann, Meike J; Stuis, Hanna; Metzler, Dirk

2018-01-01

It is now widely accepted that genetic processes such as inbreeding depression and loss of genetic variation can increase the extinction risk of small populations. However, it is generally unclear whether extinction risk from genetic causes gradually increases with decreasing population size or whether there is a sharp transition around a specific threshold population size. In the ecological literature, such threshold phenomena are called 'strong Allee effects' and they can arise for example from mate limitation in small populations. In this study, we aim to (i) develop a meaningful notion of a 'strong genetic Allee effect', (ii) explore whether and under what conditions such an effect can arise from inbreeding depression due to recessive deleterious mutations, and (iii) quantify the interaction of potential genetic Allee effects with the well-known mate-finding Allee effect. We define a strong genetic Allee effect as a genetic process that causes a population's survival probability to be a sigmoid function of its initial size. The inflection point of this function defines the critical population size. To characterize survival-probability curves, we develop and analyse simple stochastic models for the ecology and genetics of small populations. Our results indicate that inbreeding depression can indeed cause a strong genetic Allee effect, but only if individuals carry sufficiently many deleterious mutations (lethal equivalents). Populations suffering from a genetic Allee effect often first grow, then decline as inbreeding depression sets in and then potentially recover as deleterious mutations are purged. Critical population sizes of ecological and genetic Allee effects appear to be often additive, but even superadditive interactions are possible. Many published estimates for the number of lethal equivalents in birds and mammals fall in the parameter range where strong genetic Allee effects are expected. Unfortunately, extinction risk due to genetic Allee effects can easily be underestimated as populations with genetic problems often grow initially, but then crash later. Also interactions between ecological and genetic Allee effects can be strong and should not be neglected when assessing the viability of endangered or introduced populations. © 2016 The Authors. Journal of Animal Ecology © 2016 British Ecological Society.

Cumulative impact of common genetic variants and other risk factors on colorectal cancer risk in 42,103 individuals

PubMed Central

Dunlop, Malcolm G.; Tenesa, Albert; Farrington, Susan M.; Ballereau, Stephane; Brewster, David H.; Pharoah, Paul DP.; Schafmayer, Clemens; Hampe, Jochen; Völzke, Henry; Chang-Claude, Jenny; Hoffmeister, Michael; Brenner, Hermann; von Holst, Susanna; Picelli, Simone; Lindblom, Annika; Jenkins, Mark A.; Hopper, John L.; Casey, Graham; Duggan, David; Newcomb, Polly; Abulí, Anna; Bessa, Xavier; Ruiz-Ponte, Clara; Castellví-Bel, Sergi; Niittymäki, Iina; Tuupanen, Sari; Karhu, Auli; Aaltonen, Lauri; Zanke, Brent W.; Hudson, Thomas J.; Gallinger, Steven; Barclay, Ella; Martin, Lynn; Gorman, Maggie; Carvajal-Carmona, Luis; Walther, Axel; Kerr, David; Lubbe, Steven; Broderick, Peter; Chandler, Ian; Pittman, Alan; Penegar, Steven; Campbell, Harry; Tomlinson, Ian; Houlston, Richard S.

2016-01-01

Objective Colorectal cancer (CRC) has a substantial heritable component. Common genetic variation has been shown to contribute to CRC risk. In a large, multi-population study, we set out to assess the feasibility of CRC risk prediction using common genetic variant data, combined with other risk factors. We built a risk prediction model and applied it to the Scottish population using available data. Design Nine populations of European descent were studied to develop and validate colorectal cancer risk prediction models. Binary logistic regression was used to assess the combined effect of age, gender, family history (FH) and genotypes at 10 susceptibility loci that individually only modestly influence colorectal cancer risk. Risk models were generated from case-control data incorporating genotypes alone (n=39,266), and in combination with gender, age and family history (n=11,324). Model discriminatory performance was assessed using 10-fold internal cross-validation and externally using 4,187 independent samples. 10-year absolute risk was estimated by modelling genotype and FH with age- and gender-specific population risks. Results Median number of risk alleles was greater in cases than controls (10 vs 9, p<2.2×10−16), confirmed in external validation sets (Sweden p=1.2×10−6, Finland p=2×10−5). Mean per-allele increase in risk was 9% (OR 1.09; 95% CI 1.05–1.13). Discriminative performance was poor across the risk spectrum (area under curve (AUC) for genotypes alone - 0.57; AUC for genotype/age/gender/FH - 0.59). However, modelling genotype data, FH, age and gender with Scottish population data shows the practicalities of identifying a subgroup with >5% predicted 10-year absolute risk. Conclusion We show that genotype data provides additional information that complements age, gender and FH as risk factors. However, individualized genetic risk prediction is not currently feasible. Nonetheless, the modelling exercise suggests public health potential, since it is possible to stratify the population into CRC risk categories, thereby informing targeted prevention and surveillance. PMID:22490517

Lifestyle Advice Combined with Personalized Estimates of Genetic or Phenotypic Risk of Type 2 Diabetes, and Objectively Measured Physical Activity: A Randomized Controlled Trial

PubMed Central

van Sluijs, Esther M. F.; Marteau, Theresa M.; Sutton, Stephen

2016-01-01

Background Information about genetic and phenotypic risk of type 2 diabetes is now widely available and is being incorporated into disease prevention programs. Whether such information motivates behavior change or has adverse effects is uncertain. We examined the effect of communicating an estimate of genetic or phenotypic risk of type 2 diabetes in a parallel group, open, randomized controlled trial. Methods and Findings We recruited 569 healthy middle-aged adults from the Fenland Study, an ongoing population-based, observational study in the east of England (Cambridgeshire, UK). We used a computer-generated random list to assign participants in blocks of six to receive either standard lifestyle advice alone (control group, n = 190) or in combination with a genetic (n = 189) or a phenotypic (n = 190) risk estimate for type 2 diabetes (intervention groups). After 8 wk, we measured the primary outcome, objectively measured physical activity (kJ/kg/day), and also measured several secondary outcomes (including self-reported diet, self-reported weight, worry, anxiety, and perceived risk). The study was powered to detect a between-group difference of 4.1 kJ/kg/d at follow-up. 557 (98%) participants completed the trial. There were no significant intervention effects on physical activity (difference in adjusted mean change from baseline: genetic risk group versus control group 0.85 kJ/kg/d (95% CI −2.07 to 3.77, p = 0.57); phenotypic risk group versus control group 1.32 (95% CI −1.61 to 4.25, p = 0.38); and genetic risk group versus phenotypic risk group −0.47 (95% CI −3.40 to 2.46, p = 0.75). No significant differences in self-reported diet, self-reported weight, worry, and anxiety were observed between trial groups. Estimates of perceived risk were significantly more accurate among those who received risk information than among those who did not. Key limitations include the recruitment of a sample that may not be representative of the UK population, use of self-reported secondary outcome measures, and a short follow-up period. Conclusions In this study, we did not observe short-term changes in behavior associated with the communication of an estimate of genetic or phenotypic risk of type 2 diabetes. We also did not observe changes in worry or anxiety in the study population. Additional research is needed to investigate the conditions under which risk information might enhance preventive strategies. (Current Controlled Trials ISRCTN09650496; Date applied: April 4, 2011; Date assigned: June 10, 2011). Trial Registration The trial is registered with Current Controlled Trials, ISRCTN09650496. PMID:27898672

Lifestyle Advice Combined with Personalized Estimates of Genetic or Phenotypic Risk of Type 2 Diabetes, and Objectively Measured Physical Activity: A Randomized Controlled Trial.

PubMed

Godino, Job G; van Sluijs, Esther M F; Marteau, Theresa M; Sutton, Stephen; Sharp, Stephen J; Griffin, Simon J

2016-11-01

Information about genetic and phenotypic risk of type 2 diabetes is now widely available and is being incorporated into disease prevention programs. Whether such information motivates behavior change or has adverse effects is uncertain. We examined the effect of communicating an estimate of genetic or phenotypic risk of type 2 diabetes in a parallel group, open, randomized controlled trial. We recruited 569 healthy middle-aged adults from the Fenland Study, an ongoing population-based, observational study in the east of England (Cambridgeshire, UK). We used a computer-generated random list to assign participants in blocks of six to receive either standard lifestyle advice alone (control group, n = 190) or in combination with a genetic (n = 189) or a phenotypic (n = 190) risk estimate for type 2 diabetes (intervention groups). After 8 wk, we measured the primary outcome, objectively measured physical activity (kJ/kg/day), and also measured several secondary outcomes (including self-reported diet, self-reported weight, worry, anxiety, and perceived risk). The study was powered to detect a between-group difference of 4.1 kJ/kg/d at follow-up. 557 (98%) participants completed the trial. There were no significant intervention effects on physical activity (difference in adjusted mean change from baseline: genetic risk group versus control group 0.85 kJ/kg/d (95% CI -2.07 to 3.77, p = 0.57); phenotypic risk group versus control group 1.32 (95% CI -1.61 to 4.25, p = 0.38); and genetic risk group versus phenotypic risk group -0.47 (95% CI -3.40 to 2.46, p = 0.75). No significant differences in self-reported diet, self-reported weight, worry, and anxiety were observed between trial groups. Estimates of perceived risk were significantly more accurate among those who received risk information than among those who did not. Key limitations include the recruitment of a sample that may not be representative of the UK population, use of self-reported secondary outcome measures, and a short follow-up period. In this study, we did not observe short-term changes in behavior associated with the communication of an estimate of genetic or phenotypic risk of type 2 diabetes. We also did not observe changes in worry or anxiety in the study population. Additional research is needed to investigate the conditions under which risk information might enhance preventive strategies. (Current Controlled Trials ISRCTN09650496; Date applied: April 4, 2011; Date assigned: June 10, 2011). The trial is registered with Current Controlled Trials, ISRCTN09650496.

An exploration of shared genetic risk factors between periodontal disease and cancers: a prospective co-twin study.

PubMed

Arora, Manish; Weuve, Jennifer; Fall, Katja; Pedersen, Nancy L; Mucci, Lorelei A

2010-01-15

Biologic mechanisms underlying associations of periodontal disease with cancers remain unknown. The authors propose that both conditions share common genetic risk factors. They analyzed associations between baseline periodontal disease, measured by questionnaire-recorded tooth mobility, and incident cancers, identified by linkage with national registries, between 1963 and 2004 in 15,333 Swedish twins. The authors used co-twin analyses to control for familial factors and undertook analyses restricted to monozygotic twins to further control for confounding by genetic factors. They observed 4,361 cancer cases over 548,913 person-years. After adjustment for covariates, baseline periodontal disease was associated with increased risk of several cancers ranging from 15% for total cancer (proportional hazard ratio (HR) = 1.15, 95% confidence interval (CI): 1.01, 1.32) to 120% for corpus uterine cancer (HR = 2.20, 95% CI: 1.16, 4.18). Periodontal disease was also associated with increased risk of colorectal (HR = 1.62, 95% CI: 1.13, 2.33), pancreatic (HR = 2.06, 95% CI: 1.14, 3.75), and prostate (HR = 1.47, 95% CI: 1.04, 2.07) cancers. In co-twin analyses, dizygotic twins with baseline periodontal disease showed a 50% increase in total cancer risk (HR = 1.50, 95% CI: 1.04, 2.17), but in monozygotic twins this association was markedly attenuated (HR = 1.07, 95% CI: 0.63, 1.81). Similar patterns emerged for digestive tract cancers, suggesting that shared genetic risk factors may partially explain associations between periodontal disease and cancers.

An Exploration of Shared Genetic Risk Factors Between Periodontal Disease and Cancers: A Prospective Co-Twin Study

PubMed Central

Arora, Manish; Weuve, Jennifer; Fall, Katja; Pedersen, Nancy L.; Mucci, Lorelei A.

2010-01-01

Biologic mechanisms underlying associations of periodontal disease with cancers remain unknown. The authors propose that both conditions share common genetic risk factors. They analyzed associations between baseline periodontal disease, measured by questionnaire-recorded tooth mobility, and incident cancers, identified by linkage with national registries, between 1963 and 2004 in 15,333 Swedish twins. The authors used co-twin analyses to control for familial factors and undertook analyses restricted to monozygotic twins to further control for confounding by genetic factors. They observed 4,361 cancer cases over 548,913 person-years. After adjustment for covariates, baseline periodontal disease was associated with increased risk of several cancers ranging from 15% for total cancer (proportional hazard ratio (HR) = 1.15, 95% confidence interval (CI): 1.01, 1.32) to 120% for corpus uterine cancer (HR = 2.20, 95% CI: 1.16, 4.18). Periodontal disease was also associated with increased risk of colorectal (HR = 1.62, 95% CI: 1.13, 2.33), pancreatic (HR = 2.06, 95% CI: 1.14, 3.75), and prostate (HR = 1.47, 95% CI: 1.04, 2.07) cancers. In co-twin analyses, dizygotic twins with baseline periodontal disease showed a 50% increase in total cancer risk (HR = 1.50, 95% CI: 1.04, 2.17), but in monozygotic twins this association was markedly attenuated (HR = 1.07, 95% CI: 0.63, 1.81). Similar patterns emerged for digestive tract cancers, suggesting that shared genetic risk factors may partially explain associations between periodontal disease and cancers. PMID:19969528

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

PubMed

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

2017-05-01

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

Short communication: Genetic association between schizophrenia and cannabis use.

PubMed

Verweij, Karin J H; Abdellaoui, Abdel; Nivard, Michel G; Sainz Cort, Alberto; Ligthart, Lannie; Draisma, Harmen H M; Minică, Camelia C; Gillespie, Nathan A; Willemsen, Gonneke; Hottenga, Jouke-Jan; Boomsma, Dorret I; Vink, Jacqueline M

2017-02-01

Previous studies have shown a relationship between schizophrenia and cannabis use. As both traits are substantially heritable, a shared genetic liability could explain the association. We use two recently developed genomics methods to investigate the genetic overlap between schizophrenia and cannabis use. Firstly, polygenic risk scores for schizophrenia were created based on summary statistics from the largest schizophrenia genome-wide association (GWA) meta-analysis to date. We analysed the association between these schizophrenia polygenic scores and multiple cannabis use phenotypes (lifetime use, regular use, age at initiation, and quantity and frequency of use) in a sample of 6,931 individuals. Secondly, we applied LD-score regression to the GWA summary statistics of schizophrenia and lifetime cannabis use to calculate the genome-wide genetic correlation. Polygenic risk scores for schizophrenia were significantly (α<0.05) associated with five of the eight cannabis use phenotypes, including lifetime use, regular use, and quantity of use, with risk scores explaining up to 0.5% of the variance. Associations were not significant for age at initiation of use and two measures of frequency of use analyzed in lifetime users only, potentially because of reduced power due to a smaller sample size. The LD-score regression revealed a significant genetic correlation of r g =0.22 (SE=0.07, p=0.003) between schizophrenia and lifetime cannabis use. Common genetic variants underlying schizophrenia and lifetime cannabis use are partly overlapping. Individuals with a stronger genetic predisposition to schizophrenia are more likely to initiate cannabis use, use cannabis more regularly, and consume more cannabis over their lifetime. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Communicating Genetic and Genomic Information: Health Literacy and Numeracy Considerations

PubMed Central

Lea, D.H.; Kaphingst, K.A.; Bowen, D.; Lipkus, I.; Hadley, D.W.

2011-01-01

Genomic research is transforming our understanding of the role of genes in health and disease. These advances, and their application to common diseases that affect large segments of the general population, suggest that researchers and practitioners in public health genomics will increasingly be called upon to translate genomic information to individuals with varying levels of health literacy and numeracy. This paper discusses the current state of research regarding public understanding of genetics and genomics, the influence of health literacy and numeracy on genetic communication, and behavioral responses to genetic and genomic information. The existing research suggests that members of the general public have some familiarity with genetic and genomic terms but have gaps in understanding of underlying concepts. Findings from the limited research base to date indicate that health literacy affects understanding of print and oral communications about genetic and genomic information. Numeracy is also likely to be an important predictor of being able to understand and apply this information, although little research has been conducted in this area to date. In addition, although some research has examined behavior change in response to the receipt of information about genetic risk for familial disorders and genomic susceptibility to common, complex diseases, the effects of health literacy and numeracy on these responses have not been examined. Potential areas in which additional research is needed are identified and practical suggestions for presenting numeric risk information are outlined. Public health genomics researchers and practitioners are uniquely positioned to engage in research that explores how different audiences react to and use genomic risk information. PMID:20407217

Musculoskeletal complaints, anxiety-depression symptoms, and neuroticism: A study of middle-aged twins.

PubMed

Vassend, Olav; Røysamb, Espen; Nielsen, Christopher Sivert; Czajkowski, Nikolai Olavi

2017-08-01

Musculoskeletal (MS) complaints are reported commonly, but the extent to which such complaints reflect the severity of site-specific pathology or a more generalized susceptibility to feel pain/discomfort is uncertain. Both site-specific and more widespread MS conditions have been shown to be linked to anxiety and depression, but the nature of this relationship is poorly understood. In the present study the role of neuroticism as a shared risk factor that may possibly explain the co-occurrence between anxiety-depression and MS complaints was investigated. The sample consisted of 746 monozygotic and 770 dizygotic twins in the age group of 50-65 years (M = 57.11, SD = 4.5). Using Cholesky modeling, genetic and environmental influences on neuroticism, anxiety-depression and MS symptoms, and the associations among these phenotypes were determined. A single factor accounted for about 50% of the overall variance in MS symptom reporting. The best-fitting biometric model included sex-specific additive genetic and individual-specific environmental effects. All 3 phenotypes were strongly influenced by genetic factors, heritability (h2) = 0.41-0.56. Furthermore, while there was a considerable overlap in genetic risk factors among the 3 phenotypes, a substantial proportion of the genetic risk shared between MS complaints and anxiety-depression was independent of neuroticism. Evidence for a common underlying susceptibility to report MS symptoms, genetically linked to both neuroticism and anxiety-depression symptoms, was found. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Genetic alterations in the NO-cGMP pathway and cardiovascular risk.

PubMed

Wobst, Jana; Schunkert, Heribert; Kessler, Thorsten

2018-06-01

In the past ten years, several chromosomal loci have been identified by genome-wide association studies to influence the risk of coronary artery disease (CAD) and its risk factors. The GUCY1A3 gene encoding the α 1 subunit of the soluble guanylyl cyclase (sGC) resides at one of these loci and has been strongly associated with blood pressure and CAD risk. More recently, further genes in the pathway encoding the endothelial nitric oxide synthase, the phosphodiesterases 3A and 5A, and the inositol 1,4,5-trisphosphate receptor I-associated protein (IRAG), i.e., NOS3, PDE3A, PDE5A, and MRVI1, respectively, were likewise identified as CAD risk genes. In this review, we highlight the genetic findings linking variants in NO-cGMP signaling and cardiovascular disease, discuss the potential underlying mechanisms which might propagate the development of atherosclerosis, and speculate about therapeutic implications. Copyright © 2018 Elsevier Inc. All rights reserved.

Impact of literacy and numeracy on motivation for behavior change after diabetes genetic risk testing.

PubMed

Vassy, Jason L; O'Brien, Kelsey E; Waxler, Jessica L; Park, Elyse R; Delahanty, Linda M; Florez, Jose C; Meigs, James B; Grant, Richard W

2012-01-01

Type 2 diabetes genetic risk testing might motivate at-risk patients to adopt diabetes prevention behaviors. However, the influence of literacy and numeracy on patient response to diabetes genetic risk is unknown. The authors investigated the association of health literacy, genetic literacy, and health numeracy with patient responses to diabetes genetic risk. and Measurements Overweight patients at high phenotypic risk for type 2 diabetes were recruited for a clinical trial of diabetes genetic risk testing. At baseline, participants predicted how their motivation for lifestyle modification to prevent diabetes might change in response to hypothetical scenarios of receiving "high" and "low" genetic risk results. Responses were analyzed according to participants' health literacy, genetic literacy, and health numeracy. Two-thirds (67%) of participants (n = 175) reported very high motivation to prevent diabetes. Despite high health literacy (92% at high school level), many participants had limited health numeracy (30%) and genetic literacy (38%). Almost all (98%) reported that high-risk genetic results would increase their motivation for lifestyle modification. In contrast, response to low-risk genetic results varied. Higher levels of health literacy (P = 0.04), genetic literacy (P = 0.02), and health numeracy (P = 0.02) were associated with an anticipated decrease in motivation for lifestyle modification in response to low-risk results. While patients reported that high-risk genetic results would motivate them to adopt healthy lifestyle changes, response to low-risk results varied by patient numeracy and literacy. However, anticipated responses may not correlate with true behavior change. If future research justifies the clinical use of genetic testing to motivate behavior change, it may be important to assess how patient characteristics modify that motivational effect.

Evidence for shared genetic risk between ADHD symptoms and reduced mathematics ability: a twin study

PubMed Central

Greven, Corina U.; Kovas, Yulia; Willcutt, Erik G.; Petrill, Stephen A.; Plomin, Robert

2013-01-01

Background Attention-deficit/hyperactivity disorder (ADHD) symptoms and mathematics ability are associated, but little is known about the genetic and environmental influences underlying this association. Methods Data came from more than 6,000 12-year-old twin pairs from the U.K. population-representative Twins Early Development Study. Parents rated each twin’s behaviour using a DSM-IV-based 18-item questionnaire of inattentive and hyperactive-impulsive ADHD symptoms. Mathematics tests based on the U.K. National Curriculum were completed by each twin. The twins also completed standardised tests of reading and general cognitive ability. Multivariate twin model fitting was applied. Results Inattentive and hyperactive-impulsive ADHD symptoms were highly heritable (67% and 73%, respectively). Mathematics ability was moderately heritable (46%). Mathematics ability and inattentiveness showed a significantly greater phenotypic correlation (rp=−0.26) and genetic correlation (rA=−0.41) than mathematics ability and hyperactivity-impulsivity (rp=−0.18; rA=−0.22). The genetic correlation between inattentiveness and mathematics ability was largely independent from hyperactivity-impulsivity, and was only partially accounted for by genetic influences related to reading and general cognitive ability. Conclusions Results revealed the novel finding that mathematics ability shows significantly stronger phenotypic and genetic associations with inattentiveness than with hyperactivity-impulsivity. Genetic associations between inattentiveness and mathematics ability could only partially be accounted for by hyperactivity-impulsivity, reading and general cognitive ability. Results suggest that mathematics ability is associated with ADHD symptoms largely because it shares genetic risk factors with inattentiveness, and provide further evidence for considering inattentiveness and hyperactivity-impulsivity separately. DNA markers for ADHD symptoms (especially inattentiveness) may also be candidate risk factors for mathematics ability and vice versa. PMID:23731013

Evidence for shared genetic risk between ADHD symptoms and reduced mathematics ability: a twin study.

PubMed

Greven, Corina U; Kovas, Yulia; Willcutt, Erik G; Petrill, Stephen A; Plomin, Robert

2014-01-01

Attention-deficit/hyperactivity disorder (ADHD) symptoms and mathematics ability are associated, but little is known about the genetic and environmental influences underlying this association. Data came from more than 6,000 twelve-year-old twin pairs from the UK population-representative Twins Early Development Study. Parents rated each twin's behaviour using a DSM-IV-based 18-item questionnaire of inattentive and hyperactive-impulsive ADHD symptoms. Mathematics tests based on the UK National Curriculum were completed by each twin. The twins also completed standardised tests of reading and general cognitive ability. Multivariate twin model fitting was applied. Inattentive and hyperactive-impulsive ADHD symptoms were highly heritable (67% and 73% respectively). Mathematics ability was moderately heritable (46%). Mathematics ability and inattentiveness showed a significantly greater phenotypic correlation (r(p) = -.26) and genetic correlation (r(A) = -.41) than mathematics ability and hyperactivity-impulsivity (r(p) = -.18; r(A) = -.22). The genetic correlation between inattentiveness and mathematics ability was largely independent from hyperactivity-impulsivity, and was only partially accounted for by genetic influences related to reading and general cognitive ability. Results revealed the novel finding that mathematics ability shows significantly stronger phenotypic and genetic associations with inattentiveness than with hyperactivity-impulsivity. Genetic associations between inattentiveness and mathematics ability could only partially be accounted for by hyperactivity-impulsivity, reading and general cognitive ability. Results suggest that mathematics ability is associated with ADHD symptoms largely because it shares genetic risk factors with inattentiveness, and provide further evidence for considering inattentiveness and hyperactivity-impulsivity separately. DNA markers for ADHD symptoms (especially inattentiveness) may also be candidate risk factors for mathematics ability and vice versa. © 2013 The Authors. Journal of Child Psychology and Psychiatry © 2013 Association for Child and Adolescent Mental Health.

Developing a multi-component immune model for evaluating the risk of respiratory illness in athletes.

PubMed

Gleeson, Maree; Pyne, David B; Elkington, Lisa J; Hall, Sharron T; Attia, John R; Oldmeadow, Christopher; Wood, Lisa G; Callister, Robin

2017-01-01

Clinical and laboratory identification of the underlying risk of respiratory illness in athletes has proved problematic. The aim of this study was to determine whether clinical data, combined with immune responses to standardised exercise protocols and genetic cytokine polymorphism status, could identify the risk of respiratory illness (symptoms) in a cohort of highly-trained athletes. Male endurance athletes (n=16; VO2max 66.5 ± 5.1 mL.kg-1.min-1) underwent a clinical evaluation of known risk factors by a physician and comprehensive laboratory analysis of immune responses both at rest and after two cycling ergometer tests: 60 min at 65% VO2max (LONG); and 6 x 3 min intervals at 90% VO2max (INTENSE). Blood tests were performed to determine Epstein Barr virus (EBV) status and DNA was genotyped for a panel of cytokine gene polymorphisms. Saliva was collected for measurement of IgA and detection of EBV DNA. Athletes were then followed for 9 months for self-reported episodes of respiratory illness, with confirmation of the underlying cause by a sports physician. There were no associations with risk of respiratory illness identified for any parameter assessed in the clinical evaluations. The laboratory parameters associated with an increased risk of respiratory illnesses in highly-trained athletes were cytokine gene polymorphisms for the high expression of IL-6 and IFN-ɣ; expression of EBV-DNA in saliva; and low levels of salivary IgA concentration. A genetic risk score was developed for the cumulative number of minor alleles for the cytokines evaluated. Athletes prone to recurrent respiratory illness were more likely to have immune disturbances that allow viral reactivation, and a genetic predisposition to pro-inflammatory cytokine responses to intense exercise. Copyright © 2016 International Society of Exercise and Immunology. All rights reserved.

Empirical Bayes Estimation of Semi-parametric Hierarchical Mixture Models for Unbiased Characterization of Polygenic Disease Architectures

PubMed Central

Nishino, Jo; Kochi, Yuta; Shigemizu, Daichi; Kato, Mamoru; Ikari, Katsunori; Ochi, Hidenori; Noma, Hisashi; Matsui, Kota; Morizono, Takashi; Boroevich, Keith A.; Tsunoda, Tatsuhiko; Matsui, Shigeyuki

2018-01-01

Genome-wide association studies (GWAS) suggest that the genetic architecture of complex diseases consists of unexpectedly numerous variants with small effect sizes. However, the polygenic architectures of many diseases have not been well characterized due to lack of simple and fast methods for unbiased estimation of the underlying proportion of disease-associated variants and their effect-size distribution. Applying empirical Bayes estimation of semi-parametric hierarchical mixture models to GWAS summary statistics, we confirmed that schizophrenia was extremely polygenic [~40% of independent genome-wide SNPs are risk variants, most within odds ratio (OR = 1.03)], whereas rheumatoid arthritis was less polygenic (~4 to 8% risk variants, significant portion reaching OR = 1.05 to 1.1). For rheumatoid arthritis, stratified estimations revealed that expression quantitative loci in blood explained large genetic variance, and low- and high-frequency derived alleles were prone to be risk and protective, respectively, suggesting a predominance of deleterious-risk and advantageous-protective mutations. Despite genetic correlation, effect-size distributions for schizophrenia and bipolar disorder differed across allele frequency. These analyses distinguished disease polygenic architectures and provided clues for etiological differences in complex diseases. PMID:29740473

Pulmonary Complications Resulting from Genetic Cardiovascular Disease in Two Rat Models

EPA Science Inventory

Underlying cardiovascular disease (CVD) has been considered a risk factor for exacerbation of air pollution health effects. Therefore, rodent models of CVD are increasingly used to examine mechanisms of variation in susceptibility. Pulmonary complications and altered iron homeost...

Performance of genetic risk factors in prediction of trichloroethylene induced hypersensitivity syndrome.

PubMed

Dai, Yufei; Chen, Ying; Huang, Hanlin; Zhou, Wei; Niu, Yong; Zhang, Mingrong; Bin, Ping; Dong, Haiyan; Jia, Qiang; Huang, Jianxun; Yi, Juan; Liao, Qijun; Li, Haishan; Teng, Yanxia; Zang, Dan; Zhai, Qingfeng; Duan, Huawei; Shen, Juan; He, Jiaxi; Meng, Tao; Sha, Yan; Shen, Meili; Ye, Meng; Jia, Xiaowei; Xiang, Yingping; Huang, Huiping; Wu, Qifeng; Shi, Mingming; Huang, Xianqing; Yang, Huanming; Luo, Longhai; Li, Sai; Li, Lin; Zhao, Jinyang; Li, Laiyu; Wang, Jun; Zheng, Yuxin

2015-07-20

Trichloroethylene induced hypersensitivity syndrome is dose-independent and potentially life threatening disease, which has become one of the serious occupational health issues and requires intensive treatment. To discover the genetic risk factors and evaluate the performance of risk prediction model for the disease, we conducted genomewide association study and replication study with total of 174 cases and 1761 trichloroethylene-tolerant controls. Fifty seven SNPs that exceeded the threshold for genome-wide significance (P < 5 × 10(-8)) were screened to relate with the disease, among which two independent SNPs were identified, that is rs2857281 at MICA (odds ratio, 11.92; P meta = 1.33 × 10(-37)) and rs2523557 between HLA-B and MICA (odds ratio, 7.33; P meta = 8.79 × 10(-35)). The genetic risk score with these two SNPs explains at least 20.9% of the disease variance and up to 32.5-fold variation in inter-individual risk. Combining of two SNPs as predictors for the disease would have accuracy of 80.73%, the area under receiver operator characteristic curves (AUC) scores was 0.82 with sensitivity of 74% and specificity of 85%, which was considered to have excellent discrimination for the disease, and could be considered for translational application for screening employees before exposure.

Evolutionary Meta-Analysis of Association Studies Reveals Ancient Constraints Affecting Disease Marker Discovery

PubMed Central

Dudley, Joel T.; Chen, Rong; Sanderford, Maxwell; Butte, Atul J.; Kumar, Sudhir

2012-01-01

Genome-wide disease association studies contrast genetic variation between disease cohorts and healthy populations to discover single nucleotide polymorphisms (SNPs) and other genetic markers revealing underlying genetic architectures of human diseases. Despite scores of efforts over the past decade, many reproducible genetic variants that explain substantial proportions of the heritable risk of common human diseases remain undiscovered. We have conducted a multispecies genomic analysis of 5,831 putative human risk variants for more than 230 disease phenotypes reported in 2,021 studies. We find that the current approaches show a propensity for discovering disease-associated SNPs (dSNPs) at conserved genomic positions because the effect size (odds ratio) and allelic P value of genetic association of an SNP relates strongly to the evolutionary conservation of their genomic position. We propose a new measure for ranking SNPs that integrates evolutionary conservation scores and the P value (E-rank). Using published data from a large case-control study, we demonstrate that E-rank method prioritizes SNPs with a greater likelihood of bona fide and reproducible genetic disease associations, many of which may explain greater proportions of genetic variance. Therefore, long-term evolutionary histories of genomic positions offer key practical utility in reassessing data from existing disease association studies, and in the design and analysis of future studies aimed at revealing the genetic basis of common human diseases. PMID:22389448

The Genetic and Environmental Sources of Resemblance Between Normative Personality and Personality Disorder Traits.

PubMed

Kendler, K S; Aggen, S H; Gillespie, Nathan; Neale, M C; Knudsen, G P; Krueger, R F; Czajkowski, Nikolai; Ystrom, Eivind; Reichborn-Kjennerud, T

2017-04-01

Recent work has suggested a high level of congruence between normative personality, most typically represented by the "big five" factors, and abnormal personality traits. In 2,293 Norwegian adult twins ascertained from a population-based registry, the authors evaluated the degree of sharing of genetic and environmental influences on normative personality, assessed by the Big Five Inventory (BFI), and personality disorder traits (PDTs), assessed by the Personality Inventory for DSM-5-Norwegian Brief Form (PID-5-NBF). For four of the five BFI dimensions, the strongest genetic correlation was observed with the expected PID-5-NBF dimension (e.g., neuroticism with negative affectivity [+], conscientiousness with disinhibition [-]). However, neuroticism, conscientiousness, and agreeableness had substantial genetic correlations with other PID-5-NBF dimensions (e.g., neuroticism with compulsivity [+], agreeableness with detachment [-]). Openness had no substantial genetic correlations with any PID-5-NBF dimension. The proportion of genetic risk factors shared in aggregate between the BFI traits and the PID-5-NBF dimensions was quite high for conscientiousness and neuroticism, relatively robust for extraversion and agreeableness, but quite low for openness. Of the six PID-5-NBF dimensions, three (negative affectivity, detachment, and disinhibition) shared, in aggregate, most of their genetic risk factors with normative personality traits. Genetic factors underlying psychoticism, antagonism, and compulsivity were shared to a lesser extent, suggesting that they are influenced by etiological factors not well indexed by the BFI.

Design of a randomized trial of diabetes genetic risk testing to motivate behavior change: the Genetic Counseling/lifestyle Change (GC/LC) Study for Diabetes Prevention.

PubMed

Grant, Richard W; Meigs, James B; Florez, Jose C; Park, Elyse R; Green, Robert C; Waxler, Jessica L; Delahanty, Linda M; O'Brien, Kelsey E

2011-10-01

The efficacy of diabetes genetic risk testing to motivate behavior change for diabetes prevention is currently unknown. This paper presents key issues in the design and implementation of one of the first randomized trials (The Genetic Counseling/Lifestyle Change (GC/LC) Study for Diabetes Prevention) to test whether knowledge of diabetes genetic risk can motivate patients to adopt healthier behaviors. Because individuals may react differently to receiving 'higher' vs 'lower' genetic risk results, we designed a 3-arm parallel group study to separately test the hypotheses that: (1) patients receiving 'higher' diabetes genetic risk results will increase healthy behaviors compared to untested controls, and (2) patients receiving 'lower' diabetes genetic risk results will decrease healthy behaviors compared to untested controls. In this paper we describe several challenges to implementing this study, including: (1) the application of a novel diabetes risk score derived from genetic epidemiology studies to a clinical population, (2) the use of the principle of Mendelian randomization to efficiently exclude 'average' diabetes genetic risk patients from the intervention, and (3) the development of a diabetes genetic risk counseling intervention that maintained the ethical need to motivate behavior change in both 'higher' and 'lower' diabetes genetic risk result recipients. Diabetes genetic risk scores were developed by aggregating the results of 36 diabetes-associated single nucleotide polymorphisms. Relative risk for type 2 diabetes was calculated using Framingham Offspring Study outcomes, grouped by quartiles into 'higher', 'average' (middle two quartiles) and 'lower' genetic risk. From these relative risks, revised absolute risks were estimated using the overall absolute risk for the study group. For study efficiency, we excluded all patients receiving 'average' diabetes risk results from the subsequent intervention. This post-randomization allocation strategy was justified because genotype represents a random allocation of parental alleles ('Mendelian randomization'). Finally, because it would be unethical to discourage participants to participate in diabetes prevention behaviors, we designed our two diabetes genetic risk counseling interventions (for 'higher' and 'lower' result recipients) so that both groups would be motivated despite receiving opposing results. For this initial assessment of the clinical implementation of genetic risk testing we assessed intermediate outcomes of attendance at a 12-week diabetes prevention course and changes in self-reported motivation. If effective, longer term studies with larger sample sizes will be needed to assess whether knowledge of diabetes genetic risk can help patients prevent diabetes. We designed a randomized clinical trial designed to explore the motivational impact of disclosing both higher than average and lower than average genetic risk for type 2 diabetes. This design allowed exploration of both increased risk and false reassurance, and has implications for future studies in translational genomics.

Genetic polymorphisms in ALDH2 are associated with drug addiction in a Chinese Han population

PubMed Central

Zhang, Chan; Ding, Heng; Cheng, Yujing; Chen, Wanlu; Li, Qi; Li, Qing; Dai, Run; Luo, Manlin

2017-01-01

We investigated the association between single nucleotide polymorphisms (SNPs) in ALDH2, which has been associated with alcohol dependence and several types of diseases, and the risk of drug addiction in a Chinese Han population. In a case-control study that included 692 cases and 700 healthy controls, eight SNPs in ALDH2 were selected and genotyped using the Sequenom MassARRAY platform. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression after adjusting for age and gender. We determined that rs671 is significantly associated with a 1.551-fold increased drug addiction risk (95% CI = 1.263-1.903; p < 0.001). In the genetic model analysis, we found that rs671 is associated with an increased risk of drug addiction under additive, dominant and recessive models (p < 0.001), while rs886205, rs441 and rs4646778 displayed a decreased drug addiction risk under additive and recessive model, respectively (p < 0.05). SNP rs671 remained significant after Bonferroni correction (p<0.00125). Additionally, we observed that haplotype “GTCAC” was associated with increased drug addiction risk (OR = 1.668; 95% CI, 1.328–2.094, p < 0.001); in contrast, “ATCGC” was a protective haplotype for drug addiction risk (OR = 0.444; 95% CI, 0.281–0.704, p < 0.001). Our findings showed that ALDH2 polymorphisms are significantly associated with the risk of drug addiction in the Chinese Han population. PMID:28052001

Genetic polymorphisms in ALDH2 are associated with drug addiction in a Chinese Han population.

PubMed

Zhang, Chan; Ding, Heng; Cheng, Yujing; Chen, Wanlu; Li, Qi; Li, Qing; Dai, Run; Luo, Manlin

2017-01-31

We investigated the association between single nucleotide polymorphisms (SNPs) in ALDH2, which has been associated with alcohol dependence and several types of diseases, and the risk of drug addiction in a Chinese Han population. In a case-control study that included 692 cases and 700 healthy controls, eight SNPs in ALDH2 were selected and genotyped using the Sequenom MassARRAY platform. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression after adjusting for age and gender. We determined that rs671 is significantly associated with a 1.551-fold increased drug addiction risk (95% CI = 1.263-1.903; p < 0.001). In the genetic model analysis, we found that rs671 is associated with an increased risk of drug addiction under additive, dominant and recessive models (p < 0.001), while rs886205, rs441 and rs4646778 displayed a decreased drug addiction risk under additive and recessive model, respectively (p < 0.05). SNP rs671 remained significant after Bonferroni correction (p<0.00125). Additionally, we observed that haplotype "GTCAC" was associated with increased drug addiction risk (OR = 1.668; 95% CI, 1.328-2.094, p < 0.001); in contrast, "ATCGC" was a protective haplotype for drug addiction risk (OR = 0.444; 95% CI, 0.281-0.704, p < 0.001). Our findings showed that ALDH2 polymorphisms are significantly associated with the risk of drug addiction in the Chinese Han population.

Problems and solutions in the estimation of genetic risks from radiation and chemicals

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

Russell, W. L.

1980-01-01

Extensive investigations with mice on the effects of various physical and biological factors, such as dose rate, sex and cell stage, on radiation-induced mutation have provided an evaluation of the genetics hazards of radiation in man. The mutational results obtained in both sexes with progressive lowering of the radiation dose rate have permitted estimation of the mutation frequency expected under the low-level radiation conditions of most human exposure. Supplementing the studies on mutation frequency are investigations on the phenotypic effects of mutations in mice, particularly anatomical disorders of the skeleton, which allow an estimation of the degree of human handicapmore » associated with the occurrence of parallel defects in man. Estimation of the genetic risk from chemical mutagens is much more difficult, and the research is much less advanced. Results on transmitted mutations in mice indicate a poor correlation with mutation induction in non-mammalian organisms.« less

Familial Risks of Tourette Syndrome and Chronic Tic Disorders. A Population-Based Cohort Study.

PubMed

Mataix-Cols, David; Isomura, Kayoko; Pérez-Vigil, Ana; Chang, Zheng; Rück, Christian; Larsson, K Johan; Leckman, James F; Serlachius, Eva; Larsson, Henrik; Lichtenstein, Paul

2015-08-01

Tic disorders, including Tourette syndrome (TS) and chronic tic disorders (CTDs), are assumed to be strongly familial and heritable. Although gene-searching efforts are well under way, precise estimates of familial risk and heritability are lacking. Previous controlled family studies were small and typically conducted within specialist clinics, resulting in potential ascertainment biases. They were also underpowered to disentangle genetic from environmental factors that contribute to the observed familiality. Twin studies have been either very small or based on parent-reported tics in population-based (nonclinical) twin samples. To provide unbiased estimates of familial risk and heritability of tic disorders at the population level. In this population cohort, multigenerational family study, we used a validated algorithm to identify 4826 individuals diagnosed as having TS or CTDs (76.2% male) in the Swedish National Patient Register from January 1, 1969, through December 31, 2009. We studied risks for TS or CTDs in all biological relatives of probands compared with relatives of unaffected individuals (matched on a 1:10 ratio) from the general population. Structural equation modeling was used to estimate the heritability of tic disorders. The risk for tic disorders among relatives of probands with tic disorders increased proportionally to the degree of genetic relatedness. The risks for first-degree relatives (odds ratio [OR], 18.69; 95% CI, 14.53-24.05) were significantly higher than for second-degree relatives (OR, 4.58; 95% CI, 3.22-6.52) and third-degree relatives (OR, 3.07; 95% CI, 2.08-4.51). First-degree relatives at similar genetic distances (eg, parents, siblings, and offspring) had similar risks for tic disorders despite different degrees of shared environment. The risks for full siblings (50% genetic similarity; OR, 17.68; 95% CI, 12.90-24.23) were significantly higher than those for maternal half siblings (25% genetic similarity; OR, 4.41; 95% CI, 2.24-8.67) despite similar environmental exposures. The heritability of tic disorders was estimated to be 0.77 (95% CI, 0.70-0.85). There were no differences in familial risk or heritability between male and female patients. Tic disorders, including TS and CTDs, cluster in families primarily because of genetic factors and appear to be among the most heritable neuropsychiatric conditions.

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

PubMed

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

2011-08-10

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

Understanding the major risk factors in the beginning and the progression of rheumatoid arthritis: current scenario and future prospects.

PubMed

Verma, Mahendra Kumar; Sobha, Kota

2015-09-01

Rheumatoid arthritis (RA), a chronic progressive inflammatory autoimmune disorder characterized by chronic pain and swelling primarily, affects the peripheral joints. RA had attained global concern in the last few decades, affecting more than 1.5 % of the world's population with higher female percentage than male. In the advanced stage, the disease is associated with the destruction of cartilage and bone along with a variety of systemic manifestations leading to functional disability. Inadequate early/preliminary diagnosis and non-specific therapeutics are the major challenges in the management of RA. Till date, the exact cause(s) of the disease remain(s) obscure, and several genetic, hormonal, and environmental factors are associated with the beginning and the progression of the disease. Rheumatoid factor is the only clinically approved bio-marker for the diagnosis, and RA is not restricted to bones, but also affects several vital organs in the advanced stages. Genome-wide association studies have explored novel genetic loci underlying common autoimmune diseases including RA. Recent discoveries of risk alleles have made it possible to define genetic risk profiles of patients with RA. The conventional non-steroidal anti-inflammatory drugs and steroidal drugs are still the choice for the treatment of RA under acute and chronic pathological conditions respectively. However, disease-modifying anti-rheumatic drugs have shown remarkable success in the last decade. The present review provides a comprehensive understanding of the major risk factors and the molecular biology involved in the initiation and the progression of RA with a note on the recent trends in RA therapy.

Molecular responses of genetically modified maize to abiotic stresses as determined through proteomic and metabolomic analyses

PubMed Central

Benevenuto, Rafael Fonseca; Agapito-Tenfen, Sarah Zanon; Vilperte, Vinicius; Wikmark, Odd-Gunnar; van Rensburg, Peet Jansen; Nodari, Rubens Onofre

2017-01-01

Some genetically modified (GM) plants have transgenes that confer tolerance to abiotic stressors. Meanwhile, other transgenes may interact with abiotic stressors, causing pleiotropic effects that will affect the plant physiology. Thus, physiological alteration might have an impact on the product safety. However, routine risk assessment (RA) analyses do not evaluate the response of GM plants exposed to different environmental conditions. Therefore, we here present a proteome profile of herbicide-tolerant maize, including the levels of phytohormones and related compounds, compared to its near-isogenic non-GM variety under drought and herbicide stresses. Twenty differentially abundant proteins were detected between GM and non-GM hybrids under different water deficiency conditions and herbicide sprays. Pathway enrichment analysis showed that most of these proteins are assigned to energetic/carbohydrate metabolic processes. Among phytohormones and related compounds, different levels of ABA, CA, JA, MeJA and SA were detected in the maize varieties and stress conditions analysed. In pathway and proteome analyses, environment was found to be the major source of variation followed by the genetic transformation factor. Nonetheless, differences were detected in the levels of JA, MeJA and CA and in the abundance of 11 proteins when comparing the GM plant and its non-GM near-isogenic variety under the same environmental conditions. Thus, these findings do support molecular studies in GM plants Risk Assessment analyses. PMID:28245233

Let Food Be Thy Medicine: Diet, Nutrition, and Biomarkers’ Risk of Alzheimer’s Disease

PubMed Central

Mosconi, Lisa; McHugh, Pauline F.

2015-01-01

Epidemiological evidence linking diet—one of the most important modifiable lifestyle factors—and risk of Alzheimer’s disease (AD)—the most common cause of dementia—is rapidly increasing. However, the biological mechanisms underlying the relationship between dietary nutrients, brain aging, and risk of AD are largely unexplored. Recent studies using brain imaging and biological markers of AD have begun to clarify how diet and nutrition modulate risk of AD in cognitively normal individuals, especially those at increased genetic risk. Such knowledge is critical prior to implementing dietary recommendations for prevention and treatment of disease. PMID:26167396

Use of Longitudinal Data in Genetic Studies in the Genome-wide Association Studies Era: Summary of Group 14

PubMed Central

Kerner, Berit; North, Kari E; Fallin, M Daniele

2010-01-01

Participants analyzed actual and simulated longitudinal data from the Framingham Heart Study for various metabolic and cardiovascular traits. The genetic information incorporated into these investigations ranged from selected single-nucleotide polymorphisms to genome-wide association arrays. Genotypes were incorporated using a broad range of methodological approaches including conditional logistic regression, linear mixed models, generalized estimating equations, linear growth curve estimation, growth modeling, growth mixture modeling, population attributable risk fraction based on survival functions under the proportional hazards models, and multivariate adaptive splines for the analysis of longitudinal data. The specific scientific questions addressed by these different approaches also varied, ranging from a more precise definition of the phenotype, bias reduction in control selection, estimation of effect sizes and genotype associated risk, to direct incorporation of genetic data into longitudinal modeling approaches and the exploration of population heterogeneity with regard to longitudinal trajectories. The group reached several overall conclusions: 1) The additional information provided by longitudinal data may be useful in genetic analyses. 2) The precision of the phenotype definition as well as control selection in nested designs may be improved, especially if traits demonstrate a trend over time or have strong age-of-onset effects. 3) Analyzing genetic data stratified for high-risk subgroups defined by a unique development over time could be useful for the detection of rare mutations in common multi-factorial diseases. 4) Estimation of the population impact of genomic risk variants could be more precise. The challenges and computational complexity demanded by genome-wide single-nucleotide polymorphism data were also discussed. PMID:19924713

Principles in genetic risk assessment.

PubMed

Baptista, Pedro Viana

2005-03-01

Risk assessment constitutes an essential component of genetic counseling and testing, and the genetic risk should be estimated as accurately as possible for individual and family decision making. All relevant information retrieved from population studies and pedigree and genetic testing enhances the accuracy of the assessment of an individual's genetic risk. This review will focus on the following general aspects implicated in risk assessment: the increasing genetic information regarding disease; complex traits versus Mendelian disorders; and the influence of the environment and disease susceptibility. The influence of these factors on risk assessment will be discussed.

Principles in genetic risk assessment

PubMed Central

Baptista, Pedro Viana

2005-01-01

Risk assessment constitutes an essential component of genetic counseling and testing, and the genetic risk should be estimated as accurately as possible for individual and family decision making. All relevant information retrieved from population studies and pedigree and genetic testing enhances the accuracy of the assessment of an individual's genetic risk. This review will focus on the following general aspects implicated in risk assessment: the increasing genetic information regarding disease; complex traits versus Mendelian disorders; and the influence of the environment and disease susceptibility. The influence of these factors on risk assessment will be discussed. PMID:18360538

Parent depressive symptomatology moderates the etiology of externalizing behavior in childhood: An examination of gene-environment interaction effects.

PubMed

Clark, D Angus; Klump, Kelly L; Burt, S Alexandra

2018-04-26

Parent depressive symptomatology is robust risk factor for externalizing behavior in childhood (Goodman et al., 2011). Although the precise mechanisms underlying this association have yet to be fully illuminated, there is some evidence that parent depression can impact externalizing behavior via both genetic and environmental pathways. In the current study, we investigated the extent to which genetic and environmental influences on externalizing behavior are moderated by parent depressive symptoms (i.e., genotype-environment interaction) in a sample of 2,060, 6- to 11-year-old twins. Results suggest that genetic influences explain more variance in externalizing behavior as maternal depressive symptoms increase, whereas shared environmental effects decrease. These findings were specific to maternal depressive symptoms, however, and did not extend to not paternal depressive symptoms. Findings are critical for understanding the role of parental depression as a risk factor for problematic child behavior, and informing programs that seek to minimize the impact of this risk factor. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Moderate Multiple Parentage and Low Genetic Variation Reduces the Potential for Genetic Incompatibility Avoidance Despite High Risk of Inbreeding

PubMed Central

Tuni, Cristina; Goodacre, Sara; Bechsgaard, Jesper; Bilde, Trine

2012-01-01

Background Polyandry is widespread throughout the animal kingdom. In the absence of direct benefits of mating with different males, the underlying basis for polyandry is enigmatic because it can carry considerable costs such as elevated exposure to sexual diseases, physical injury or other direct fitness costs. Such costs may be balanced by indirect genetic benefits to the offspring of polyandrous females. We investigated polyandry and patterns of parentage in the spider Stegodyphus lineatus. This species experiences relatively high levels of inbreeding as a result of its spatial population structure, philopatry and limited male mating dispersal. Polyandry may provide an opportunity for post mating inbreeding avoidance that reduces the risk of genetic incompatibilities arising from incestuous matings. However, multiple mating carries direct fitness costs to females suggesting that genetic benefits must be substantial to counter direct costs. Methodology/Principal Findings Genetic parentage analyses in two populations from Israel and a Greek island, showed mixed-brood parentage in approximately 50% of the broods. The number of fathers ranged from 1–2 indicating low levels of multiple parentage and there was no evidence for paternity bias in mixed-broods from both populations. Microsatellite loci variation suggested limited genetic variation within populations, especially in the Greek island population. Relatedness estimates among females in the maternal generation and potentially interacting individuals were substantial indicating full-sib and half-sib relationships. Conclusions/Significance Three lines of evidence indicate limited potential to obtain substantial genetic benefits in the form of reduced inbreeding. The relatively low frequency of multiple parentage together with low genetic variation among potential mates and the elevated risk of mating among related individuals as corroborated by our genetic data suggest that there are limited actual outbreeding opportunities for polyandrous females. Polyandry in S. lineatus is thus unlikely to be maintained through adaptive female choice. PMID:22235316

PTSD and Gene Variants: New Pathways and New Thinking

PubMed Central

Skelton, Kelly; Ressler, Kerry J.; Norrholm, Seth D.; Jovanovic, Tanja; Bradley-Davino, Bekh

2011-01-01

Posttraumatic Stress Disorder (PTSD) is an anxiety disorder which can develop as a result of exposure to a traumatic event and is associated with significant functional impairment. Family and twin studies have found that risk for PTSD is associated with an underlying genetic vulnerability and that more than 30% of the variance associated with PTSD is related to a heritable component. Using a fear conditioning model to conceptualize the neurobiology of PTSD, three primary neuronal systems have been investigated – the hypothalamic-pituitary-adrenal axis, the locus coeruleus-noradrenegic system, and neurocircuitry interconnecting the limbic system and frontal cortex. The majority of the initial investigations into main effects of candidate genes hypothesized to be associated with PTSD risk have been negative, but studies examining the interaction of genetic polymorphisms with specific environments in predicting PTSD have produced several positive results which have increased our understanding of the determinants of risk and resilience in the aftermath of trauma. Promising avenues of inquiry into the role of epigenetic modification have also been proposed to explain the enduring impact of environmental exposures which occur during key, often early, developmental periods on gene expression. Studies of PTSD endophenotypes, which are heritable biomarkers associated with a circumscribed trait within the more complex psychiatric disorder, may be more directly amenable to analysis of the underlying genetics and neural pathways and have provided promising targets for elucidating the neurobiology of PTSD. Knowledge of the genetic underpinnings and neuronal pathways involved in the etiology and maintenance of PTSD will allow for improved targeting of primary prevention amongst vulnerable individuals or populations, as well as timely, targeted treatment interventions. PMID:21356219

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

PubMed Central

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

2013-01-01

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

Developmental trajectories of DSM-IV symptoms of attention-deficit/hyperactivity disorder: genetic effects, family risk and associated psychopathology.

PubMed

Larsson, Henrik; Dilshad, Rezin; Lichtenstein, Paul; Barker, Edward D

2011-09-01

DSM-IV specifies three ADHD subtypes; the combined, the hyperactive-impulsive and the inattentive. Little is known about the developmental relationships underlying these subtypes. The objective of this study was to describe the development of parent-reported hyperactivity-impulsivity and inattention symptoms from childhood to adolescence and to study their associations with genetic factors, family risk, and later adjustment problems in early adulthood. Data in this study comes from 1,450 twin pairs participating in a population-based, longitudinal twin study. Developmental trajectories were defined using parent-ratings of hyperactivity-impulsivity and inattention symptoms at age 8-9, 13-14, and 16-17. Twin methods were used to explore genetic influences on trajectories. Family risk measures included low socioeconomic status, large family size and divorce. Self-ratings of externalizing and internalizing problems in early adulthood were used to examine adjustment problems related to the different trajectory combinations. We found two hyperactivity-impulsivity trajectories (low, high/decreasing) and two inattention trajectories (low, high/increasing). Twin modeling revealed a substantial genetic component underlying both the hyperactivity-impulsivity and the inattention trajectory. Joint trajectory analyses identified four groups of adolescents with distinct developmental patterns of hyperactivity-impulsivity and inattention: a low/low group, a primarily hyperactive, a primarily inattentive and a combined (high/high) trajectory type. These trajectory combinations showed discriminant relations to adjustment problems in early adulthood. The hyperactive, inattentive and combined trajectory subtypes were associated with higher rates of family risk environments compared to the low/low group. Study results showed that for those on a high trajectory, hyperactivity decreased whereas inattention increased. The combinations of these trajectories lend developmental insight into how children shift from (i) a combined to inattentive subtype, and (ii) a hyperactive-impulsive to a combined subtype. This study suggests that ADHD subtypes cannot be viewed as discrete and stable categories. © 2011 The Authors. Journal of Child Psychology and Psychiatry © 2011 Association for Child and Adolescent Mental Health.

Under the Influence of Genetics: How Transdisciplinarity Leads Us to Rethink Social Pathways to Illness

PubMed Central

Pescosolido, Bernice A.; Perry, Brea L.; Long, J. Scott; Martin, Jack K.; Nurnberger, John I.; Hesselbrock, Victor

2015-01-01

To extend our understanding of how social structures and social processes impact behavior, sociologists have been challenged to incorporate the potential explanatory role of genetics in their models. Here, we draw propositions from three major understandings of illness causation offered by social theory – fundamental causes, social stress processes, and social safety net theories. We tailor hypotheses to the case of alcohol dependence, long considered a multifaceted problem, defying simple explanation and having both biological and social roots. After briefly reviewing current appeals for transdisciplinary research, we describe both sociological and genetic theories, and derive propositions expected under each and under a transdisciplinary theoretical frame. Analyses of a later wave of the preeminent medical science study, the Collaborative Study on the Genetics of Alcoholism (COGA), reveals a complex interplay of how the GABRA2 gene works with and against social structural factors to produce cases meeting DSM/ICD diagnoses. When both genetic and social factors are controlled, virtually equivalent effects of each remain; and, only modest evidence suggests that genetic influence works through social structural conditions and experiences. Further exploratory analyses using multiplicative terms reveal enhanced gene-environment interactions: 1) women are largely unaffected in their risk for alcohol dependence by allele status at this candidate gene; 2) family support attenuates genetic influence; 3) childhood deprivation exacerbates genetic predispositions. We discuss how these findings lead us to consider the essential intradisciplinary tension in sociological theories (i.e., the role of proximal and distal influences in social processes). Overall, our findings point to the promise of theories blending social and genetic influences by focusing directly on dynamic, networked sequences that produce different pathways to health and illness. PMID:19569404

Prediction of Adulthood Obesity Using Genetic and Childhood Clinical Risk Factors in the Cardiovascular Risk in Young Finns Study.

PubMed

Seyednasrollah, Fatemeh; Mäkelä, Johanna; Pitkänen, Niina; Juonala, Markus; Hutri-Kähönen, Nina; Lehtimäki, Terho; Viikari, Jorma; Kelly, Tanika; Li, Changwei; Bazzano, Lydia; Elo, Laura L; Raitakari, Olli T

2017-06-01

Obesity is a known risk factor for cardiovascular disease. Early prediction of obesity is essential for prevention. The aim of this study is to assess the use of childhood clinical factors and the genetic risk factors in predicting adulthood obesity using machine learning methods. A total of 2262 participants from the Cardiovascular Risk in YFS (Young Finns Study) were followed up from childhood (age 3-18 years) to adulthood for 31 years. The data were divided into training (n=1625) and validation (n=637) set. The effect of known genetic risk factors (97 single-nucleotide polymorphisms) was investigated as a weighted genetic risk score of all 97 single-nucleotide polymorphisms (WGRS97) or a subset of 19 most significant single-nucleotide polymorphisms (WGRS19) using boosting machine learning technique. WGRS97 and WGRS19 were validated using external data (n=369) from BHS (Bogalusa Heart Study). WGRS19 improved the accuracy of predicting adulthood obesity in training (area under the curve [AUC=0.787 versus AUC=0.744, P <0.0001) and validation data (AUC=0.769 versus AUC=0.747, P =0.026). WGRS97 improved the accuracy in training (AUC=0.782 versus AUC=0.744, P <0.0001) but not in validation data (AUC=0.749 versus AUC=0.747, P =0.785). Higher WGRS19 associated with higher body mass index at 9 years and WGRS97 at 6 years. Replication in BHS confirmed our findings that WGRS19 and WGRS97 are associated with body mass index. WGRS19 improves prediction of adulthood obesity. Predictive accuracy is highest among young children (3-6 years), whereas among older children (9-18 years) the risk can be identified using childhood clinical factors. The model is helpful in screening children with high risk of developing obesity. © 2017 American Heart Association, Inc.

Vantage Sensitivity: Environmental Sensitivity to Positive Experiences as a Function of Genetic Differences.

PubMed

Pluess, Michael

2017-02-01

A large number of gene-environment interaction studies provide evidence that some people are more likely to be negatively affected by adverse experiences as a function of specific genetic variants. However, such "risk" variants are surprisingly frequent in the population. Evolutionary analysis suggests that genetic variants associated with increased risk for maladaptive development under adverse environmental conditions are maintained in the population because they are also associated with advantages in response to different contextual conditions. These advantages may include (a) coexisting genetic resilience pertaining to other adverse influences, (b) a general genetic susceptibility to both low and high environmental quality, and (c) a coexisting propensity to benefit disproportionately from positive and supportive exposures, as reflected in the recent framework of vantage sensitivity. After introducing the basic properties of vantage sensitivity and highlighting conceptual similarities and differences with diathesis-stress and differential susceptibility patterns of gene-environment interaction, selected and recent empirical evidence for the notion of vantage sensitivity as a function of genetic differences is reviewed. The unique contribution that the new perspective of vantage sensitivity may make to our understanding of social inequality will be discussed after suggesting neurocognitive and molecular mechanisms hypothesized to underlie the propensity to benefit disproportionately from benevolent experiences. © 2015 Wiley Periodicals, Inc.

Child-evoked maternal negativity from 9 to 27 months: evidence of gene-environment correlation and its moderation by marital distress

PubMed Central

Fearon, R.M. Pasco; Reiss, David; Leve, Leslie D.; Shaw, Daniel S.; Scaramella, Laura V.; Ganiban, Jody M.; Neiderhiser, Jenae M.

2014-01-01

Past research has documented pervasive genetic influences on emotional and behavioral disturbance across the lifespan and on liability to adult psychiatric disorder. Increasingly, interest is turning to mechanisms of gene-environment interplay in attempting to understand the earliest manifestations of genetic risk. We report findings from a prospective adoption study, which aimed to test the role of evocative gene-environment correlation in early development. 561 infants adopted at birth were studied between 9 and 27 months with their adoptive parents and birth mothers. Birth mother psychiatric diagnoses and symptoms scales were used as indicators of genetic influence, and multiple self-report measures were used to index adoptive mother parental negativity. We hypothesized that birth parent psychopathology would be associated with greater adoptive parent negativity, and that such evocative effects would be amplified under conditions of high family adversity. The findings suggested that genetic factors linked to birth mother externalizing psychopathology may evoke negative reactions in adoptive mothers in the first year of life, but primarily when the adoptive family environment was characterized by marital problems. The observed maternal negativity mediated the effects of genetic risk on child adjustment at 27 months. The results underline the importance of genetically-influenced evocative processes in early development. PMID:25216383

Child-evoked maternal negativity from 9 to 27 months: Evidence of gene-environment correlation and its moderation by marital distress.

PubMed

Fearon, R M Pasco; Reiss, David; Leve, Leslie D; Shaw, Daniel S; Scaramella, Laura V; Ganiban, Jody M; Neiderhiser, Jenae M

2015-11-01

Past research has documented pervasive genetic influences on emotional and behavioral disturbance across the life span and on liability to adult psychiatric disorder. Increasingly, interest is turning to mechanisms of gene-environment interplay in attempting to understand the earliest manifestations of genetic risk. We report findings from a prospective adoption study, which aimed to test the role of evocative gene-environment correlation in early development. Included in the study were 561 infants adopted at birth and studied between 9 and 27 months, along with their adoptive parents and birth mothers. Birth mother psychiatric diagnoses and symptoms scales were used as indicators of genetic influence, and multiple self-report measures were used to index adoptive mother parental negativity. We hypothesized that birth mother psychopathology would be associated with greater adoptive parent negativity and that such evocative effects would be amplified under conditions of high adoptive family adversity. The findings suggested that genetic factors associated with birth mother externalizing psychopathology may evoke negative reactions in adoptive mothers in the first year of life, but only when the adoptive family environment is characterized by marital problems. Maternal negativity mediated the effects of genetic risk on child adjustment at 27 months. The results underscore the importance of genetically influenced evocative processes in early development.

HUMAN GENETICS AS A TOOL TO IDENTIFY PROGRANULIN REGULATORS

PubMed Central

Nicholson, Alexandra M.; Finch, NiCole A.; Rademakers, Rosa

2012-01-01

Frontotemporal lobar degeneration (FTLD) is a common neurodegenerative disorder that predominantly affects individuals under the age of 65. It is known that the most common pathological subtype is FTLD with TAR DNA-binding protein 43 inclusions (FTLD-TDP). FTLD has a strong genetic component with about 50% of cases having a positive family history. Mutations identified in the progranulin gene (GRN) have been shown to cause FTLD-TDP as a result of progranulin haploinsufficiency. These findings suggest a progranulin-dependent mechanism in this pathological FTLD subtype. Thus, identifying regulators of progranulin levels is essential for new therapies and treatments for FTLD and related disorders. In this review, we discuss the role of genetic studies in identifying progranulin regulators, beginning with the discovery of pathogenic GRN mutations and additional GRN risk variants. We also cover more recent genetic advances, including the detection of variants in the transmembrane protein 106 B gene that increase FTLD-TDP risk presumably by modulating progranulin levels and the identification of a potential progranulin receptor, sortilin. This review highlights the importance of genetic studies in the context of FTLD and further emphasizes the need for future genetic and cell biology research to continue the effort in finding a cure for progranulin-related diseases. PMID:21626010

Polygenic risk score and heritability estimates reveals a genetic relationship between ASD and OCD.

PubMed

Guo, W; Samuels, J F; Wang, Y; Cao, H; Ritter, M; Nestadt, P S; Krasnow, J; 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; Cullen, B A; Piacentini, J; Pauls, D L; Bienvenu, O J; Stewart, S E; Goes, F S; Maher, B; Pulver, A E; Valle, D; Mattheisen, M; Qian, J; Nestadt, G; Shugart, Y Y

2017-07-01

Obsessive-compulsive disorder (OCD) and Autism spectrum disorder (ASD) are both highly heritable neurodevelopmental disorders that conceivably share genetic risk factors. However, the underlying genetic determinants remain largely unknown. In this work, the authors describe a combined genome-wide association study (GWAS) of ASD and OCD. The OCD dataset includes 2998 individuals in nuclear families. The ASD dataset includes 6898 individuals in case-parents trios. GWAS summary statistics were examined for potential enrichment of functional variants associated with gene expression levels in brain regions. The top ranked SNP is rs4785741 (chromosome 16) with P value=6.9×10 -7 in our re-analysis. Polygenic risk score analyses were conducted to investigate the genetic relationship within and across the two disorders. These analyses identified a significant polygenic component of ASD, predicting 0.11% of the phenotypic variance in an independent OCD data set. In addition, we examined the genomic architecture of ASD and OCD by estimating heritability on different chromosomes and different allele frequencies, analyzing genome-wide common variant data by using the Genome-wide Complex Trait Analysis (GCTA) program. The estimated global heritability of OCD is 0.427 (se=0.093) and 0.174 (se=0.053) for ASD in these imputed data. Published by Elsevier B.V.

Barriers to genetic testing for breast cancer risk among ethnic minority women: an exploratory study.

PubMed

Glenn, Beth A; Chawla, Neetu; Bastani, Roshan

2012-01-01

To assess awareness of genetic testing for breast cancer risk and identify influences on the decision-making process regarding counseling and testing among an ethnically-diverse sample of women. Semi-structured interviews were conducted with 33 women who were breast or ovarian cancer survivors or first degree relatives of survivors. Interviews were audiotaped, translated, and transcribed. Analysis of transcripts identified relevant themes and quotes were extracted for illustration. Low levels of awareness were observed in minority women, including those with a significant family history of cancer. A number of potential influences on the decision-making process emerged including beliefs about risk factors for cancer and opinions about the options following testing. Distinct issues were identified within ethnic groups that may function as barriers such as concern about the misuse of genetic information (African Americans), unfamiliarity with Western preventive medicine (Asians), and women prioritizing family obligations over personal health needs (Latinas). Results suggest there may be a need for interventions to raise awareness about genetic counseling and testing among minorities. Our findings contribute to the literature by using in-depth interviews to uncover potential barriers and facilitators to counseling and testing and by including Asians and Latinas, groups under-represented in previous research.

Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials.

PubMed

Mega, J L; Stitziel, N O; Smith, J G; Chasman, D I; Caulfield, M; Devlin, J J; Nordio, F; Hyde, C; Cannon, C P; Sacks, F; Poulter, N; Sever, P; Ridker, P M; Braunwald, E; Melander, O; Kathiresan, S; Sabatine, M S

2015-06-06

Genetic variants have been associated with the risk of coronary heart disease. In this study, we tested whether or not a composite of these variants could ascertain the risk of both incident and recurrent coronary heart disease events and identify those individuals who derive greater clinical benefit from statin therapy. A community-based cohort study (the Malmo Diet and Cancer Study) and four randomised controlled trials of both primary prevention (JUPITER and ASCOT) and secondary prevention (CARE and PROVE IT-TIMI 22) with statin therapy, comprising a total of 48,421 individuals and 3477 events, were included in these analyses. We studied the association of a genetic risk score based on 27 genetic variants with incident or recurrent coronary heart disease, adjusting for traditional clinical risk factors. We then investigated the relative and absolute risk reductions in coronary heart disease events with statin therapy stratified by genetic risk. We combined data from the different studies using a meta-analysis. When individuals were divided into low (quintile 1), intermediate (quintiles 2-4), and high (quintile 5) genetic risk categories, a significant gradient in risk for incident or recurrent coronary heart disease was shown. Compared with the low genetic risk category, the multivariable-adjusted hazard ratio for coronary heart disease for the intermediate genetic risk category was 1·34 (95% CI 1·22-1·47, p<0·0001) and that for the high genetic risk category was 1·72 (1·55-1·92, p<0·0001). In terms of the benefit of statin therapy in the four randomised trials, we noted a significant gradient (p=0·0277) of increasing relative risk reductions across the low (13%), intermediate (29%), and high (48%) genetic risk categories. Similarly, we noted greater absolute risk reductions in those individuals in higher genetic risk categories (p=0·0101), resulting in a roughly threefold decrease in the number needed to treat to prevent one coronary heart disease event in the primary prevention trials. Specifically, in the primary prevention trials, the number needed to treat to prevent one such event in 10 years was 66 in people at low genetic risk, 42 in those at intermediate genetic risk, and 25 in those at high genetic risk in JUPITER, and 57, 47, and 20, respectively, in ASCOT. A genetic risk score identified individuals at increased risk for both incident and recurrent coronary heart disease events. People with the highest burden of genetic risk derived the largest relative and absolute clinical benefit from statin therapy. National Institutes of Health. Copyright © 2015 Elsevier Ltd. All rights reserved.

An audit of clinical service examining the uptake of genetic testing by at-risk family members.

PubMed

Forrest, Laura; Delatycki, Martin; Curnow, Lisette; Gen Couns, M; Skene, Loane; Aitken, Maryanne

2012-01-01

The aim of this study was to investigate the uptake of genetic testing by at-risk family members for four genetic conditions: chromosomal translocations, fragile X syndrome, Huntington disease, and spinal muscular atrophy. A clinical audit was undertaken using genetics files from Genetic Health Services Victoria. Data were extracted from the files regarding the number of at-risk family members and the proportion tested. Information was also collected about whether discussion of at-risk family members and family communication during the genetic consultation was recorded. The proportion of at-risk family members who had genetic testing ranged from 11% to 18%. First-degree family members were most frequently tested and the proportion of testing decreased by degree of relatedness to the proband. Smaller families were significantly more likely to have genetic testing for all conditions except Huntington disease. Female at-risk family members were significantly more likely to have testing for fragile X syndrome. The majority of at-risk family members do not have genetic testing. Family communication is likely to influence the uptake of genetic testing by at-risk family members and therefore it is important that families are supported while communicating to ensure that at-risk family members are able to make informed decisions about genetic testing.

Structured parenting of toddlers at high versus low genetic risk: two pathways to child problems.

PubMed

Leve, Leslie D; Harold, Gordon T; Ge, Xiaojia; Neiderhiser, Jenae M; Shaw, Daniel; Scaramella, Laura V; Reiss, David

2009-11-01

Little is known about how parenting might offset genetic risk to prevent the onset of child problems during toddlerhood. We used a prospective adoption design to separate genetic and environmental influences and test whether associations between structured parenting and toddler behavior problems were conditioned by genetic risk for psychopathology. The sample included 290 linked sets of adoptive families and birth mothers and 95 linked birth fathers. Genetic risk was assessed via birth mother and birth father psychopathology (anxiety, depression, antisociality, and drug use). Structured parenting was assessed via microsocial coding of adoptive mothers' behavior during a cleanup task. Toddler behavior problems were assessed with the Child Behavior Checklist. Controlling for temperamental risk at 9 months, there was an interaction between birth mother psychopathology and adoptive mothers' parenting on toddler behavior problems at 18 months. The interaction indicated two pathways to child problems: structured parenting was beneficial for toddlers at high genetic risk but was related to behavior problems for toddlers at low genetic risk. This crossover interaction pattern was replicated with birth father psychopathology as the index of genetic risk. The effects of structured parenting on toddler behavior problems varied as a function of genetic risk. Children at genetic risk might benefit from parenting interventions during toddlerhood that enhance structured parenting.

Polygenic risk predicts obesity in both white and black young adults.

PubMed

Domingue, Benjamin W; Belsky, Daniel W; Harris, Kathleen Mullan; Smolen, Andrew; McQueen, Matthew B; Boardman, Jason D

2014-01-01

To test transethnic replication of a genetic risk score for obesity in white and black young adults using a national sample with longitudinal data. A prospective longitudinal study using the National Longitudinal Study of Adolescent Health Sibling Pairs (n = 1,303). Obesity phenotypes were measured from anthropometric assessments when study members were aged 18-26 and again when they were 24-32. Genetic risk scores were computed based on published genome-wide association study discoveries for obesity. Analyses tested genetic associations with body-mass index (BMI), waist-height ratio, obesity, and change in BMI over time. White and black young adults with higher genetic risk scores had higher BMI and waist-height ratio and were more likely to be obese compared to lower genetic risk age-peers. Sibling analyses revealed that the genetic risk score was predictive of BMI net of risk factors shared by siblings. In white young adults only, higher genetic risk predicted increased risk of becoming obese during the study period. In black young adults, genetic risk scores constructed using loci identified in European and African American samples had similar predictive power. Cumulative information across the human genome can be used to characterize individual level risk for obesity. Measured genetic risk accounts for only a small amount of total variation in BMI among white and black young adults. Future research is needed to identify modifiable environmental exposures that amplify or mitigate genetic risk for elevated BMI.

Introducing genetic testing for cardiovascular disease in primary care: a qualitative study.

PubMed

Middlemass, Jo B; Yazdani, Momina F; Kai, Joe; Standen, Penelope J; Qureshi, Nadeem

2014-05-01

While primary care systematically offers conventional cardiovascular risk assessment, genetic tests for coronary heart disease (CHD) are increasingly commercially available to patients. It is unclear how individuals may respond to these new sources of risk information. To explore how patients who have had a recent conventional cardiovascular risk assessment, perceive additional information from genetic testing for CHD. Qualitative interview study in 12 practices in Nottinghamshire from both urban and rural settings. Interviews were conducted with 29 adults, who consented to genetic testing after having had a conventional cardiovascular risk assessment. Individuals' principal motivation for genetic testing was their family history of CHD and a desire to convey the results to their children. After testing, however, there was limited recall of genetic test results and scepticism about the value of informing their children. Participants dealt with conflicting findings from the genetic test, family history, and conventional assessment by either focusing on genetic risk or environmental lifestyle factors. In some participants, genetic test results appeared to reinforce healthy behaviour but others were falsely reassured, despite having an 'above-average' conventional cardiovascular risk score. Although genetic testing was acceptable, participants were unclear how to interpret genetic risk results. To facilitate healthy behaviour, health professionals should explore patients' understanding of genetic test results in light of their family history and conventional risk assessment.

A Genetic Investigation of Sex Bias in the Prevalence of Attention-Deficit/Hyperactivity Disorder.

PubMed

Martin, Joanna; Walters, Raymond K; Demontis, Ditte; Mattheisen, Manuel; Lee, S Hong; Robinson, Elise; Brikell, Isabell; Ghirardi, Laura; Larsson, Henrik; Lichtenstein, Paul; Eriksson, Nicholas; Werge, Thomas; Mortensen, Preben Bo; Pedersen, Marianne Giørtz; Mors, Ole; Nordentoft, Merete; Hougaard, David M; Bybjerg-Grauholm, Jonas; Wray, Naomi R; Franke, Barbara; Faraone, Stephen V; O'Donovan, Michael C; Thapar, Anita; Børglum, Anders D; Neale, Benjamin M

2018-06-15

Attention-deficit/hyperactivity disorder (ADHD) shows substantial heritability and is two to seven times more common in male individuals than in female individuals. We examined two putative genetic mechanisms underlying this sex bias: sex-specific heterogeneity and higher burden of risk in female cases. We analyzed genome-wide autosomal common variants from the Psychiatric Genomics Consortium and iPSYCH Project (n = 20,183 cases, n = 35,191 controls) and Swedish population register data (n = 77,905 cases, n = 1,874,637 population controls). Genetic correlation analyses using two methods suggested near complete sharing of common variant effects across sexes, with r g estimates close to 1. Analyses of population data, however, indicated that female individuals with ADHD may be at especially high risk for certain comorbid developmental conditions (i.e., autism spectrum disorder and congenital malformations), potentially indicating some clinical and etiological heterogeneity. Polygenic risk score analysis did not support a higher burden of ADHD common risk variants in female cases (odds ratio [confidence interval] = 1.02 [0.98-1.06], p = .28). In contrast, epidemiological sibling analyses revealed that the siblings of female individuals with ADHD are at higher familial risk for ADHD than the siblings of affected male individuals (odds ratio [confidence interval] = 1.14 [1.11-1.18], p = 1.5E-15). Overall, this study supports a greater familial burden of risk in female individuals with ADHD and some clinical and etiological heterogeneity, based on epidemiological analyses. However, molecular genetic analyses suggest that autosomal common variants largely do not explain the sex bias in ADHD prevalence. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Simulated climate change conditions unveil the toxic potential of the fungicide pyrimethanil on the midge Chironomus riparius: a multigeneration experiment

PubMed Central

Müller, Ruth; Seeland, Anne; Jagodzinski, Lucas S; Diogo, Joao B; Nowak, Carsten; Oehlmann, Jörg

2012-01-01

Although it has been suggested that temperature increase may alter the toxic potential of environmental pollutants, few studies have investigated the potential risk of chemical stressors for wildlife under Global Climate Change (GCC) impact. We applied a bifactorial multigeneration study in order to test if GCC conditions alter the effects of low pesticide concentrations on life history and genetic diversity of the aquatic model organism Chironomus riparius. Experimental populations of the species were chronically exposed to a low concentration of the fungicide pyrimethanil (half of the no-observed-adverse-effect concentration: NOAEC/2) under two dynamic present-day temperature simulations (11.0–22.7°C; 14.0–25.2°C) and one future scenario (16.5–28.1°C). During the 140-day multigeneration study, survival, emergence, reproduction, population growth, and genetic diversity of C. riparius were analyzed. Our results reveal that high temperature and pyrimethanil act synergistically on the midge C. riparius. In simulated present-day scenarios, a NOAEC/2 of pyrimethanil as derived from a life-cycle toxicity test provoked only slight-to-moderate beneficial or adverse effects on C. riparius. In contrast, exposure to a NOAEC/2 concentration of pyrimethanil at a thermal situation likely for a summer under GCC conditions uncovered adverse effects on mortality and population growth rate. In addition, genetic diversity was considerably reduced by pyrimethanil in the future scenario, but only slightly under current climatic conditions. Our multigeneration study under near-natural (climatic) conditions indicates that not only the impact of climate change, but also low concentrations of pesticides may pose a reasonable risk for aquatic insects in future. PMID:22408736

A randomized trial Examining The Impact Of Communicating Genetic And Lifestyle Risks For Obesity.

PubMed

Wang, Catharine; Gordon, Erynn S; Norkunas, Tricia; Wawak, Lisa; Liu, Ching-Ti; Winter, Michael; Kasper, Rachel S; Christman, Michael F; Green, Robert C; Bowen, Deborah J

2016-12-01

Genetic testing for obesity is available directly to consumers, yet little is understood about its behavioral impact and its added value to nongenetic risk communication efforts based on lifestyle factors. A randomized trial examined the short-term impact of providing personalized obesity risk information, using a 2 × 2 factorial design. Participants were recruited from the Coriell Personalized Medicine Collaborative (CPMC) and randomized to receive (1) no risk information (control), (2) genetic risk, (3) lifestyle risk, or (4) combined genetic/lifestyle risks. Baseline and 3-month follow-up survey data were collected. Analyses examined the impact of risk feedback on intentions to lose weight and self-reported weight. A total of 696 participants completed the study. A significant interaction effect was observed for genetic and lifestyle information on intent to lose weight (P = 0.0150). Those who received genetic risk alone had greater intentions at follow-up, compared with controls (P = 0.0034). The impact of receiving elevated risk information on intentions varied by source and combination of risks presented. Non-elevated genetic risk did not lower intentions. No group differences were observed for self-reported weight. Genetic risk information for obesity may add value to lifestyle risk information depending on the context in which it is presented. © 2016 The Obesity Society.

Risk Perception and Psychological Distress in Genetic Counselling for Hereditary Breast and/or Ovarian Cancer.

PubMed

Cicero, G; De Luca, R; Dorangricchia, P; Lo Coco, G; Guarnaccia, C; Fanale, D; Calò, V; Russo, A

2017-10-01

Oncological Genetic Counselling (CGO) allows the identification of a genetic component that increases the risk of developing a cancer. Individuals' psychological reactions are influenced by both the content of the received information and the subjective perception of their own risk of becoming ill or being a carrier of a genetic mutation. This study included 120 participants who underwent genetic counselling for breast and/or ovarian cancer. The aim of the study was to examine the relation between their cancer risk perception and the genetic risk during CGO before receiving genetic test results, considering the influence of some psychological variables, in particular distress, anxiety and depression. Participants completed the following tools during a psychological interview: a socio-demographic form, Cancer Risk Perception (CRP) and Genetic Risk Perception (GRP), Hospital Anxiety and Depression Scale (HADS) and Distress Thermometer (DT). The data seem to confirm our hypothesis. Positive and significant correlations were found between the observed variables. Moreover, genetic risk perception determined an increase in depressive symptomatology and cancer risk perception led to an increase in anxious symptomatology, specifically in participants during cancer treatment. The present results suggest the importance of assessing genetic and cancer risk perception in individuals who undergo CGO, to identify those who are at risk of a decrease in psychological well-being and of developing greater psychological distress.

American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.

PubMed

2003-06-15

As the leading organization representing cancer specialists involved in patient care and clinical research, the American Society of Clinical Oncology (ASCO) reaffirms its commitment to integrating cancer risk assessment and management, including molecular analysis of cancer predisposition genes, into the practice of oncology and preventive medicine. The primary goal of this effort is to foster expanded access to, and continued advances in, medical care provided to patients and families affected by hereditary cancer syndromes. The 1996 ASCO Statement on Genetic Testing for Cancer Susceptibility set forth specific recommendations relating to clinical practice, research needs, educational opportunities, requirement for informed consent, indications for genetic testing, regulation of laboratories, and protection from discrimination, as well as access to and reimbursement for cancer genetics services. In updating this Statement, ASCO endorses the following principles: Indications for Genetic Testing: ASCO recommends that genetic testing be offered when 1) the individual has personal or family history features suggestive of a genetic cancer susceptibility condition, 2) the test can be adequately interpreted, and 3) the results will aid in diagnosis or influence the medical or surgical management of the patient or family members at hereditary risk of cancer. ASCO recommends that genetic testing only be done in the setting of pre- and post-test counseling, which should include discussion of possible risks and benefits of cancer early detection and prevention modalities. Special Issues in Testing Children for Cancer Susceptibility: ASCO recommends that the decision to offer testing to potentially affected children should take into account the availability of evidence-based risk-reduction strategies and the probability of developing a malignancy during childhood. Where risk-reduction strategies are available or cancer predominantly develops in childhood, ASCO believes that the scope of parental authority encompasses the right to decide for or against testing. In the absence of increased risk of a childhood malignancy, ASCO recommends delaying genetic testing until an individual is of sufficient age to make an informed decision regarding such tests. As in other areas of pediatric care, the clinical cancer genetics professional should be an advocate for the best interests of the child. Counseling About Medical Management After Testing: ASCO recommends that oncologists include in pre- and post-test counseling the discussion of possible risks and benefits of cancer early-detection and prevention modalities, some of which have presumed but unproven efficacy for individuals at increased hereditary risk of cancer. Regulation of Genetic Testing: ASCO recommends strengthening regulatory oversight of laboratories that provide clinical cancer predisposition tests. These quality assurance mechanisms should include oversight of the reagents used in genetic testing, interlaboratory comparisons of reference samples, standardization of laboratory genetic test reports, and proficiency testing. Protection From Insurance and Employment Discrimination: ASCO supports establishing a federal law to prohibit discrimination by health insurance providers and employers on the basis of an individual's inherited susceptibility to cancer. Protections against genetic discrimination should apply to those with group coverage, those with individual health insurance policies, and the uninsured. Coverage of Services: ASCO supports efforts to ensure that all individuals at significantly increased risk of hereditary cancer have access to appropriate genetic counseling, testing, screening, surveillance, and all related medical and surgical interventions, which should be covered without penalty by public and private third-party payers. Confidentiality and Communication of Familial Risk: ASCO recommends that providers make concerted efforts to protect the confidentiality of genetic information. However, they should remind patients of the importance of communicating test results to family members, as part of pretest counseling and informed consent discussions. ASCO believes that the cancer care provider's obligations (if any) to at-risk relatives are best fulfilled by communication of familial risk to the person undergoing testing, emphasizing the importance of sharing this information with family members so that they may also benefit. Educational Opportunities in Genetics: ASCO is committed to continuing to provide educational opportunities for physicians and other health care providers regarding the methods of cancer risk assessment, the clinical characteristics of hereditary cancer susceptibility syndromes, and the range of issues related to genetic testing, including pre- and post-test genetic counseling, and risk management, so that health professionals may responsibly integrate the care of persons at increased genetic risk of cancer into the practice of clinical and preventive oncology. Special Issues Relating to Genetic Research on Human Tissues:ASCO recommends that all researchers proposing to use or store human biologic specimens for genetic studies should consult either the responsible institutional review board (IRB) or a comparable body specifically constituted to assess human tissue research, to determine the requirements for protection specific to the study under consideration. This consultation should take place before the project is initiated. The determination of the need for informed consent or authorization in such studies should depend on whether the research involves tests for genetic markers of known clinical significance and whether research data will be linked to protected health information, as well as other considerations specific to the study proposed. Special attention should also be paid to 1) whether future research findings will be disclosed to the research participants, 2) whether future contact of participants is planned, 3) whether and how protected health information about the tissue donors will be stored, and what will happen to study specimens after the trial ends. In addition, ASCO affirms the right of people contributing tissue to a databank to rescind their permission, in accordance with federal privacy regulations.

Replication of TPMT and ABCC3 genetic variants highly associated with cisplatin-induced hearing loss in children.

PubMed

Pussegoda, K; Ross, C J; Visscher, H; Yazdanpanah, M; Brooks, B; Rassekh, S R; Zada, Y F; Dubé, M-P; Carleton, B C; Hayden, M R

2013-08-01

Cisplatin is a widely used chemotherapeutic agent for the treatment of solid tumors. A serious complication of cisplatin treatment is permanent hearing loss. The aim of this study was to replicate previous genetic findings in an independent cohort of 155 pediatric patients. Associations were replicated for genetic variants in TPMT (rs12201199, P = 0.0013, odds ratio (OR) 6.1) and ABCC3 (rs1051640, P = 0.036, OR 1.8). A predictive model combining variants in TPMT, ABCC3, and COMT with clinical variables (patient age, vincristine treatment, germ-cell tumor, and cranial irradiation) significantly improved the prediction of hearing-loss development as compared with using clinical risk factors alone (area under the curve (AUC) 0.786 vs. 0.708, P = 0.00048). The novel combination of genetic and clinical factors predicted the risk of hearing loss with a sensitivity of 50.3% and a specificity of 92.7%. These findings provide evidence to support the importance of TPMT, COMT, and ABCC3 in the prediction of cisplatin-induced hearing loss in children.

Replication of TPMT and ABCC3 Genetic Variants Highly Associated With Cisplatin-Induced Hearing Loss in Children

PubMed Central

Pussegoda, K; Ross, CJ; Visscher, H; Yazdanpanah, M; Brooks, B; Rassekh, SR; Zada, YF; Dubé, M-P; Carleton, BC; Hayden, MR

2014-01-01

Cisplatin is a widely used chemotherapeutic agent for the treatment of solid tumors. A serious complication of cisplatin treatment is permanent hearing loss. The aim of this study was to replicate previous genetic findings in an independent cohort of 155 pediatric patients. Associations were replicated for genetic variants in TPMT (rs12201199, P = 0.0013, odds ratio (OR) 6.1) and ABCC3 (rs1051640, P = 0.036, OR 1.8). A predictive model combining variants in TPMT, ABCC3, and COMT with clinical variables (patient age, vincristine treatment, germ-cell tumor, and cranial irradiation) significantly improved the prediction of hearing-loss development as compared with using clinical risk factors alone (area under the curve (AUC) 0.786 vs. 0.708, P = 0.00048). The novel combination of genetic and clinical factors predicted the risk of hearing loss with a sensitivity of 50.3% and a specificity of 92.7%. These findings provide evidence to support the importance of TPMT, COMT, and ABCC3 in the prediction of cisplatin-induced hearing loss in children. PMID:23588304

Shifting the focus toward rare variants in schizophrenia to close the gap from genotype to phenotype.

PubMed

Bustamante, M Leonor; Herrera, Luisa; Gaspar, Pablo A; Nieto, Rodrigo; Maturana, Alejandro; Villar, María José; Salinas, Valeria; Silva, Hernán

2017-10-01

Schizophrenia (SZ) is a disorder with a high heritability and a complex architecture. Several dozen genetic variants have been identified as risk factors through genome-wide association studies including large population-based samples. However, the bulk of the risk cannot be accounted for by the genes associated to date. Rare mutations have been historically seen as relevant only for some infrequent, Mendelian forms of psychosis. Recent findings, however, show that the subset of patients that present a mutation with major effect is larger than expected. We discuss some of the molecular findings of these studies. SZ is clinically and genetically heterogeneous. To identify the genetic variation underlying the disorder, research should be focused on features that are more likely a product of genetic heterogeneity. Based on the phenotypical correlations with rare variants, cognition emerges as a relevant domain to study. Cognitive disturbances could be useful in selecting cases that have a higher probability of carrying deleterious mutations, as well as on the correct ascertainment of sporadic cases for the identification of de novo variants. © 2017 Wiley Periodicals, Inc.

Genomewide Association Study Identifies Novel Genetic Loci That Modify Antiplatelet Effects and Pharmacokinetics of Clopidogrel

PubMed Central

Zhong, W‐P; Wu, H; Chen, J‐Y; Li, X‐X; Lin, H‐M; Zhang, B; Zhang, Z‐W; Ma, D‐L; Sun, S; Li, H‐P; Mai, L‐P; He, G‐D; Wang, X‐P; Lei, H‐P; Zhou, H‐K; Tang, L; Liu, S‐W

2017-01-01

Genetic variants in the pharmacokinetic (PK) mechanism are the main underlying factors affecting the antiplatelet response to clopidogrel. Using a genomewide association study (GWAS) to identify new genetic loci that modify antiplatelet effects in Chinese patients with coronary heart disease, we identified novel variants in two transporter genes (SLC14A2 rs12456693, ATP‐binding cassette [ABC]A1 rs2487032) and in N6AMT1 (rs2254638) associated with P2Y12 reaction unit (PRU) and plasma active metabolite (H4) concentration. These new variants dramatically improved the predictability of PRU variability to 37.7%. The associations between these loci and PK parameters of clopidogrel and H4 were observed in additional patients, and its function on the activation of clopidogrel was validated in liver S9 fractions (P < 0.05). Rs2254638 was further identified to exert a marginal risk effect for major adverse cardiac events in an independent cohort. In conclusion, new genetic variants were systematically identified as risk factors for the reduced efficacy of clopidogrel treatment. PMID:27981573

A systematic review of interventions to provide genetics education for primary care.

PubMed

Paneque, Milena; Turchetti, Daniela; Jackson, Leigh; Lunt, Peter; Houwink, Elisa; Skirton, Heather

2016-07-22

At least 10 % of patients seen in primary care are said to have a condition in which genetics has an influence. However, patients at risk of genetic disease may not be recognised, while those who seek advice may not be referred or managed appropriately. Primary care practitioners lack knowledge of genetics and genetic testing relevant for daily practice and feel inadequate to deliver genetic services. The aim of this systematic review was to evaluate genetics educational interventions in the context of primary care. Following the process for systematic reviews developed by the Centre for Reviews and Dissemination, we conducted a search of five relevant electronic databases. Primary research papers were eligible for inclusion if they included data on outcomes of interventions regarding genetics education for primary care practitioners. The results from each paper were coded and grouped under themes. Eleven studies were included in the review. The five major themes identified inductively (post hoc) were: prior experience, changes in confidence, changes in knowledge, changes in practice, satisfaction and feedback. In five of the studies, knowledge of practitioners was improved following the educational programmes, but this tended to be in specific topic areas, while practitioner confidence improved in six studies. However, there was little apparent change to practice. There are insufficient studies of relevant quality to inform educational interventions in genetics for primary care practitioners. Educational initiatives should be assessed using changes in practice, as well as in confidence and knowledge, to determine if they are effective in causing significant changes in practice in genetic risk assessment and appropriate management of patients.

Genetic, Psychological, and Personal Network Factors Associated With Changes in Binge Drinking Over 2 Years Among Mexican Heritage Adolescents in the USA.

PubMed

Song, Sunmi; Marcum, Christopher Steven; Wilkinson, Anna V; Shete, Sanjay; Koehly, Laura M

2018-04-24

Despite prevalent binge drinking and alcohol-dependent symptoms among Hispanics, few studies have examined how multidimensional factors influence Hispanic adolescents' binge drinking. Purpose This study examines the effects of genetic, psychological, and social network factors on binge drinking over time among Mexican heritage adolescents in the USA and whether there are correlations among genetic variants that are associated with binge drinking and psychological and network characteristics. Mexican heritage adolescents (n = 731) participated in a longitudinal study, which included genetic testing at baseline, alcohol use assessments at first and second follow-ups, and questionnaires on sensation seeking, impulsivity, and peer and family network characteristics at second follow-up. Logistic regression and Spearman correlation analyses were performed. After adjusting for demographic characteristics, underlying genetic clustering, and binge drinking at first follow-up, two genetic variants on tryptophan hydroxylase 2 (TPH2; rs17110451, rs7963717), sensation seeking and impulsivity, and having a greater fraction of peers who drink or encourage drinking alcohol were associated with greater risk whereas another genetic variant on TPH2 (rs11178999) and having a greater fraction of close family relationships were associated with reduced risk for binge drinking at second follow-up. Genetic variants in TPH1 (rs591556) were associated with sensation seeking and impulsivity, while genetic variants in TPH2 (rs17110451) were associated with the fraction of drinkers in family. Results reveal that genetic variants in the serotonin pathway, behavioral disinhibition traits, and social networks exert joint influences on binge drinking in Mexican heritage adolescents in the USA.

The integration of epigenetics and genetics in nutrition research for CVD risk factors.

PubMed

Ma, Yiyi; Ordovas, Jose M

2017-08-01

There is increasing evidence documenting gene-by-environment (G × E) interactions for CVD related traits. However, the underlying mechanisms are still unclear. DNA methylation may represent one of such potential mechanisms. The objective of this review paper is to summarise the current evidence supporting the interplay among DNA methylation, genetic variants, and environmental factors, specifically (1) the association between SNP and DNA methylation; (2) the role that DNA methylation plays in G × E interactions. The current evidence supports the notion that genotype-dependent methylation may account, in part, for the mechanisms underlying observed G × E interactions in loci such as APOE, IL6 and ATP-binding cassette A1. However, these findings should be validated using intervention studies with high level of scientific evidence. The ultimate goal is to apply the knowledge and the technology generated by this research towards genetically based strategies for the development of personalised nutrition and medicine.

Polygenic risk, rapid childhood growth, and the development of obesity: evidence from a 4-decade longitudinal study.

PubMed

Belsky, Daniel W; Moffitt, Terrie E; Houts, Renate; Bennett, Gary G; Biddle, Andrea K; Blumenthal, James A; Evans, James P; Harrington, Honalee; Sugden, Karen; Williams, Benjamin; Poulton, Richie; Caspi, Avshalom

2012-06-01

To test how genomic loci identified in genome-wide association studies influence the development of obesity. A 38-year prospective longitudinal study of a representative birth cohort. The Dunedin Multidisciplinary Health and Development Study, Dunedin, New Zealand. One thousand thirty-seven male and female study members. We assessed genetic risk with a multilocus genetic risk score. The genetic risk score was composed of single-nucleotide polymorphisms identified in genome-wide association studies of obesity-related phenotypes. We assessed family history from parent body mass index data collected when study members were 11 years of age. Body mass index growth curves, developmental phenotypes of obesity, and adult obesity outcomes were defined from anthropometric assessments at birth and at 12 subsequent in-person interviews through 38 years of age. Individuals with higher genetic risk scores were more likely to be chronically obese in adulthood. Genetic risk first manifested as rapid growth during early childhood. Genetic risk was unrelated to birth weight. After birth, children at higher genetic risk gained weight more rapidly and reached adiposity rebound earlier and at a higher body mass index. In turn, these developmental phenotypes predicted adult obesity, mediating about half the genetic effect on adult obesity risk. Genetic associations with growth and obesity risk were independent of family history, indicating that the genetic risk score could provide novel information to clinicians. Genetic variation linked with obesity risk operates, in part, through accelerating growth in the early childhood years after birth. Etiological research and prevention strategies should target early childhood to address the obesity epidemic.

Use of allele scores as instrumental variables for Mendelian randomization

PubMed Central

Burgess, Stephen; Thompson, Simon G

2013-01-01

Background An allele score is a single variable summarizing multiple genetic variants associated with a risk factor. It is calculated as the total number of risk factor-increasing alleles for an individual (unweighted score), or the sum of weights for each allele corresponding to estimated genetic effect sizes (weighted score). An allele score can be used in a Mendelian randomization analysis to estimate the causal effect of the risk factor on an outcome. Methods Data were simulated to investigate the use of allele scores in Mendelian randomization where conventional instrumental variable techniques using multiple genetic variants demonstrate ‘weak instrument’ bias. The robustness of estimates using the allele score to misspecification (for example non-linearity, effect modification) and to violations of the instrumental variable assumptions was assessed. Results Causal estimates using a correctly specified allele score were unbiased with appropriate coverage levels. The estimates were generally robust to misspecification of the allele score, but not to instrumental variable violations, even if the majority of variants in the allele score were valid instruments. Using a weighted rather than an unweighted allele score increased power, but the increase was small when genetic variants had similar effect sizes. Naive use of the data under analysis to choose which variants to include in an allele score, or for deriving weights, resulted in substantial biases. Conclusions Allele scores enable valid causal estimates with large numbers of genetic variants. The stringency of criteria for genetic variants in Mendelian randomization should be maintained for all variants in an allele score. PMID:24062299

Multi-system Component Phenotypes of Bipolar Disorder for Genetic Investigations of Extended Pedigrees

PubMed Central

Fears, Scott C.; Service, Susan K.; Kremeyer, Barbara; Araya, Carmen; Araya, Xinia; Bejarano, Julio; Ramirez, Margarita; Castrillón, Gabriel; Gomez-Franco, Juliana; Lopez, Maria C.; Montoya, Gabriel; Montoya, Patricia; Aldana, Ileana; Teshiba, Terri M.; Abaryan, Zvart; Al-Sharif, Noor B.; Ericson, Marissa; Jalbrzikowski, Maria; Luykx, Jurjen J.; Navarro, Linda; Tishler, Todd A.; Altshuler, Lori; Bartzokis, George; Escobar, Javier; Glahn, David C.; Ospina-Duque, Jorge; Risch, Neil; Ruiz-Linares, Andrés; Thompson, Paul M.; Cantor, Rita M.; Lopez-Jaramillo, Carlos; Macaya, Gabriel; Molina, Julio; Reus, Victor I.; Sabatti, Chiara; Freimer, Nelson B.; Bearden, Carrie E.

2014-01-01

IMPORTANCE Genetic factors contribute to risk for bipolar disorder (BP), yet its pathogenesis remains poorly understood. A focus on measuring multi-system quantitative traits that may be components of BP psychopathology may enable genetic dissection of this complex disorder, and investigation of extended pedigrees from genetically isolated populations may facilitate the detection of specific genetic variants that impact on BP as well as its component phenotypes. OBJECTIVE To identify quantitative neurocognitive, temperament-related, and neuroanatomic phenotypes that appear heritable and associated with severe bipolar disorder (BP-I), and therefore suitable for genetic linkage and association studies aimed at identifying variants contributing to BP-I risk. DESIGN Multi-generational pedigree study in two closely related, genetically isolated populations: the Central Valley of Costa Rica (CVCR) and Antioquia, Colombia (ANT). PARTICIPANTS 738 individuals, all from CVCR and ANT pedigrees, of whom 181 are affected with BP-I. MAIN OUTCOME MEASURE Familial aggregation (heritability) and association with BP-I of 169 quantitative neurocognitive, temperament, magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) phenotypes. RESULTS Seventy-five percent (126) of the phenotypes investigated were significantly heritable, and 31% (53) were associated with BP-I. About 1/4 of the phenotypes, including measures from each phenotype domain, were both heritable and associated with BP-I. Neuroimaging phenotypes, particularly cortical thickness in prefrontal and temporal regions, and volume and microstructural integrity of the corpus callosum, represented the most promising candidate traits for genetic mapping related to BP based on strong heritability and association with disease. Analyses of phenotypic and genetic covariation identified substantial correlations among the traits, at least some of which share a common underlying genetic architecture. CONCLUSIONS AND RELEVANCE This is the most extensive investigation of BP-relevant component phenotypes to date. Our results identify brain and behavioral quantitative traits that appear to be genetically influenced and show a pattern of BP-I-association within families that is consistent with expectations from case-control studies. Together these phenotypes provide a basis for identifying loci contributing to BP-I risk and for genetic dissection of the disorder. PMID:24522887

Neural Tube Defects

PubMed Central

Greene, Nicholas D.E.; Copp, Andrew J.

2015-01-01

Neural tube defects (NTDs), including spina bifida and anencephaly, are severe birth defects of the central nervous system that originate during embryonic development when the neural tube fails to close completely. Human NTDs are multifactorial, with contributions from both genetic and environmental factors. The genetic basis is not yet well understood, but several nongenetic risk factors have been identified as have possibilities for prevention by maternal folic acid supplementation. Mechanisms underlying neural tube closure and NTDs may be informed by experimental models, which have revealed numerous genes whose abnormal function causes NTDs and have provided details of critical cellular and morphological events whose regulation is essential for closure. Such models also provide an opportunity to investigate potential risk factors and to develop novel preventive therapies. PMID:25032496

Prevention of type 2 diabetes mellitus in women with previous gestational diabetes mellitus

PubMed Central

Moon, Joon Ho; Kwak, Soo Heon; Jang, Hak C.

2017-01-01

Gestational diabetes mellitus (GDM), defined as any degree of glucose intolerance with onset or first recognition during pregnancy, is characterized by underlying maternal defects in the β-cell response to insulin during pregnancy. Women with a previous history of GDM have a greater than 7-fold higher risk of developing postpartum diabetes compared with women without GDM. Various risk factors for postpartum diabetes have been identified, including maternal age, glucose levels in pregnancy, family history of diabetes, pre-pregnancy and postpartum body mass index, dietary patterns, physical activity, and breastfeeding. Genetic studies revealed that GDM shares common genetic variants with type 2 diabetes. A number of lifestyle interventional trials that aimed to ameliorate modifiable risk factors, including diet, exercise, and breastfeeding, succeeded in reducing the incidence of postpartum diabetes, weight retention, and other obesity-related morbidities. The present review summarizes the findings of previous studies on the incidence and risk factors of postpartum diabetes and discusses recent lifestyle interventional trials that attempted to prevent postpartum diabetes. PMID:28049284

Prevention of type 2 diabetes mellitus in women with previous gestational diabetes mellitus.

PubMed

Moon, Joon Ho; Kwak, Soo Heon; Jang, Hak C

2017-01-01

Gestational diabetes mellitus (GDM), defined as any degree of glucose intolerance with onset or first recognition during pregnancy, is characterized by underlying maternal defects in the β-cell response to insulin during pregnancy. Women with a previous history of GDM have a greater than 7-fold higher risk of developing postpartum diabetes compared with women without GDM. Various risk factors for postpartum diabetes have been identified, including maternal age, glucose levels in pregnancy, family history of diabetes, pre-pregnancy and postpartum body mass index, dietary patterns, physical activity, and breastfeeding. Genetic studies revealed that GDM shares common genetic variants with type 2 diabetes. A number of lifestyle interventional trials that aimed to ameliorate modifiable risk factors, including diet, exercise, and breastfeeding, succeeded in reducing the incidence of postpartum diabetes, weight retention, and other obesity-related morbidities. The present review summarizes the findings of previous studies on the incidence and risk factors of postpartum diabetes and discusses recent lifestyle interventional trials that attempted to prevent postpartum diabetes.

Framingham risk score can predict cognitive decline progression in Alzheimer's disease.

PubMed

Viticchi, Giovanna; Falsetti, Lorenzo; Buratti, Laura; Boria, Cristiano; Luzzi, Simona; Bartolini, Marco; Provinciali, Leandro; Silvestrini, Mauro

2015-11-01

The role of vascular factors in influencing cognitive decline has been extensively investigated, and some difficulties in defining their weight in dementia pathogenesis have emerged. The aim of the study was to investigate the relevance of the Framingham cardiovascular risk profile (FCRP) in influencing cognitive deterioration in a population of Alzheimer's disease (AD) patients. Two hundred eighty-four consecutive AD patients were enrolled. For each patient, FCRP score was calculated. We did a 1-year follow-up to quantify the cognitive decline by recording changes in the Clinical Dementia Rating score. The FCRP score predicted cognitive deterioration with an area under the curve of 0.63 (95% confidence interval: 0.57-0.69; p < 0.0001). In the subpopulation of patients with a genetic increased predisposition to develop cognitive deterioration and with an advanced vascular impairment, the FCRP predictive value significantly increased with an area under the curve of 0.77 (95% confidence interval: 0.52-0.93; p < 0.05). Our findings show that FCRP can predict the progression of deterioration in AD patients. This was particularly evident in patients with major genetic and atherosclerotic risk factors. Copyright © 2015 Elsevier Inc. All rights reserved.

Curbing the burden of lung cancer.

PubMed

Urman, Alexandra; Hosgood, H Dean

2016-06-01

Lung cancer contributes substantially to the global burden of disease and healthcare costs. New screening modalities using low-dose computerized tomography are promising tools for early detection leading to curative surgery. However, the screening and follow-up diagnostic procedures of these techniques may be costly. Focusing on prevention is an important factor to reduce the burden of screening, treatment, and lung cancer deaths. The International Agency for Research on Cancer has identified several lung carcinogens, which we believe can be considered actionable when developing prevention strategies. To curb the societal burden of lung cancer, healthcare resources need to be focused on early detection and screening and on mitigating exposure(s) of a person to known lung carcinogens, such as active tobacco smoking, household air pollution (HAP), and outdoor air pollution. Evidence has also suggested that these known lung carcinogens may be associated with genetic predispositions, supporting the hypothesis that lung cancers attributed to differing exposures may have developed from unique underlying genetic mechanisms attributed to the exposure of interest. For instance, smokingattributed lung cancer involves novel genetic markers of risk compared with HAP-attributed lung cancer. Therefore, genetic risk markers may be used in risk stratification to identify subpopulations that are at a higher risk for developing lung cancer attributed to a given exposure. Such targeted prevention strategies suggest that precision prevention strategies may be possible in the future; however, much work is needed to determine whether these strategies will be viable.

Early identification and high-risk strategies for bipolar disorder.

PubMed

Correll, Christoph U; Penzner, Julie B; Lencz, Todd; Auther, Andrea; Smith, Christopher W; Malhotra, Anil K; Kane, John M; Cornblatt, Barbara A

2007-06-01

To describe and compare the relative merits of different identification strategies for individuals at risk for bipolar disorder (BPD). Selective review of data that support early identification in BPD, with a particular focus on emerging clinical high-risk strategies. Early detection of individuals at risk for BPD can utilize genetic, endophenotypic and clinical methods. Most published work focuses on genetic familial endophenotypic risk markers for BPD. However, despite encouraging results, problems with specificity and sensitivity limit the application of these data to early prevention programs. In addition, offspring studies of BPD patients systematically exclude the majority of subjects without a first-degree bipolar relative. On the other hand, emerging work in the clinical-high-risk arena has already produced encouraging results. Although still preliminary, the identification of individuals in subsyndromal or attenuated symptom 'prodromal' stages of BPD seems to be an under-researched area that holds considerable promise deserving increased attention. Required next steps include the development of rating tools for attenuated and subsyndromal manic and depressive symptoms and of prodromal criteria that will allow prodromal symptomatology to be systematically studied in patients with recent-onset bipolar, as well as in prospective population-based phenomenology trials and attenuated symptom-based high-risk studies. Given the current limitations of each early identification method, combining clinical, endophenotypic and genetic strategies will increase prediction accuracy. Since reliable biological markers for BPD have not been established and since most patients with BPD lack a first-degree relative with this disorder, clinical high-risk approaches have great potential to inform early identification and intervention programs.

Shared and unique common genetic determinants between pediatric and adult celiac disease.

PubMed

Senapati, Sabyasachi; Sood, Ajit; Midha, Vandana; Sood, Neena; Sharma, Suresh; Kumar, Lalit; Thelma, B K

2016-07-22

Based on age of presentation, celiac disease (CD) is categorised as pediatric CD and adult CD. It however remains unclear if these are genetically and/or phenotypically distinct disorders or just different spectrum of the same disease. We therefore explored the common genetic components underlying pediatric and adult CD in a well characterized north Indian cohort. A retrospective analysis of children (n = 531) and adult (n = 871) patients with CD between January 2001 and December 2010 was done. The database included basic demographic characteristics, clinical presentations, associated diseases and complications, if any. The genotype dataset was acquired for children (n = 217) and adult CD patients (n = 340) and controls (n = 736) using Immunochip. Association analysis was performed using logistic regression model to identify susceptibility genetic variants. The predominant form of CD was classical CD in both pediatric and adult CD groups. There was remarkable similarity between pediatric and adult CD except for quantitative differences between the two groups such as female preponderance, non-classical presentation, co-occurrence of other autoimmune diseases being more common amongst adult CD. Notably, same HLA-DQ2 and -DQ8 haplotypes were established as the major risk factors in both types of CD. In addition, a few suggestively associated (p < 5 × 10(-4)) non-HLA markers were identified of which only ANK3 (rs4948256-A; rs10994257-T) was found to be shared and explain risk for ~45 % of CD patients with HLA allele. Overall phenotypic similarity between pediatric and adult CD groups can be explained by contribution of same HLA risk alleles. Different non-HLA genes/loci with minor risk seem to play crucial role in disease onset and extra intestinal manifestation of CD. None of the non-HLA risk variants reached genome-wide significance, however most of them were shown to have functional implication to disease pathogenesis. Functional relevance of our findings needs to be investigated to address clinical heterogeneity of CD. This present study is the first comparative study based on common genetic markers to suggest that CD in pediatric age group and in adults are the spectrum of the same disease with novel and shared genetic risk determinants. Follow-up fine mapping studies with larger study cohorts are warranted for further genetic investigation.

Detectable signals of episodic risk effects on acute HIV transmission: Strategies for analyzing transmission systems using genetic data

PubMed Central

Alam, Shah Jamal; Zhang, Xinyu; Romero-Severson, Ethan Obie; Henry, Christopher; Zhong, Lin; Volz, Erik M.; Brenner, Bluma G.; Koopman, James S.

2013-01-01

Episodic high-risk sexual behavior is common and can have a profound effect on HIV transmission. In a model of HIV transmission among men who have sex with men (MSM), changing the frequency, duration and contact rates of high-risk episodes can take endemic prevalence from zero to 50% and more than double transmissions during acute HIV infection (AHI). Undirected test and treat could be inefficient in the presence of strong episodic risk effects. Partner services approaches that use a variety of control options will be likely to have better effects under these conditions, but the question remains: What data will reveal if a population is experiencing episodic risk effects? HIV sequence data from Montreal reveals genetic clusters whose size distribution stabilizes over time and reflects the size distribution of acute infection outbreaks (AIOs). Surveillance provides complementary behavioral data. In order to use both types of data efficiently, it is essential to examine aspects of models that affect both the episodic risk effects and the shape of transmission trees. As a demonstration, we use a deterministic compartmental model of episodic risk to explore the determinants of the fraction of transmissions during acute HIV infection (AHI) at the endemic equilibrium. We use a corresponding individual-based model to observe AIO size distributions and patterns of transmission within AIO. Episodic risk parameters determining whether AHI transmission trees had longer chains, more clustered transmissions from single individuals, or different mixes of these were explored. Encouragingly for parameter estimation, AIO size distributions reflected the frequency of transmissions from acute infection across divergent parameter sets. Our results show that episodic risk dynamics influence both the size and duration of acute infection outbreaks, thus providing a possible link between genetic cluster size distributions and episodic risk dynamics. PMID:23438430

Introducing genetic testing for cardiovascular disease in primary care: a qualitative study

PubMed Central

Middlemass, Jo B; Yazdani, Momina F; Kai, Joe; Standen, Penelope J; Qureshi, Nadeem

2014-01-01

Background While primary care systematically offers conventional cardiovascular risk assessment, genetic tests for coronary heart disease (CHD) are increasingly commercially available to patients. It is unclear how individuals may respond to these new sources of risk information. Aim To explore how patients who have had a recent conventional cardiovascular risk assessment, perceive additional information from genetic testing for CHD. Design and setting Qualitative interview study in 12 practices in Nottinghamshire from both urban and rural settings. Method Interviews were conducted with 29 adults, who consented to genetic testing after having had a conventional cardiovascular risk assessment. Results Individuals’ principal motivation for genetic testing was their family history of CHD and a desire to convey the results to their children. After testing, however, there was limited recall of genetic test results and scepticism about the value of informing their children. Participants dealt with conflicting findings from the genetic test, family history, and conventional assessment by either focusing on genetic risk or environmental lifestyle factors. In some participants, genetic test results appeared to reinforce healthy behaviour but others were falsely reassured, despite having an ‘above-average’ conventional cardiovascular risk score. Conclusion Although genetic testing was acceptable, participants were unclear how to interpret genetic risk results. To facilitate healthy behaviour, health professionals should explore patients’ understanding of genetic test results in light of their family history and conventional risk assessment. PMID:24771842

Serum uric acid concentrations and SLC2A9 genetic variation in Hispanic children: the Viva La Familia Study1234

PubMed Central

Voruganti, V Saroja; Laston, Sandra; Haack, Karin; Mehta, Nitesh R; Cole, Shelley A; Butte, Nancy F; Comuzzie, Anthony G

2015-01-01

Background: Elevated concentrations of serum uric acid are associated with increased risk of gout and renal and cardiovascular diseases. Genetic studies in adults have consistently identified associations of solute carrier family 2, member 9 (SLC2A9), polymorphisms with variation in serum uric acid. However, it is not known whether the association of serum uric acid with SLC2A9 polymorphisms manifests in children. Objective: The aim was to investigate whether variation in serum uric acid is under genetic influence and whether the association with SLC2A9 polymorphisms generalizes to Hispanic children of the Viva La Familia Study. Design: We conducted a genomewide association study with 1.1 million genetic markers in 815 children. Results: We found serum uric acid to be significantly heritable [h2 ± SD = 0.45 ± 0.08, P = 5.8 × 10−11] and associated with SLC2A9 variants (P values between 10−16 and 10−7). Several of the significantly associated polymorphisms were previously identified in studies in adults. We also found positive genetic correlations between serum uric acid and BMI z score (ρG = 0.45, P = 0.002), percentage of body fat (ρG = 0.28, P = 0.04), fat mass (ρG = 0.34, P = 0.02), waist circumference (ρG = 0.42, P = 0.003), and waist-to-height ratio (ρG = 0.46, P = 0.001). Conclusions: Our results show that variation in serum uric acid in Hispanic children is under considerable genetic influence and is associated with obesity-related phenotypes. As in adults, genetic variation in SLC2A9 is associated with serum uric acid concentrations, an important biomarker of renal and cardiovascular disease risk, in Hispanic children. PMID:25833971

The current state of play on the molecular genetics of depression.

PubMed

Cohen-Woods, S; Craig, I W; McGuffin, P

2013-04-01

It has been well established that both genes and non-shared environment contribute substantially to the underlying aetiology of major depressive disorder (MDD). A comprehensive overview of genetic research in MDD is presented. Method Papers were retrieved from PubMed up to December 2011, using many keywords including: depression, major depressive disorder, genetics, rare variants, gene-environment, whole genome, epigenetics, and specific candidate genes and variants. These were combined in a variety of permutations. Linkage studies have yielded some promising chromosomal regions in MDD. However, there is a continued lack of consistency in association studies, in both candidate gene and genome-wide association studies (GWAS). Numerous factors may account for variable results including the use of different diagnostic approaches, small samples in early studies, population stratification, epigenetic phenomena, copy number variation (CNV), rare variation, and phenotypic and allelic heterogeneity. The conflicting results are also probably, in part, a consequence of environmental factors not being considered or controlled for. Each research group has to identify what issues their sample may best address. We suggest that, where possible, more emphasis should be placed on the environment in molecular behavioural genetics to identify individuals at environmental high risk in addition to genetic high risk. Sequencing should be used to identify rare and alternative variation that may act as a risk factor, and a systems biology approach including gene-gene interactions and pathway analyses would be advantageous. GWAS may require even larger samples with reliably defined (sub)phenotypes.

Parent and peer influences on emerging adult substance use disorder: A genetically informed study

PubMed Central

Bountress, Kaitlin; Chassin, Laurie; Lemery-Chalfant, Kathryn

2017-01-01

The present study utilizes longitudinal data from a high-risk community sample to examine the unique effects of genetic risk, parental knowledge about the daily activities of adolescents, and peer substance use on emerging adult substance use disorders (SUDs). These effects are examined over and above a polygenic risk score. In addition, this polygenic risk score is used to examine gene–environment correlation and interaction. The results show that during older adolescence, higher adolescent genetic risk for SUDs predicts less parental knowledge, but this relation is nonsignificant in younger adolescence. Parental knowledge (using mother report) mediates the effects of parental alcohol use disorder (AUD) and adolescent genetic risk on risk for SUD, and peer substance use mediates the effect of parent AUD on offspring SUD. Finally, there are significant gene–environment interactions such that, for those at the highest levels of genetic risk, less parental knowledge and more peer substance use confers greater risk for SUDs. However, for those at medium and low genetic risk, these effects are attenuated. These findings suggest that the evocative effects of adolescent genetic risk on parenting increase with age across adolescence. They also suggest that some of the most important environmental risk factors for SUDs exert effects that vary across level of genetic propensity. PMID:26753847

Performance of genetic risk factors in prediction of trichloroethylene induced hypersensitivity syndrome

PubMed Central

Dai, Yufei; Chen, Ying; Huang, Hanlin; Zhou, Wei; Niu, Yong; Zhang, Mingrong; Bin, Ping; Dong, Haiyan; Jia, Qiang; Huang, Jianxun; Yi, Juan; Liao, Qijun; Li, Haishan; Teng, Yanxia; Zang, Dan; Zhai, Qingfeng; Duan, Huawei; Shen, Juan; He, Jiaxi; Meng, Tao; Sha, Yan; Shen, Meili; Ye, Meng; Jia, Xiaowei; Xiang, Yingping; Huang, Huiping; Wu, Qifeng; Shi, Mingming; Huang, Xianqing; Yang, Huanming; Luo, Longhai; Li, Sai; Li, Lin; Zhao, Jinyang; Li, Laiyu; Wang, Jun; Zheng, Yuxin

2015-01-01

Trichloroethylene induced hypersensitivity syndrome is dose-independent and potentially life threatening disease, which has become one of the serious occupational health issues and requires intensive treatment. To discover the genetic risk factors and evaluate the performance of risk prediction model for the disease, we conducted genomewide association study and replication study with total of 174 cases and 1761 trichloroethylene-tolerant controls. Fifty seven SNPs that exceeded the threshold for genome-wide significance (P < 5 × 10−8) were screened to relate with the disease, among which two independent SNPs were identified, that is rs2857281 at MICA (odds ratio, 11.92; Pmeta = 1.33 × 10−37) and rs2523557 between HLA-B and MICA (odds ratio, 7.33; Pmeta = 8.79 × 10−35). The genetic risk score with these two SNPs explains at least 20.9% of the disease variance and up to 32.5-fold variation in inter-individual risk. Combining of two SNPs as predictors for the disease would have accuracy of 80.73%, the area under receiver operator characteristic curves (AUC) scores was 0.82 with sensitivity of 74% and specificity of 85%, which was considered to have excellent discrimination for the disease, and could be considered for translational application for screening employees before exposure. PMID:26190474

Machine learning derived risk prediction of anorexia nervosa.

PubMed

Guo, Yiran; Wei, Zhi; Keating, Brendan J; Hakonarson, Hakon

2016-01-20

Anorexia nervosa (AN) is a complex psychiatric disease with a moderate to strong genetic contribution. In addition to conventional genome wide association (GWA) studies, researchers have been using machine learning methods in conjunction with genomic data to predict risk of diseases in which genetics play an important role. In this study, we collected whole genome genotyping data on 3940 AN cases and 9266 controls from the Genetic Consortium for Anorexia Nervosa (GCAN), the Wellcome Trust Case Control Consortium 3 (WTCCC3), Price Foundation Collaborative Group and the Children's Hospital of Philadelphia (CHOP), and applied machine learning methods for predicting AN disease risk. The prediction performance is measured by area under the receiver operating characteristic curve (AUC), indicating how well the model distinguishes cases from unaffected control subjects. Logistic regression model with the lasso penalty technique generated an AUC of 0.693, while Support Vector Machines and Gradient Boosted Trees reached AUC's of 0.691 and 0.623, respectively. Using different sample sizes, our results suggest that larger datasets are required to optimize the machine learning models and achieve higher AUC values. To our knowledge, this is the first attempt to assess AN risk based on genome wide genotype level data. Future integration of genomic, environmental and family-based information is likely to improve the AN risk evaluation process, eventually benefitting AN patients and families in the clinical setting.

Genetic Variants in the Wnt/β-Catenin Signaling Pathway as Indicators of Bladder Cancer Risk.

PubMed

Pierzynski, Jeanne A; Hildebrandt, Michelle A; Kamat, Ashish M; Lin, Jie; Ye, Yuanqing; Dinney, Colin P N; Wu, Xifeng

2015-12-01

Genetic factors that influence bladder cancer risk remain largely unknown. Previous research has suggested that there is a strong genetic component underlying the risk of bladder cancer. The Wnt/β-catenin signaling pathway is a key modulator of cellular proliferation through its regulation of stem cell homeostasis. Furthermore, variants in the Wnt/β-catenin signaling pathway have been implicated in the development of other cancers, leading us to believe that this pathway may have a vital role in bladder cancer development. A total of 230 single nucleotide polymorphisms in 40 genes in the Wnt/β-catenin signaling pathway were genotyped in 803 bladder cancer cases and 803 healthy controls. A total of 20 single nucleotide polymorphisms were nominally significant for risk. Individuals with 2 variants of LRP6: rs10743980 were associated with a decreased risk of bladder cancer in the recessive model in the initial analysis (OR 0.76, 95% CI 0.58-0.99, p=0.039). This was validated using the bladder genome-wide association study chip (OR 0.51, 95% CI 0.27-1.00, p=0.049 and for combined analysis p=0.007). Together these findings implicate variants in the Wnt/β-catenin stem cell pathway as having a role in bladder cancer etiology. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Psychiatric Aspects of Extreme Sports: Three Case Studies

PubMed Central

Tofler, Ian R; Hyatt, Brandon M; Tofler, David S

2018-01-01

Extreme sports, defined as sporting or adventure activities involving a high degree of risk, have boomed since the 1990s. These types of sports attract men and women who can experience a life-affirming transcendence or “flow” as they participate in dangerous activities. Extreme sports also may attract people with a genetic predisposition for risk, risk-seeking personality traits, or underlying psychiatric disorders in which impulsivity and risk taking are integral to the underlying problem. In this report, we attempt to illustrate through case histories the motivations that lead people to repeatedly risk their lives and explore psychiatry’s role in extreme sports. A sports psychiatrist can help with therapeutic management, neuromodulation of any comorbid psychiatric diagnosis, and performance enhancement (eg, risk minimization) to cultivate improved judgment which could include identifying alternative safer recreational options. Because flirting with death is critical to the extreme sports ethos, practitioners must gain further understanding of this field and its at-risk participants. PMID:29401052

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

PubMed Central

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

2011-01-01

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

Exploring Women’s Perceptions of Their Risk of Developing Breast Cancer

DTIC Science & Technology

2008-06-01

into thrce categories based on its underlying etiology. Hereditary breast cancer comprises 5%-10%1 of cases and is attributed to known genetic muta...iavwomen did not recognize aec as a breast cancer risk - - ft~ctur after receiving extensive education on the subject. Other studies have suggeskd that...this issue. Limitations The limitations ofthis study should be considered to properly temper any conclusions drawn. The results were based on a

Polygenic Risk, Rapid Childhood Growth, and the Development of Obesity

PubMed Central

Belsky, Daniel W.; Moffitt, Terrie E.; Houts, Renate; Bennett, Gary G.; Biddle, Andrea K.; Blumenthal, James A.; Evans, James P.; Harrington, HonaLee; Sugden, Karen; Williams, Benjamin; Poulton, Richie; Caspi, Avshalom

2012-01-01

Objective To test how genomic loci identified in genome-wide association studies influence the development of obesity. Design A 38-year prospective longitudinal study of a representative birth cohort. Setting The Dunedin Multidisciplinary Health and Development Study, Dunedin, New Zealand. Participants One thousand thirty-seven male and female study members. Main Exposures We assessed genetic risk with a multilocus genetic risk score. The genetic risk score was composed of single-nucleotide polymorphisms identified in genome-wide association studies of obesity-related phenotypes. We assessed family history from parent body mass index data collected when study members were 11 years of age. Main Outcome Measures Body mass index growth curves, developmental phenotypes of obesity, and adult obesity outcomes were defined from anthropometric assessments at birth and at 12 subsequent in-person interviews through 38 years of age. Results Individuals with higher genetic risk scores were more likely to be chronically obese in adulthood. Genetic risk first manifested as rapid growth during early childhood. Genetic risk was unrelated to birth weight. After birth, children at higher genetic risk gained weight more rapidly and reached adiposity rebound earlier and at a higher body mass index. In turn, these developmental phenotypes predicted adult obesity, mediating about half the genetic effect on adult obesity risk. Genetic associations with growth and obesity risk were independent of family history, indicating that the genetic risk score could provide novel information to clinicians. Conclusions Genetic variation linked with obesity risk operates, in part, through accelerating growth in the early childhood years after birth. Etiological research and prevention strategies should target early childhood to address the obesity epidemic. PMID:22665028

Exercise, Heart and Health

PubMed Central

2011-01-01

Regular physical activity provides a variety of health benefits, including improvement in cardiopulmonary or metabolic status, reduction of the risk of coronary artery disease or stroke, prevention of cancer, and decrease in total mortality. Exercise-related cardiac events are occasionally reported during highly competitive sports activity or vigorous exercises. However, the risk of sudden death is extremely low during vigorous exercise, and habitual vigorous exercise actually decreases the risk of sudden death during exercise. The cause of sudden death is ischemic in older subjects (≥35 years old), while cardiomyopathies or genetic ion channel diseases are important underlying pathology in younger (<35 years old) victims. The subgroup of patients who are particularly at higher risk of exercise-related sudden death may be identified in different ways, such as pre-participation history taking, physical examination and/or supplementary cardiac evaluation. Limitations exist because current diagnostic tools are not sufficient to predict a coronary artery plaque with potential risk of disruption and/or an acute thrombotic occlusion. Proper and cost-effective methods for identification of younger subjects with cardiac structural problems or genetic ion channel diseases are still controversial. PMID:21519508

Early-onset dementias: diagnostic and etiological considerations

PubMed Central

2013-01-01

This paper summarizes the body of literature about early-onset dementia (EOD) that led to recommendations from the Fourth Canadian Consensus Conference on the Diagnosis and Treatment of Dementia. A broader differential diagnosis is required for EOD compared with late-onset dementia. Delays in diagnosis are common, and the social impact of EOD requires special care teams. The etiologies underlying EOD syndromes should take into account family history and comorbid diseases, such as cerebrovascular risk factors, that may influence the clinical presentation and age at onset. For example, although many EODs are more likely to have Mendelian genetic and/or metabolic causes, the presence of comorbidities may drive the individual at risk for late-onset dementia to manifest the symptoms at an earlier age, which contributes further to the observed heterogeneity and may confound diagnostic investigation. A personalized medicine approach to diagnosis should therefore be considered depending on the age at onset, clinical presentation, and comorbidities. Genetic counseling and testing as well as specialized biochemical screening are often required, especially in those under the age of 40 and in those with a family history of autosomal dominant or recessive disease. Novel treatments in the drug development pipeline for EOD, such as genetic forms of Alzheimer's disease, should target the specific pathogenic cascade implicated by the mutation or biochemical defect. PMID:24565469

Impact of Genetic Testing and Family Health History Based Risk Counseling on Behavior Change and Cognitive Precursors for Type 2 Diabetes.

PubMed

Wu, R Ryanne; Myers, Rachel A; Hauser, Elizabeth R; Vorderstrasse, Allison; Cho, Alex; Ginsburg, Geoffrey S; Orlando, Lori A

2017-02-01

Family health history (FHH) in the context of risk assessment has been shown to positively impact risk perception and behavior change. The added value of genetic risk testing is less certain. The aim of this study was to determine the impact of Type 2 Diabetes (T2D) FHH and genetic risk counseling on behavior and its cognitive precursors. Subjects were non-diabetic patients randomized to counseling that included FHH +/- T2D genetic testing. Measurements included weight, BMI, fasting glucose at baseline and 12 months and behavioral and cognitive precursor (T2D risk perception and control over disease development) surveys at baseline, 3, and 12 months. 391 subjects enrolled of which 312 completed the study. Behavioral and clinical outcomes did not differ across FHH or genetic risk but cognitive precursors did. Higher FHH risk was associated with a stronger perceived T2D risk (p Kendall  < 0.001) and with a perception of "serious" risk (p Kendall  < 0.001). Genetic risk did not influence risk perception, but was correlated with an increase in perception of "serious" risk for moderate (p Kendall  = 0.04) and average FHH risk subjects (p Kendall  = 0.01), though not for the high FHH risk group. Perceived control over T2D risk was high and not affected by FHH or genetic risk. FHH appears to have a strong impact on cognitive precursors of behavior change, suggesting it could be leveraged to enhance risk counseling, particularly when lifestyle change is desirable. Genetic risk was able to alter perceptions about the seriousness of T2D risk in those with moderate and average FHH risk, suggesting that FHH could be used to selectively identify individuals who may benefit from genetic risk testing.

Pediatric Predispositional Genetic Risk Communication: Potential Utility for Prevention and Control of Melanoma Risk as an Exemplar.

PubMed

Wu, Yelena P; Mays, Darren; Kohlmann, Wendy; Tercyak, Kenneth P

2017-10-01

Predispositional genetic testing among minor children is intensely debated due to the potential benefits and harms of providing this type of genetic information to children and their families. Existing guidelines on pediatric genetic testing state that predispositional testing could be appropriate for minors if preventive services exist that mitigate children's risk for or severity of the health condition in question. We use the example of hereditary melanoma to illustrate the rationale for and potential application of genetic risk communication for an adult-onset cancer to a pediatric population where childhood behaviors may reduce risk of disease later in life. We draw from the adult melanoma genetic risk communication and pediatric health behavior change literatures to suggest ways in which genetic test reporting and complementary education could be delivered to children who carry a hereditary risk for melanoma and their families in order to foster children's engagement in melanoma preventive behaviors. Genetic discoveries will continue to yield new opportunities to provide predispositional genetic risk information to unaffected individuals, including children, and could be delivered within programs that provide personalized and translational approaches to cancer prevention.

Can genetic risk information for age-related macular degeneration influence motivation to stop smoking? A pilot study

PubMed Central

Rennie, C A; Stinge, A; King, E A; Sothirachagan, S; Osmond, C; Lotery, A J

2012-01-01

Aims Smoking can increase the risk of macular degeneration and this is more than additive if a person also has a genetic risk. The purpose of this study was to examine whether knowledge of genetic risk for age-related macular degeneration (AMD) could influence motivation to quit smoking. Methods A questionnaire-based study of hypothetical case scenarios given to 49 smokers without AMD. Participants were randomly allocated to a generic risk, high genetic risk, or low genetic risk of developing AMD scenario. Results Forty-seven percent knew of the link between smoking and eye disease. In all, 76%, 67%, and 46% for the high risk, generic, and low risk groups, respectively, would rethink quitting (Pfor trend=0.082). In all, 67%, 40%, and 38.5%, respectively, would be likely, very likely, or would definitely quit in the following month (Pfor trend=0.023). Few participants (<16% of any group) were very likely to or would definitely attend a quit smoking session with no difference across groups. In all, 75.5% of participants would consider taking a genetic test for AMD. Conclusion In this pilot study, a trend was seen for the group given high genetic risk information to be more likely to quit than the generic or low genetic risk groups. Participants were willing to take a genetic test but further work is needed to address the cost benefits of routine genetic testing for risk of AMD. More generic risk information should be given to the public, and health warnings on cigarette packets that ‘smoking causes blindness' is a good way to achieve this. PMID:22037055

Adaptive genetic potential of coniferous forest tree species under climate change: implications for sustainable forest management

NASA Astrophysics Data System (ADS)

Mihai, Georgeta; Birsan, Marius-Victor; Teodosiu, Maria; Dumitrescu, Alexandru; Daia, Mihai; Mirancea, Ionel; Ivanov, Paula; Alin, Alexandru

2017-04-01

Mountain ecosystems are extremely vulnerable to climate change. The real potential for adaptation depends upon the existence of a wide genetic diversity in trees populations, upon the adaptive genetic variation, respectively. Genetic diversity offers the guarantee that forest species can survive, adapt and evolve under the influence of changing environmental conditions. The aim of this study is to evaluate the genetic diversity and adaptive genetic potential of two local species - Norway spruce and European silver fir - in the context of regional climate change. Based on data from a long-term provenance experiments network and climate variables spanning over more than 50 years, we have investigated the impact of climatic factors on growth performance and adaptation of tree species. Our results indicate that climatic and geographic factors significantly affect forest site productivity. Mean annual temperature and annual precipitation amount were found to be statistically significant explanatory variables. Combining the additive genetic model with the analysis of nuclear markers we obtained different images of the genetic structure of tree populations. As genetic indicators we used: gene frequencies, genetic diversity, genetic differentiation, genetic variance, plasticity. Spatial genetic analyses have allowed identifying the genetic centers holding high genetic diversity which will be valuable sources of gene able to buffer the negative effects of future climate change. Correlations between the marginal populations and in the optimal vegetation, between the level of genetic diversity and ecosystem stability, will allow the assessment of future risks arising from current genetic structure. Therefore, the strategies for sustainable forest management have to rely on the adaptive genetic variation and local adaptation of the valuable genetic resources. This work was realized within the framework of the project GENCLIM (Evaluating the adaptive potential of the main coniferous species for a sustainable forest management in the context of climate change), financed by the Executive Agency for Higher Education, Research, Development and Innovation Funding, grant number PN-II-PC-PCCA-2013-4-0695.

Genetic Risk Prediction of Atrial Fibrillation

PubMed Central

Lubitz, Steven A.; Yin, Xiaoyan; Lin, Henry J.; Kolek, Matthew; Smith, J. Gustav; Trompet, Stella; Rienstra, Michiel; Rost, Natalia S.; Teixeira, Pedro L.; Almgren, Peter; Anderson, Christopher D.; Chen, Lin Y.; Engström, Gunnar; Ford, Ian; Furie, Karen L.; Guo, Xiuqing; Larson, Martin G.; Lunetta, Kathryn L.; Macfarlane, Peter W.; Psaty, Bruce M.; Soliman, Elsayed Z.; Sotoodehnia, Nona; Stott, David J.; Taylor, Kent D.; Weng, Lu-Chen; Yao, Jie; Geelhoed, Bastiaan; Verweij, Niek; Siland, Joylene E.; Kathiresan, Sekar; Roselli, Carolina; Roden, Dan; van der Harst, Pim; Darbar, Dawood; Jukema, J. Wouter; Melander, Olle; Rosand, Jonathan; Rotter, Jerome I.; Heckbert, Susan R.; Ellinor, Patrick T.; Alonso, Alvaro; Benjamin, Emelia J.

2017-01-01

Background Atrial fibrillation (AF) is common and has a substantial genetic basis. Identification of individuals at greatest AF risk could minimize the incidence of cardioembolic stroke. Methods To determine whether genetic data can stratify risk for development of AF, we examined associations between AF genetic risk scores and incident AF in five prospective studies comprising 18,919 individuals of European ancestry. We examined associations between AF genetic risk scores and ischemic stroke in a separate study of 509 ischemic stroke cases (202 cardioembolic [40%]) and 3,028 controls. Scores were based on 11 to 719 common variants (≥5%) associated with AF at P-values ranging from <1×10−3 to <1×10−8 in a prior independent genetic association study. Results Incident AF occurred in 1,032 (5.5%) individuals. AF genetic risk scores were associated with new-onset AF after adjusting for clinical risk factors. The pooled hazard ratio for incident AF for the highest versus lowest quartile of genetic risk scores ranged from 1.28 (719 variants; 95%CI, 1.13–1.46; P=1.5×10−4) to 1.67 (25 variants; 95%CI, 1.47–1.90; P=9.3×10−15). Discrimination of combined clinical and genetic risk scores varied across studies and scores (maximum C statistic, 0.629–0.811; maximum ΔC statistic from clinical score alone, 0.009–0.017). AF genetic risk was associated with stroke in age- and sex-adjusted models. For example, individuals in the highest quartile of a 127-variant score had a 2.49-fold increased odds of cardioembolic stroke, versus those in the lowest quartile (95%CI, 1.39–4.58; P=2.7×10−3). The effect persisted after excluding individuals (n=70) with known AF (odds ratio, 2.25; 95%CI, 1.20–4.40; P=0.01). Conclusions Comprehensive AF genetic risk scores were associated with incident AF beyond clinical AF risk factors, with magnitudes of risk comparable to other clinical risk factors, though offered small improvements in discrimination. AF genetic risk was also associated with cardioembolic stroke in age- and sex-adjusted analyses. Efforts to determine whether AF genetic risk may improve identification of subclinical AF or distinguish stroke mechanisms are warranted. PMID:27793994

Analysis of the Genetic Basis of Disease in the Context of Worldwide Human Relationships and Migration

PubMed Central

Corona, Erik; Chen, Rong; Sikora, Martin; Morgan, Alexander A.; Patel, Chirag J.; Ramesh, Aditya; Bustamante, Carlos D.; Butte, Atul J.

2013-01-01

Genetic diversity across different human populations can enhance understanding of the genetic basis of disease. We calculated the genetic risk of 102 diseases in 1,043 unrelated individuals across 51 populations of the Human Genome Diversity Panel. We found that genetic risk for type 2 diabetes and pancreatic cancer decreased as humans migrated toward East Asia. In addition, biliary liver cirrhosis, alopecia areata, bladder cancer, inflammatory bowel disease, membranous nephropathy, systemic lupus erythematosus, systemic sclerosis, ulcerative colitis, and vitiligo have undergone genetic risk differentiation. This analysis represents a large-scale attempt to characterize genetic risk differentiation in the context of migration. We anticipate that our findings will enable detailed analysis pertaining to the driving forces behind genetic risk differentiation. PMID:23717210

Finding Risk Groups by Optimizing Artificial Neural Networks on the Area under the Survival Curve Using Genetic Algorithms.

PubMed

Kalderstam, Jonas; Edén, Patrik; Ohlsson, Mattias

2015-01-01

We investigate a new method to place patients into risk groups in censored survival data. Properties such as median survival time, and end survival rate, are implicitly improved by optimizing the area under the survival curve. Artificial neural networks (ANN) are trained to either maximize or minimize this area using a genetic algorithm, and combined into an ensemble to predict one of low, intermediate, or high risk groups. Estimated patient risk can influence treatment choices, and is important for study stratification. A common approach is to sort the patients according to a prognostic index and then group them along the quartile limits. The Cox proportional hazards model (Cox) is one example of this approach. Another method of doing risk grouping is recursive partitioning (Rpart), which constructs a decision tree where each branch point maximizes the statistical separation between the groups. ANN, Cox, and Rpart are compared on five publicly available data sets with varying properties. Cross-validation, as well as separate test sets, are used to validate the models. Results on the test sets show comparable performance, except for the smallest data set where Rpart's predicted risk groups turn out to be inverted, an example of crossing survival curves. Cross-validation shows that all three models exhibit crossing of some survival curves on this small data set but that the ANN model manages the best separation of groups in terms of median survival time before such crossings. The conclusion is that optimizing the area under the survival curve is a viable approach to identify risk groups. Training ANNs to optimize this area combines two key strengths from both prognostic indices and Rpart. First, a desired minimum group size can be specified, as for a prognostic index. Second, the ability to utilize non-linear effects among the covariates, which Rpart is also able to do.

Association of polymorphisms in survivin gene with the risk of hepatocellular carcinoma in Chinese han population: a case control study

PubMed Central

2012-01-01

Background Survivin, one of the strongest apoptosis inhibitors, plays a critical role in the development and progression of hepatocellular carcinoma (HCC). By comparison, relatively little is known about the effect of survivin gene polymorphisms on HCC susceptibility. Our study aimed to investigate the association of survivin gene polymorphisms with the risk of HCC in Chinese han population. Methods A case-control study was conducted in Chinese han population consisting of 178 HCC cases and 196 cancer-free controls. Information on demographic data and related risk factors was collected for all subjects. Polymorphisms of the survivin gene, including three loci of rs8073069, rs9904341 and rs1042489, were selected and genotyped by a polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) technique. Association analysis of genotypes/alleles and haplotypes from these loci with the risk of HCC was conducted under different genetic models. Results Using univariate analysis of rs8073069, rs9904341 and rs1042489 under different genetic models, no statistically significant difference was found in genotype or allele distribution of HCC cases relative to the controls (P > 0.05). Linkage disequilibrium (LD) analysis showed that these loci were in LD. Multivariate logistic regression indicated that with no G-C-T haplotype as reference, the haplotype of G-C-T from these loci was associated with a lower risk for HCC under the recessive model (OR = 0.46, 95% confidence interval (CI): 0.24~0.90, P = 0.023). Both HBsAg+ and the medical history of viral hepatitis type B were risk factors for HCC. However, no statistically significant haplotype-environment interaction existed. Conclusions No association between rs8073069, rs9904341 or rs1042489 in survivin gene and the risk of HCC is found in Chinese han population, but rs8073069G-rs9904341C- rs1042489T is perhaps a protective haplotype for HCC. PMID:22214342

Gene × Environment Interactions in Schizophrenia: Evidence from Genetic Mouse Models

PubMed Central

Marr, Julia; Bock, Gavin; Desbonnet, Lieve; Waddington, John

2016-01-01

The study of gene × environment, as well as epistatic interactions in schizophrenia, has provided important insight into the complex etiopathologic basis of schizophrenia. It has also increased our understanding of the role of susceptibility genes in the disorder and is an important consideration as we seek to translate genetic advances into novel antipsychotic treatment targets. This review summarises data arising from research involving the modelling of gene × environment interactions in schizophrenia using preclinical genetic models. Evidence for synergistic effects on the expression of schizophrenia-relevant endophenotypes will be discussed. It is proposed that valid and multifactorial preclinical models are important tools for identifying critical areas, as well as underlying mechanisms, of convergence of genetic and environmental risk factors, and their interaction in schizophrenia. PMID:27725886

Genetic architecture for human aggression: A study of gene-phenotype relationship in OMIM.

PubMed

Zhang-James, Yanli; Faraone, Stephen V

2016-07-01

Genetic studies of human aggression have mainly focused on known candidate genes and pathways regulating serotonin and dopamine signaling and hormonal functions. These studies have taught us much about the genetics of human aggression, but no genetic locus has yet achieved genome-significance. We here present a review based on a paradoxical hypothesis that studies of rare, functional genetic variations can lead to a better understanding of the molecular mechanisms underlying complex multifactorial disorders such as aggression. We examined all aggression phenotypes catalogued in Online Mendelian Inheritance in Man (OMIM), an Online Catalog of Human Genes and Genetic Disorders. We identified 95 human disorders that have documented aggressive symptoms in at least one individual with a well-defined genetic variant. Altogether, we retrieved 86 causal genes. Although most of these genes had not been implicated in human aggression by previous studies, the most significantly enriched canonical pathways had been previously implicated in aggression (e.g., serotonin and dopamine signaling). Our findings provide strong evidence to support the causal role of these pathways in the pathogenesis of aggression. In addition, the novel genes and pathways we identified suggest additional mechanisms underlying the origins of human aggression. Genome-wide association studies with very large samples will be needed to determine if common variants in these genes are risk factors for aggression. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Endoplasmic reticulum aminopeptidase-1 alleles associated with increased risk of ankylosing spondylitis reduce HLA-B27 mediated presentation of multiple antigens.

PubMed

Seregin, Sergey S; Rastall, David P W; Evnouchidou, Irini; Aylsworth, Charles F; Quiroga, Dionisia; Kamal, Ram P; Godbehere-Roosa, Sarah; Blum, Christopher F; York, Ian A; Stratikos, Efstratios; Amalfitano, Andrea

2013-12-01

Ankylosing spondylitis (AS) is a chronic systemic arthritic disease that leads to significant disability and loss of quality of life in the ∼0.5% of the worldwide human population it affects. There is currently no cure for AS and mechanisms underlying its pathogenesis remain unclear. AS is highly genetic, with over 70% of the genetic risk being associated with the presence of HLA-B27 and endoplasmic reticulum aminopeptidase-1 (ERAP1) alleles. Furthermore, gene-gene interactions between HLA-B27 and ERAP1 AS risk alleles have recently been confirmed. Here, we demonstrate that various ERAP1 alleles can differentially mediate surface expression of antigens presented by HLA-B27 on human cells. Specifically, for all peptides tested, we found that an ERAP1 variant containing high AS risk SNPs reduced the amount of the peptide presented by HLA-B27, relative to low AS risk ERAP1 variants. These results were further validated using peptide catalysis assays in vitro, suggesting that high AS risk alleles have an enhanced catalytic activity that more rapidly destroys many HLA-B27-destined peptides, a result that correlated with decreased HLA-B27 presentation of the same peptides. These findings suggest that one mechanism underlying AS pathogenesis may involve an altered ability for AS patients harboring both HLA-B27 and high AS risk ERAP1 alleles to correctly display a variety of peptides to the adaptive arm of the immune system, potentially exposing such individuals to higher AS risk due to abnormal display of pathogen or self-derived peptides by the adaptive immune system.

Endoplasmic reticulum aminopeptidase-1 alleles associated with increased risk of Ankylosing Spondylitis reduce HLA-B27 mediated presentation of multiple antigens

PubMed Central

Seregin, Sergey S.; Rastall, David P.W.; Evnouchidou, Irini; Aylsworth, Charles F.; Quiroga, Dionisia; Kamal, Ram P.; Godbehere-Roosa, Sarah; Blum, Christopher F.; York, Ian A.; Stratikos, Efstratios; Amalfitano, Andrea

2014-01-01

Ankylosing spondylitis (AS) is a chronic systemic arthritic disease that leads to significant disability and loss of quality of life in the ~0.5% of the worldwide human population it affects. There is currently no cure for AS and mechanisms underlying its pathogenesis remain unclear. AS is highly genetic, with over 70% of the genetic risk being associated with the presence of HLA-B27 and endoplasmic reticulum aminopeptidase-1 (ERAP1) alleles. Furthermore, gene-gene interactions between HLA-B27 and ERAP1 AS risk alleles have recently been confirmed. Here, we demonstrate that various ERAP1 alleles can differentially mediate surface expression of antigens presented by HLA-B27 on human cells. Specifically, for all peptides tested, we found that an ERAP1 variant containing high AS risk SNPs reduced the amount of the peptide presented by HLA-B27, relative to low AS risk ERAP1 variants. These results were further validated using peptide catalysis assays in vitro, suggesting that high AS risk alleles have an enhanced catalytic activity that more rapidly destroys many HLA-B27-destined peptides, a result that correlated with decreased HLA-B27 presentation of the same peptides. These findings suggest that one mechanism underlying AS pathogenesis may involve an altered ability for AS patients harboring both HLA-B27 and high AS risk ERAP1 alleles to correctly display a variety of peptides to the adaptive arm of the immune system, potentially exposing such individuals to higher AS risk due to abnormal display of pathogen or self derived peptides by the adaptive immune system. PMID:24028501

Identification of gene networks underlying dystocia in dairy cattle

USDA-ARS?s Scientific Manuscript database

Dystocia is a trait with a high impact in the dairy industry. Among its risk factors are calf weight, gestation length, breed and conformation. Biological networks have been proposed to capture the genetic architecture of complex traits, where GWAS show limitations. The objective of this study was t...

40 CFR 725.450 - Procedural requirements for the Tier II exemption.

Code of Federal Regulations, 2010 CFR

2010-07-01

... ascertainable by the person that would permit EPA to determine that use of the microorganism, under the conditions specified in the request, will not present an unreasonable risk of injury to health or the... microorganism, the introduced genetic material, the physical containment and control technologies. ...

Factors affecting the presence of human-associated and fecal indicator real-time quantitative PCR genetic markers in urban-impacted recreational beaches

EPA Science Inventory

Urban runoff can carry a variety of pollutants into recreational beaches, often including bacterial pathogens and indicators of fecal contamination. To develop complete recreational criteria and risk assessments, it is necessary to understand conditions under which human contamin...

The integration of epigenetics and genetics in nutrition research for CVD risk factors

USDA-ARS?s Scientific Manuscript database

There is increasing evidence documenting gene-by-environment (G x E) interactions for CVD related traits. However, the underlying mechanisms are still unclear. DNA methylation may represent one of such potential mechanisms. The objective of this review paper is to summarise the current evidence supp...

Novel genetic predictors of venous thromboembolism risk in African Americans

PubMed Central

Hernandez, Wenndy; Gamazon, Eric R.; Smithberger, Erin; O’Brien, Travis J.; Harralson, Arthur F.; Tuck, Matthew; Barbour, April; Kittles, Rick A.; Cavallari, Larisa H.

2016-01-01

Venous thromboembolism (VTE) is the third most common life-threatening cardiovascular condition in the United States, with African Americans (AAs) having a 30% to 60% higher incidence compared with other ethnicities. The mechanisms underlying population differences in the risk of VTE are poorly understood. We conducted the first genome-wide association study in AAs, comprising 578 subjects, followed by replication of highly significant findings in an independent cohort of 159 AA subjects. Logistic regression was used to estimate the association between genetic variants and VTE risk. Through bioinformatics analysis of the top signals, we identified expression quantitative trait loci (eQTLs) in whole blood and investigated the messenger RNA expression differences in VTE cases and controls. We identified and replicated single-nucleotide polymorphisms on chromosome 20 (rs2144940, rs2567617, and rs1998081) that increased risk of VTE by 2.3-fold (P < 6 × 10−7). These risk variants were found in higher frequency among populations of African descent (>20%) compared with other ethnic groups (<10%). We demonstrate that SNPs on chromosome 20 are cis-eQTLs for thrombomodulin (THBD), and the expression of THBD is lower among VTE cases compared with controls (P = 9.87 × 10−6). We have identified novel polymorphisms associated with increased risk of VTE in AAs. These polymorphisms are predominantly found among populations of African descent and are associated with THBD gene expression. Our findings provide new molecular insight into a mechanism regulating VTE susceptibility and identify common genetic variants that increase the risk of VTE in AAs, a population disproportionately affected by this disease. PMID:26888256

Psychopathology, temperament and unintentional injury: cross-sectional and longitudinal relationships.

PubMed

Rowe, Richard; Simonoff, Emily; Silberg, Judy L

2007-01-01

Growing evidence indicates a link between unintentional injury and both disruptive and emotional psychopathology. We present further evidence of these associations and address the underlying mechanisms. We also examine the genetic contribution to unintentional injury. The Virginia Twin Study of Adolescent Behavioral Development provides genetically informative multi-wave and multi-informant data regarding common psychopathology using the Child and Adolescent Psychiatric Assessment interview. The EASI temperament scales and child injury involvement were measured in parent-report questionnaires. Unintentional injury showed significant genetic effects in girls and significant shared environmental effects in boys and girls. Symptoms of over-anxious disorder (OAD), and the EASI temperament scales were independently associated with injury. Longitudinal modeling showed impulsivity and OAD symptoms were related prospectively to injury involvement. Injuries did not increase risk for later impulsivity or OAD symptoms but were related prospectively to separation anxiety disorder symptoms. Impulsivity and OAD symptoms increased risk of later injury. We discuss the processes that may be involved in these relationships.

Population structure and infectious disease risk in southern Africa.

PubMed

Uren, Caitlin; Möller, Marlo; van Helden, Paul D; Henn, Brenna M; Hoal, Eileen G

2017-06-01

The KhoeSan populations are the earliest known indigenous inhabitants of southern Africa. The relatively recent expansion of Bantu-speaking agropastoralists, as well as European colonial settlement along the south-west coast, dramatically changed patterns of genetic diversity in a region which had been largely isolated for thousands of years. Owing to this unique history, population structure in southern Africa reflects both the underlying KhoeSan genetic diversity as well as differential recent admixture. This population structure has a wide range of biomedical and sociocultural implications; such as changes in disease risk profiles. Here, we consolidate information from various population genetic studies that characterize admixture patterns in southern Africa with an aim to better understand differences in adverse disease phenotypes observed among groups. Our review confirms that ancestry has a direct impact on an individual's immune response to infectious diseases. In addition, we emphasize the importance of collaborative research, especially for populations in southern Africa that have a high incidence of potentially fatal infectious diseases such as HIV and tuberculosis.

A genetic stochastic process model for genome-wide joint analysis of biomarker dynamics and disease susceptibility with longitudinal data.

PubMed

He, Liang; Zhbannikov, Ilya; Arbeev, Konstantin G; Yashin, Anatoliy I; Kulminski, Alexander M

2017-11-01

Unraveling the underlying biological mechanisms or pathways behind the effects of genetic variations on complex diseases remains one of the major challenges in the post-GWAS (where GWAS is genome-wide association study) era. To further explore the relationship between genetic variations, biomarkers, and diseases for elucidating underlying pathological mechanism, a huge effort has been placed on examining pleiotropic and gene-environmental interaction effects. We propose a novel genetic stochastic process model (GSPM) that can be applied to GWAS and jointly investigate the genetic effects on longitudinally measured biomarkers and risks of diseases. This model is characterized by more profound biological interpretation and takes into account the dynamics of biomarkers during follow-up when investigating the hazards of a disease. We illustrate the rationale and evaluate the performance of the proposed model through two GWAS. One is to detect single nucleotide polymorphisms (SNPs) having interaction effects on type 2 diabetes (T2D) with body mass index (BMI) and the other is to detect SNPs affecting the optimal BMI level for protecting from T2D. We identified multiple SNPs that showed interaction effects with BMI on T2D, including a novel SNP rs11757677 in the CDKAL1 gene (P = 5.77 × 10 -7 ). We also found a SNP rs1551133 located on 2q14.2 that reversed the effect of BMI on T2D (P = 6.70 × 10 -7 ). In conclusion, the proposed GSPM provides a promising and useful tool in GWAS of longitudinal data for interrogating pleiotropic and interaction effects to gain more insights into the relationship between genes, quantitative biomarkers, and risks of complex diseases. © 2017 WILEY PERIODICALS, INC.

The etiology of autistic traits in preschoolers: a population-based twin study.

PubMed

de Zeeuw, Eveline L; van Beijsterveldt, Catharina E M; Hoekstra, Rosa A; Bartels, Meike; Boomsma, Dorret I

2017-08-01

Autism Spectrum Disorders (ASD) are highly heritable, but the exact etiological mechanisms underlying the condition are still unclear. Using a multiple rater twin design in a large sample of general population preschool twins, this study aimed to (a) estimate the contribution of genetic and environmental factors to autistic traits, controlling for the possible effects of rater bias, (b) to explore possible sex differences in etiology and (c) to investigate the discordance in autistic traits in monozygotic and same-sex dizygotic twin pairs. The Netherlands Twin Register collected maternal and paternal ratings on autistic traits from a general population of 38,798 three-year-old twins. Autistic traits were assessed with the DSM-oriented Pervasive Developmental Problems scale of the Child Behavior Check List for preschoolers (1½-5 years). Mother and fathers showed high agreement in their assessment of autistic traits (r = .60-.66). Differences between children in autistic traits were largely accounted for by genetic effects (boys: 78% and girls: 83%). Environmental effects that are unique to a child also played a modest role. Environmental effects shared by children growing up in the same family were negligible, once rater bias was controlled for. While the prevalence for clinical ASD is higher in boys than in girls, this study did not find evidence for striking differences in the etiology of autistic traits across the sexes. Even though the heritability was high, 29% of MZ twin pairs were discordant for high autistic traits (clinical range vs. normal development), suggesting that despite high genetic risk, environmental factors might lead to resilience, unaffected status in the context of genetic risk, in some children. It is important to focus future research on risk factors that might interplay with a genetic disposition for ASD, but also on protective factors that make a difference in the lives of children at genetic risk. © 2017 Association for Child and Adolescent Mental Health.

Genotype-Specific Minimal Residual Disease Interpretation Improves Stratification in Pediatric Acute Lymphoblastic Leukemia

PubMed Central

O’Connor, David; Enshaei, Amir; Bartram, Jack; Hancock, Jeremy; Harrison, Christine J.; Hough, Rachael; Samarasinghe, Sujith; Schwab, Claire; Vora, Ajay; Wade, Rachel; Moppett, John; Moorman, Anthony V.; Goulden, Nick

2018-01-01

Purpose Minimal residual disease (MRD) and genetic abnormalities are important risk factors for outcome in acute lymphoblastic leukemia. Current risk algorithms dichotomize MRD data and do not assimilate genetics when assigning MRD risk, which reduces predictive accuracy. The aim of our study was to exploit the full power of MRD by examining it as a continuous variable and to integrate it with genetics. Patients and Methods We used a population-based cohort of 3,113 patients who were treated in UKALL2003, with a median follow-up of 7 years. MRD was evaluated by polymerase chain reaction analysis of Ig/TCR gene rearrangements, and patients were assigned to a genetic subtype on the basis of immunophenotype, cytogenetics, and fluorescence in situ hybridization. To examine response kinetics at the end of induction, we log-transformed the absolute MRD value and examined its distribution across subgroups. Results MRD was log normally distributed at the end of induction. MRD distributions of patients with distinct genetic subtypes were different (P < .001). Patients with good-risk cytogenetics demonstrated the fastest disease clearance, whereas patients with high-risk genetics and T-cell acute lymphoblastic leukemia responded more slowly. The risk of relapse was correlated with MRD kinetics, and each log reduction in disease level reduced the risk by 20% (hazard ratio, 0.80; 95% CI, 0.77 to 0.83; P < .001). Although the risk of relapse was directly proportional to the MRD level within each genetic risk group, absolute relapse rate that was associated with a specific MRD value or category varied significantly by genetic subtype. Integration of genetic subtype–specific MRD values allowed more refined risk group stratification. Conclusion A single threshold for assigning patients to an MRD risk group does not reflect the response kinetics of the different genetic subtypes. Future risk algorithms should integrate genetics with MRD to accurately identify patients with the lowest and highest risk of relapse. PMID:29131699

Disclosing Genetic Risk for Coronary Heart Disease: Attitudes Toward Personal Information in Health Records.

PubMed

Brown, Sherry-Ann; Jouni, Hayan; Marroush, Tariq S; Kullo, Iftikhar J

2017-04-01

Incorporating genetic risk information in electronic health records (EHRs) will facilitate implementation of genomic medicine in clinical practice. However, little is known about patients' attitudes toward incorporation of genetic risk information as a component of personal health information in EHRs. This study investigated whether disclosure of a genetic risk score (GRS) for coronary heart disease influences attitudes toward incorporation of personal health information including genetic risk in EHRs. Participants aged 45-65 years with intermediate 10-year coronary heart disease risk were randomized to receive a conventional risk score (CRS) alone or with a GRS from a genetic counselor, followed by shared decision making with a physician using the same standard presentation and information templates for all study participants. The CRS and GRS were then incorporated into the EHR and made accessible to both patients and physicians. Baseline and post-disclosure surveys were completed to assess whether attitudes differed by GRS disclosure. Data were collected from 2013 to 2015 and analyzed in 2015-2016. GRS and CRS participants reported similar positive attitudes toward incorporation of genetic risk information in the EHR. Compared with CRS participants, participants with high GRS were more concerned about the confidentiality of genetic risk information (OR=3.67, 95% CI=1.29, 12.32, p=0.01). Post-disclosure, frequency of patient portal access was associated with positive attitudes. Participants in this study of coronary heart disease risk disclosure overall had positive attitudes toward incorporation of genetic risk information in EHRs, although those who received genetic risk information had concerns about confidentiality. Copyright © 2016 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

Primer Part 1-The building blocks of epilepsy genetics.

PubMed

Helbig, Ingo; Heinzen, Erin L; Mefford, Heather C

2016-06-01

This is the first of a two-part primer on the genetics of the epilepsies within the Genetic Literacy Series of the Genetics Commission of the International League Against Epilepsy. In Part 1, we cover the foundations of epilepsy genetics including genetic epidemiology and the range of genetic variants that can affect the risk for developing epilepsy. We discuss various epidemiologic study designs that have been applied to the genetics of the epilepsies including population studies, which provide compelling evidence for a strong genetic contribution in many epilepsies. We discuss genetic risk factors varying in size, frequency, inheritance pattern, effect size, and phenotypic specificity, and provide examples of how genetic risk factors within the various categories increase the risk for epilepsy. We end by highlighting trends in epilepsy genetics including the increasing use of massive parallel sequencing technologies. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

Do Health Professionals Need Additional Competencies for Stratified Cancer Prevention Based on Genetic Risk Profiling?

PubMed Central

Chowdhury, Susmita; Henneman, Lidewij; Dent, Tom; Hall, Alison; Burton, Alice; Pharoah, Paul; Pashayan, Nora; Burton, Hilary

2015-01-01

There is growing evidence that inclusion of genetic information about known common susceptibility variants may enable population risk-stratification and personalized prevention for common diseases including cancer. This would require the inclusion of genetic testing as an integral part of individual risk assessment of an asymptomatic individual. Front line health professionals would be expected to interact with and assist asymptomatic individuals through the risk stratification process. In that case, additional knowledge and skills may be needed. Current guidelines and frameworks for genetic competencies of non-specialist health professionals place an emphasis on rare inherited genetic diseases. For common diseases, health professionals do use risk assessment tools but such tools currently do not assess genetic susceptibility of individuals. In this article, we compare the skills and knowledge needed by non-genetic health professionals, if risk-stratified prevention is implemented, with existing competence recommendations from the UK, USA and Europe, in order to assess the gaps in current competences. We found that health professionals would benefit from understanding the contribution of common genetic variations in disease risk, the rationale for a risk-stratified prevention pathway, and the implications of using genomic information in risk-assessment and risk management of asymptomatic individuals for common disease prevention. PMID:26068647

Genetic Risk, Coronary Heart Disease Events, and the Clinical Benefit of Statin Therapy

PubMed Central

Smith, JG; Chasman, DI; Caulfield, M; Devlin, JJ; Nordio, F; Hyde, C; Cannon, CP; Sacks, F; Poulter, N; Sever, P; Ridker, PM; Braunwald, E; Melander, O

2015-01-01

Background Genetic variants have been associated with the risk of coronary heart disease (CHD). We tested whether a composite of these variants could identify the risk of both incident as well as recurrent CHD events and distinguish individuals who derived greater clinical benefit from statin therapy. Methods A community-based cohort and four randomized controlled trials of both primary (JUPITER and ASCOT) and secondary (CARE and PROVE IT-TIMI 22) prevention with statin therapy totaling 48,421 individuals and 3,477 events were included in these analyses. We examined the association of a genetic risk score based on 27 genetic variants with incident or recurrent CHD, adjusting for established clinical predictors. We then investigated the relative and absolute risk reductions in CHD events with statin therapy stratified by genetic risk. Data from studies were combined using meta-analysis. Findings When individuals were divided into low (quintile 1), intermediate (quintiles 2-4), and high (quintile 5) genetic risk categories, a significant gradient of risk for incident or recurrent CHD was demonstrated with the multivariable-adjusted HRs (95% CI) for CHD for the intermediate and high genetic risk categories vs. low genetic risk category being 1.32 (1.20-1.46, P<0.0001) and 1.71 (1.54-1.91, P<0.0001), respectively. In terms of the benefit of statin therapy in the four randomized trials, there was a significant gradient of increasing relative risk reduction across the low, intermediate, and high genetic risk categories (13%, 29%, and 48%, P=0.0277). Similarly, greater absolute risk reductions were seen in those individuals in higher genetic risk categories (P=0.0101), resulting in an approximate three-fold gradient in the number needed to treat (NNT) in the primary prevention trials. Specifically, in the primary prevention trials, the NNT to prevent one MACE over 10 years for the low, intermediate, and high GRS individuals was 66, 42, and 25 in JUPITER and 57, 47, and 20 in ASCOT. Interpretation A genetic risk score identified individuals at increased risk for both incident and recurrent CHD events. Individuals with the highest burden of genetic risk derived the largest relative and absolute clinical benefit with statin therapy. PMID:25748612

Association of colorectal cancer susceptibility variants with esophageal cancer in a Chinese population.

PubMed

Geng, Ting-Ting; Xun, Xiao-Jie; Li, Sen; Feng, Tian; Wang, Li-Ping; Jin, Tian-Bo; Hou, Peng

2015-06-14

To investigate the association between colorectal cancer (CRC) genetic susceptibility variants and esophageal cancer in a Chinese Han population. A case-control study was conducted including 360 esophageal cancer patients and 310 healthy controls. Thirty-one single-nucleotide polymorphisms (SNPs) associated with CRC risk from previous genome-wide association studies were analyzed. SNPs were genotyped using Sequenom Mass-ARRAY technology, and genotypic frequencies in controls were tested for departure from Hardy-Weinberg equilibrium using a Fisher's exact test. The allelic frequencies were compared between cases and controls using a χ(2) test. Associations between the SNPs and the risk of esophageal cancer were tested using various genetic models (codominant, dominant, recessive, overdominant, and additive). ORs and 95%CIs were calculated by unconditional logistic regression with adjustments for age and sex. The minor alleles of rs1321311 and rs4444235 were associated with a 1.53-fold (95%CI: 1.15-2.06; P = 0.004) and 1.28-fold (95%CI: 1.03-1.60; P = 0.028) increased risk of esophageal cancer in the allelic model analysis, respectively. In the genetic model analysis, the C/C genotype of rs3802842 was associated with a reduced risk of esophageal cancer in the codominant model (OR = 0.52, 95%CI: 0.31-0.88; P = 0.033) and recessive model (OR = 0.55, 95%CI: 0.34-0.87; P = 0.010). The rs4939827 C/T-T/T genotype was associated with a 0.67-fold (95%CI: 0.46-0.98; P = 0.038) decreased esophageal cancer risk under the dominant model. In addition, rs6687758, rs1321311, and rs4444235 were associated with an increased risk. In particular, the T/T genotype of rs1321311 was associated with an 8.06-fold (95%CI: 1.96-33.07; P = 0.004) increased risk in the codominant model. These results provide evidence that known genetic variants associated with CRC risk confer risk for esophageal cancer, and may bring risk for other digestive system tumors.

Cardiovascular Disease, Psychosocial Factors, and Genetics: The Case of Depression

PubMed Central

Mulle, Jennifer Gladys; Vaccarino, Viola

2013-01-01

Psychosocial factors are associated with cardiovascular disease, but little is known about the role of genetics in this relationship. Focusing on the well-studied phenotype of depression, current data show that there are shared genetic factors that may give rise to both depression and CVD, and these genetic risks appear to be modified by gender. This pleiotropic effect suggests that a single pathway, when perturbed, gives rise to the dual phenotypes of CVD and depression. The data also suggest that women contribute disproportionately to the depression-CVD comorbidity, and this unbalanced contribution is attributable, in part, to genetic factors. While the underlying biology behind this relationship is unclear, recent data support contributions from inflammatory or serotonergic pathways toward the comorbidity between CVD and depression. Even without knowledge of a specific mechanism, epidemiological observations offer new directions to explain the relationship between depression and CVD that have both research and clinical applications. PMID:23621965

[Genetic obesity: new diagnostic options].

PubMed

de Vries, T I; Alsters, S I M; Kleinendorst, L; van Haaften, G; van der Zwaag, B; Van Haelst, M M

2017-01-01

- Obesity is an important risk factor for morbidity and premature death, as well as a contributing factor to psychosocial problems. The incidence of obesity has increased dramatically over the last few decades.- Obesity is considered to be a multifactorial condition in which both environmental factors and genetic factors play a part.- In approximately 5% of patients with morbid obesity, a monogenic cause can be identified. Mutations in the MC4R gene are the most frequently occurring monogenic cause of obesity.- The department of Genetics at the VU University Medical Center Amsterdam offers morbidly obese patients a diagnostic analysis of 50 obesity-associated genes. - An underlying obesity-associated genetic defect can influence patient response to certain treatments. Therefore, if the gene defect is known, it can be taken into account when considering treatment options.- The understanding of the genetics of obesity will significantly contribute to research into the development of personalized treatment options.

Predicting evolutionary rescue via evolving plasticity in stochastic environments

PubMed Central

Baskett, Marissa L.

2016-01-01

Phenotypic plasticity and its evolution may help evolutionary rescue in a novel and stressful environment, especially if environmental novelty reveals cryptic genetic variation that enables the evolution of increased plasticity. However, the environmental stochasticity ubiquitous in natural systems may alter these predictions, because high plasticity may amplify phenotype–environment mismatches. Although previous studies have highlighted this potential detrimental effect of plasticity in stochastic environments, they have not investigated how it affects extinction risk in the context of evolutionary rescue and with evolving plasticity. We investigate this question here by integrating stochastic demography with quantitative genetic theory in a model with simultaneous change in the mean and predictability (temporal autocorrelation) of the environment. We develop an approximate prediction of long-term persistence under the new pattern of environmental fluctuations, and compare it with numerical simulations for short- and long-term extinction risk. We find that reduced predictability increases extinction risk and reduces persistence because it increases stochastic load during rescue. This understanding of how stochastic demography, phenotypic plasticity, and evolution interact when evolution acts on cryptic genetic variation revealed in a novel environment can inform expectations for invasions, extinctions, or the emergence of chemical resistance in pests. PMID:27655762

The Pathogenesis of Autoimmune Liver Disease.

PubMed

Arndtz, Katherine; Hirschfield, Gideon M

Autoimmune liver disease (AILD) encompasses 3 main distinct clinical diseases: autoimmune hepatitis, primary biliary cholangitis (formally known as cirrhosis, PBC) and primary sclerosing cholangitis (PSC). These conditions are an important, yet under-appreciated cause of patient morbidity and mortality with ongoing unmet needs for further research and clinical advances. There is observational evidence for genetic predisposition, with all 3 conditions being more common in first degree relatives. AILD is associated with the presence of auto-antibodies and higher risks of other non-hepatic auto-immune conditions. Genetic risk association studies have identified HLA and non-HLA risk loci for the development of disease, with some HLA loci providing prognostic information. This re-enforces the concept that genetic predisposition to autoimmunity is important, likely in the context of environmental exposures. Such environmental triggers are unclear but relevant risks include smoking, drug and xenobiotic exposure as well as the complexities of the microbiome. There is evidence for a loss of immune tolerance to self-antigens playing a part in the development of these conditions. In particular the IL-2 and IL-12 regulatory pathways have been implicated in pre-disposing to an unopposed inflammatory response within the liver. Main immunological themes revolve around loss of immune tolerance leading to T-cell mediated injury, imbalance in the regulation of immune cells and defective immune response to foreign antigens. For PBC and PSC, there is then the added complexity of the consequences of cholestasis on hepato-biliary injury, immune regulation and liver fibrosis. Whilst specific disease causes and triggers are still lacking, AILD arises on the background of collective genetic and environmental risk, leading to chronic and abnormal hepato-biliary immune responses. Effective and more rational therapy will ultimately be developed when the multiple pathways to liver injury are better understood. © 2016 S. Karger AG, Basel.

Gender differences in the induction of chromosomal aberrations and gene mutations in rodent germ cells

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

Adler, Ilse-Dore; Carere, Angelo; Eichenlaub-Ritter, Ursula

2007-05-15

Germ cell mutagenicity testing provides experimental data to quantify genetic risk for exposed human populations. The majority of tests are performed with exposure of males, and female data are relatively rare. The reason for this paucity lies in the differences between male and female germ cell biology. Male germ cells are produced throughout reproductive life and all developmental stages can be ascertained by appropriate breeding schemes. In contrast, the female germ cell pool is limited, meiosis begins during embryogenesis and oocytes are arrested over long periods of time until maturation processes start for small numbers of oocytes during the oestrusmore » cycle in mature females. The literature data are reviewed to point out possible gender differences of germ cells to exogenous agents such as chemicals or ionizing radiation. From the limited information, it can be concluded that male germ cells are more sensitive than female germ cells to the induction of chromosomal aberrations and gene mutations. However, exceptions are described which shed doubt on the extrapolation of experimental data from male rodents to the genetic risk of the human population. Furthermore, the female genome may be more sensitive to mutation induction during peri-conceptional stages compared to the male genome of the zygote. With few exceptions, germ cell experiments have been carried out under high acute exposure to optimize the effects and to compensate for the limited sample size in animal experiments. Human exposure to environmental agents, on the other hand, is usually chronic and involves low doses. Under these conditions, gender differences may become apparent that have not been studied so far. Additionally, data are reviewed that suggest a false impression of safety when responses are negative under high acute exposure of male rodents while a mutational response is induced by low chronic exposure. The classical (morphological) germ cell mutation tests are not performed anymore because they are animal and time consuming. Nevertheless, information is needed to place genetic risk extrapolations on more solid grounds and thereby to prevent an increased genetic burden to future generations. It is pointed out that modern molecular methodologies are available now to experimentally address the open questions.« less

Genetic determinants of heart failure: facts and numbers.

PubMed

Czepluch, Frauke S; Wollnik, Bernd; Hasenfuß, Gerd

2018-06-01

The relevance of gene mutations leading to heart diseases and hence heart failure has become evident. The risk for and the course of heart failure depends on genomic variants and mutations underlying the so-called genetic predisposition. Genetic contribution to heart failure is highly heterogenous and complex. For any patient with a likely inherited heart failure syndrome, genetic counselling is recommended and important. In the last few years, novel sequencing technologies (named next-generation sequencing - NGS) have dramatically improved the availability of molecular testing, the efficiency of genetic analyses, and moreover reduced the cost for genetic testing. Due to this development, genetic testing has become increasingly accessible and NGS-based sequencing is now applied in clinical routine diagnostics. One of the most common reasons of heart failure are cardiomyopathies such as the dilated or the hypertrophic cardiomyopathy. Nearly 100 disease-associated genes have been identified for cardiomyopathies. The knowledge of a pathogenic mutation can be used for genetic counselling, risk and prognosis determination, therapy guidance and hence for a more effective treatment. Besides, family cascade screening for a known familial, pathogenic mutation can lead to an early diagnosis in affected individuals. At that timepoint, a preventative intervention could be used to avoid or delay disease onset or delay disease progression. Understanding the cellular basis of genetic heart failure syndromes in more detail may provide new insights into the molecular biology of physiological and impaired cardiac (cell) function. As our understanding of the molecular and genetic pathophysiology of heart failure will increase, this might help to identify novel therapeutic targets and may lead to the development of new and specific treatment options in patients with heart failure. © 2018 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.

Hopes and Expectations Regarding Genetic Testing for Schizophrenia Among Young Adults at Clinical High-Risk for Psychosis.

PubMed

Friesen, Phoebe; Lawrence, Ryan E; Brucato, Gary; Girgis, Ragy R; Dixon, Lisa

2016-11-01

Genetic tests for schizophrenia could introduce both risks and benefits. Little is known about the hopes and expectations of young adults at clinical high-risk for psychosis concerning genetic testing for schizophrenia, despite the fact that these youth could be among those highly affected by such tests. We conducted semistructured interviews with 15 young adults at clinical high-risk for psychosis to ask about their interest, expectations, and hopes regarding genetic testing for schizophrenia. Most participants reported a high level of interest in genetic testing for schizophrenia, and the majority said they would take such a test immediately if it were available. Some expressed far-reaching expectations for a genetic test, such as predicting symptom severity and the timing of symptom onset. Several assumed that genetic testing would be accompanied by interventions to prevent schizophrenia. Participants anticipated mixed reactions on finding out they had a genetic risk for schizophrenia, suggesting that they might feel both a sense of relief and a sense of hopelessness. We suggest that genetic counseling could play an important role in counteracting a culture of genetic over-optimism and helping young adults at clinical high-risk for psychosis understand the limitations of genetic testing. Counseling sessions could also invite individuals to explore how receiving genetic risk information might impact their well-being, as early evidence suggests that some psychological factors help individuals cope, whereas others heighten distress related to genetic test results.

Cancer Genetics Risk Assessment and Counseling (PDQ®)—Health Professional Version

Cancer.gov

Cancer genetics risk assessment and genetic counseling includes family history, psychosocial assessments, and education on hereditary cancer syndromes, testing, and risk. Get more information including the ethical, legal, and social implications of genetic testing in this summary for clinicians.

Frailty Models for Familial Risk with Application to Breast Cancer.

PubMed

Gorfine, Malka; Hsu, Li; Parmigiani, Giovanni

2013-12-01

In evaluating familial risk for disease we have two main statistical tasks: assessing the probability of carrying an inherited genetic mutation conferring higher risk; and predicting the absolute risk of developing diseases over time, for those individuals whose mutation status is known. Despite substantial progress, much remains unknown about the role of genetic and environmental risk factors, about the sources of variation in risk among families that carry high-risk mutations, and about the sources of familial aggregation beyond major Mendelian effects. These sources of heterogeneity contribute substantial variation in risk across families. In this paper we present simple and efficient methods for accounting for this variation in familial risk assessment. Our methods are based on frailty models. We implemented them in the context of generalizing Mendelian models of cancer risk, and compared our approaches to others that do not consider heterogeneity across families. Our extensive simulation study demonstrates that when predicting the risk of developing a disease over time conditional on carrier status, accounting for heterogeneity results in a substantial improvement in the area under the curve of the receiver operating characteristic. On the other hand, the improvement for carriership probability estimation is more limited. We illustrate the utility of the proposed approach through the analysis of BRCA1 and BRCA2 mutation carriers in the Washington Ashkenazi Kin-Cohort Study of Breast Cancer.

Modifiable pathways in Alzheimer's disease: Mendelian randomisation analysis.

PubMed

Larsson, Susanna C; Traylor, Matthew; Malik, Rainer; Dichgans, Martin; Burgess, Stephen; Markus, Hugh S

2017-12-06

To determine which potentially modifiable risk factors, including socioeconomic, lifestyle/dietary, cardiometabolic, and inflammatory factors, are associated with Alzheimer's disease. Mendelian randomisation study using genetic variants associated with the modifiable risk factors as instrumental variables. International Genomics of Alzheimer's Project. 17 008 cases of Alzheimer's disease and 37 154 controls. Odds ratio of Alzheimer's per genetically predicted increase in each modifiable risk factor estimated with Mendelian randomisation analysis. This study included analyses of 24 potentially modifiable risk factors. A Bonferroni corrected threshold of P=0.002 was considered to be significant, and P<0.05 was considered suggestive of evidence for a potential association. Genetically predicted educational attainment was significantly associated with Alzheimer's. The odds ratios were 0.89 (95% confidence interval 0.84 to 0.93; P=2.4×10 -6 ) per year of education completed and 0.74 (0.63 to 0.86; P=8.0×10 -5 ) per unit increase in log odds of having completed college/university. The correlated trait intelligence had a suggestive association with Alzheimer's (per genetically predicted 1 SD higher intelligence: 0.73, 0.57 to 0.93; P=0.01). There was suggestive evidence for potential associations between genetically predicted higher quantity of smoking (per 10 cigarettes a day: 0.69, 0.49 to 0.99; P=0.04) and 25-hydroxyvitamin D concentrations (per 20% higher levels: 0.92, 0.85 to 0.98; P=0.01) and lower odds of Alzheimer's and between higher coffee consumption (per one cup a day: 1.26, 1.05 to 1.51; P=0.01) and higher odds of Alzheimer's. Genetically predicted alcohol consumption, serum folate, serum vitamin B 12 , homocysteine, cardiometabolic factors, and C reactive protein were not associated with Alzheimer's disease. These results provide support that higher educational attainment is associated with a reduced risk of Alzheimer's disease. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Mapping genes underlying ethnic differences in disease risk by linkage disequilibrium in recently admixed populations.

PubMed Central

McKeigue, P M

1997-01-01

Where recent admixture has occurred between two populations that have different disease rates for genetic reasons, family-based association studies can be used to map the genes underlying these differences, if the ancestry of the alleles at each locus examined can be assigned to one of the two founding populations. This article explores the statistical power and design requirements of this approach. Markers suitable for assigning the ancestry of genomic regions could be defined by grouping alleles at closely spaced microsatellite loci into haplotypes, or generated by representational difference analysis. For a given relative risk between populations, the sample size required to detect a disease locus that accounts for this relative risk by linkage-disequilibrium mapping in an admixed population is not critically dependent on assumptions about genotype penetrances or allele frequencies. Using the transmission-disequilibrium test to search the genome for a locus that accounts for a relative risk of between 2 and 3 in a high-risk population, compared with a low-risk population, generally requires between 150 and 800 case-parent pairs of mixed descent. The optimal strategy is to conduct an initial study using markers spaced at < or = 10 cM with cases from the second and third generations of mixed descent, and then to map the disease loci more accurately in a subsequent study of a population with a longer history of admixture. This approach has greater statistical power than allele-sharing designs and has obvious applications to the genetics of hypertension, non-insulin-dependent diabetes, and obesity. PMID:8981962

Mechanisms underlying cellular responses of cells from haemopoietic tissue to low

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

Kadhim, Munira A

2012-08-22

The above studies will provide fundamental mechanistic information relating genetic predisposition to important low dose phenomena, and will aid in the development of Department of Energy policy, as well as radiation risk policy for the public and the workplace. We believe the proposed studies accurately reflect the goals of the DOE low dose program. To accurately define the risks associated with human exposure to relevant environmental doses of low LET ionizing radiation, it is necessary to completely understand the biological effects at very low doses (i.e. less than 0.1 Gy), including the lowest possible dose, that of a single electronmore » track traversal. At such low doses, a range of studies have shown responses in biological systems which are not related to the direct interaction of radiation tracks with DNA. The role of these "non-targeted responses in critical tissues is poorly understood and little is known regarding the underlying mechanisms. Although critical for dosimetry and risk assessment, the role of individual genetic susceptibility in radiation risk is not satisfactorily defined at present. The aim of the proposed grant is to critically evaluate non-targeted effects of ionizing radiation with a focus on the induction of genomic instability (GI) in key stem cell populations from haemopoietic tissue. Using stem cells from two mouse strains (CBA/CaH and C57BL/6J) known to differ in their susceptibility to radiation effects, we plan to carefully dissect the role of genetic predisposition in these models on genomic instability. We will specifically focus on the effects of low doses of low LET radiation, down to the dose of 10mGy (0.01Gy) X-rays. Using conventional X-ray and we will be able to assess the role of genetic variation under various conditions at a range of doses down to the very low dose of 0.01Gy. Irradiations will be carried out using facilities in routine operation for such studies. Mechanistic studies of instability in different cell lineages will include the role of cytokines which have been shown to be in the initiation of instability. These studies also aim to uncover the possible mechanism of the initiation, perpetuation and delayed pathways of the instability response using relevant biological endpoints i.e. chromosomal instability, apoptosis induction, cytokine and gene array analysis. Integral to these studies will be an assessment of the role of genetic susceptibility in these responses, using CBA/CaH and C57BL/6J mice. The overall results suggest that low dose low LET X-irradiation induced delayed GI in both CBA/CaH and C57BL/6J haemopoeitic tissue. Using several biological approaches, some key strain and dose-specific differences have been identified in radiation-induced signalling in the initiation and perpetuation of the instability process. Furthermore, the induction of non-targeted radiation effects and genetic dependency may be linked to the use of alternative signalling pathways and mechanisms which have potential implications on evaluation of non-targeted effects in radiation risk assessment.« less

Knowledge and expectations of women undergoing cancer genetic risk assessment: a qualitative analysis of free-text questionnaire comments.

PubMed

Phelps, C; Wood, F; Bennett, P; Brain, K; Gray, J

2007-08-01

Individuals undergoing cancer genetic risk assessment have been found to have a poor understanding of the process, which may affect how well they cope with learning their risk. This paper reports free-text data from questionnaires completed by women undergoing a randomised controlled trial of a psychological intervention. Of the 268 women undergoing genetic assessment for familial breast/ovarian cancer risk who were invited to take part in the trial, 157 women returned research questionnaires. Of these, 97 women provided free-text comments upon referral to a cancer genetics clinic, 62 provided comments whilst waiting for risk information (average, moderate or high), and 36 women provided comments following notification of risk. This paper reports a thematic analysis of the free-text data. Themes reflected individuals' poor knowledge and uncertainty about genetic risk assessment. How well individuals responded to learning their risk depended upon whether expectations had been met. Regardless of risk, individuals undergoing cancer genetic risk assessment are likely to benefit from increased information about its process and timescales, and access to increased psychological support. Free-text comments can provide valuable data about individuals' expectations and knowledge of genetics services.

New technologies provide insights into genetic basis of psychiatric disorders and explain their co-morbidity.

PubMed

Rudan, Igor

2010-06-01

The completion of Human Genome Project and the "HapMap" project was followed by translational activities from companies within the private sector. This led to the introduction of genome-wide scans based on hundreds of thousands of single nucleotide polymorphysms (SNP). These scans were based on common genetic variants in human populations. This new and powerful technology was then applied to the existing DNA-based datasets with information on psychiatric disorders. As a result, an unprecedented amount of novel scientific insights related to the underlying biology and genetics of psychiatric disorders was obtained. The dominant design of these studies, so called "genome-wide association studies" (GWAS), used statistical methods which minimized the risk of false positive reports and provided much greater power to detect genotype-phenotype associations. All findings were entirely data-driven rather than hypothesis-driven, which often made it difficult for researchers to understand or interpret the findings. Interestingly, this work in genetics is indicating how non-specific some genes are for psychiatric disorders, having associations in common for schizophrenia, bipolar disorder and autism. This suggests that the earlier stages of psychiatric disorders may be multi-valent and that early detection, coupled with a clearer understanding of the environmental factors, may allow prevention. At the present time, the rich "harvest" from GWAS still has very limited power to predict the variation in psychiatric disease status at individual level, typically explaining less than 5% of the total risk variance. The most recent studies of common genetic variation implicated the role of major histocompatibility complex in schizophrenia and other disorders. They also provided molecular evidence for a substantial polygenic component to the risk of psychiatric diseases, involving thousands of common alleles of very small effect. The studies of structural genetic variation, such as copy number variants (CNV), coupled with the efforts targeting rare genetic variation (using the emerging whole-genome "deep" sequencing technologies) will become the area of the greatest interest in the field of genetic epidemiology. This will be complemented by the studies of epigenetic phoenomena, changes of expression at a large scale and understanding gene-gene interactions in complex networks using systems biology approaches. A deeper understanding of the underlying biology of psychiatric disorders is essential to improve diagnoses and therapies of these diseases. New technologies - genome-wide association studies, imaging and the optical manipulation of neural circuits - are promising to provide novel insights and lead to new treatments.

A survey of genetic counselors about the needs of 18-25 year olds from families with hereditary breast and ovarian cancer syndrome.

PubMed

Werner-Lin, Allison; Ratner, Rachel; Hoskins, Lindsey M; Lieber, Caroline

2015-02-01

As a result of modern treatments, the life of women who test positive for BRCA mutations may be plotted along the arc of preventive medicine rather than the slope of diagnostics. Despite evidence supporting the benefits of risk reduction, protocols for early detection and prevention among women from families affected by hereditary breast and ovarian cancer (HBOC) are not yet proven, and clinical trials have not been undertaken for patients aged 18 to 25. The absence of psychosocial data may leave genetic counselors without uniform guidance on how to manage the care of these patients. This project sought to investigate perspectives on counseling 18-25 year-old patients from families with hereditary cancer syndromes, with specific emphasis on HBOC, given their unique developmental, familial, and medical challenges. Certified genetic counselors were recruited through the NSGC's Cancer Genetics Special Interest Group listserv. Researchers constructed an online survey which included 41 items and elicited information about: counselor demographics, training, and practice settings; approaches to cancer risk assessment; and common challenges in work with 18- to 25-year-old patients. The survey was also informed by previous work by researchers with 18 to 25-year-olds with BRCA gene mutations. Eighty-six surveys were completed. Researchers used a combination of grounded theory and content analysis for open-ended responses, supported and triangulated with statistical analysis to maximize the interpretation of data. Genetic counselors who responded to this survey experience 18-25 year old patients presenting for cancer risk assessment differently than older patients, and some reported adapting their counseling style to address these differences. Respondents differed in the extent to which they felt well-versed in the developmental needs of patients in this age group. Respondents aged 39 and under reported feeling familiar with this stage in life, having more recently completed it; respondents aged 40 and over reported they were less familiar with, and more interested in learning about, this age group. A primary challenge in cancer risk assessment of these patients, reported primarily by counselors aged 39 and under, is navigating family dynamics in counseling sessions and addressing the developmentally labile young adult. With respect to BRCA-related cancer risk, where penetrance is incomplete, onset in early adulthood is rare. Evidence-based treatment/prevention options exist, but providers may not have clarity regarding how or when to provide directive counsel. A rich understanding of the themes inherent in how people grow and change over time might enhance the counselor's capacity to assess patients and their family members. The integration of a developmental approach to genetic counseling has the potential to reduce the imperative for non-directive counseling.

Explanatory Models of Genetics and Genetic Risk among a Selected Group of Students.

PubMed

Goltz, Heather Honoré; Bergman, Margo; Goodson, Patricia

2016-01-01

This exploratory qualitative study focuses on how college students conceptualize genetics and genetic risk, concepts essential for genetic literacy (GL) and genetic numeracy (GN), components of overall health literacy (HL). HL is dependent on both the background knowledge and culture of a patient, and lower HL is linked to increased morbidity and mortality for a number of chronic health conditions (e.g., diabetes and cancer). A purposive sample of 86 students from three Southwestern universities participated in eight focus groups. The sample ranged in age from 18 to 54 years, and comprised primarily of female (67.4%), single (74.4%), and non-White (57%) participants, none of whom were genetics/biology majors. A holistic-content approach revealed broad categories concerning participants' explanatory models (EMs) of genetics and genetic risk. Participants' EMs were grounded in highly contextualized narratives that only partially overlapped with biomedical models. While higher education levels should be associated with predominately knowledge-based EM of genetic risk, this study shows that even in well-educated populations cultural factors can dominate. Study findings reveal gaps in how this sample of young adults obtains, processes, and understands genetic/genomic concepts. Future studies should assess how individuals with low GL and GN obtain and process genetics and genetic risk information and incorporate this information into health decision making. Future work should also address the interaction of communication between health educators, providers, and genetic counselors, to increase patient understanding of genetic risk.

Genetic predisposition to higher blood pressure increases risk of incident hypertension and cardiovascular diseases in Chinese.

PubMed

Lu, Xiangfeng; Huang, Jianfeng; Wang, Laiyuan; Chen, Shufeng; Yang, Xueli; Li, Jianxin; Cao, Jie; Chen, Jichun; Li, Ying; Zhao, Liancheng; Li, Hongfan; Liu, Fangcao; Huang, Chen; Shen, Chong; Shen, Jinjin; Yu, Ling; Xu, Lihua; Mu, Jianjun; Wu, Xianping; Ji, Xu; Guo, Dongshuang; Zhou, Zhengyuan; Yang, Zili; Wang, Renping; Yang, Jun; Yan, Weili; Gu, Dongfeng

2015-10-01

Although multiple genetic markers associated with blood pressure have been identified by genome-wide association studies, their aggregate effect on risk of incident hypertension and cardiovascular disease is uncertain, particularly among East Asian who may have different genetic and environmental exposures from Europeans. We aimed to examine the association between genetic predisposition to higher blood pressure and risk of incident hypertension and cardiovascular disease in 26 262 individuals in 2 Chinese population-based prospective cohorts. A genetic risk score was calculated based on 22 established variants for blood pressure in East Asian. We found the genetic risk score was significantly and independently associated with linear increases in blood pressure and risk of incident hypertension and cardiovascular disease (P range from 4.57×10(-3) to 3.10×10(-6)). In analyses adjusted for traditional risk factors including blood pressure, individuals carrying most blood pressure-related risk alleles (top quintile of genetic score distribution) had 40% (95% confidence interval, 18-66) and 26% (6-45) increased risk for incident hypertension and cardiovascular disease, respectively, when compared with individuals in the bottom quintile. The genetic risk score also significantly improved discrimination for incident hypertension and cardiovascular disease and led to modest improvements in risk reclassification for cardiovascular disease (all the P<0.05). Our data indicate that genetic predisposition to higher blood pressure is an independent risk factor for blood pressure increase and incident hypertension and cardiovascular disease and provides modest incremental information to cardiovascular disease risk prediction. The potential clinical use of this panel of blood pressure-associated polymorphisms remains to be determined. © 2015 American Heart Association, Inc.

Alerting the general population to genetic risks: the value of health messages communicating the existence of genetic risk factors for public health promotion.

PubMed

Smerecnik, Chris M R; Mesters, Ilse; de Vries, Nanne K; de Vries, Hein

2009-11-01

Health messages alerting the public to previously unknown genetic risk factors for multifactorial diseases are a potentially useful strategy to create public awareness, and may be an important first step in promoting public health. However, there is a lack of evidence-based insight into its impact on individuals who were unaware of the existence of genetic risk factors at the moment of information exposure. The authors conducted 3 experimental studies with health messages communicating information about genetic risk factors for salt sensitivity (Studies 1A and 1B) and heightened cholesterol (Study 2) compared with general information without reference to genetic risk factors as a between-subjects variable and risk perception and intention to engage in preventive behavior as dependent variables. All 3 studies revealed lower perceived susceptibility among participants who received information on genetic risk factors, which was associated with lowered intentions to engage in preventive behavior. In Studies 1A and 1B, these effects were observed only for previously unaware individuals, whereas in Study 2, they were observed for the entire sample. Alerting the public to the existence of genetic risk factors may not necessarily be beneficial to public health. Public health promoters should be aware of the possible adverse effects of alerting the general population to genetic risk factors, and should simultaneously educate the public about the meaning and consequences of such factors. PsycINFO Database Record (c) 2009 APA, all rights reserved.

Polygenic Risk, Appetite Traits, and Weight Gain in Middle Childhood: A Longitudinal Study.

PubMed

Steinsbekk, Silje; Belsky, Daniel; Guzey, Ismail Cuneyt; Wardle, Jane; Wichstrøm, Lars

2016-02-01

Genome-wide association studies have identified genetic risks for obesity. These genetic risks influence development of obesity partly by accelerating weight gain in childhood. Research is needed to identify mechanisms to inform intervention. Cross-sectional studies suggest appetite traits as a candidate mechanism. Longitudinal studies are needed to test whether appetite traits mediate genetic influences on children's weight gain. To test whether genetic risk for obesity predicts accelerated weight gain in middle childhood (ages 4-8 years) and whether genetic association with accelerated weight gain is mediated by appetite traits. Longitudinal study of a representative birth cohort at the Trondheim Early Secure Study, Trondheim, Norway, enrolled at age 4 years during 2007 to 2008, with follow-ups at ages 6 and 8 years. Participants were sampled from all children born in 2003 or 2004 who attended regular community health checkups for 4-year-olds (97.2% attendance; 82.0% consent rate, n = 2475). Nine hundred ninety-five children participated at age 4 years, 795 at age 6 years, and 699 at age 8 years. Analyses included 652 children with genotype, adiposity, and appetite data. Outcomes were body mass index and body-fat phenotypes measured from anthropometry (ages 4, 6, and 8 years) and bioelectrical impedance (ages 6 and 8 years). Genetic risk for obesity was measured using a genetic risk score composed of 32 single-nucleotide polymorphisms previously discovered in genome-wide association studies of adult body mass index. Appetite traits were measured at age 6 years with the Children's Eating Behavior Questionnaire. Of the 652 genotyped child participants, 323 (49.5%) were female, 58 (8.9%) were overweight, and 1 (0.2%) was obese. Children at higher genetic risk for obesity had higher baseline body mass index and fat mass compared with lower genetic risk peers, and they gained weight and fat mass more rapidly during follow-up. Each SD increase in genetic risk score was associated with a 0.22-point increase in BMI at age-4 baseline (for the intercept, unstandardized path coefficient B = 0.22 [95% CI, 0.06-0.38]; P = .008. Children with higher genetic risk scores also gained BMI points more rapidly from ages 4 to 6 years (B = 0.11 [95% CI, 0.03-0.20]; P = .01 ; β = 0.12) and from 6 to 8 years (B = 0.09 [95% CI, 0.00-0.19]; P = .05; β = 0.10), compared with their lower genetic risk peers. Children at higher genetic risk had higher levels of alleged obesogenic appetite traits than peers with lower genetic risk at age 6 years, but appetite traits did not mediate genetic associations with weight gain. The sum of the 5 indirect effects was B = -0.001 (95% CI, -0.02 -0.01); P = .86; β = 0.00. Genetic risk for obesity is associated with accelerated childhood weight gain. Interventions targeting childhood weight gain may provide one path to mitigating genetic risk. However, middle childhood appetite traits may not be a promising target for such interventions. Studies of early-childhood samples are needed to test whether appetite traits explain how genetic risks accelerate growth earlier in development.

Determining causes of genetic isolation in a large carnivore (Ursus americanus) population to direct contemporary conservation measures

PubMed Central

Obbard, Martyn E.; Harnden, Matthew; McConnell, Sabine; Howe, Eric J.; Burrows, Frank G.; White, Bradley N.; Kyle, Christopher J.

2017-01-01

The processes leading to genetic isolation influence a population’s local extinction risk, and should thus be identified before conservation actions are implemented. Natural or human-induced circumstances can result in historical or contemporary barriers to gene flow and/or demographic bottlenecks. Distinguishing between these hypotheses can be achieved by comparing genetic diversity and differentiation in isolated vs. continuous neighboring populations. In Ontario, American black bears (Ursus americanus) are continuously distributed, genetically diverse, and exhibit an isolation-by-distance structuring pattern, except on the Bruce Peninsula (BP). To identify the processes that led to the genetic isolation of BP black bears, we modelled various levels of historical and contemporary migration and population size reductions using forward simulations. We compared simulation results with empirical genetic indices from Ontario black bear populations under different levels of geographic isolation, and conducted additional simulations to determine if translocations could help achieve genetic restoration. From a genetic standpoint, conservation concerns for BP black bears are warranted because our results show that: i) a recent demographic bottleneck associated with recently reduced migration best explains the low genetic diversity on the BP; and ii) under sustained isolation, BP black bears could lose between 70% and 80% of their rare alleles within 100 years. Although restoring migration corridors would be the most effective method to enhance long-term genetic diversity and prevent inbreeding, it is unrealistic to expect connectivity to be re-established. Current levels of genetic diversity could be maintained by successfully translocating 10 bears onto the peninsula every 5 years. Such regular translocations may be more practical than landscape restoration, because areas connecting the peninsula to nearby mainland black bear populations have been irreversibly modified by humans, and form strong barriers to movement. PMID:28235066

Genetic variants in oxytocin receptor gene (OXTR) and childhood physical abuse collaborate to modify the risk of aggression in chinese adolescents.

PubMed

Zhang, Yanmei; Wu, Chunxia; Chang, Hongjuan; Yan, Qiuge; Wu, Linguo; Yuan, Shanshan; Xiang, Jingjing; Hao, Wen; Yu, Yizhen

2018-03-15

Accumulating evidence suggests that genetic and environmental factors may influence aggression susceptibility. However, the etiology of aggressive behavior remains unknown. Compared to some extensively studied candidate genes of aggression, very little is known about the OXTR gene. The objective of this study was to determine whether OXTR genetic variants were associated with aggression risk and whether these polymorphisms showed interactive effects with childhood maltreatment on aggression in Chinese adolescents. A total of 996 participants including 488 cases and 488 controls were selected in our study. Aggression, childhood maltreatment were measured by self-reported questionnaire. Buccal cells were collected. Genotyping was performed using SNPscan. Logistic regressions were used to estimate both main effects of OXTR polymorphisms and the interactive effects with childhood maltreatment on aggressive behavior. Participants who carried the rs237885 TT genotypes in OXTR had a higher risk of aggression compared to those who carried GG or GT genotypes under the recessive model (OR=1.40, 95% CI, 1.04-1.89) after controlling for potential confounders. In addition, we also found that the polymorphism had a synergic additive interaction with childhood physical abuse on the aggression risk. The subjects in the present study were only males, thus our findings and conclusions could not be generalized to females. The present study provides evidence that OXTR genetic variants may contribute to aggression susceptibility. Moreover, this is the first study reporting significant interactive effects of OXTR polymorphism and childhood physical abuse on aggressive behavior in Chinese adolescents. Copyright © 2018 Elsevier B.V. All rights reserved.

Common genetic variants are significant risk factors for early menopause: results from the Breakthrough Generations Study.

PubMed

Murray, Anna; Bennett, Claire E; Perry, John R B; Weedon, Michael N; Jacobs, Patricia A; Morris, Danielle H; Orr, Nicholas; Schoemaker, Minouk J; Jones, Michael; Ashworth, Alan; Swerdlow, Anthony J

2011-01-01

Women become infertile approximately 10 years before menopause, and as more women delay childbirth into their 30s, the number of women who experience infertility is likely to increase. Tests that predict the timing of menopause would allow women to make informed reproductive decisions. Current predictors are only effective just prior to menopause, and there are no long-range indicators. Age at menopause and early menopause (EM) are highly heritable, suggesting a genetic aetiology. Recent genome-wide scans have identified four loci associated with variation in the age of normal menopause (40-60 years). We aimed to determine whether theses loci are also risk factors for EM. We tested the four menopause-associated genetic variants in a cohort of approximately 2000 women with menopause≤45 years from the Breakthrough Generations Study (BGS). All four variants significantly increased the odds of having EM. Comparing the 4.5% of individuals with the lowest number of risk alleles (two or three) with the 3.0% with the highest number (eight risk alleles), the odds ratio was 4.1 (95% CI 2.4-7.1, P=4.0×10(-7)). In combination, the four variants discriminated EM cases with a receiver operator characteristic area under the curve of 0.6. Four common genetic variants identified by genome-wide association studies, had a significant impact on the odds of having EM in an independent cohort from the BGS. The discriminative power is still limited, but as more variants are discovered they may be useful for predicting reproductive lifespan.

BRCA1 genetic mutation and its link to ovarian cancer: implications for advanced practice nurses.

PubMed

Brunsvold, Amy N; Wung, Shu-Fen; Merkle, Carrie J

2005-12-01

The purpose of this paper is to review (a) the linkage between the BRCA1 gene and ovarian cancer and (b) BRCA1 testing and its related issues. This review is aimed for nurse practitioners (NPs), who may be in positions to identify those at risk for BRCA1-associated ovarian cancer and to assist patients with related issues. Data sources include reviews and original research from scholarly journals and Internet sites. Ovarian cancer is a deadly disease. Identification of those at risk because of BRCA1 mutation is possible through genetic testing. Testing for BRCA1 gene mutations has many implications whether results are positive or negative. Those with positive results will be faced with decisions regarding the best management strategies. Negative results do not completely eliminate ovarian cancer risk. Current management options for carriers of the BRCA1 mutation include taking no action, increasing surveillance for ovarian cancer, and chemoprevention with oral contraceptives or prophylactic oophorectomy for those who have completed childbearing. It is essential that NPs have knowledge underlying the issues and concerns of patients and their families at risk for BRCA1-associated ovarian cancer. NPs are in a unique position to help identify BRCA1 mutation carriers and to assist them and their families with the complex issues involving genetic testing and management options. Understanding these issues will allow NPs to give appropriate care that may include making appropriate referrals to certified genetic counselors and having balanced discussions on treatment options. Such measurements may improve early diagnosis of ovarian cancer and increase survival from this disease.

Motivational state and reward content determine choice behavior under risk in mice.

PubMed

Leblond, Mona; Fan, David; Brynildsen, Julia K; Yin, Henry H

2011-01-01

Risk is a ubiquitous feature of the environment for most organisms, who must often choose between a small and certain reward and a larger but less certain reward. To study choice behavior under risk in a genetically well characterized species, we trained mice (C57BL/6) on a discrete trial, concurrent-choice task in which they must choose between two levers. Pressing one lever (safe choice) is always followed by a small reward. Pressing the other lever (risky choice) is followed by a larger reward, but only on some of the trials. The overall payoff is the same on both levers. When mice were not food deprived, they were indifferent to risk, choosing both levers with equal probability regardless of the level of risk. In contrast, following food or water deprivation, mice earning 10% sucrose solution were risk-averse, though the addition of alcohol to the sucrose solution dose-dependently reduced risk aversion, even before the mice became intoxicated. Our results falsify the budget rule in optimal foraging theory often used to explain behavior under risk. Instead, they suggest that the overall demand or desired amount for a particular reward determines risk preference. Changes in motivational state or reward identity affect risk preference by changing demand. Any manipulation that increases the demand for a reward also increases risk aversion, by selectively increasing the frequency of safe choices without affecting frequency of risky choices.

Lifestyle Risk Factors Among People Who Have Had Cancer Genetic Testing.

PubMed

Quillin, John M

2016-10-01

Hereditary cancer genetic counseling often focuses on medically intensive risk-reduction strategies, like imaging and risk-reducing surgeries. Lifestyle factors also influence cancer risk, but health behavior counseling is not common in genetic counseling. Information about typical lifestyle risk factors among patients seeking hereditary cancer risk is sparse. The current study describes cancer risk-relevant lifestyle factors for people who have had cancer genetic testing. Data came from the Health Information National Trends Survey (HINTS 4) collected in 2013. Analytic variables represented American Cancer Society nutrition and physical activity guidelines. Lifestyle factors were assessed for people who had undergone testing for BRCA1, BRCA2, or Lynch Syndrome genes. Among 3016 HINTS respondents, 135 had cancer genetic testing. Of these, 58 % were overweight or obese. Eighteen percent reported no moderate-intensity physical activity. Average sedentary screen-time was 3.4 h (SE = 0.472) daily. Sixty-three percent drank non-diet soda, and 23 % of these people drank soda every day. Between 18 and 36 % consumed less than 2 ½ cups fruits/vegetables daily. Twenty-four percent were current smokers. Lifestyle risk factors were not different between people who had genetic testing and those who had not. In conclusion, most people who had genetic testing for cancer susceptibility have at least one modifiable risk factor. Genetic counselors have opportunities to impact a counselee's cancer risk not only through risk-tailored medical procedures, but also through lifestyle modification recommendations. Results of the current study may foster a broader discussion of genetic counselors' roles in healthy lifestyle education.

Arranging marriage; negotiating risk: genetics and society in Qatar.

PubMed

Kilshaw, Susie; Al Raisi, Tasneem; Alshaban, Fouad

2015-01-01

This paper considers how the globalized discourse of genetic risk in cousin marriage is shaped, informed and taken up in local moral worlds within the context of Qatar. This paper investigates the way Qataris are negotiating the discourse on genetics and risk. It is based on data from ongoing ethnographic research in Qatar and contributes to anthropological knowledge about this understudied country. Participants were ambivalent about genetic risks and often pointed to other theories of causation in relation to illness and disability. The discourse on genetic risk associated with marrying in the family was familiar, but for some participants the benefits of close marriage outweighed potential risks. Furthermore, the introduction of mandatory pre-marital screening gave participants confidence that risks were monitored and minimized.

Plasticity as Phenotype: G x E Interaction in a Freshwater Snail

NASA Astrophysics Data System (ADS)

Brunkow, P. E.; Calloway, S. A.

2005-05-01

Plasticity in morphological development allows species to accommodate environmental variation experienced during growth; however, genetic variation for phenotypic plasticity per se has been relatively under-studied. We utilized the well-documented plastic response of shell development to predator cues in a freshwater snail to quantify genetic variation for plasticity in growth rate and shell shape. Field-caught pairs of snails reproduced in the laboratory to create families of full siblings, which were then divided and allowed to grow in control and predator cue treatments. Predator (crayfish) cues had significant effects on both size-corrected growth rate and shell shape; family identity also significantly affected both final shell shape and growth rate. The interaction between predator treatment and family identity significantly affected snail growth rate but not final shell shape, suggesting genetic variation in the plastic response to predator cues for a physiological variable (growth rate) but not for a variable known to mechanically reduce the risk of predation (shell shape), at least in this population of snails. The possibility that risk of multiple modes of predation (i.e., both fish and crayfish) in some populations might maintain genetic variation in morphological plasticity is discussed.

Exome sequencing in an admixed isolated population indicates NFXL1 variants confer a risk for specific language impairment.

PubMed

Villanueva, Pía; Nudel, Ron; Hoischen, Alexander; Fernández, María Angélica; Simpson, Nuala H; Gilissen, Christian; Reader, Rose H; Jara, Lillian; Echeverry, María Magdalena; Echeverry, Maria Magdalena; Francks, Clyde; Baird, Gillian; Conti-Ramsden, Gina; O'Hare, Anne; Bolton, Patrick F; Hennessy, Elizabeth R; Palomino, Hernán; Carvajal-Carmona, Luis; Veltman, Joris A; Cazier, Jean-Baptiste; De Barbieri, Zulema; Fisher, Simon E; Newbury, Dianne F

2015-03-01

Children affected by Specific Language Impairment (SLI) fail to acquire age appropriate language skills despite adequate intelligence and opportunity. SLI is highly heritable, but the understanding of underlying genetic mechanisms has proved challenging. In this study, we use molecular genetic techniques to investigate an admixed isolated founder population from the Robinson Crusoe Island (Chile), who are affected by a high incidence of SLI, increasing the power to discover contributory genetic factors. We utilize exome sequencing in selected individuals from this population to identify eight coding variants that are of putative significance. We then apply association analyses across the wider population to highlight a single rare coding variant (rs144169475, Minor Allele Frequency of 4.1% in admixed South American populations) in the NFXL1 gene that confers a nonsynonymous change (N150K) and is significantly associated with language impairment in the Robinson Crusoe population (p = 2.04 × 10-4, 8 variants tested). Subsequent sequencing of NFXL1 in 117 UK SLI cases identified four individuals with heterozygous variants predicted to be of functional consequence. We conclude that coding variants within NFXL1 confer an increased risk of SLI within a complex genetic model.

Neuroblastoma Survivors are at Increased Risk for Second Malignancies: A Report from the International Neuroblastoma Risk Group Project

PubMed Central

Applebaum, Mark A.; Vaksman, Zalman; Lee, Sang Mee; Hungate, Eric A.; Henderson, Tara O.; London, Wendy B.; Pinto, Navin; Volchenboum, Samuel L.; Park, Julie R.; Naranjo, Arlene; Hero, Barbara; Pearson, Andrew D.; Stranger, Barbara E.; Cohn, Susan L.; Diskin, Sharon J.

2017-01-01

Background The incidence of SMN within the first ten years of diagnosis in high-risk neuroblastoma patients treated with modern, intensive therapy is unknown. Further, the underlying germline genetics that contribute to SMN in these survivors are not known. Methods The International Neuroblastoma Risk Group (INRG) database of patients diagnosed from 1990–2010 was analyzed. SMN risk was accessed by cumulative incidence, standardized incidence ratios (SIR), and absolute excess risk (AER). A candidate gene-based association study evaluated genetic susceptibility to SMN in neuroblastoma survivors. Results Of the 5,987 patients in the INRG database with SMN data enrolled in a clinical trial, 43 (0.72%) developed a SMN. The 10-year cumulative incidence of SMN for high-risk patients was 1.8% (95% CI 1.0–2.6%) compared to 0.38% (95% CI: 0.22–0.94%) for low-risk patients (P=0.01). High-risk patients had an almost 18-fold higher incidence of SMN compared to age and sex matched controls (SIR=17.5 (95% CI: 11.4–25.3), AER=27.6). For patients treated on high- and intermediate-risk clinical trials, the SIR of acute myelogenous leukemia (AML) was 106.8 (95% CI: 28.7–273.4) and 127.7 (95%CI: 25.7–373.3), respectively. Variants implicating DNA repair genes XRCC3 (rs861539: P=0.006; Odds Ratio: 2.04, 95%CI: 1.19–3.46) and MSH2 (rs17036651: P=0.009; Odds Ratio: 0.26, 95% CI: 0.08–0.81) were associated with SMN. Conclusion The intensive multi-modality treatment strategy currently used to treat high-risk neuroblastoma is associated with a significantly increased risk of secondary AML. Defining the interactions of treatment exposures and genetic factors that promote the development of SMN is critical for optimizing survivorship care PMID:28033528

The Impact of Population Demography and Selection on the Genetic Architecture of Complex Traits

PubMed Central

Lohmueller, Kirk E.

2014-01-01

Population genetic studies have found evidence for dramatic population growth in recent human history. It is unclear how this recent population growth, combined with the effects of negative natural selection, has affected patterns of deleterious variation, as well as the number, frequency, and effect sizes of mutations that contribute risk to complex traits. Because researchers are performing exome sequencing studies aimed at uncovering the role of low-frequency variants in the risk of complex traits, this topic is of critical importance. Here I use simulations under population genetic models where a proportion of the heritability of the trait is accounted for by mutations in a subset of the exome. I show that recent population growth increases the proportion of nonsynonymous variants segregating in the population, but does not affect the genetic load relative to a population that did not expand. Under a model where a mutation's effect on a trait is correlated with its effect on fitness, rare variants explain a greater portion of the additive genetic variance of the trait in a population that has recently expanded than in a population that did not recently expand. Further, when using a single-marker test, for a given false-positive rate and sample size, recent population growth decreases the expected number of significant associations with the trait relative to the number detected in a population that did not expand. However, in a model where there is no correlation between a mutation's effect on fitness and the effect on the trait, common variants account for much of the additive genetic variance, regardless of demography. Moreover, here demography does not affect the number of significant associations detected. These findings suggest recent population history may be an important factor influencing the power of association tests and in accounting for the missing heritability of certain complex traits. PMID:24875776

Impact of genetic risk information and type of disease on perceived risk, anticipated affect, and expected consequences of genetic tests.

PubMed

Cameron, Linda D; Sherman, Kerry A; Marteau, Theresa M; Brown, Paul M

2009-05-01

Genetic tests vary in their prediction of disease occurrence, with some mutations conferring relatively low risk and others indicating near certainty. The authors assessed how increments in absolute risk of disease influence risk perceptions, interest, and expected consequences of genetic tests for diseases of varying severity. Adults (N = 752), recruited from New Zealand, Australia, and the United Kingdom for an online analogue study, were randomly assigned to receive information about a test of genetic risk for diabetes, heart disease, colon cancer, or lung cancer. The lifetime risk varied across conditions by 10% increments, from 20% to 100%. Participants completed measures of perceived likelihood of disease for individuals with mutations, risk-related affect, interest, and testing consequences. Analyses revealed two increment clusters yielding differences in likelihood perceptions: A "moderate-risk" cluster (20%-70%), and a "high-risk" cluster (80%-100%). Risk increment influenced anticipated worry, feelings of risk, testing-induced distress, and family obligations, with nonlinear patterns including disproportionately high responses for the 50% increment. Risk increment did not alter testing interest or perceived benefits. These patterns of effects held across the four diseases. Magnitude of risk from genetic testing has a nonlinear influence on risk-related appraisals and affect but is unrelated to test interest.

Genetic risk factors for the posterior cortical atrophy variant of Alzheimer's disease.

PubMed

Schott, Jonathan M; Crutch, Sebastian J; Carrasquillo, Minerva M; Uphill, James; Shakespeare, Tim J; Ryan, Natalie S; Yong, Keir X; Lehmann, Manja; Ertekin-Taner, Nilufer; Graff-Radford, Neill R; Boeve, Bradley F; Murray, Melissa E; Khan, Qurat Ul Ain; Petersen, Ronald C; Dickson, Dennis W; Knopman, David S; Rabinovici, Gil D; Miller, Bruce L; González, Aida Suárez; Gil-Néciga, Eulogio; Snowden, Julie S; Harris, Jenny; Pickering-Brown, Stuart M; Louwersheimer, Eva; van der Flier, Wiesje M; Scheltens, Philip; Pijnenburg, Yolande A; Galasko, Douglas; Sarazin, Marie; Dubois, Bruno; Magnin, Eloi; Galimberti, Daniela; Scarpini, Elio; Cappa, Stefano F; Hodges, John R; Halliday, Glenda M; Bartley, Lauren; Carrillo, Maria C; Bras, Jose T; Hardy, John; Rossor, Martin N; Collinge, John; Fox, Nick C; Mead, Simon

2016-08-01

The genetics underlying posterior cortical atrophy (PCA), typically a rare variant of Alzheimer's disease (AD), remain uncertain. We genotyped 302 PCA patients from 11 centers, calculated risk at 24 loci for AD/DLB and performed an exploratory genome-wide association study. We confirm that variation in/near APOE/TOMM40 (P = 6 × 10(-14)) alters PCA risk, but with smaller effect than for typical AD (PCA: odds ratio [OR] = 2.03, typical AD: OR = 2.83, P = .0007). We found evidence for risk in/near CR1 (P = 7 × 10(-4)), ABCA7 (P = .02) and BIN1 (P = .04). ORs at variants near INPP5D and NME8 did not overlap between PCA and typical AD. Exploratory genome-wide association studies confirmed APOE and identified three novel loci: rs76854344 near CNTNAP5 (P = 8 × 10(-10) OR = 1.9 [1.5-2.3]); rs72907046 near FAM46A (P = 1 × 10(-9) OR = 3.2 [2.1-4.9]); and rs2525776 near SEMA3C (P = 1 × 10(-8), OR = 3.3 [2.1-5.1]). We provide evidence for genetic risk factors specifically related to PCA. We identify three candidate loci that, if replicated, may provide insights into selective vulnerability and phenotypic diversity in AD. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

What Are the Risks and Limitations of Genetic Testing?

MedlinePlus

... does it take to get the results? Will health insurance cover the costs of genetic testing? What are the benefits of genetic testing? What are the risks and limitations of genetic testing? What is genetic ...

Melanoma risk prediction using a multilocus genetic risk score in the Women's Health Initiative cohort.

PubMed

Cho, Hyunje G; Ransohoff, Katherine J; Yang, Lingyao; Hedlin, Haley; Assimes, Themistocles; Han, Jiali; Stefanick, Marcia; Tang, Jean Y; Sarin, Kavita Y

2018-07-01

Single-nucleotide polymorphisms (SNPs) associated with melanoma have been identified though genome-wide association studies. However, the combined impact of these SNPs on melanoma development remains unclear, particularly in postmenopausal women who carry a lower melanoma risk. We examine the contribution of a combined polygenic risk score on melanoma development in postmenopausal women. Genetic risk scores were calculated using 21 genome-wide association study-significant SNPs. Their combined effect on melanoma development was evaluated in 19,102 postmenopausal white women in the clinical trial and observational study arms of the Women's Health Initiative dataset. Compared to the tertile of weighted genetic risk score with the lowest genetic risk, the women in the tertile with the highest genetic risk were 1.9 times more likely to develop melanoma (95% confidence interval 1.50-2.42). The incremental change in c-index from adding genetic risk scores to age were 0.075 (95% confidence interval 0.041-0.109) for incident melanoma. Limitations include a lack of information on nevi count, Fitzpatrick skin type, family history of melanoma, and potential reporting and selection bias in the Women's Health Initiative cohort. Higher genetic risk is associated with increased melanoma prevalence and incidence in postmenopausal women, but current genetic information may have a limited role in risk prediction when phenotypic information is available. Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Genome-wide interaction of genotype by erythrocyte n-3 PUFAs contributes to phenotypic variance of diabetes-related traits

USDA-ARS?s Scientific Manuscript database

While genome-wide association studies (GWAS) and candidate gene approach have identified many genetic variants that contribute to disease risk as main effects, the impact of genotype by environment (GxE) interactions remains rather under-surveyed. The present study aimed to examine variance contribu...

Attentional Threat Avoidance and Familial Risk are Independently Associated with Childhood Anxiety Disorders

ERIC Educational Resources Information Center

Brown, Hannah M.; McAdams, Tom A.; Lester, Kathryn J.; Goodman, Robert; Clark, David M.; Eley, Thalia C.

2013-01-01

Background: Twin studies in children reveal that familial aggregation of anxiety disorders is due to both genetic and environmental factors. Cognitive biases for threat information are considered a robust characteristic of childhood anxiety. However, little is known regarding the underlying aetiology of such biases and their role in anxiety…

Breed-Predispositions to Cancer in Pedigree Dogs

PubMed Central

Dobson, Jane M.

2013-01-01

Cancer is a common problem in dogs and although all breeds of dog and crossbred dogs may be affected, it is notable that some breeds of pedigree dogs appear to be at increased risk of certain types of cancer suggesting underlying genetic predisposition to cancer susceptibility. Although the aetiology of most cancers is likely to be multifactorial, the limited genetic diversity seen in purebred dogs facilitates genetic linkage or association studies on relatively small populations as compared to humans, and by using newly developed resources, genome-wide association studies in dog breeds are proving to be a powerful tool for unravelling complex disorders. This paper will review the literature on canine breed susceptibility to histiocytic sarcoma, osteosarcoma, haemangiosarcoma, mast cell tumours, lymphoma, melanoma, and mammary tumours including the recent advances in knowledge through molecular genetic, cytogenetic, and genome wide association studies. PMID:23738139

The impact of genetic counselling on risk perception and mental health in women with a family history of breast cancer.

PubMed

Watson, M; Lloyd, S; Davidson, J; Meyer, L; Eeles, R; Ebbs, S; Murday, V

1999-02-01

The present study investigated: (1) perception of genetic risk and, (2) the psychological effects of genetic counselling in women with a family history of breast cancer. Using a prospective design, with assessment pre- and post-genetic counselling at clinics and by postal follow-up at 1, 6 and 12 months, attenders at four South London genetic clinics were assessed. Participants included 282 women with a family history of breast cancer. Outcome was measured in terms of mental health, cancer-specific distress and risk perception. High levels of cancer-specific distress were found pre-genetic counselling, with 28% of participants reporting that they worried about breast cancer 'frequently or constantly' and 18% that worry about breast cancer was 'a severe or definite problem'. Following genetic counselling, levels of cancer-specific distress were unchanged. General mental health remained unchanged over time (33% psychiatric cases detected pre-genetic counselling, 27% at 12 months after genetic counselling). Prior to their genetics consultation, participants showed poor knowledge of their lifetime risk of breast cancer since there was no association between their perceived lifetime risk (when they were asked to express this as a 1 in x odds ratio) and their actual risk, when the latter was calculated by the geneticist at the clinic using the CASH model. In contrast, women were more accurate about their risk of breast cancer pre-genetic counselling when this was assessed in broad categorical terms (i.e. very much lower/very much higher than the average woman) with a significant association between this rating and the subsequently calculated CASH risk figure (P = 0.001). Genetic counselling produced a modest shift in the accuracy of perceived lifetime risk, expressed as an odds ratio, which was maintained at 12 months' follow-up. A significant minority failed to benefit from genetic counselling; 77 women continued to over-estimate their risk and maintain high levels of cancer-related worry. Most clinic attenders were inaccurate in their estimates of the population risk of breast cancer with only 24% able to give the correct figure prior to genetic counselling and 36% over-estimating this risk. There was some improvement following genetic counselling with 62% able to give the correct figure, but this information was poorly retained and this figure had dropped to 34% by the 1-year follow-up. The study showed that women attending for genetic counselling are worried about breast cancer, with 34% indicating that they had initiated the referral to the genetic clinic themselves. This anxiety is not alleviated by genetic counselling, although women reported that it was less of a problem at follow-up. Women who continue to over-estimate their risk and worry about breast cancer are likely to go on seeking unnecessary screening if they are not reassured.

Common variants in FTO, MC4R, TMEM18, PRL, AIF1, and PCSK1 show evidence of association with adult obesity in the Greek population.

PubMed

Rouskas, Konstantinos; Kouvatsi, Anastasia; Paletas, Konstantinos; Papazoglou, Dimitrios; Tsapas, Apostolos; Lobbens, Stéphane; Vatin, Vincent; Durand, Emmanuelle; Labrune, Yann; Delplanque, Jérôme; Meyre, David; Froguel, Philippe

2012-02-01

Twenty-four single-nucleotide polymorphisms (SNPs) have been reproducibly associated with obesity. We performed a follow-up study for obesity in the Greek adult population. A total of 510 obese and 469 lean adults were genotyped for 24 SNPs. We tested the association with obesity status using logistic regression and we evaluated the combined genetic risk of 24 SNPs by calculating the area under the receiver-operating characteristic (ROC) curves. We nominally replicated the association with obesity (BMI ≥30 kg/m(2)) of six SNPs in or near the FTO, MC4R, TMEM18, PRL, AIF1, and PCSK1 loci (1.28 ≤ odds ratio (OR) ≤ 1.35; 0.004 ≤ P ≤ 0.043). The discrimination ability for obesity was slightly stronger (P = 9.59 × 10(-6)) when the genetic information of the 24 SNPs was added to nongenetic risk factors (area under the curve (AUC) = 0.722) in comparison with nongenetic factors analyzed alone (AUC = 0.685). Our data suggest that SNPs in or near the FTO, MC4R, TMEM18, PRL, AIF1, and PCSK1 loci contribute to obesity risk in the Greek population.

Brain function in carriers of a genome-wide supported bipolar disorder variant.

PubMed

Erk, Susanne; Meyer-Lindenberg, Andreas; Schnell, Knut; Opitz von Boberfeld, Carola; Esslinger, Christine; Kirsch, Peter; Grimm, Oliver; Arnold, Claudia; Haddad, Leila; Witt, Stephanie H; Cichon, Sven; Nöthen, Markus M; Rietschel, Marcella; Walter, Henrik

2010-08-01

The neural abnormalities underlying genetic risk for bipolar disorder, a severe, common, and highly heritable psychiatric condition, are largely unknown. An opportunity to define these mechanisms is provided by the recent discovery, through genome-wide association, of a single-nucleotide polymorphism (rs1006737) strongly associated with bipolar disorder within the CACNA1C gene, encoding the alpha subunit of the L-type voltage-dependent calcium channel Ca(v)1.2. To determine whether the genetic risk associated with rs1006737 is mediated through hippocampal function. Functional magnetic resonance imaging study. University hospital. A total of 110 healthy volunteers of both sexes and of German descent in the Hardy-Weinberg equilibrium for rs1006737. Blood oxygen level-dependent signal during an episodic memory task and behavioral and psychopathological measures. Using an intermediate phenotype approach, we show that healthy carriers of the CACNA1C risk variant exhibit a pronounced reduction of bilateral hippocampal activation during episodic memory recall and diminished functional coupling between left and right hippocampal regions. Furthermore, risk allele carriers exhibit activation deficits of the subgenual anterior cingulate cortex, a region repeatedly associated with affective disorders and the mediation of adaptive stress-related responses. The relevance of these findings for affective disorders is supported by significantly higher psychopathology scores for depression, anxiety, obsessive-compulsive thoughts, interpersonal sensitivity, and neuroticism in risk allele carriers, correlating negatively with the observed regional brain activation. Our data demonstrate that rs1006737 or genetic variants in linkage disequilibrium with it are functional in the human brain and provide a neurogenetic risk mechanism for bipolar disorder backed by genome-wide evidence.

A genetic study and meta-analysis of the genetic predisposition of prostate cancer in a Chinese population.

PubMed

Marzec, Jacek; Mao, Xueying; Li, Meiling; Wang, Meilin; Feng, Ninghan; Gou, Xin; Wang, Guomin; Sun, Zan; Xu, Jianfeng; Xu, Hua; Zhang, Xiaoping; Zhao, Shan-Chao; Ren, Guoping; Yu, Yongwei; Wu, Yudong; Wu, Ji; Xue, Yao; Zhou, Bo; Zhang, Yanling; Xu, Xingxing; Li, Jie; He, Weiyang; Benlloch, Sara; Ross-Adams, Helen; Chen, Li; Li, Jucong; Hong, Yingqia; Kote-Jarai, Zsofia; Cui, Xingang; Hou, Jianguo; Guo, Jianming; Xu, Lei; Yin, Changjun; Zhou, Yuanping; Neal, David E; Oliver, Tim; Cao, Guangwen; Zhang, Zhengdong; Easton, Douglas F; Chelala, Claude; Al Olama, Ali Amin; Eeles, Rosalind A; Zhang, Hongwei; Lu, Yong-Jie

2016-04-19

Prostate cancer predisposition has been extensively investigated in European populations, but there have been few studies of other ethnic groups. To investigate prostate cancer susceptibility in the under-investigated Chinese population, we performed single-nucleotide polymorphism (SNP) array analysis on a cohort of Chinese cases and controls and then meta-analysis with data from the existing Chinese prostate cancer genome-wide association study (GWAS). Genotyping 211,155 SNPs in 495 cases and 640 controls of Chinese ancestry identified several new suggestive Chinese prostate cancer predisposition loci. However, none of them reached genome-wide significance level either by meta-analysis or replication study. The meta-analysis with the Chinese GWAS data revealed that four 8q24 loci are the main contributors to Chinese prostate cancer risk and the risk alleles from three of them exist at much higher frequencies in Chinese than European populations. We also found that several predisposition loci reported in Western populations have different effect on Chinese men. Therefore, this first extensive single-nucleotide polymorphism study of Chinese prostate cancer in comparison with European population indicates that four loci on 8q24 contribute to a great risk of prostate cancer in a considerable large proportion of Chinese men. Based on those four loci, the top 10% of the population have six- or two-fold prostate cancer risk compared with men of the bottom 10% or median risk respectively, which may facilitate the design of prostate cancer genetic risk screening and prevention in Chinese men. These findings also provide additional insights into the etiology and pathogenesis of prostate cancer.

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome.

PubMed

Wiseman, Frances K; Al-Janabi, Tamara; Hardy, John; Karmiloff-Smith, Annette; Nizetic, Dean; Tybulewicz, Victor L J; Fisher, Elizabeth M C; Strydom, André

2015-09-01

Down syndrome, which arises in individuals carrying an extra copy of chromosome 21, is associated with a greatly increased risk of early-onset Alzheimer disease. It is thought that this risk is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP)--an Alzheimer disease risk factor--although the possession of extra copies of other chromosome 21 genes may also play a part. Further study of the mechanisms underlying the development of Alzheimer disease in people with Down syndrome could provide insights into the mechanisms that cause dementia in the general population.

Communication and Technology in Genetic Counseling for Familial Cancer

PubMed Central

Lynch, Henry T.; Snyder, Carrie; Stacey, Mark; Olson, Brooke; Peterson, Susan; Buxbaum, Sarah; Shaw, Trudy; Lynch, Patrick

2015-01-01

When a cancer predisposing germline mutation is detected in an index case, the presence of the underlying syndrome is confirmed and the potential for predictive testing of at-risk relatives is established. However, the reporting of a positive family history does not routinely lead to communication of information about risk to close, much less distant relatives. This review summarizes information technology utilized to address penetration or “reach” of knowledge of risk within extended families, including the use of telephone and video counseling to reach distant patients, and anticipate novel internet-based processes for communication between investigators and relatives. PMID:24355094

Gene network analysis shows immune-signaling and ERK1/2 as novel genetic markers for multiple addiction phenotypes: alcohol, smoking and opioid addiction.

PubMed

Reyes-Gibby, Cielito C; Yuan, Christine; Wang, Jian; Yeung, Sai-Ching J; Shete, Sanjay

2015-06-05

Addictions to alcohol and tobacco, known risk factors for cancer, are complex heritable disorders. Addictive behaviors have a bidirectional relationship with pain. We hypothesize that the associations between alcohol, smoking, and opioid addiction observed in cancer patients have a genetic basis. Therefore, using bioinformatics tools, we explored the underlying genetic basis and identified new candidate genes and common biological pathways for smoking, alcohol, and opioid addiction. Literature search showed 56 genes associated with alcohol, smoking and opioid addiction. Using Core Analysis function in Ingenuity Pathway Analysis software, we found that ERK1/2 was strongly interconnected across all three addiction networks. Genes involved in immune signaling pathways were shown across all three networks. Connect function from IPA My Pathway toolbox showed that DRD2 is the gene common to both the list of genetic variations associated with all three addiction phenotypes and the components of the brain neuronal signaling network involved in substance addiction. The top canonical pathways associated with the 56 genes were: 1) calcium signaling, 2) GPCR signaling, 3) cAMP-mediated signaling, 4) GABA receptor signaling, and 5) G-alpha i signaling. Cancer patients are often prescribed opioids for cancer pain thus increasing their risk for opioid abuse and addiction. Our findings provide candidate genes and biological pathways underlying addiction phenotypes, which may be future targets for treatment of addiction. Further study of the variations of the candidate genes could allow physicians to make more informed decisions when treating cancer pain with opioid analgesics.

Occupational reproductive health risks.

PubMed

Filkins, K; Kerr, M J

1993-01-01

The potentially harmful effects on women of certain workplace exposures are widely appreciated, and steps to control these have included legislative efforts such as right-to-know laws of well as corporate policies mandating selective restriction of fertile women, which are illegal under federal civil rights laws. This chapter reviews the various occupational health risks reproductive women face in the workplace but also considers the effects of other genetic, medical, social, infectious, and environmental factors which may be of even greater concern than most occupational factors.

Making sense of genetic risk: A qualitative focus-group study of healthy participants in genomic research.

PubMed

Viberg Johansson, Jennifer; Segerdahl, Pär; Ugander, Ulrika Hösterey; Hansson, Mats G; Langenskiöld, Sophie

2018-03-01

It is well known that research participants want to receive genetic risk information that is about high risks, serious diseases and potential preventive measures. The aim of this study was to explore, by qualitative means, something less well known: how do healthy research participants themselves make sense of genetic risk information? A phenomenographic approach was chosen to explore research participants' understanding and assessment of genetic risk. We conducted four focus-group (N=16) interviews with participants in a research programme designed to identify biomarkers for cardiopulmonary disease. Among the research participants, we found four ways of understanding genetic risk: as a binary concept, as an explanation, as revealing who I am (knowledge of oneself) and as affecting life ahead. Research participants tend to understand genetic risk as a binary concept. This does not necessarily imply a misunderstanding of, or an irrational approach to, genetic risk. Rather, it may have a heuristic function in decision-making. Risk communication may be enhanced by tailoring the communication to the participants' own lay conceptions. For example, researchers and counselors should address risk in binary terms, maybe looking out for how individual participants search for threshold figures. Copyright © 2017 Elsevier B.V. All rights reserved.

The schizophrenia risk gene ZNF804A: clinical associations, biological mechanisms and neuronal functions.

PubMed

Chang, H; Xiao, X; Li, M

2017-07-01

ZNF804A (zinc-finger protein 804A) has been recognized as a schizophrenia risk gene across multiple world populations. Its intronic single-nucleotide polymorphism (SNP) rs1344706 is among one of the strongest susceptibility variants that have achieved genome-wide significance in genome-wide association studies (GWAS) for schizophrenia and has been widely and intensively studied. To elucidate the biological mechanisms underlying the genetic risk conferred by rs1344706, we retrospectively analyzed the progresses in brain gene expression quantitative trait loci (eQTL) analyses, ZNF804A-induced pathway alterations in neural cells and changes in synaptic phenotypes associated with ZNF804A expression. Based on these data, we hypothesize a potential biological mechanism for a genetic risk allele of ZNF804A in schizophrenia pathogenesis. We also review the efforts being made to characterize the affected intermediate phenotypes using neuroimaging and neuropsychological approaches. We then discuss additional common and rare ZNF804A variants in schizophrenia susceptibility and the potential genetic heterogeneity of these genomic loci between Europeans and Asians. This review for we believe the first time systematically presents the evidence for ZNF804A, describing its discovery and likely roles in brain development and schizophrenia pathogenesis. We believe that this work has summarized this information with a systemic and broad assessment of recent findings.

Mechanisms underlying cellular responses of cells from haemopoietic tissue to low dose/low LET radiation

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

Munira A Kadhim

2010-03-05

To accurately define the risks associated with human exposure to relevant environmental doses of low LET ionizing radiation, it is necessary to completely understand the biological effects at very low doses (i.e., less than 0.1 Gy), including the lowest possible dose, that of a single electron track traversal. At such low doses, a range of studies have shown responses in biological systems which are not related to the direct interaction of radiation tracks with DNA. The role of these “non-targeted” responses in critical tissues is poorly understood and little is known regarding the underlying mechanisms. Although critical for dosimetry andmore » risk assessment, the role of individual genetic susceptibility in radiation risk is not satisfactorily defined at present. The aim of the proposed grant is to critically evaluate radiation-induced genomic instability and bystander responses in key stem cell populations from haemopoietic tissue. Using stem cells from two mouse strains (CBA/H and C57BL/6J) known to differ in their susceptibility to radiation effects, we plan to carefully dissect the role of genetic predisposition on two non-targeted radiation responses in these models; the bystander effect and genomic instability, which we believe are closely related. We will specifically focus on the effects of low doses of low LET radiation, down to doses approaching a single electron traversal. Using conventional X-ray and γ-ray sources, novel dish separation and targeted irradiation approaches, we will be able to assess the role of genetic variation under various bystander conditions at doses down to a few electron tracks. Irradiations will be carried out using facilities in routine operation for bystander targeted studies. Mechanistic studies of instability and the bystander response in different cell lineages will focus initially on the role of cytokines which have been shown to be involved in bystander signaling and the initiation of instability. These studies also aim to uncover protein mediators of the bystander responses using advanced proteomic screening of factors released from irradiated, bystander and unstable cells. Integral to these studies will be an assessment of the role of genetic susceptibility in these responses, using CBA/H and C57BL/6J mice. The relevance of in vivo interactions between stem cells and the stem cell niche will be explored in the future by re-implantation techniques of previously irradiated cells. The above studies will provide fundamental mechanistic information relating genetic predisposition to important low dose phenomena, and will aid in the development of Department of Energy policy, as well as radiation risk policy for the public and the workplace. We believe the proposed studies accurately reflect the goals of the DOE low dose program.« less

Problem formulation and option assessment (PFOA) linking governance and environmental risk assessment for technologies: a methodology for problem analysis of nanotechnologies and genetically engineered organisms.

PubMed

Nelson, Kristen C; Andow, David A; Banker, Michael J

2009-01-01

Societal evaluation of new technologies, specifically nanotechnology and genetically engineered organisms (GEOs), challenges current practices of governance and science. Employing environmental risk assessment (ERA) for governance and oversight assumes we have a reasonable ability to understand consequences and predict adverse effects. However, traditional ERA has come under considerable criticism for its many shortcomings and current governance institutions have demonstrated limitations in transparency, public input, and capacity. Problem Formulation and Options Assessment (PFOA) is a methodology founded on three key concepts in risk assessment (science-based consideration, deliberation, and multi-criteria analysis) and three in governance (participation, transparency, and accountability). Developed through a series of international workshops, the PFOA process emphasizes engagement with stakeholders in iterative stages, from identification of the problem(s) through comparison of multiple technology solutions that could be used in the future with their relative benefits, harms, and risk. It provides "upstream public engagement" in a deliberation informed by science that identifies values for improved decision making.

Cytogenetic risks in chromosomally normal infertile men.

PubMed

Tempest, Helen G; Martin, Renee H

2009-06-01

Infertility is a growing problem that affects a surprisingly high number of couples (15%) of which the causes often remain 'unexplained'. However, more and more genetic causes underlying male infertility are emerging. Research has begun to shed light on the causes of previously unexplained male infertility with clear links now established with infertility and meiotic defects in pairing, synapsis and recombination as well as increased levels of sperm aneuploidy. However, many have questioned whether this increase in sperm aneuploidy is observed in conceptuses or live birth; research suggests that this increase in aneuploidy is in fact paralleled in intracytoplasmic sperm injection (ICSI) conceptions. Further research is warranted investigating the relationship between sperm aneuploidy and risk to ICSI conceptuses. Several infertility phenotypes have clearly been identified having a higher risk of sperm aneuploidy and may benefit from sperm aneuploidy screening prior to ICSI. Such screening would ultimately assist couples in deciding on the relative risk of undertaking ICSI and enable them to make informed decisions on whether to proceed with ICSI or to combine it with further screening such as preimplantation genetic diagnosis.

Association between gestational diabetes mellitus exposure and childhood adiposity is not substantially explained by offspring genetic risk of obesity.

PubMed

Raghavan, S; Zhang, W; Yang, I V; Lange, L A; Lange, E M; Fingerlin, T E; Dabelea, D

2017-12-01

To examine the extent to which offspring obesity-associated genetic risk explains the association between gestational diabetes mellitus and childhood adiposity. We studied 282 children aged 7-12 years who were enrolled in the Exploring Perinatal Outcomes in Children Study. A genetic risk score for BMI was calculated as the count of 91 established BMI-raising risk alleles. Multivariable linear and logistic regression models were used to estimate associations between the offspring genetic risk score and exposure to gestational diabetes and childhood adiposity (BMI and waist circumference), adjusting for clinical and demographic covariates. The contribution of offspring genetic risk to associations between maternal gestational diabetes and childhood outcomes was estimated by comparing the regression coefficients for the gestational diabetes variable in models with and without the genetic risk score. The offspring BMI genetic risk score was associated with childhood BMI (P = 0.006) and waist circumference (P = 0.02), and marginally with gestational diabetes (P = 0.05). Offspring BMI genetic risk did not contribute significantly to associations between gestational diabetes and childhood BMI [7.7% (95% CI -3.3, 18.8)] or waist circumference [5.8% (95% CI -3.1, 14.8); P = 0.2 for both]. Offspring obesity genetic risk does not explain a significant proportion of the association between gestational diabetes exposure and childhood adiposity. The association between gestational diabetes and childhood adiposity is probably explained through alternative pathways, including direct intrauterine effects or a shared postnatal environment. © 2017 Diabetes UK.

Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: a systematic review to update the U.S. Preventive Services Task Force recommendation.

PubMed

Nelson, Heidi D; Pappas, Miranda; Zakher, Bernadette; Mitchell, Jennifer Priest; Okinaka-Hu, Leila; Fu, Rongwei

2014-02-18

Mutations in breast cancer susceptibility genes (BRCA1 and BRCA2) are associated with increased risks for breast, ovarian, and other types of cancer. To review new evidence on the benefits and harms of risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women. MEDLINE and PsycINFO between 2004 and 30 July 2013, the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews from 2004 through the second quarter of 2013, Health Technology Assessment during the fourth quarter of 2012, Scopus, and reference lists. English-language studies about accuracy of risk assessment and benefits and harms of genetic counseling, genetic testing, and interventions to reduce cancer incidence and mortality. Individual investigators extracted data on participants, study design, analysis, follow-up, and results, and a second investigator confirmed key data. Investigators independently dual-rated study quality and applicability by using established criteria. Five referral models accurately estimated individual risk for BRCA mutations. Genetic counseling increased the accuracy of risk perception and decreases the intention for genetic testing among unlikely carriers and cancer-related worry, anxiety, and depression. No trials evaluated the effectiveness of intensive screening or risk-reducing medications in mutation carriers, although false-positive rates, unneeded imaging, and unneeded surgeries were higher with screening. Among high-risk women and mutation carriers, risk-reducing mastectomy decreased breast cancer by 85% to 100% and breast cancer mortality by 81% to 100% compared with women without surgery; risk-reducing salpingo-oophorectomy decreased breast cancer incidence by 37% to 100%, ovarian cancer by 69% to 100%, and all-cause mortality by 55% to 100%. The analysis included only English-language articles;efficacy trials in mutation carriers were lacking. Studies of risk assessment, genetic counseling, genetic testing, and interventions to reduce cancer and mortality indicate potential benefits and harms that vary according to risk.

Breastfeeding duration and offspring conduct problems: The moderating role of genetic risk.

PubMed

Jackson, Dylan B

2016-10-01

A sizable body of research has examined associations between breastfeeding and various facets of offspring development, including childhood behavioral problems. Notwithstanding the number of studies on the topic, breastfeeding has not consistently been linked to child misbehaviors. Moreover, empirical examinations of whether breastfeeding is differentially predictive of conduct problems among individuals with varying degrees of genetic risk are lacking. The present study examines whether a short duration of breastfeeding and genetic risk interact to predict conduct problems during childhood. A genetically informative design is employed to examine a subsample of twins from the Early Childhood Longitudinal Study: Birth Cohort (ECLS-B), a nationally representative sample of American children. The findings suggest that a shorter duration of breastfeeding only enhances the risk of offspring conduct problems among children who possess high levels of genetic risk. Conversely, longer breastfeeding durations were found to protect against childhood behavioral problems when genetic risk was high. Indicators of genetic risk may help to distinguish individuals whose behavioral development is most sensitive to the duration of breastfeeding. Future research should seek to replicate and extend these findings by considering genetic factors as potential markers of differential susceptibility to breastfeeding duration. Copyright © 2016 Elsevier Ltd. All rights reserved.

Exploring Genetic Numeracy Skills in a Sample of U.S. University Students

PubMed Central

Bergman, Margo W.; Goodson, Patricia; Goltz, Heather Honoré

2017-01-01

Misconceptions concerning numerical genetic risk exist even within educated populations. To more fully characterize and understand the extent of these risk misunderstandings, which have large potential impact on clinical care, we analyzed the responses from 2,576 students enrolled at 2 Southwestern universities using the PGRID tool, a 138-item web-based survey comprising measures of understanding of genetics, genetic disease, and genetic risk. The primary purpose of this study was to characterize the intersection of risk perception and knowledge, termed genetic numeracy (GN). Additionally, we identify sociodemographic factors that might shape varying levels of GN skills within the study sample and explore the impact of GN on genetic testing intentions using both the Marascuilo procedure and logistic regression analysis. Despite having some college coursework or at least one college degree, most respondents lacked high-level aptitude in understanding genetic inheritance risk, especially with respect to recessive disorders. Prior education about genetics and biology, as well as exposure to biomedical models of genetics, was associated with higher GN levels; exposure to popular media models of genetics was inversely associated with higher GN levels. Differing GN levels affects genetic testing intentions. GN will become more relevant as genetic testing is increasingly incorporated into general clinical care. PMID:28900615

Exploring Genetic Numeracy Skills in a Sample of U.S. University Students.

PubMed

Bergman, Margo W; Goodson, Patricia; Goltz, Heather Honoré

2017-01-01

Misconceptions concerning numerical genetic risk exist even within educated populations. To more fully characterize and understand the extent of these risk misunderstandings, which have large potential impact on clinical care, we analyzed the responses from 2,576 students enrolled at 2 Southwestern universities using the PGRID tool, a 138-item web-based survey comprising measures of understanding of genetics, genetic disease, and genetic risk. The primary purpose of this study was to characterize the intersection of risk perception and knowledge, termed genetic numeracy (GN). Additionally, we identify sociodemographic factors that might shape varying levels of GN skills within the study sample and explore the impact of GN on genetic testing intentions using both the Marascuilo procedure and logistic regression analysis. Despite having some college coursework or at least one college degree, most respondents lacked high-level aptitude in understanding genetic inheritance risk, especially with respect to recessive disorders. Prior education about genetics and biology, as well as exposure to biomedical models of genetics, was associated with higher GN levels; exposure to popular media models of genetics was inversely associated with higher GN levels. Differing GN levels affects genetic testing intentions. GN will become more relevant as genetic testing is increasingly incorporated into general clinical care.

Evaluating the performance of the breast cancer genetic risk models BOADICEA, IBIS, BRCAPRO and Claus for predicting BRCA1/2 mutation carrier probabilities: a study based on 7352 families from the German Hereditary Breast and Ovarian Cancer Consortium.

PubMed

Fischer, Christine; Kuchenbäcker, Karoline; Engel, Christoph; Zachariae, Silke; Rhiem, Kerstin; Meindl, Alfons; Rahner, Nils; Dikow, Nicola; Plendl, Hansjörg; Debatin, Irmgard; Grimm, Tiemo; Gadzicki, Dorothea; Flöttmann, Ricarda; Horvath, Judit; Schröck, Evelin; Stock, Friedrich; Schäfer, Dieter; Schwaab, Ira; Kartsonaki, Christiana; Mavaddat, Nasim; Schlegelberger, Brigitte; Antoniou, Antonis C; Schmutzler, Rita

2013-06-01

Risk prediction models are widely used in clinical genetic counselling. Despite their frequent use, the genetic risk models BOADICEA, BRCAPRO, IBIS and extended Claus model (eCLAUS), used to estimate BRCA1/2 mutation carrier probabilities, have never been comparatively evaluated in a large sample from central Europe. Additionally, a novel version of BOADICEA that incorporates tumour pathology information has not yet been validated. Using data from 7352 German families we estimated BRCA1/2 carrier probabilities under each model and compared their discrimination and calibration. The incremental value of using pathology information in BOADICEA was assessed in a subsample of 4928 pedigrees with available data on breast tumour molecular markers oestrogen receptor, progesterone receptor and human epidermal growth factor 2. BRCAPRO (area under receiver operating characteristic curve (AUC)=0.80 (95% CI 0.78 to 0.81)) and BOADICEA (AUC=0.79 (0.78-0.80)), had significantly higher diagnostic accuracy than IBIS and eCLAUS (p<0.001). The AUC increased when pathology information was used in BOADICEA: AUC=0.81 (95% CI 0.80 to 0.83, p<0.001). At carrier thresholds of 10% and 15%, the net reclassification index was +3.9% and +5.4%, respectively, when pathology was included in the model. Overall, calibration was best for BOADICEA and worst for eCLAUS. With eCLAUS, twice as many mutation carriers were predicted than observed. Our results support the use of BRCAPRO and BOADICEA for decision making regarding genetic testing for BRCA1/2 mutations. However, model calibration has to be improved for this population. eCLAUS should not be used for estimating mutation carrier probabilities in clinical settings. Whenever possible, breast tumour molecular marker information should be taken into account.

Contrasting effects of climate change in continental vs. oceanic environments on population persistence and microevolution of Atlantic salmon.

PubMed

Piou, Cyril; Prévost, Etienne

2013-03-01

Facing climate change (CC), species are prone to multiple modifications in their environment that can lead to extinction, migration or adaptation. Identifying the role and interplay of different potential stressors becomes a key question. Anadromous fishes will be exposed to both river and oceanic habitat changes. For Atlantic salmon, the river water temperature, river flow and oceanic growth conditions appear as three main stressing factors. They could act on population dynamics or as selective forces on life-history pathways. Using an individual-based demo-genetic model, we assessed the effects of these factors (1) to compare risks of extinction resulting from CC in river and ocean, and (2) to assess CC effects on life-history pathways including the evolution of underlying genetic control of phenotypic plasticity. We focused on Atlantic salmon populations from Southern Europe for a time horizon of three decades. We showed that CC in river alone should not lead to extinction of Southern European salmon populations. In contrast, the reduced oceanic growth appeared as a significant threat for population persistence. An increase in river flow amplitude increased the risk of local extinction in synergy with the oceanic effects, but river temperature rise reduced this risk. In terms of life-history modifications, the reduced oceanic growth increased the age of return of individuals through plastic and genetic responses. The river temperature rise increased the proportion of sexually mature parr, but the genetic evolution of the maturation threshold lowered the maturation rate of male parr. This was identified as a case of environmentally driven plastic response that masked an underlying evolutionary response of plasticity going in the opposite direction. We concluded that to counteract oceanic effects, river flow management represented the sole potential force to reduce the extinction probability of Atlantic salmon populations in Southern Europe, although this might not impede changes in migration life history. © 2012 Blackwell Publishing Ltd.

Polygenic Risk, Appetite Traits, and Weight Gain in Middle Childhood

PubMed Central

Steinsbekk, Silje; Belsky, Daniel; Guzey, Ismail Cuneyt; Wardle, Jane; Wichstrøm, Lars

2018-01-01

IMPORTANCE Genome-wide association studies have identified genetic risks for obesity. These genetic risks influence development of obesity partly by accelerating weight gain in childhood. Research is needed to identify mechanisms to inform intervention. Cross-sectional studies suggest appetite traits as a candidate mechanism. Longitudinal studies are needed to test whether appetite traits mediate genetic influences on children’s weight gain. OBJECTIVE To test whether genetic risk for obesity predicts accelerated weight gain in middle childhood (ages 4–8 years) and whether genetic association with accelerated weight gain is mediated by appetite traits. DESIGN, SETTING, AND PARTICIPANTS Longitudinal study of a representative birth cohort at the Trondheim Early Secure Study, Trondheim, Norway, enrolled at age 4 years during 2007 to 2008, with follow-ups at ages 6 and 8 years. Participants were sampled from all children born in 2003 or 2004 who attended regular community health checkups for 4-year-olds (97.2%attendance; 82.0%consent rate, n = 2475). Nine hundred ninety-five children participated at age 4 years, 795 at age 6 years, and 699 at age 8 years. Analyses included 652 children with genotype, adiposity, and appetite data. MAIN OUTCOMES AND MEASURES Outcomes were body mass index and body-fat phenotypes measured from anthropometry (ages 4, 6, and 8 years) and bioelectrical impedance (ages 6 and 8 years). Genetic risk for obesity was measured using a genetic risk score composed of 32 single-nucleotide polymorphisms previously discovered in genome-wide association studies of adult body mass index. Appetite traits were measured at age 6 years with the Children’s Eating Behavior Questionnaire. RESULTS Of the 652 genotyped child participants, 323 (49.5%) were female, 58 (8.9%) were overweight, and 1 (0.2%) was obese. Children at higher genetic risk for obesity had higher baseline body mass index and fat mass compared with lower genetic risk peers, and they gained weight and fat mass more rapidly during follow-up. Each SD increase in genetic risk score was associated with a 0.22-point increase in BMI at age-4 baseline (for the intercept, unstandardized path coefficient B = 0.22 [95%CI, 0.06–0.38]; P = .008. Children with higher genetic risk scores also gained BMI points more rapidly from ages 4 to 6 years (B = 0.11 [95% CI, 0.03–0.20]; P = .01 ; β = 0.12) and from 6 to 8 years (B = 0.09 [95%CI, 0.00–0.19]; P = .05; β = 0.10), compared with their lower genetic risk peers. Children at higher genetic risk had higher levels of alleged obesogenic appetite traits than peers with lower genetic risk at age 6 years, but appetite traits did not mediate genetic associations with weight gain. The sum of the 5 indirect effects was B = −0.001 (95%CI, −0.02 –0.01); P = .86; β = 0.00. CONCLUSIONS AND RELEVANCE Genetic risk for obesity is associated with accelerated childhood weight gain. Interventions targeting childhood weight gain may provide one path to mitigating genetic risk. However, middle childhood appetite traits may not be a promising target for such interventions. Studies of early-childhood samples are needed to test whether appetite traits explain how genetic risks accelerate growth earlier in development. PMID:26830872

The Effect of Genetic Risk Information and Health Risk Assessment on Compliance with Preventive Behaviors.

ERIC Educational Resources Information Center

Bamberg, Richard; And Others

1990-01-01

Results from a study of 82 males provide no statistical support and limited encouragement that genetic risk information may motivate persons to make positive changes in preventive health behaviors. Health risk assessments were used to identify subjects at risk for coronary heart disease or lung cancer because of genetic factors. (IAH)

Gender, genetic risk, and criminal behavior.

PubMed

Vaske, Jamie; Wright, John Paul; Boisvert, Danielle; Beaver, Kevin Michael

2011-02-28

The threshold hypothesis asserts that the prevalence of offending is lower among females because females have a higher threshold for risk than males. As a result, females who do offend should exhibit greater concentrations of genetic and environmental risk than male offenders. In light of these statements, the current study examines the role of genetic factors in the etiology of female offending using data from the National Longitudinal Study of Adolescent Health. The results reveal that the genetic risk threshold is higher for females than for males. However, contrary to the threshold hypothesis, female offenders exhibit fewer genetic risks than male offenders. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Influence of Environmental and Genetic Factors Linked to Celiac Disease Risk on Infant Gut Colonization by Bacteroides Species▿

PubMed Central

Sánchez, Ester; De Palma, Giada; Capilla, Amalia; Nova, Esther; Pozo, Tamara; Castillejo, Gemma; Varea, Vicente; Marcos, Ascensión; Garrote, José Antonio; Polanco, Isabel; López, Ana; Ribes-Koninckx, Carmen; García-Novo, Maria Dolores; Calvo, Carmen; Ortigosa, Luis; Palau, Francesc; Sanz, Yolanda

2011-01-01

Celiac disease (CD) is an immune-mediated enteropathy involving genetic and environmental factors whose interaction might influence disease risk. The aim of this study was to determine the effects of milk-feeding practices and the HLA-DQ genotype on intestinal colonization of Bacteroides species in infants at risk of CD development. This study included 75 full-term newborns with at least one first-degree relative suffering from CD. Infants were classified according to milk-feeding practice (breast-feeding or formula feeding) and HLA-DQ genotype (high or low genetic risk). Stools were analyzed at 7 days, 1 month, and 4 months by PCR and denaturing gradient gel electrophoresis (DGGE). The Bacteroides species diversity index was higher in formula-fed infants than in breast-fed infants. Breast-fed infants showed a higher prevalence of Bacteroides uniformis at 1 and 4 months of age, while formula-fed infants had a higher prevalence of B. intestinalis at all sampling times, of B. caccae at 7 days and 4 months, and of B. plebeius at 4 months. Infants with high genetic risk showed a higher prevalence of B. vulgatus, while those with low genetic risk showed a higher prevalence of B. ovatus, B. plebeius, and B. uniformis. Among breast-fed infants, the prevalence of B. uniformis was higher in those with low genetic risk than in those with high genetic risk. Among formula-fed infants, the prevalence of B. ovatus and B. plebeius was increased in those with low genetic risk, while the prevalence of B. vulgatus was higher in those with high genetic risk. The results indicate that both the type of milk feeding and the HLA-DQ genotype influence the colonization process of Bacteroides species, and possibly the disease risk. PMID:21642397

26 CFR 54.9802-3T - Additional requirements prohibiting discrimination based on genetic information (temporary).

Code of Federal Regulations, 2012 CFR

2012-04-01

... history. (ii) Conclusion. In this Example 1, the health risk assessment includes a request for genetic... the health risk assessment includes a request for genetic information (that is, the individual's... about family medical history on the health risk assessment are a request for genetic information for...

26 CFR 54.9802-3T - Additional requirements prohibiting discrimination based on genetic information (temporary).

Code of Federal Regulations, 2013 CFR

2013-04-01

... history. (ii) Conclusion. In this Example 1, the health risk assessment includes a request for genetic... the health risk assessment includes a request for genetic information (that is, the individual's... about family medical history on the health risk assessment are a request for genetic information for...

26 CFR 54.9802-3T - Additional requirements prohibiting discrimination based on genetic information (temporary).

Code of Federal Regulations, 2011 CFR

2011-04-01

... history. (ii) Conclusion. In this Example 1, the health risk assessment includes a request for genetic... the health risk assessment includes a request for genetic information (that is, the individual's... about family medical history on the health risk assessment are a request for genetic information for...

26 CFR 54.9802-3T - Additional requirements prohibiting discrimination based on genetic information (temporary).

Code of Federal Regulations, 2014 CFR

2014-04-01

... history. (ii) Conclusion. In this Example 1, the health risk assessment includes a request for genetic... the health risk assessment includes a request for genetic information (that is, the individual's... about family medical history on the health risk assessment are a request for genetic information for...

Genetics of variation in HOMA-IR and cardiovascular risk factors in Mexican-Americans.

PubMed

Voruganti, V Saroja; Lopez-Alvarenga, Juan C; Nath, Subrata D; Rainwater, David L; Bauer, Richard; Cole, Shelley A; Maccluer, Jean W; Blangero, John; Comuzzie, Anthony G

2008-03-01

Insulin resistance is a major biochemical defect underlying the pathogenesis of cardiovascular disease (CVD). Mexican-Americans are known to have an unfavorable cardiovascular profile. Thus, the aim of this study was to investigate the genetic effect on variation in HOMA-IR and to evaluate its genetic correlations with other phenotypes related to risk of CVD in Mexican-Americans. The homeostatic model assessment method (HOMA-IR) is one of several approaches that are used to measure insulin resistance and was used here to generate a quantitative phenotype for genetic analysis. For 644 adults who had participated in the San Antonio Family Heart Study (SAFHS), estimates of genetic contribution were computed using a variance components method implemented in SOLAR. Traits that exhibited significant heritabilities were body mass index (BMI) (h (2) = 0.43), waist circumference (h (2) = 0.48), systolic blood pressure (h (2) = 0.30), diastolic blood pressure (h (2) = 0.21), pulse pressure (h (2) = 0.32), triglycerides (h (2) = 0.51), LDL cholesterol (h (2) = 0.31), HDL cholesterol (h (2) = 0.24), C-reactive protein (h (2) = 0.17), and HOMA-IR (h (2) = 0.33). A genome-wide scan for HOMA-IR revealed significant evidence of linkage on chromosome 12q24 (close to PAH (phenylalanine hydroxylase), LOD = 3.01, p < 0.001). Bivariate analyses demonstrated significant genetic correlations (p < 0.05) of HOMA-IR with BMI (rho (G) = 0.36), waist circumference (rho (G) = 0.47), pulse pressure (rho (G) = 0.39), and HDL cholesterol (rho (G) = -0.18). Identification of significant linkage for HOMA-IR on chromosome 12q replicates previous family-based studies reporting linkage of phenotypes associated with type 2 diabetes in the same chromosomal region. Significant genetic correlations between HOMA-IR and phenotypes related to CVD risk factors suggest that a common set of gene(s) influence the regulation of these phenotypes.

Clinical Application of Epilepsy Genetics in Africa: Is Now the Time?

PubMed Central

Esterhuizen, Alina I.; Carvill, Gemma L.; Ramesar, Rajkumar S.; Kariuki, Symon M.; Newton, Charles R.; Poduri, Annapurna; Wilmshurst, Jo M.

2018-01-01

Over 80% of people with epilepsy live in low- to middle-income countries where epilepsy is often undiagnosed and untreated due to limited resources and poor infrastructure. In Africa, the burden of epilepsy is exacerbated by increased risk factors such as central nervous system infections, perinatal insults, and traumatic brain injury. Despite the high incidence of these etiologies, the cause of epilepsy in over 60% of African children is unknown, suggesting a possible genetic origin. Large-scale genetic and genomic research in Europe and North America has revealed new genes and variants underlying disease in a range of epilepsy phenotypes. The relevance of this knowledge to patient care is especially evident among infants with early-onset epilepsies, where early genetic testing can confirm the diagnosis and direct treatment, potentially improving prognosis and quality of life. In Africa, however, genetic epilepsies are among the most under-investigated neurological disorders, and little knowledge currently exists on the genetics of epilepsy among African patients. The increased diversity on the continent may yield unique, important epilepsy-associated genotypes, currently absent from the North American or European diagnostic testing protocols. In this review, we propose that there is strong justification for developing the capacity to offer genetic testing for children with epilepsy in Africa, informed mostly by the existing counseling and interventional needs. Initial simple protocols involving well-recognized epilepsy genes will not only help patients but will give rise to further clinically relevant research, thus increasing knowledge and capacity. PMID:29770117

Privacy-preserving genomic testing in the clinic: a model using HIV treatment

PubMed Central

McLaren, Paul J.; Raisaro, Jean Louis; Aouri, Manel; Rotger, Margalida; Ayday, Erman; Bartha, István; Delgado, Maria B.; Vallet, Yannick; Günthard, Huldrych F.; Cavassini, Matthias; Furrer, Hansjakob; Doco-Lecompte, Thanh; Marzolini, Catia; Schmid, Patrick; Di Benedetto, Caroline; Decosterd, Laurent A.; Fellay, Jacques; Hubaux, Jean-Pierre; Telenti, Amalio

2016-01-01

Purpose: The implementation of genomic-based medicine is hindered by unresolved questions regarding data privacy and delivery of interpreted results to health-care practitioners. We used DNA-based prediction of HIV-related outcomes as a model to explore critical issues in clinical genomics. Genet Med 18 8, 814–822. Methods: We genotyped 4,149 markers in HIV-positive individuals. Variants allowed for prediction of 17 traits relevant to HIV medical care, inference of patient ancestry, and imputation of human leukocyte antigen (HLA) types. Genetic data were processed under a privacy-preserving framework using homomorphic encryption, and clinical reports describing potentially actionable results were delivered to health-care providers. Genet Med 18 8, 814–822. Results: A total of 230 patients were included in the study. We demonstrated the feasibility of encrypting a large number of genetic markers, inferring patient ancestry, computing monogenic and polygenic trait risks, and reporting results under privacy-preserving conditions. The average execution time of a multimarker test on encrypted data was 865 ms on a standard computer. The proportion of tests returning potentially actionable genetic results ranged from 0 to 54%. Genet Med 18 8, 814–822. Conclusions: The model of implementation presented herein informs on strategies to deliver genomic test results for clinical care. Data encryption to ensure privacy helps to build patient trust, a key requirement on the road to genomic-based medicine. Genet Med 18 8, 814–822. PMID:26765343

Prediction of peripheral neuropathy in multiple myeloma patients receiving bortezomib and thalidomide: a genetic study based on a single nucleotide polymorphism array.

PubMed

García-Sanz, Ramón; Corchete, Luis Antonio; Alcoceba, Miguel; Chillon, María Carmen; Jiménez, Cristina; Prieto, Isabel; García-Álvarez, María; Puig, Noemi; Rapado, Immaculada; Barrio, Santiago; Oriol, Albert; Blanchard, María Jesús; de la Rubia, Javier; Martínez, Rafael; Lahuerta, Juan José; González Díaz, Marcos; Mateos, María Victoria; San Miguel, Jesús Fernando; Martínez-López, Joaquín; Sarasquete, María Eugenia

2017-12-01

Bortezomib- and thalidomide-based therapies have significantly contributed to improved survival of multiple myeloma (MM) patients. However, treatment-induced peripheral neuropathy (TiPN) is a common adverse event associated with them. Risk factors for TiPN in MM patients include advanced age, prior neuropathy, and other drugs, but there are conflicting results about the role of genetics in predicting the risk of TiPN. Thus, we carried out a genome-wide association study based on more than 300 000 exome single nucleotide polymorphisms in 172 MM patients receiving therapy involving bortezomib and thalidomide. We compared patients developing and not developing TiPN under similar treatment conditions (GEM05MAS65, NCT00443235). The highest-ranking single nucleotide polymorphism was rs45443101, located in the PLCG2 gene, but no significant differences were found after multiple comparison correction (adjusted P = .1708). Prediction analyses, cytoband enrichment, and pathway analyses were also performed, but none yielded any significant findings. A copy number approach was also explored, but this gave no significant results either. In summary, our study did not find a consistent genetic component associated with TiPN under bortezomib and thalidomide therapies that could be used for prediction, which makes clinical judgment essential in the practical management of MM treatment. Copyright © 2016 John Wiley & Sons, Ltd.

Association of genetic predisposition to obesity with type 2 diabetes risk in Han Chinese individuals.

PubMed

Zhu, Jingwen; Zong, Geng; Lu, Ling; Gan, Wei; Ji, Linong; Hu, Renming; Ye, Xingwang; Sun, Liang; Loos, Ruth J F; Li, Huaixing; Lin, Xu

2014-09-01

Obesity is a major risk factor for type 2 diabetes, but little is known about the contribution of BMI-associated loci to type 2 diabetes risk in East Asian populations. In this study, 30 known BMI-associated variants and a genetic risk score (GRS) calculated by summing the BMI-increasing alleles of these variants were tested for associations with type 2 diabetes and related glycaemic traits in 1,873 cases of type 2 diabetes and 1,839 controls in Han Chinese individuals. Logistic and linear regression analyses were performed to determine the association with type 2 diabetes risk or related glycaemic traits, respectively, under an additive model with or without adjustment for BMI. The GRS was significantly associated with increased BMI (β [SE] 0.070 [0.016]; p = 1.33 × 0(-5)) in the overall population. Each additional BMI-increasing allele in the GRS increased type 2 diabetes risk by 1.029-fold (95% CI 1.008, 1.050; p = 0.0056) without adjustment for BMI, and the association was slightly attenuated after adjustment for BMI (OR 1.022; 95% CI 1.002, 1.043; p = 0.035). In non-diabetic controls, the GRS was also associated with HOMA of beta cell function (HOMA-B) with adjustment for BMI (β [SE] -0.876 [0.345]; p = 0.011). Notably, the association of GRS with type 2 diabetes was abolished after adjusting for HOMA-B (OR 1.012; 95% CI 0.986, 1.039; p = 0.380). Our results suggested that genetic predisposition to obesity leads to increased risk of type 2 diabetes, independent of BMI and partly through impaired beta cell function.

Risks of allergic reactions to biotech proteins in foods: perception and reality.

PubMed

Lehrer, S B; Bannon, G A

2005-05-01

In recent years, significant attention has been paid to the use of biotechnology to improve the quality and quantity of the food supply due in part to the projected growth in the world population, plus limited options available for increasing the amount of land under cultivation. Alterations in the food supply induced by classical breeding and selection methods typically involve the movement of large portions of genomic DNA between different plant varieties to obtain the desired trait. This is in contrast to techniques of genetic engineering which allows the selection and transfers specific genes from one species to another. The primary allergy risk to consumers from genetically modified crops may be placed into one of three categories. The first represents the highest risk to the allergic consumer is the transfer of known allergen or cross-reacting allergen into a food crop. The second category, representing an intermediate risk to the consumer, is the potential for replacing the endogenous allergenicity of a genetically-modified crop. The last category involves expression of novel proteins that may become allergens in man and generally represents a relatively low risk to the consumer, although this possibility has received attention of late. In order to mitigate the three categories of potential allergy risk associated with biotech crops, all genes introduced into food crops undergo a series of tests designed to determine if the biotech protein exhibits properties of known food allergens. The result of this risk assessment process to date is that no biotech proteins in foods have been documented to cause allergic reactions. These results indicate that the current assessment process is robust, although as science of allergy and allergens evolves, new information and new technology should help further the assessment process for potential allergenicity.

A Non-Degenerate Code of Deleterious Variants in Mendelian Loci Contributes to Complex Disease Risk

PubMed Central

Blair, David R.; Lyttle, Christopher S.; Mortensen, Jonathan M.; Bearden, Charles F.; Jensen, Anders Boeck; Khiabanian, Hossein; Melamed, Rachel; Rabadan, Raul; Bernstam, Elmer V.; Brunak, Søren; Jensen, Lars Juhl; Nicolae, Dan; Shah, Nigam H.; Grossman, Robert L.; Cox, Nancy J.; White, Kevin P.; Rzhetsky, Andrey

2013-01-01

Summary Whereas countless highly penetrant variants have been associated with Mendelian disorders, the genetic etiologies underlying complex diseases remain largely unresolved. Here, we examine the extent to which Mendelian variation contributes to complex disease risk by mining the medical records of over 110 million patients. We detect thousands of associations between Mendelian and complex diseases, revealing a non-degenerate, phenotypic code that links each complex disorder to a unique collection of Mendelian loci. Using genome-wide association results, we demonstrate that common variants associated with complex diseases are enriched in the genes indicated by this “Mendelian code.” Finally, we detect hundreds of comorbidity associations among Mendelian disorders, and we use probabilistic genetic modeling to demonstrate that Mendelian variants likely contribute non-additively to the risk for a subset of complex diseases. Overall, this study illustrates a complementary approach for mapping complex disease loci and provides unique predictions concerning the etiologies of specific diseases. PMID:24074861

Genomic analyses of pneumococci from children with sickle cell disease expose host-specific bacterial adaptations and deficits in current interventions

PubMed Central

Muller, Martha; Obert, Caroline; Burnham, Corinna; Mann, Beth; Li, Yimei; Hayden, Randall T; Pestina, Tamara; Persons, Derek; Camilli, Andrew

2014-01-01

Summary Sickle cell disease (SCD) patients are at high risk of contracting pneumococcal infection. To address this risk, they receive pneumococcal vaccines, and antibiotic prophylaxis and treatment. To assess the impact of SCD and these interventions on pneumococcal genetic architecture, we examined the genomes of over 300 pneumococcal isolates from SCD patients over 20 years. Modern SCD strains retained invasive capacity but shifted away from the serotypes used in vaccines. These strains had specific genetic changes related to antibiotic resistance, capsule biosynthesis, metabolism and metal transport. A murine SCD model coupled with Tn-seq mutagenesis identified 60 non-capsular pneumococcal genes under differential selective pressure in SCD, which correlated with aspects of SCD pathophysiology. Further, virulence determinants in the SCD context were distinct from the general population and protective capacity of potential antigens was lost over time in SCD. This highlights the importance of understanding bacterial pathogenesis in the context of high-risk individuals. PMID:24832453

Toward an Integration of Cognitive and Genetic Models of Risk for Depression

PubMed Central

Gibb, Brandon E.; Beevers, Christopher G.; McGeary, John E.

2012-01-01

There is growing interest in integrating cognitive and genetic models of depression risk. We review two ways in which these models can be meaningfully integrated. First, information-processing biases may represent intermediate phenotypes for specific genetic influences. These genetic influences may represent main effects on specific cognitive processes or may moderate the impact of environmental influences on information-processing biases. Second, cognitive and genetic influences may combine to increase reactivity to environmental stressors, increasing risk for depression in a gene × cognition × environment model of risk. There is now growing support for both of these ways of integrating cognitive and genetic models of depression risk. Specifically, there is support for genetic influences on information-processing biases, particularly the link between 5-HTTLPR and attentional biases, from both genetic association and gene × environment (G × E) studies. There is also initial support for gene × cognition × environment models of risk in which specific genetic influences contribute to increased reactivity to environmental influences. We review this research and discuss important areas of future research, particularly the need for larger samples that allow for a broader examination of genetic and epigenetic influences as well as the combined influence of variability across a number of genes. PMID:22920216

Scientific reporting is suboptimal for aspects that characterize genetic risk prediction studies: a review of published articles based on the Genetic RIsk Prediction Studies statement.

PubMed

Iglesias, Adriana I; Mihaescu, Raluca; Ioannidis, John P A; Khoury, Muin J; Little, Julian; van Duijn, Cornelia M; Janssens, A Cecile J W

2014-05-01

Our main objective was to raise awareness of the areas that need improvements in the reporting of genetic risk prediction articles for future publications, based on the Genetic RIsk Prediction Studies (GRIPS) statement. We evaluated studies that developed or validated a prediction model based on multiple DNA variants, using empirical data, and were published in 2010. A data extraction form based on the 25 items of the GRIPS statement was created and piloted. Forty-two studies met our inclusion criteria. Overall, more than half of the evaluated items (34 of 62) were reported in at least 85% of included articles. Seventy-seven percentage of the articles were identified as genetic risk prediction studies through title assessment, but only 31% used the keywords recommended by GRIPS in the title or abstract. Seventy-four percentage mentioned which allele was the risk variant. Overall, only 10% of the articles reported all essential items needed to perform external validation of the risk model. Completeness of reporting in genetic risk prediction studies is adequate for general elements of study design but is suboptimal for several aspects that characterize genetic risk prediction studies such as description of the model construction. Improvements in the transparency of reporting of these aspects would facilitate the identification, replication, and application of genetic risk prediction models. Copyright © 2014 Elsevier Inc. All rights reserved.

Disclosing genetic risk for coronary heart disease: effects on perceived personal control and genetic counseling satisfaction.

PubMed

Robinson, C L; Jouni, H; Kruisselbrink, T M; Austin, E E; Christensen, K D; Green, R C; Kullo, I J

2016-02-01

We investigated whether disclosure of coronary heart disease (CHD) genetic risk influences perceived personal control (PPC) and genetic counseling satisfaction (GCS). Participants (n = 207, age: 45-65 years) were randomized to receive estimated 10-year risk of CHD based on a conventional risk score (CRS) with or without a genetic risk score (GRS). Risk estimates were disclosed by a genetic counselor who also reviewed how GRS altered risk in those randomized to CRS+GRS. Each participant subsequently met with a physician and then completed surveys to assess PPC and GCS. Participants who received CRS+GRS had higher PPC than those who received CRS alone although the absolute difference was small (25.2 ± 2.7 vs 24.1 ± 3.8, p = 0.04). A greater proportion of CRS+GRS participants had higher GCS scores (17.3 ± 5.3 vs 15.9 ± 6.3, p = 0.06). In the CRS+GRS group, PPC and GCS scores were not correlated with GRS. Within both groups, PPC and GCS scores were similar in patients with or without family history (p = NS). In conclusion, patients who received their genetic risk of CHD had higher PPC and tended to have higher GCS. Our findings suggest that disclosure of genetic risk of CHD together with conventional risk estimates is appreciated by patients. Whether this results in improved outcomes needs additional investigation. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Psychological and behavioral effects of genetic risk testing for obesity: a systematic review.

PubMed

Cheera, Emily K; Klarich, DawnKylee S; Hong, Mee Young

2016-05-01

Interest is growing in the use of genetic risk testing for lifestyle-related chronic diseases, including obesity, to promote health behavior change. A systematic review of the literature was conducted to determine the effects that genetic risk feedback for obesity may have on psychological and behavioral factors influencing weight. The MEDLINE/PubMed online database was searched using predefined search terms. The studies revealed that risk feedback may increase motivation to improve health behaviors, especially among individuals at higher genetic risk. Overweight and obese individuals seemed to experience additional psychological benefits when provided an external explanation for their weight status. While the psychological benefits are promising, the clinical utility of genetic risk testing for obesity remains uncertain.

The impact of multiplex genetic testing on disease risk perceptions.

PubMed

Shiloh, S; deHeer, H D; Peleg, S; Hensley Alford, S; Skapinsky, K; Roberts, J S; Hadley, D W

2015-02-01

This study assessed the effects of multiplex genetic testing on disease risk perceptions among 216 healthy adults. Participants, aged 25-40, were recruited through the Multiplex Initiative, which offered a genetic susceptibility test for eight common diseases. Participants completed baseline telephone and web-based surveys prior to making the testing decision. Three months after the receipt of mailed test results, participants completed a follow-up telephone survey. Risk perceptions for the eight diseases were measured at baseline and follow-up, along with beliefs about genetic causation of those diseases. The main results were: (i) mean risk perceptions were considerably stable from baseline to follow-up; (ii) the best predictors of follow-up risk perceptions were the corresponding baseline perceptions and family history; and (iii) within-individuals, most participants increased or decreased their risk perceptions for specific diseases in concordance with the number of risk markers they carry, their family history and their beliefs about genetic causality of diseases. In conclusion, participants presented a vigilant approach to the interpretation of genetic test results, which provides reassurance with regard to a potential inflation of risk perceptions in the population because of multiplex genetic testing. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Effect of genetic testing for risk of type 2 diabetes mellitus on health behaviors and outcomes: study rationale, development and design.

PubMed

Cho, Alex H; Killeya-Jones, Ley A; O'Daniel, Julianne M; Kawamoto, Kensaku; Gallagher, Patrick; Haga, Susanne; Lucas, Joseph E; Trujillo, Gloria M; Joy, Scott V; Ginsburg, Geoffrey S

2012-01-18

Type 2 diabetes is a prevalent chronic condition globally that results in extensive morbidity, decreased quality of life, and increased health services utilization. Lifestyle changes can prevent the development of diabetes, but require patient engagement. Genetic risk testing might represent a new tool to increase patients' motivation for lifestyle changes. Here we describe the rationale, development, and design of a randomized controlled trial (RCT) assessing the clinical and personal utility of incorporating type 2 diabetes genetic risk testing into comprehensive diabetes risk assessments performed in a primary care setting. Patients are recruited in the laboratory waiting areas of two primary care clinics and enrolled into one of three study arms. Those interested in genetic risk testing are randomized to receive either a standard risk assessment (SRA) for type 2 diabetes incorporating conventional risk factors plus upfront disclosure of the results of genetic risk testing ("SRA+G" arm), or the SRA alone ("SRA" arm). Participants not interested in genetic risk testing will not receive the test, but will receive SRA (forming a third, "no-test" arm). Risk counseling is provided by clinic staff (not study staff external to the clinic). Fasting plasma glucose, insulin levels, body mass index (BMI), and waist circumference are measured at baseline and 12 months, as are patients' self-reported behavioral and emotional responses to diabetes risk information. Primary outcomes are changes in insulin resistance and BMI after 12 months; secondary outcomes include changes in diet patterns, physical activity, waist circumference, and perceived risk of developing diabetes. The utility, feasibility, and efficacy of providing patients with genetic risk information for common chronic diseases in primary care remain unknown. The study described here will help to establish whether providing type 2 diabetes genetic risk information in a primary care setting can help improve patients' clinical outcomes, risk perceptions, and/or their engagement in healthy behavior change. In addition, study design features such as the use of existing clinic personnel for risk counseling could inform the future development and implementation of care models for the use of individual genetic risk information in primary care. ClinicalTrials.gov: NCT00849563.

High-risk individuals' perceptions of reproductive genetic testing for CDH1 mutations.

PubMed

Hallowell, Nina; Badger, Shirlene; Richardson, Sue; Caldas, Carlos; Hardwick, Richard H; Fitzgerald, Rebecca C; Lawton, Julia

2017-10-01

Reproductive genetic testing- PreNatal Diagnosis (PND) and Preimplantation Genetic Diagnosis (PGD)-for CDH1 mutations associated with Hereditary Diffuse Gastric Cancer (HDGC)is available in the UK. This qualitative interview study examined high-risk individuals' (n = 35) views of CDH1 reproductive genetic testing. Interviewees generally regarded reproductive genetic testing as an acceptable form of HDGC risk management. However, some were concerned that their genetic risks required them to plan reproduction and anticipated difficulties communicating this to reproductive partners. Individuals had a preference for PGD over PND because it avoided the need for a termination of pregnancy. However, those who had not yet had children expressed concerns about having to undergo IVF procedures and worries about their effectiveness and the need for embryo selection in PGD. It is suggested that high-risk individuals are provided with access to reproductive genetic counselling.

Genetic susceptibility to lung cancer—light at the end of the tunnel?

PubMed Central

Christiani, David C.

2013-01-01

Lung cancer is one of the most common and deadliest cancers in the world. The major socio-environmental risk factor involved in the development of lung cancer is cigarette smoking. Additionally, there are multiple genetic factors, which may also play a role in lung cancer risk. Early work focused on the presence of relatively prevalent but low-penetrance alterations in candidate genes leading to increased risk of lung cancer. Development of new technologies such as genomic profiling and genome-wide association studies has been helpful in the detection of new genetic variants likely involved in lung cancer risk. In this review, we discuss the role of multiple genetic variants and review their putative role in the risk of lung cancer. Identifying genetic biomarkers and patterns of genetic risk may be useful in the earlier detection and treatment of lung cancer patients. PMID:23349013

Health care professionals' attitudes towards population-based genetic testing and risk-stratification for ovarian cancer: a cross-sectional survey.

PubMed

Hann, Katie E J; Fraser, Lindsay; Side, Lucy; Gessler, Sue; Waller, Jo; Sanderson, Saskia C; Freeman, Madeleine; Jacobs, Ian; Lanceley, Anne

2017-12-16

Ovarian cancer is usually diagnosed at a late stage when outcomes are poor. Personalised ovarian cancer risk prediction, based on genetic and epidemiological information and risk stratified management in adult women could improve outcomes. Examining health care professionals' (HCP) attitudes to ovarian cancer risk stratified management, willingness to support women, self-efficacy (belief in one's own ability to successfully complete a task), and knowledge about ovarian cancer will help identify training needs in anticipation of personalised ovarian cancer risk prediction being introduced. An anonymous survey was distributed online to HCPs via relevant professional organisations in the UK. Kruskal-Wallis tests and pairwise comparisons were used to compare knowledge and self-efficacy scores between different types of HCPs, and attitudes toward population-based genetic testing and risk stratified management were described. Content analysis was undertaken of free text responses concerning HCPs willingness to discuss risk management options with women. One hundred forty-six eligible HCPs completed the survey: oncologists (31%); genetics clinicians (30%); general practitioners (22%); gynaecologists (10%); nurses (4%); and 'others'. Scores for knowledge of ovarian cancer and genetics, and self-efficacy in conducting a cancer risk consultation were generally high but significantly lower for general practitioners compared to genetics clinicians, oncologists, and gynaecologists. Support for population-based genetic testing was not high (<50%). Attitudes towards ovarian cancer risk stratification were mixed, although the majority of participants indicated a willingness to discuss management options with patients. Larger samples are required to investigate attitudes to population-based genetic testing for ovarian cancer risk and to establish why some HCPs are hesitant to offer testing to all adult female patients. If ovarian cancer risk assessment using genetic testing and non-genetic information including epidemiological information is rolled out on a population basis, training will be needed for HCPs in primary care to enable them to provide appropriate support to women at each stage of the process.

Shared Genetic Architecture in the Relationship between Adult Stature and Subclinical Coronary Artery Atherosclerosis

PubMed Central

Cassidy-Bushrow, Andrea E.; Bielak, Lawrence F.; Sheedy, Patrick F.; Turner, Stephen T.; Chu, Julia S.; Peyser, Patricia A.

2011-01-01

Background Short stature is associated with increased risk of coronary heart disease (CHD); although the mechanisms for this relationship are unknown, shared genetic factors have been proposed. Subclinical atherosclerosis, measured by coronary artery calcification (CAC), is associated with CHD events and represents part of the biological continuum to overt CHD. Many molecular mechanisms of CAC development are shared with bone growth. Thus, we examined whether there was evidence of shared genes (pleiotropy) between adult stature and CAC. Methods 877 asymptomatic white adults (46% men) from 625 families in a community-based sample had computed tomography measures of CAC. Pleiotropy between height and CAC was determined using maximum-likelihood estimation implemented in SOLAR. Results Adult height was significantly and inversely associated with CAC score (P=0.01). After adjusting for age, sex, and CHD risk factors, the estimated genetic correlation between height and CAC score was -0.37 and was significantly different than 0 (P=0.001) and -1 (P<0.001). The environmental correlation between height and CAC score was 0.60 and was significantly different than 0 (P=0.024). Conclusions Further studies of shared genetic factors between height and CAC may provide important insight into the complex genetic architecture of CHD, in part through increased understanding of the molecular pathways underlying the process of both normal growth and disease development. Bivariate genetic linkage analysis may provide a powerful mechanism for identifying specific genomic regions associated with both height and CAC. PMID:21937044

Shared genetic architecture in the relationship between adult stature and subclinical coronary artery atherosclerosis.

PubMed

Cassidy-Bushrow, Andrea E; Bielak, Lawrence F; Sheedy, Patrick F; Turner, Stephen T; Chu, Julia S; Peyser, Patricia A

2011-12-01

Short stature is associated with increased risk of coronary heart disease (CHD); although the mechanisms for this relationship are unknown, shared genetic factors have been proposed. Subclinical atherosclerosis, measured by coronary artery calcification (CAC), is associated with CHD events and represents part of the biological continuum to overt CHD. Many molecular mechanisms of CAC development are shared with bone growth. Thus, we examined whether there was evidence of shared genes (pleiotropy) between adult stature and CAC. 877 Asymptomatic white adults (46% men) from 625 families in a community-based sample had computed tomography measures of CAC. Pleiotropy between height and CAC was determined using maximum-likelihood estimation implemented in SOLAR. Adult height was significantly and inversely associated with CAC score (P = 0.01). After adjusting for age, sex and CHD risk factors, the estimated genetic correlation between height and CAC score was -0.37 and was significantly different than 0 (P = 0.001) and -1 (P < 0.001). The environmental correlation between height and CAC score was 0.60 and was significantly different than 0 (P = 0.024). Further studies of shared genetic factors between height and CAC may provide important insight into the complex genetic architecture of CHD, in part through increased understanding of the molecular pathways underlying the process of both normal growth and disease development. Bivariate genetic linkage analysis may provide a powerful mechanism for identifying specific genomic regions associated with both height and CAC. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

The efficiency of close inbreeding to reduce genetic adaptation to captivity

PubMed Central

Theodorou, K; Couvet, D

2015-01-01

Although ex situ conservation is indispensable for thousands of species, captive breeding is associated with negative genetic changes: loss of genetic variance and genetic adaptation to captivity that is deleterious in the wild. We used quantitative genetic individual-based simulations to model the effect of genetic management on the evolution of a quantitative trait and the associated fitness of wild-born individuals that are brought to captivity. We also examined the feasibility of the breeding strategies under a scenario of a large number of loci subject to deleterious mutations. We compared two breeding strategies: repeated half-sib mating and a method of minimizing mean coancestry (referred to as gc/mc). Our major finding was that half-sib mating is more effective in reducing genetic adaptation to captivity than the gc/mc method. Moreover, half-sib mating retains larger allelic and adaptive genetic variance. Relative to initial standing variation, the additive variance of the quantitative trait increased under half-sib mating during the sojourn in captivity. Although fragmentation into smaller populations improves the efficiency of the gc/mc method, half-sib mating still performs better in the scenarios tested. Half-sib mating shows two caveats that could mitigate its beneficial effects: low heterozygosity and high risk of extinction when populations are of low fecundity and size and one of the following conditions are met: (i) the strength of selection in captivity is comparable with that in the wild, (ii) deleterious mutations are numerous and only slightly deleterious. Experimental validation of half-sib mating is therefore needed for the advancement of captive breeding programs. PMID:25052417

Disclosure of genetics research results after the death of the patient participant: a qualitative study of the impact on relatives.

PubMed

Ormondroyd, E; Moynihan, C; Watson, M; Foster, C; Davolls, S; Ardern-Jones, A; Eeles, R

2007-08-01

When a gene mutation is identified in a research study following the death of the study participant, it is not clear whether such information should be made available to relatives. We report here an evaluation of the impact on relatives of being informed of study results that detected pathogenic BRCA2 mutations in a male relative, now deceased, who had early onset (under the age of 55) prostate cancer. The breast and ovarian cancer risk was unknown to the living relatives. Qualitative analysis of interviews with thirteen relatives indicated that those who had a higher risk perception, resulting from an awareness of cancer family history or experiential knowledge of cancer in their family, tended to adjust more easily to the results. All participants believed that genetics research results of clinical significance should be fed back to relatives. Those who were fully aware of the BRCA2 results and implications for themselves felt they had benefited from the information, irrespective of whether or not they had elected for genetic testing, because of the consequent availability of surveillance programs. Initial anxiety upon learning about the BRCA2 result was alleviated by genetic counselling. Factors influencing those who have not engaged with the information included scepticism related to the relative who attempted to inform them, young age and fear of cancer. Those who had not sought genetic counselling did not attempt further dissemination, and some were not undergoing regular screening. Implications for informed consent in genetics research programs, and the requirement for genetic counselling when research results are disclosed, are discussed.

Genetic control of the alternative pathway of complement in humans and age-related macular degeneration

PubMed Central

Hecker, Laura A.; Edwards, Albert O.; Ryu, Euijung; Tosakulwong, Nirubol; Baratz, Keith H.; Brown, William L.; Issa, Peter Charbel; Scholl, Hendrik P.; Pollok-Kopp, Beatrix; Schmid-Kubista, Katharina E.; Bailey, Kent R.; Oppermann, Martin

2010-01-01

Activation of the alternative pathway of complement is implicated in common neurodegenerative diseases including age-related macular degeneration (AMD). We explored the impact of common variation in genes encoding proteins of the alternative pathway on complement activation in human blood and in AMD. Genetic variation across the genes encoding complement factor H (CFH), factor B (CFB) and component 3 (C3) was determined. The influence of common haplotypes defining transcriptional and translational units on complement activation in blood was determined in a quantitative genomic association study. Individual haplotypes in CFH and CFB were associated with distinct and novel effects on plasma levels of precursors, regulators and activation products of the alternative pathway of complement in human blood. Further, genetic variation in CFH thought to influence cell surface regulation of complement did not alter plasma complement levels in human blood. Plasma markers of chronic activation (split-products Ba and C3d) and an activating enzyme (factor D) were elevated in AMD subjects. Most of the elevation in AMD was accounted for by the genetic variation controlling complement activation in human blood. Activation of the alternative pathway of complement in blood is under genetic control and increases with age. The genetic variation associated with increased activation of complement in human blood also increased the risk of AMD. Our data are consistent with a disease model in which genetic variation in the complement system increases the risk of AMD by a combination of systemic complement activation and abnormal regulation of complement activation in local tissues. PMID:19825847

Genome-wide association studies in Alzheimer disease.

PubMed

Waring, Stephen C; Rosenberg, Roger N

2008-03-01

The genetics of Alzheimer disease (AD) to date support an age-dependent dichotomous model whereby earlier age of disease onset (< 60 years) is explained by 3 fully penetrant genes (APP [NCBI Entrez gene 351], PSEN1 [NCBI Entrez gene 5663], and PSEN2 [NCBI Entrez gene 5664]), whereas later age of disease onset (> or = 65 years) representing most cases of AD has yet to be explained by a purely genetic model. The APOE gene (NCBI Entrez gene 348) is the strongest genetic risk factor for later onset, although it is neither sufficient nor necessary to explain all occurrences of disease. Numerous putative genetic risk alleles and genetic variants have been reported. Although all have relevance to biological mechanisms that may be associated with AD pathogenesis, they await replication in large representative populations. Genome-wide association studies have emerged as an increasingly effective tool for identifying genetic contributions to complex diseases and represent the next frontier for furthering our understanding of the underlying etiologic, biological, and pathologic mechanisms associated with chronic complex disorders. There have already been success stories for diseases such as macular degeneration and diabetes mellitus. Whether this will hold true for a genetically complex and heterogeneous disease such as AD is not known, although early reports are encouraging. This review considers recent publications from studies that have successfully applied genome-wide association methods to investigations of AD by taking advantage of the currently available high-throughput arrays, bioinformatics, and software advances. The inherent strengths, limitations, and challenges associated with study design issues in the context of AD are presented herein.

Chromosome 15q25.1 genetic markers associated with level of response to alcohol in humans.

PubMed

Joslyn, Geoff; Brush, Gerry; Robertson, Margaret; Smith, Tom L; Kalmijn, Jelger; Schuckit, Marc; White, Raymond L

2008-12-23

As with other genetically complex common psychiatric and medical conditions, multiple genetic and environmental components contribute to alcohol use disorders (AUDs), which can confound attempts to identify genetic components. Intermediate phenotypes are often more closely correlated with underlying biology and have often proven invaluable in genetic studies. Level of response (LR) to alcohol is an intermediate phenotype for AUDs, and individuals with a low LR are at increased risk. A high rate of concurrent alcohol and nicotine use and dependence suggests that these conditions may share biochemical and genetic mechanisms. Genetic association studies indicate that a genetic locus, which includes the CHRNA5-CHRNA3-CHRNB4 gene cluster, plays a role in nicotine consumption and dependence. Genetic association with alcohol dependence was also recently shown. We show here that two of the markers from the nicotine studies also show an association (multiple testing corrected P < 0.025) with several LR phenotypes in a sample of 367 siblings. Additional markers in the region were analyzed and shown to be located in a 250-kb expanse of high linkage disequilibrium containing three additional genes. These findings indicate that LR intermediate phenotypes have utility in genetic approaches to AUDs and will prove valuable in the identification of other genetic loci conferring susceptibility to AUDs.

Structured Parenting of Toddlers at High versus Low Genetic Risk: Two Pathways to Child Problems

ERIC Educational Resources Information Center

Leve, Leslie D.; Harold, Gordon T.; Ge, Xiaojia; Neiderhiser, Jenae M.; Shaw, Daniel; Scaramella, Laura V.; Reiss, David

2009-01-01

Objective: Little is known about how parenting might offset genetic risk to prevent the onset of child problems during toddlerhood. We used a prospective adoption design to separate genetic and environmental influences and test whether associations between structured parenting and toddler behavior problems were conditioned by genetic risk for…

Congenital hearing loss

PubMed Central

Korver, Anna M. H.; Smith, Richard J. H.; Van Camp, Guy; Schleiss, Mark R.; Bitner-Glindzicz, Maria A. K.; Lustig, Lawrence R.; Usami, Shin-ichi; Boudewyns, An N.

2017-01-01

Congenital hearing loss (hearing loss present at birth) is one of the most prevalent chronic conditions in children. In the majority of developed countries, neonatal hearing-screening programmes enable early detection; early intervention will prevent delays in speech and language development and have long-lasting beneficial effects on social and emotional development and quality of life. A hearing loss diagnosis is usually followed by a search for an underlying aetiology. Congenital hearing loss might be attributed to environmental and prenatal factors, which prevail in low-income settings; congenital infections, particularly cytomegalovirus, are also a common risk factor for hearing loss. Genetic causes probably account for the majority of cases in developed countries; mutations can affect any component of the hearing pathway, in particular inner ear homeostasis (endolymph production and maintenance) and mechano-electrical transduction (conversion of a mechanical stimulus into electrochemical activity). Once the underlying cause of hearing loss is established, it might direct therapeutic decision-making and guide prevention and (genetic) counseling. Management options include specific antimicrobial therapies, surgical treatment of cranio-facial abnormalities and hearing aids. An improved understanding of the pathophysiology and molecular mechanisms underlying hearing loss and increased awareness of recent advances in genetic testing will promote the development of new treatment and screening strategies. PMID:28079113

Analysis of Genetic and Environmental Risk Factors and Their Interactions in Korean Patients with Age-Related Macular Degeneration.

PubMed

Woo, Se Joon; Ahn, Jeeyun; Morrison, Margaux A; Ahn, So Yeon; Lee, Jaebong; Kim, Ki Woong; DeAngelis, Margaret M; Park, Kyu Hyung

2015-01-01

To investigate the association of genetic and environmental factors, and their interactions in Korean patients with exudative age-related macular degeneration (AMD). A total of 314 robustly characterized exudative AMD patients, including 111 PCV (polypoidal choroidal vasculopathy) and 154 typical choroidal neovascularization (CNV), and 395 control subjects without any evidence of AMD were enrolled. Full ophthalmologic examinations including fluorescein angiography (FA), indocyanine green angiography (ICG) and optical coherence tomography (OCT) were done, according to which patients were divided into either PCV or typical CNV. Standardized questionnaires were used to collect information regarding underlying systemic diseases, dietary habits, smoking history and body mass index (BMI). A total of 86 SNPs from 31 candidate genes were analyzed. Genotype association and logistic regression analyses were done and stepwise regression models to best predict disease for each AMD subtype were constructed. Age, spherical equivalent, myopia, and ever smoking were associated with exudative AMD. Age, hypertension, hyperlipidemia, spherical equivalent, and myopia were risk factors for typical CNV, while increased education and ever smoking were significantly associated with PCV (p<.05 for all). Four SNPs, ARMS2/HTRA1 rs10490924, rs11200638, and rs2736911, and CFH rs800292, showed association with exudative AMD. Two of these SNPs, ARMS2/HTRA1 rs10490924 and rs11200638, showed significant association with typical CNV and PCV specifically. There were no significant interactions between environmental and genetic factors. The most predictive disease model for exudative AMD included age, spherical equivalent, smoking, CFH rs800292, and ARMS2 rs10490924 while that for typical CNV included age, hyperlipidemia, spherical equivalent, and ARMS2 rs10490924. Smoking, spherical equivalent, and ARMS2 rs10490924 were the most predictive variables for PCV. When comparing PCV cases to CNV cases, age, BMI, and education were the most predictive risk factors of PCV. Only one locus, the ARMS2/HTRA1 was a significant genetic risk factor for Korean exudative AMD, including its subtypes, PCV and typical CNV. Stepwise regression revealed that CFH was important to risk of exudative AMD in general but not to any specific subtype. While increased education was a unique risk factor to PCV when compared to CNV, this association was independent of refractive error in this homogenous population from South Korea. No significant interactions between environmental and genetic risk factors were observed.

Communication of Information about Genetic Risks: Putting Families at the Center.

PubMed

Mendes, Álvaro; Metcalfe, Alison; Paneque, Milena; Sousa, Liliana; Clarke, Angus J; Sequeiros, Jorge

2017-07-16

Genetic information is a family affair. With the expansion of genomic technologies, many new causal genes and variants have been established and the potential for molecular diagnoses increased, with implications not only for patients but also their relatives. The need for genetic counseling and intrafamilial circulation of information on genetic risks grew accordingly. Also, the amount and, particularly, the complexity of the information to convey multiplied. Sharing information about genetic risks with family members, however, has never been an easy matter and often becomes a source of personal and familial conflicts and distress. Ethical requisites generally prevent healthcare professionals from directly contacting their consultands' relatives (affected or still at risk), who often feel unsupported throughout that process. We discuss here the communication of genetic risks to family members. We first consider genomic testing as a basis for family-centered health care, as opposed to a predominant focus on the individual. We reviewed the literature on sharing genetic risk information with family members, and the associated ethical issues for professionals. Some clinical cases are presented and discussed, and key issues for meeting the needs of individuals and families are addressed. We argue that genetic information is inextricably linked to the family and that communicating about genetic risks is a process grounded within the broader milieu of family relationships and functioning. We conclude for the need for a more family-centered approach and interventions that can promote sensitive attitudes to the provision of genetic information to and within the family, as well as its inclusion in educational and training programmes for genetic healthcare professionals. © 2017 Family Process Institute.

Polygenic susceptibility to testicular cancer: implications for personalised health care.

PubMed

Litchfield, Kevin; Mitchell, Jonathan S; Shipley, Janet; Huddart, Robert; Rajpert-De Meyts, Ewa; Skakkebæk, Niels E; Houlston, Richard S; Turnbull, Clare

2015-11-17

The increasing incidence of testicular germ cell tumour (TGCT) combined with its strong heritable basis suggests that stratified screening for the early detection of TGCT may be clinically useful. We modelled the efficiency of such a personalised screening approach, based on genetic risk profiling in combination with other diagnostic tools. We compared the number of cases potentially detectable in the population under a number of screening models. The polygenic risk scoring (PRS) model was assumed to have a log-normal relative risk distribution across the 19 currently known TGCT susceptibility variants. The diagnostic performance of testicular biopsy and non-invasive semen analysis was also assessed, within a simulated combined screening programme. The area under the curve for the TGCT PRS model was 0.72 with individuals in the top 1% of the PRS having a nine-fold increased TGCT risk compared with the population median. Results from population-screening simulations only achieved a maximal positive predictive value (PPV) of 60%, highlighting broader clinical factors that challenge such strategies, not least the rare nature of TGCT. In terms of future improvements, heritability estimates suggest that a significant number of additional genetic risk factors for TGCT remain to be discovered, identification of which would potentially yield improvement of the PPV to 80-90%. While personalised screening models may offer enhanced TGCT risk discrimination, presently the case for population-level testing is not compelling. However, future advances, such as more routine generation of whole genome data is likely to alter the landscape. More targeted screening programs may plausibly then offer clinical benefit, particularly given the significant survivorship issues associated with the successful treatment of TGCT.

Pooling-analysis on hMLH1 polymorphisms and cancer risk: evidence based on 31,484 cancer cases and 45,494 cancer-free controls.

PubMed

Li, Sha; Zheng, Yi; Tian, Tian; Wang, Meng; Liu, Xinghan; Liu, Kang; Zhai, Yajing; Dai, Cong; Deng, Yujiao; Li, Shanli; Dai, Zhijun; Lu, Jun

2017-11-03

To elucidate the veritable relationship between three hMLH1 polymorphisms (rs1800734, rs1799977, rs63750447) and cancer risk, we performed this meta-analysis based on overall published data up to May 2017, from PubMed, Web of knowledge, VIP, WanFang and CNKI database, and the references of the original studies or review articles. 57 publications including 31,484 cancer cases and 45,494 cancer-free controls were obtained. The quality assessment of six articles obtained a summarized score less than 6 in terms of the Newcastle-Ottawa Scale (NOS). All statistical analyses were calculated with the software STATA (Version 14.0; Stata Corp, College Station, TX). We found all the three polymorphisms can enhance overall cancer risk, especially in Asians, under different genetic comparisons. In the subgroup analysis by cancer type, we found a moderate association between rs1800734 and the risk of gastric cancer (allele model: OR = 1.14, P = 0.017; homozygote model: OR = 1.33, P = 0.019; dominant model: OR = 1.27, P = 0.024) and lung cancer in recessive model (OR = 1.27, P = 0.024). The G allele of rs1799977 polymorphism was proved to connect with susceptibility of colorectal cancer (allele model: OR = 1.21, P = 0.023; dominate model: OR = 1.32, P <0.0001) and prostate cancer (dominate model: OR = 1.36, P <0.0001). Rs63750447 showed an increased risk of colorectal cancer, endometrial cancer and gastric cancer under all genetic models. These findings provide evidence that hMLH1 polymorphisms may associate with cancer risk, especially in Asians.

Polygenic Risk, Personality Dimensions, and Adolescent Alcohol Use Problems: A Longitudinal Study

PubMed Central

Li, James J.; Savage, Jeanne E.; Kendler, Kenneth S.; Hickman, Matthew; Mahedy, Liam; Macleod, John; Kaprio, Jaakko; Rose, Richard J.; Dick, Danielle M.

2017-01-01

Objective: Alcohol use problems are common during adolescence and can predict serious negative outcomes in adulthood, including substance dependence and psychopathology. The current study examines the notion that alcohol use problems are driven by polygenic influences and that genetic influences may indirectly affect alcohol use problems through multiple pathways of risk, including variations in personality. Method: We used a genome-wide approach to examine associations between genetic risk for alcohol use problems, personality dimensions, and adolescent alcohol use problems in two separate longitudinal population-based samples, the Finnish Twin Cohort (FinnTwin12) and the Avon Longitudinal Study of Parents and Children (ALSPAC). Participants were 1,035 young adults from FinnTwin12 and 3,160 adolescents from ALSPAC. Polygenic risk scores (PRS) were calculated for ALSPAC using genome-wide association results (on alcohol dependence symptoms as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) from FinnTwin12. A parallel multiple mediator model was tested to examine whether the association between PRS and alcohol use problems assessed at age 16 could be explained by variations in personality dimensions assessed at age 13, including sensation seeking and negative emotionality. Results: PRS were marginally predictive of age 16 alcohol use problems; this association was partially mediated by sensation seeking. Polygenic variation underlying risk for alcohol use problems may directly influence the effects of sensation seeking, which in turn influence the development of alcohol use problems in later adolescence. Conclusions: These findings contribute to the increasing evidence regarding the salience of sensation seeking during early adolescence as a potential constituent in the risk pathway underlying the development of alcohol use problems. PMID:28499112

Autism Spectrum Disorder (ASD) and Fragile X Syndrome (FXS): Two Overlapping Disorders Reviewed through Electroencephalography—What Can be Interpreted from the Available Information?

PubMed Central

Mc Devitt, Niamh; Gallagher, Louise; Reilly, Richard B.

2015-01-01

Autism Spectrum Disorder (ASD) and Fragile X syndrome (FXS) are neurodevelopmental disorders with different but potentially related neurobiological underpinnings, which exhibit significant overlap in their behavioural symptoms. FXS is a neurogenetic disorder of known cause whereas ASD is a complex genetic disorder, with both rare and common genetic risk factors and likely genetic and environmental interaction effects. A comparison of the phenotypic presentation of the two disorders may highlight those symptoms that are more likely to be under direct genetic control, for example in FXS as opposed to shared symptoms that are likely to be under the control of multiple mechanisms. This review is focused on the application and analysis of electroencephalography data (EEG) in ASD and FXS. Specifically, Event Related Potentials (ERP) and resting state studies (rEEG) studies investigating ASD and FXS cohorts are compared. This review explores the electrophysiological similarities and differences between the two disorders in addition to the potentially associated neurobiological mechanisms at play. A series of pertinent research questions which are suggested in the literature are also posed within the review. PMID:25826237

Obesity and diabetes genes are associated with being born small for gestational age: Results from the Auckland Birthweight Collaborative study

PubMed Central

2010-01-01

Background Individuals born small for gestational age (SGA) are at increased risk of rapid postnatal weight gain, later obesity and diseases in adulthood such as type 2 diabetes, hypertension and cardiovascular diseases. Environmental risk factors for SGA are well established and include smoking, low pregnancy weight, maternal short stature, maternal diet, ethnic origin of mother and hypertension. However, in a large proportion of SGA, no underlying cause is evident, and these individuals may have a larger genetic contribution. Methods In this study we tested the association between SGA and polymorphisms in genes that have previously been associated with obesity and/or diabetes. We undertook analysis of 54 single nucleotide polymorphisms (SNPs) in 546 samples from the Auckland Birthweight Collaborative (ABC) study. 227 children were born small for gestational age (SGA) and 319 were appropriate for gestational age (AGA). Results and Conclusion The results demonstrated that genetic variation in KCNJ11, BDNF, PFKP, PTER and SEC16B were associated with SGA and support the concept that genetic factors associated with obesity and/or type 2 diabetes are more prevalent in those born SGA compared to those born AGA. We have previously determined that environmental factors are associated with differences in birthweight in the ABC study and now we have demonstrated a significant genetic contribution, suggesting that the interaction between genetics and the environment are important. PMID:20712903

Developing a broad categorisation scheme to describe risk factors for mental illness, for use in prevention policy and planning.

PubMed

Furber, Gareth; Leach, Matthew; Guy, Sophie; Segal, Leonie

2017-03-01

The prevention of mental illness involves identifying and modifying those characteristics and exposures of an individual that threaten their mental health - commonly referred to as risk factors. Existing categorisations of risk factors for mental illness are either limited in their scope or oversimplified in their description. As part of a large mental health workforce and service planning project, we set out to develop a more detailed and comprehensive categorisation scheme to describe risk factors for mental illness. We conducted a rapid review of MEDLINE and Google Scholar for meta-analytic studies that examined the characteristics and exposures that typify the population with mental illness in order to identify and categorise potential risk factors. The search uncovered 1628 relevant studies, from which 10 primary and 23 secondary categories of risk factors were identified, ranging from genetic and biomedical to psychological and sociocultural. The review revealed interesting distortions in the focus of the literature, with the majority of studies focused on a few disorders (schizophrenia, depression and neurodegenerative disorders) and genetic, psychological and physiological risks. In contrast, environmental (e.g. media exposure) and occupational (e.g. employee health) were under-represented. The categorisation scheme developed in this paper is a step towards a more detailed taxonomy of risk factors for mental illness; this will be most useful in guiding clinicians, researchers and policy-makers in driving the prevention agenda forward.

Psychological study of in vitro fertilization-embryo transfer participants' attitudes toward the destiny of their supernumerary embryos.

PubMed

Laruelle, C; Englert, Y

1995-05-01

To study the motivations underlying IVF-ET participants' choice to donate or destroy their supernumerary embryos. Couples' opinions are studied through a questionnaire and a psychological interview. Two hundred couples about to undergo IVF-ET. The fertility unit of an academic hospital. Couples' choice for supernumerary embryos' destiny; opinions on embryo status, on importance of genetic lineage in the filial bonding, on gamete donation, and on multiple pregnancy risk. Donation is the most frequent choice but destruction is tolerated by almost all the couples (92%). Couples considering the embryo as a child choose destruction as frequently as donation but refuse experimentation on the embryo. Donation is highest among couples who stress education more than genetic lineage in parental bonding. This is confirmed by the choice of the couples requiring donor gametes. Couples express differing attitudes toward risks of twins and risks of triplets: twins are much more desired than triplets, which are frequently refused. Couples' opinions on the respective importance of genetic lineage and education in defining parental bonding are more determinant in their decision to destroy or to donate their supernumerary embryos than their opinions on the in vitro embryo status, which only determines their attitude toward experimentation.

Should patients with ocular genetic disorders have genetic testing?

PubMed

Zanolli, Mario T; Khetan, Vikas; Dotan, Gad; Pizzi, Laura; Levin, Alex V

2014-09-01

To discuss the risks, benefits and value of genetic testing for ocular genetic disease. Testing for ocular genetics diseases is becoming more available and successful gene therapy is being reported. Clinicians must prepare for this trend by considering diagnostic genetic testing for their patients. As advances continually occur in genetic testing for ocular genetic disorders, clinicians must develop an understanding of the potential risks and benefits for their patients.

Consequences of the genetic threshold model for observing partial migration under climate change scenarios.

PubMed

Cobben, Marleen M P; van Noordwijk, Arie J

2017-10-01

Migration is a widespread phenomenon across the animal kingdom as a response to seasonality in environmental conditions. Partially migratory populations are populations that consist of both migratory and residential individuals. Such populations are very common, yet their stability has long been debated. The inheritance of migratory activity is currently best described by the threshold model of quantitative genetics. The inclusion of such a genetic threshold model for migratory behavior leads to a stable zone in time and space of partially migratory populations under a wide range of demographic parameter values, when assuming stable environmental conditions and unlimited genetic diversity. Migratory species are expected to be particularly sensitive to global warming, as arrival at the breeding grounds might be increasingly mistimed as a result of the uncoupling of long-used cues and actual environmental conditions, with decreasing reproduction as a consequence. Here, we investigate the consequences for migratory behavior and the stability of partially migratory populations under five climate change scenarios and the assumption of a genetic threshold value for migratory behavior in an individual-based model. The results show a spatially and temporally stable zone of partially migratory populations after different lengths of time in all scenarios. In the scenarios in which the species expands its range from a particular set of starting populations, the genetic diversity and location at initialization determine the species' colonization speed across the zone of partial migration and therefore across the entire landscape. Abruptly changing environmental conditions after model initialization never caused a qualitative change in phenotype distributions, or complete extinction. This suggests that climate change-induced shifts in species' ranges as well as changes in survival probabilities and reproductive success can be met with flexibility in migratory behavior at the species level, which will reduce the risk of extinction.

Education as a moderator of genetic risk for higher body mass index: prospective cohort study from childhood to adulthood.

PubMed

Komulainen, K; Pulkki-Råback, L; Jokela, M; Lyytikäinen, L-P; Pitkänen, N; Laitinen, T; Hintsanen, M; Elovainio, M; Hintsa, T; Jula, A; Juonala, M; Pahkala, K; Viikari, J; Lehtimäki, T; Raitakari, O; Keltikangas-Järvinen, L

2018-04-01

The life-course development of body mass index (BMI) may be driven by interactions between genes and obesity-inducing social environments. We examined whether lower parental or own education accentuates the genetic risk for higher BMI over the life course, and whether diet and physical activity account for the educational differences in genetic associations with BMI. The study comprised 2441 participants (1319 women, 3-18 years at baseline) from the prospective, population-based Cardiovascular Risk in Young Finns Study. BMI (kg/m 2 ) trajectories were calculated from 18 to 49 years, using data from six time points spanning 31 years. A polygenic risk score for BMI was calculated as a weighted sum of risk alleles in 97 single-nucleotide polymorphisms. Education was assessed via self-reports, measured prospectively from participants in adulthood and from parents when participants were children. Diet and physical activity were self-reported in adulthood. Mean BMI increased from 22.6 to 26.6 kg/m 2 during the follow-up. In growth curve analyses, the genetic risk score was associated with faster BMI increase over time (b=0.02, (95% CI, 0.01-0.02, P<0.001)). The association between the genetic risk score and BMI was more pronounced among those with lower educational level in adulthood (b=-0.12 (95% CI, -0.23-0.01); P=0.036)). No interaction effect was observed between the genetic risk score and parental education (b=0.05 (95% CI, -0.09-0.18; P=0.51)). Diet and physical activity explained little of the interaction effect between the genetic risk score and adulthood education. In this prospective study, the association of a risk score of 97 genetic variants with BMI was stronger among those with low compared with high education. This suggests lower education in adulthood accentuates the risk of higher BMI in people at genetic risk.

Utility of genetic and non-genetic risk factors in predicting coronary heart disease in Singaporean Chinese.

PubMed

Chang, Xuling; Salim, Agus; Dorajoo, Rajkumar; Han, Yi; Khor, Chiea-Chuen; van Dam, Rob M; Yuan, Jian-Min; Koh, Woon-Puay; Liu, Jianjun; Goh, Daniel Yt; Wang, Xu; Teo, Yik-Ying; Friedlander, Yechiel; Heng, Chew-Kiat

2017-01-01

Background Although numerous phenotype based equations for predicting risk of 'hard' coronary heart disease are available, data on the utility of genetic information for such risk prediction is lacking in Chinese populations. Design Case-control study nested within the Singapore Chinese Health Study. Methods A total of 1306 subjects comprising 836 men (267 incident cases and 569 controls) and 470 women (128 incident cases and 342 controls) were included. A Genetic Risk Score comprising 156 single nucleotide polymorphisms that have been robustly associated with coronary heart disease or its risk factors ( p < 5 × 10 -8 ) in at least two independent cohorts of genome-wide association studies was built. For each gender, three base models were used: recalibrated Adult Treatment Panel III (ATPIII) Model (M 1 ); ATP III model fitted using Singapore Chinese Health Study data (M 2 ) and M 3 : M 2 + C-reactive protein + creatinine. Results The Genetic Risk Score was significantly associated with incident 'hard' coronary heart disease ( p for men: 1.70 × 10 -10 -1.73 × 10 -9 ; p for women: 0.001). The inclusion of the Genetic Risk Score in the prediction models improved discrimination in both genders (c-statistics: 0.706-0.722 vs. 0.663-0.695 from base models for men; 0.788-0.790 vs. 0.765-0.773 for women). In addition, the inclusion of the Genetic Risk Score also improved risk classification with a net gain of cases being reclassified to higher risk categories (men: 12.4%-16.5%; women: 10.2% (M 3 )), while not significantly reducing the classification accuracy in controls. Conclusions The Genetic Risk Score is an independent predictor for incident 'hard' coronary heart disease in our ethnic Chinese population. Inclusion of genetic factors into coronary heart disease prediction models could significantly improve risk prediction performance.

Gaps in Incorporating Germline Genetic Testing Into Treatment Decision-Making for Early-Stage Breast Cancer.

PubMed

Kurian, Allison W; Li, Yun; Hamilton, Ann S; Ward, Kevin C; Hawley, Sarah T; Morrow, Monica; McLeod, M Chandler; Jagsi, Reshma; Katz, Steven J

2017-07-10

Purpose Genetic testing for breast cancer risk is evolving rapidly, with growing use of multiple-gene panels that can yield uncertain results. However, little is known about the context of such testing or its impact on treatment. Methods A population-based sample of patients with breast cancer diagnosed in 2014 to 2015 and identified by two SEER registries (Georgia and Los Angeles) were surveyed about genetic testing experiences (N = 3,672; response rate, 68%). Responses were merged with SEER data. A patient subgroup at higher pretest risk of pathogenic mutation carriage was defined according to genetic testing guidelines. Patients' attending surgeons were surveyed about genetic testing and results management. We examined patterns and correlates of genetic counseling and testing and the impact of results on bilateral mastectomy (BLM) use. Results Six hundred sixty-six patients reported genetic testing. Although two thirds of patients were tested before surgical treatment, patients without private insurance more often experienced delays. Approximately half of patients (57% at higher pretest risk, 42% at average risk) discussed results with a genetic counselor. Patients with pathogenic mutations in BRCA1/2 or another gene had the highest rates of BLM (higher risk, 80%; average risk, 85%); however, BLM was also common among patients with genetic variants of uncertain significance (VUS; higher risk, 43%; average risk, 51%). Surgeons' confidence in discussing testing increased with volume of patients with breast cancer, but many surgeons (higher volume, 24%; lower volume, 50%) managed patients with BRCA1/2 VUS the same as patients with BRCA1/2 pathogenic mutations. Conclusion Many patients with breast cancer are tested without ever seeing a genetic counselor. Half of average-risk patients with VUS undergo BLM, suggesting a limited understanding of results that some surgeons share. These findings emphasize the need to address challenges in personalized communication about genetic testing.

Developmental Trajectories of DSM-IV Symptoms of Attention-Deficit/Hyperactivity Disorder: Genetic Effects, Family Risk and Associated Psychopathology

ERIC Educational Resources Information Center

Larsson, Henrik; Dilshad, Rezin; Lichtenstein, Paul; Barker, Edward D.

2011-01-01

Background: DSM-IV specifies three ADHD subtypes; the combined, the hyperactive-impulsive and the inattentive. Little is known about the developmental relationships underlying these subtypes. The objective of this study was to describe the development of parent-reported hyperactivity-impulsivity and inattention symptoms from childhood to…

Genetic and clinic predictors of new onset diabetes mellitus after transplantation.

PubMed

Saigi-Morgui, Núria; Quteineh, Lina; Bochud, Pierre-Yves; Crettol, Severine; Kutalik, Zoltán; Mueller, Nicolas J; Binet, Isabelle; Van Delden, Christian; Steiger, Jürg; Mohacsi, Paul; Dufour, Jean-Francois; Soccal, Paola M; Pascual, Manuel; Eap, Chin B

2017-12-27

New Onset Diabetes after Transplantation (NODAT) is a frequent complication after solid organ transplantation, with higher incidence during the first year. Several clinical and genetic factors have been described as risk factors of Type 2 Diabetes (T2DM). Additionally, T2DM shares some genetic factors with NODAT. We investigated if three genetic risk scores (w-GRS) and clinical factors were associated with NODAT and how they predicted NODAT development 1 year after transplantation. In both main (n = 725) and replication (n = 156) samples the clinical risk score was significantly associated with NODAT (OR main : 1.60 [1.36-1.90], p = 3.72*10 -8 and OR replication : 2.14 [1.39-3.41], p = 0.0008, respectively). Two w-GRS were significantly associated with NODAT in the main sample (OR w-GRS 2 :1.09 [1.04-1.15], p = 0.001 and OR w-GRS 3 :1.14 [1.01-1.29], p = 0.03) and a similar OR w-GRS 2 was found in the replication sample, although it did not reach significance probably due to a power issue. Despite the low OR of w-GRS on NODAT compared to clinical covariates, when integrating w-GRS 2 and w-GRS 3 in the clinical model, the Area under the Receiver Operating Characteristics curve (AUROC), specificity, sensitivity and accuracy were 0.69, 0.71, 0.58 and 0.68, respectively, with significant Likelihood Ratio test discrimination index (p-value 0.0004), performing better in NODAT discrimination than the clinical model alone. Twenty-five patients needed to be genotyped in order to detect one misclassified case that would have developed NODAT 1 year after transplantation if using only clinical covariates. To our knowledge, this is the first study extensively examining genetic risk scores contributing to NODAT development.

Genetic dissection of the pre-eclampsia susceptibility locus on chromosome 2q22 reveals shared novel risk factors for cardiovascular disease

PubMed Central

Johnson, Matthew P.; Brennecke, Shaun P.; East, Christine E.; Dyer, Thomas D.; Roten, Linda T.; Proffitt, J. Michael; Melton, Phillip E.; Fenstad, Mona H.; Aalto-Viljakainen, Tia; Mäkikallio, Kaarin; Heinonen, Seppo; Kajantie, Eero; Kere, Juha; Laivuori, Hannele; Austgulen, Rigmor; Blangero, John; Moses, Eric K.; Pouta, Anneli; Kivinen, Katja; Ekholm, Eeva; Hietala, Reija; Sainio, Susanna; Saisto, Terhi; Uotila, Jukka; Klemetti, Miira; Inkeri Lokki, Anna; Georgiadis, Leena; Huovari, Elina; Kortelainen, Eija; Leminen, Satu; Lähdesmäki, Aija; Mehtälä, Susanna; Salmen, Christina

2013-01-01

Pre-eclampsia is an idiopathic pregnancy disorder promoting morbidity and mortality to both mother and child. Delivery of the fetus is the only means to resolve severe symptoms. Women with pre-eclamptic pregnancies demonstrate increased risk for later life cardiovascular disease (CVD) and good evidence suggests these two syndromes share several risk factors and pathophysiological mechanisms. To elucidate the genetic architecture of pre-eclampsia we have dissected our chromosome 2q22 susceptibility locus in an extended Australian and New Zealand familial cohort. Positional candidate genes were prioritized for exon-centric sequencing using bioinformatics, SNPing, transcriptional profiling and QTL-walking. In total, we interrogated 1598 variants from 52 genes. Four independent SNP associations satisfied our gene-centric multiple testing correction criteria: a missense LCT SNP (rs2322659, P = 0.0027), a synonymous LRP1B SNP (rs35821928, P = 0.0001), an UTR-3 RND3 SNP (rs115015150, P = 0.0024) and a missense GCA SNP (rs17783344, P = 0.0020). We replicated the LCT SNP association (P = 0.02) and observed a borderline association for the GCA SNP (P = 0.07) in an independent Australian case–control population. The LRP1B and RND3 SNP associations were not replicated in this same Australian singleton cohort. Moreover, these four SNP associations could not be replicated in two additional case–control populations from Norway and Finland. These four SNPs, however, exhibit pleiotropic effects with several quantitative CVD-related traits. Our results underscore the genetic complexity of pre-eclampsia and present novel empirical evidence of possible shared genetic mechanisms underlying both pre-eclampsia and other CVD-related risk factors. PMID:23420841

Motivational State and Reward Content Determine Choice Behavior under Risk in Mice

PubMed Central

Leblond, Mona; Fan, David; Brynildsen, Julia K.; Yin, Henry H.

2011-01-01

Risk is a ubiquitous feature of the environment for most organisms, who must often choose between a small and certain reward and a larger but less certain reward. To study choice behavior under risk in a genetically well characterized species, we trained mice (C57BL/6) on a discrete trial, concurrent-choice task in which they must choose between two levers. Pressing one lever (safe choice) is always followed by a small reward. Pressing the other lever (risky choice) is followed by a larger reward, but only on some of the trials. The overall payoff is the same on both levers. When mice were not food deprived, they were indifferent to risk, choosing both levers with equal probability regardless of the level of risk. In contrast, following food or water deprivation, mice earning 10% sucrose solution were risk-averse, though the addition of alcohol to the sucrose solution dose-dependently reduced risk aversion, even before the mice became intoxicated. Our results falsify the budget rule in optimal foraging theory often used to explain behavior under risk. Instead, they suggest that the overall demand or desired amount for a particular reward determines risk preference. Changes in motivational state or reward identity affect risk preference by changing demand. Any manipulation that increases the demand for a reward also increases risk aversion, by selectively increasing the frequency of safe choices without affecting frequency of risky choices. PMID:21966504

Attitudes towards cannabis use and genetic testing for schizophrenia.

PubMed

Schiffman, Jason; Lawrence, Ryan E; Demro, Caroline; Appelbaum, Paul S; Dixon, Lisa B

2016-06-01

Within schizophrenia, genetic factors contribute greatly to risk, yet genetic testing for the disorder is not available. For some individuals with specific genotypes, cannabis use may increase risk of schizophrenia. It is possible that genetic tests could be offered in the future to inform individuals of the risk of schizophrenia if they use cannabis. Previous research, however, provides little guidance on how young adults might respond to such tests. We assessed a group of young adults (n = 83) to determine how the perceived magnitude of increased risk for schizophrenia in the presence of cannabis use influences decisions to undergo genetic testing, as well as subsequent attitudes and intentions towards cannabis use. Participants were significantly more likely to indicate willingness to get tested if the results identified a 10% risk versus a 2% risk of schizophrenia. Participants also indicated that if the results of their test reflected increased risk due to cannabis use, it would be more important to avoid cannabis in the 10% risk scenario as compared to the 2% risk scenario. These findings remained consistent among a subset of participants who indicated cannabis use. Results suggest that cannabis users and non-users were positively influenced in terms of intentions to change behaviour based on the magnitude of risk conveyed by genetic testing. These findings provide an initial step towards understanding young people's attitudes towards genetic testing and may help prepare interventions specifically tailored around cannabis use reduction for people at risk for schizophrenia. © 2014 Wiley Publishing Asia Pty Ltd.

Attitudes towards cannabis use and genetic testing for schizophrenia

PubMed Central

Schiffman, Jason; Lawrence, Ryan E.; Demro, Caroline; Appelbaum, Paul S.; Dixon, Lisa

2014-01-01

Aim Within schizophrenia, genetic factors contribute greatly to risk, yet genetic testing for the disorder is not available. For some individuals with specific genotypes, cannabis use may increase risk of schizophrenia. It is possible that genetic tests could be offered in the future to inform individuals of the risk of schizophrenia if they use cannabis. Previous research, however, provides little guidance on how young adults might respond to such tests. Methods We assessed a group of young adults (n = 83) to determine how the perceived magnitude of increased risk for schizophrenia in the presence of cannabis use influences decisions to undergo genetic testing, as well as subsequent attitudes and intentions towards cannabis use. Results Participants were significantly more likely to indicate willingness to get tested if the results identified a 10% risk versus a 2% risk of schizophrenia. Participants also indicated that if the results of their test reflected increased risk due to cannabis use, it would be more important to avoid cannabis in the 10% risk scenario as compared to the 2% risk scenario. These findings remained consistent among a subset of participants who indicated cannabis use. Conclusions Results suggest that cannabis users and non-users were positively influenced in terms of intentions to change behavior based on the magnitude of risk conveyed by genetic testing. These findings provide an initial step towards understanding young people’s attitudes towards genetic testing and may help prepare interventions specifically tailored around cannabis use reduction for people at risk for schizophrenia. PMID:24957110

Genetic architecture of white matter hyperintensities differs in hypertensive and nonhypertensive ischemic stroke.

PubMed

Adib-Samii, Poneh; Devan, William; Traylor, Matthew; Lanfranconi, Silvia; Zhang, Cathy R; Cloonan, Lisa; Falcone, Guido J; Radmanesh, Farid; Fitzpatrick, Kaitlin; Kanakis, Allison; Rothwell, Peter M; Sudlow, Cathie; Boncoraglio, Giorgio B; Meschia, James F; Levi, Chris; Dichgans, Martin; Bevan, Steve; Rosand, Jonathan; Rost, Natalia S; Markus, Hugh S

2015-02-01

Epidemiological studies suggest that white matter hyperintensities (WMH) are extremely heritable, but the underlying genetic variants are largely unknown. Pathophysiological heterogeneity is known to reduce the power of genome-wide association studies (GWAS). Hypertensive and nonhypertensive individuals with WMH might have different underlying pathologies. We used GWAS data to calculate the variance in WMH volume (WMHV) explained by common single nucleotide polymorphisms (SNPs) as a measure of heritability (SNP heritability [HSNP]) and tested the hypothesis that WMH heritability differs between hypertensive and nonhypertensive individuals. WMHV was measured on MRI in the stroke-free cerebral hemisphere of 2336 ischemic stroke cases with GWAS data. After adjustment for age and intracranial volume, we determined which cardiovascular risk factors were independent predictors of WMHV. Using the genome-wide complex trait analysis tool to estimate HSNP for WMHV overall and within subgroups stratified by risk factors found to be significant in multivariate analyses. A significant proportion of the variance of WMHV was attributable to common SNPs after adjustment for significant risk factors (HSNP=0.23; P=0.0026). HSNP estimates were higher among hypertensive individuals (HSNP=0.45; P=7.99×10(-5)); this increase was greater than expected by chance (P=0.012). In contrast, estimates were lower, and nonsignificant, in nonhypertensive individuals (HSNP=0.13; P=0.13). A quarter of variance is attributable to common SNPs, but this estimate was greater in hypertensive individuals. These findings suggest that the genetic architecture of WMH in ischemic stroke differs between hypertensives and nonhypertensives. Future WMHV GWAS studies may gain power by accounting for this interaction. © 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wolters Kluwer.

Unified Sequence-Based Association Tests Allowing for Multiple Functional Annotations and Meta-analysis of Noncoding Variation in Metabochip Data.

PubMed

He, Zihuai; Xu, Bin; Lee, Seunggeun; Ionita-Laza, Iuliana

2017-09-07

Substantial progress has been made in the functional annotation of genetic variation in the human genome. Integrative analysis that incorporates such functional annotations into sequencing studies can aid the discovery of disease-associated genetic variants, especially those with unknown function and located outside protein-coding regions. Direct incorporation of one functional annotation as weight in existing dispersion and burden tests can suffer substantial loss of power when the functional annotation is not predictive of the risk status of a variant. Here, we have developed unified tests that can utilize multiple functional annotations simultaneously for integrative association analysis with efficient computational techniques. We show that the proposed tests significantly improve power when variant risk status can be predicted by functional annotations. Importantly, when functional annotations are not predictive of risk status, the proposed tests incur only minimal loss of power in relation to existing dispersion and burden tests, and under certain circumstances they can even have improved power by learning a weight that better approximates the underlying disease model in a data-adaptive manner. The tests can be constructed with summary statistics of existing dispersion and burden tests for sequencing data, therefore allowing meta-analysis of multiple studies without sharing individual-level data. We applied the proposed tests to a meta-analysis of noncoding rare variants in Metabochip data on 12,281 individuals from eight studies for lipid traits. By incorporating the Eigen functional score, we detected significant associations between noncoding rare variants in SLC22A3 and low-density lipoprotein and total cholesterol, associations that are missed by standard dispersion and burden tests. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

The myth of natural barriers. Is transgene introgression by genetically modified crops an environmental risk?

PubMed

Guarnieri, Vincenzo; Benessia, Alice; Camino, Elena; Barbiero, Giuseppe

2008-01-01

Genetically modified (GM) crops under open field conditions are a complex and controversial issue. Ecologists are discussing about the possibility that a transgene belonging to GM plants could spread to native populations through a process known as introgression the stable incorporation of a gene in the host genome able to generate a differentiated population. The ecological consequences of a transgene introgression in plants or bacteria are not yet well understood, but could be significant. In this critical review we consider vertical and horizontal introgression. We analyse the biochemical and genetic constraints, and environmental factors that limit the possibility of transgene spread; meanwhile we show cases in which the natural barriers are overcome. Then we discuss the overall management of GM crops, noting the shortcomings and approximations of risk assessment based on linear thinking typical of the biomolecular approach. Finally we suggest to explicitly weight facts together with values and we encourage the undertaking of an ecological perspective, encompassing the complexity of (non-linear) relations between organisms and the environment.

Signs and genetics of rare cancer syndromes with gastroenterological features

PubMed Central

Bruno, William; Fornarini, Giuseppe; Ghiorzo, Paola

2015-01-01

Although the genetic bases of most hereditary cancer syndromes are known, and genetic tests are available for them, the incidence of the most rare of these syndromes is likely underestimated, partially because the clinical expression is neither fully understood nor easily diagnosed due to the variable and complex expressivity. The clinical features of a small pool of rare cancer syndromes include gastroenterological signs, though not necessarily tumors, that could require the intervention of a gastroenterologist during any of the phases of the clinical management. Herein we will attempt to spread the knowledge on these rare syndromes by summarizing the phenotype and genetic basis, and revising the peculiar gastroenterological signs whose underlying role in these rare hereditary cancer syndromes is often neglected. Close collaboration between geneticists and gastroenterologists could facilitate both the early identification of patients or relatives at-risk and the planning of multidisciplinary and tailored management of these subjects. PMID:26290627

Brain imaging in mitochondrial respiratory chain deficiency: combination of brain MRI features as a useful tool for genotype/phenotype correlations.

PubMed

Bricout, M; Grévent, D; Lebre, A S; Rio, M; Desguerre, I; De Lonlay, P; Valayannopoulos, V; Brunelle, F; Rötig, A; Munnich, A; Boddaert, N

2014-07-01

Mitochondrial diseases are characterised by a broad clinical and genetic heterogeneity that makes diagnosis difficult. Owing to the wide pattern of symptoms in mitochondrial disorders and the constantly growing number of disease genes, their genetic diagnosis is difficult and genotype/phenotype correlations remain elusive. Brain MRI appears as a useful tool for genotype/phenotype correlations. Here, we summarise the various combinations of MRI lesions observed in the most frequent mitochondrial respiratory chain deficiencies so as to direct molecular genetic test in patients at risk of such diseases. We believe that the combination of brain MRI features is of value to support respiratory chain deficiency and direct molecular genetic tests. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

The effects of inbreeding, genetic dissimilarity and phenotype on male reproductive success in a dioecious plant

PubMed Central

Austerlitz, Frédéric; Gleiser, Gabriela; Teixeira, Sara; Bernasconi, Giorgina

2012-01-01

Pollen fate can strongly affect the genetic structure of populations with restricted gene flow and significant inbreeding risk. We established an experimental population of inbred and outbred Silene latifolia plants to evaluate the effects of (i) inbreeding depression, (ii) phenotypic variation and (iii) relatedness between mates on male fitness under natural pollination. Paternity analysis revealed that outbred males sired significantly more offspring than inbred males. Independently of the effects of inbreeding, male fitness depended on several male traits, including a sexually dimorphic (flower number) and a gametophytic trait (in vitro pollen germination rate). In addition, full-sib matings were less frequent than randomly expected. Thus, inbreeding, phenotype and genetic dissimilarity simultaneously affect male fitness in this animal-pollinated plant. While inbreeding depression might threaten population persistence, the deficiency of effective matings between sibs and the higher fitness of outbred males will reduce its occurrence and counter genetic erosion. PMID:21561968

Germ line genome editing in clinics: the approaches, objectives and global society

PubMed Central

2017-01-01

Genome editing allows for the versatile genetic modification of somatic cells, germ cells and embryos. In particular, CRISPR/Cas9 is worldwide used in biomedical research. Although the first report on Cas9-mediated gene modification in human embryos focused on the prevention of a genetic disease in offspring, it raised profound ethical and social concerns over the safety of subsequent generations and the potential misuse of genome editing for human enhancement. The present article considers germ line genome editing approaches from various clinical and ethical viewpoints and explores its objectives. The risks and benefits of the following three likely objectives are assessed: the prevention of monogenic diseases, personalized assisted reproductive technology (ART) and genetic enhancement. Although genetic enhancement should be avoided, the international regulatory landscape suggests the inevitability of this misuse at ART centers. Under these circumstances, possible regulatory responses and the potential roles of public dialogue are discussed. PMID:26615180

Cancer genetic risk assessment and referral patterns in primary care.

PubMed

Vig, Hetal S; Armstrong, Joanne; Egleston, Brian L; Mazar, Carla; Toscano, Michele; Bradbury, Angela R; Daly, Mary B; Meropol, Neal J

2009-12-01

This study was undertaken to describe cancer risk assessment practices among primary care providers (PCPs). An electronic survey was sent to PCPs affiliated with a single insurance carrier. Demographic and practice characteristics associated with cancer genetic risk assessment and testing activities were described. Latent class analysis supported by likelihood ratio tests was used to define PCP profiles with respect to the level of engagement in genetic risk assessment and referral activity based on demographic and practice characteristics. 860 physicians responded to the survey (39% family practice, 29% internal medicine, 22% obstetrics/gynecology (OB/GYN), 10% other). Most respondents (83%) reported that they routinely assess hereditary cancer risk; however, only 33% reported that they take a full, three-generation pedigree for risk assessment. OB/GYN specialty, female gender, and physician access to a genetic counselor were independent predictors of referral to cancer genetics specialists. Three profiles of PCPs, based upon referral practice and extent of involvement in genetics evaluation, were defined. Profiles of physician characteristics associated with varying levels of engagement with cancer genetic risk assessment and testing can be identified. These profiles may ultimately be useful in targeting decision support tools and services.

Integrative Analysis of Genetic, Genomic, and Phenotypic Data for Ethanol Behaviors: A Network-Based Pipeline for Identifying Mechanisms and Potential Drug Targets.

PubMed

Bogenpohl, James W; Mignogna, Kristin M; Smith, Maren L; Miles, Michael F

2017-01-01

Complex behavioral traits, such as alcohol abuse, are caused by an interplay of genetic and environmental factors, producing deleterious functional adaptations in the central nervous system. The long-term behavioral consequences of such changes are of substantial cost to both the individual and society. Substantial progress has been made in the last two decades in understanding elements of brain mechanisms underlying responses to ethanol in animal models and risk factors for alcohol use disorder (AUD) in humans. However, treatments for AUD remain largely ineffective and few medications for this disease state have been licensed. Genome-wide genetic polymorphism analysis (GWAS) in humans, behavioral genetic studies in animal models and brain gene expression studies produced by microarrays or RNA-seq have the potential to produce nonbiased and novel insight into the underlying neurobiology of AUD. However, the complexity of such information, both statistical and informational, has slowed progress toward identifying new targets for intervention in AUD. This chapter describes one approach for integrating behavioral, genetic, and genomic information across animal model and human studies. The goal of this approach is to identify networks of genes functioning in the brain that are most relevant to the underlying mechanisms of a complex disease such as AUD. We illustrate an example of how genomic studies in animal models can be used to produce robust gene networks that have functional implications, and to integrate such animal model genomic data with human genetic studies such as GWAS for AUD. We describe several useful analysis tools for such studies: ComBAT, WGCNA, and EW_dmGWAS. The end result of this analysis is a ranking of gene networks and identification of their cognate hub genes, which might provide eventual targets for future therapeutic development. Furthermore, this combined approach may also improve our understanding of basic mechanisms underlying gene x environmental interactions affecting brain functioning in health and disease.

INTEGRATIVE ANALYSIS OF GENETIC, GENOMIC AND PHENOTYPIC DATA FOR ETHANOL BEHAVIORS: A NETWORK-BASED PIPELINE FOR IDENTIFYING MECHANISMS AND POTENTIAL DRUG TARGETS

PubMed Central

Bogenpohl, James W.; Mignogna, Kristin M.; Smith, Maren L.; Miles, Michael F.

2016-01-01

Complex behavioral traits, such as alcohol abuse, are caused by an interplay of genetic and environmental factors, producing deleterious functional adaptations in the central nervous system. The long-term behavioral consequences of such changes are of substantial cost to both the individual and society. Substantial progress has been made in the last two decades in understanding elements of brain mechanisms underlying responses to ethanol in animal models and risk factors for alcohol use disorder (AUD) in humans. However, treatments for AUD remain largely ineffective and few medications for this disease state have been licensed. Genome-wide genetic polymorphism analysis (GWAS) in humans, behavioral genetic studies in animal models and brain gene expression studies produced by microarrays or RNA-seq have the potential to produce non-biased and novel insight into the underlying neurobiology of AUD. However, the complexity of such information, both statistical and informational, has slowed progress toward identifying new targets for intervention in AUD. This chapter describes one approach for integrating behavioral, genetic, and genomic information across animal model and human studies. The goal of this approach is to identify networks of genes functioning in the brain that are most relevant to the underlying mechanisms of a complex disease such as AUD. We illustrate an example of how genomic studies in animal models can be used to produce robust gene networks that have functional implications, and to integrate such animal model genomic data with human genetic studies such as GWAS for AUD. We describe several useful analysis tools for such studies: ComBAT, WGCNA and EW_dmGWAS. The end result of this analysis is a ranking of gene networks and identification of their cognate hub genes, which might provide eventual targets for future therapeutic development. Furthermore, this combined approach may also improve our understanding of basic mechanisms underlying gene x environmental interactions affecting brain functioning in health and disease. PMID:27933543

Estimating the contribution of genetic variants to difference in incidence of disease between population groups.

PubMed

Moonesinghe, Ramal; Ioannidis, John P A; Flanders, W Dana; Yang, Quanhe; Truman, Benedict I; Khoury, Muin J

2012-08-01

Genome-wide association studies have identified multiple genetic susceptibility variants to several complex human diseases. However, risk-genotype frequency at loci showing robust associations might differ substantially among different populations. In this paper, we present methods to assess the contribution of genetic variants to the difference in the incidence of disease between different population groups for different scenarios. We derive expressions for the contribution of a single genetic variant, multiple genetic variants, and the contribution of the joint effect of a genetic variant and an environmental factor to the difference in the incidence of disease. The contribution of genetic variants to the difference in incidence increases with increasing difference in risk-genotype frequency, but declines with increasing difference in incidence between the two populations. The contribution of genetic variants also increases with increasing relative risk and the contribution of joint effect of genetic and environmental factors increases with increasing relative risk of the gene-environmental interaction. The contribution of genetic variants to the difference in incidence between two populations can be expressed as a function of the population attributable risks of the genetic variants in the two populations. The contribution of a group of genetic variants to the disparity in incidence of disease could change considerably by adding one more genetic variant to the group. Any estimate of genetic contribution to the disparity in incidence of disease between two populations at this stage seems to be an elusive goal.

Estimating the contribution of genetic variants to difference in incidence of disease between population groups

PubMed Central

Moonesinghe, Ramal; Ioannidis, John PA; Flanders, W Dana; Yang, Quanhe; Truman, Benedict I; Khoury, Muin J

2012-01-01

Genome-wide association studies have identified multiple genetic susceptibility variants to several complex human diseases. However, risk-genotype frequency at loci showing robust associations might differ substantially among different populations. In this paper, we present methods to assess the contribution of genetic variants to the difference in the incidence of disease between different population groups for different scenarios. We derive expressions for the contribution of a single genetic variant, multiple genetic variants, and the contribution of the joint effect of a genetic variant and an environmental factor to the difference in the incidence of disease. The contribution of genetic variants to the difference in incidence increases with increasing difference in risk-genotype frequency, but declines with increasing difference in incidence between the two populations. The contribution of genetic variants also increases with increasing relative risk and the contribution of joint effect of genetic and environmental factors increases with increasing relative risk of the gene–environmental interaction. The contribution of genetic variants to the difference in incidence between two populations can be expressed as a function of the population attributable risks of the genetic variants in the two populations. The contribution of a group of genetic variants to the disparity in incidence of disease could change considerably by adding one more genetic variant to the group. Any estimate of genetic contribution to the disparity in incidence of disease between two populations at this stage seems to be an elusive goal. PMID:22333905

Genetic testing and genetic counseling in patients with sudden death risk due to heritable arrhythmias.

PubMed

Spoonamore, Katherine G; Ware, Stephanie M

2016-03-01

Sudden cardiac death due to heritable ventricular arrhythmias is an important cause of mortality, especially in young healthy individuals. The identification of the genetic basis of Mendelian diseases associated with arrhythmia has allowed the integration of this information into the diagnosis and clinical management of patients and at-risk family members. The rapid expansion of genetic testing options and the increasing complexity involved in the interpretation of results creates unique opportunities and challenges. There is a need for competency to incorporate genetics into clinical management and to provide appropriate family-based risk assessment and information. In addition, disease-specific genetic knowledge is required to order and correctly interpret and apply genetic testing results. Importantly, genetic diagnosis has a critical role in the risk stratification and clinical management of family members. This review summarizes the approach to genetic counseling and genetic testing for inherited arrhythmias and highlights specific genetic principles that apply to long QT syndrome, short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Biological variation in musculoskeletal injuries: current knowledge, future research and practical implications.

PubMed

Collins, Malcolm; September, Alison V; Posthumus, Michael

2015-12-01

Evidence from familial and genetic association studies have reported that DNA sequence variants play an important role, together with non-genetic factors, in the aetiology of both exercise-associated and occupational-associated acute and chronic musculoskeletal soft tissue injuries. The associated variants, which have been identified to date, may contribute to the interindividual variation in the structure and, by implication, mechanical properties of the collagen fibril and surrounding matrix within musculoskeletal soft tissues, as well as their response to mechanical loading and other stimuli. Future work should focus on the establishment of multidisciplinary international consortia for the identification of biologically relevant variants involved in modulating injury risk. These consortia will improve the limitations of the published hypothesis-driven genetic association studies, since they will allow resources to be pooled in recruiting large well-characterised cohorts required for whole-genome screening. Finally, clinicians and coaches need to be aware that many direct-to-consumer companies are currently marketing genetic tests directly to athletes without it being requested by an appropriately qualified healthcare professional, and without interpretation alongside other clinical indicators or lifestyle factors. These specific genetic tests are premature and are not necessarily required to evaluate susceptibility to musculoskeletal soft tissue injury. Current practice should rather consider susceptibility through known risk factors such as a positive family history of a specific injury, a history of other tendon and/or ligament injuries and participation in activities associated with the specific musculoskeletal injuries. Potential susceptible athletes may then be individually managed to reduce their risk profile. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

The Impact of the Emerging Genomics Data on the Management of Agerelated Phenotypes in the Context of Cellular Senescence.

PubMed

Montesanto, Alberto; Geracitano, Silvana; Garasto, Sabrina; Fusco, Sergio; Lattanzio, Fabrizia; Passarino, Giuseppe; Corsonello, Andrea

2016-01-01

Before the last decade, attempts to identify the genetic factors involved in the susceptibility to age-related complex diseases such as cardiovascular disease, diabetes and cancer had very limited success. Recently, two important advancements have provided new opportunities to improve our knowledge in this field. Firstly, it has emerged the concept of studying the molecular mechanisms underlying the age related decline of the organism (such as cellular senescence), rather than the genetics of single disorders. In addition, advances in DNA technology have uncovered an incredible number of common susceptibility variants for several complex traits. Despite these progresses, the translation of these discoveries into clinical practice has been very difficult. To date, several attempts in translating genomics to medicine are being carried out to look for the best way by which genomic discoveries may improve our understanding of fundamental issues in the prediction and prevention of some complex diseases. The successful strategy seems to be testing simultaneously multiple susceptibility variants in combination with traditional risk factors. In fact, such approach showed that genetic factors substantially improve the prediction of complex diseases especially for coronary heart disease and prostate cancer, making possible appropriate behavioural and medical interventions. In the future, the identification of new genetic variants and their inclusion into current risk profile models will probably improve the discrimination power of these models for other complex diseases such as type 2 diabetes mellitus and breast cancer. On the other hand, for traits with low heritability, this improvement will probably be negligible, and this will urge further researches on the role played by traditional and newly discovered non-genetic risk factors.

The (FTO) gene polymorphism is associated with metabolic syndrome risk in Egyptian females: a case- control study.

PubMed

Khella, Mina S; Hamdy, Nadia M; Amin, Ashraf I; El-Mesallamy, Hala O

2017-09-16

Variations within fat mass and obesity associated (FTO) gene had crosstalk with obesity risk in European and some Asian populations. This study was designed to investigate FTO rs9939609 association with metabolic syndrome (MetS) as well as biochemical parameters as plasma glucose, serum triacylglycerol (TAG), total cholesterol (TC) and transaminases enzymes in Arab female population from Egypt. In order to achieve that, FTO gene rs9939609 (A < T) was genotyped using TaqMan SNP Genotyping Assay in a total of 197 females which were enrolled in this study. Fasting levels of serum insulin, lipid profile and plasma glucose, in addition to liver transaminases were measured. The association between the genotype distribution and MetS risk was evaluated using Chi-square and logistic regression tests in a case-control design under different genetic models. The association of genotype distribution with MetS was significant (χ2 = 8.6/P = 0.014) with an increased odds ratio under dominant model (OR = 1.97, P = 0.029 and 95%C.I = 1.07-3.6) and recessive model (OR = 2.95, P = 0.017 and 95%C.I = 1.22-7.22). Moreover, (AA) subjects showed significant lower HDL-C levels (P = 0.009) when compared to (TT) ones. In addition, interestingly subjects with (AA) genotype have significantly higher ALT levels (P = 0.02) that remained significant after correction of major confounders as body mass index and serum triacylglycerols but not after conservative Bonferroni adjustment. The present study shows for first time that FTO gene rs9939609 is genetic risk factor for metabolic syndrome in Egyptian population which may help in understanding the biology of this complex syndrome and highlighted that this association may be through HDL-C component. The association of this genetic polymorphism with ALT levels needs to be studied in other populations with larger sample size.

Genetic predisposition to coronary heart disease and stroke using an additive genetic risk score: a population-based study in Greece

USDA-ARS?s Scientific Manuscript database

Objective: To determine the extent to which the risk for incident coronary heart disease (CHD) increases in relation to a genetic risk score (GRS) that additively integrates the influence of high-risk alleles in nine documented single nucleotide polymorphisms (SNPs) for CHD, and to examine whether t...

Using genetic prediction from known complex disease Loci to guide the design of next-generation sequencing experiments.

PubMed

Jostins, Luke; Levine, Adam P; Barrett, Jeffrey C

2013-01-01

A central focus of complex disease genetics after genome-wide association studies (GWAS) is to identify low frequency and rare risk variants, which may account for an important fraction of disease heritability unexplained by GWAS. A profusion of studies using next-generation sequencing are seeking such risk alleles. We describe how already-known complex trait loci (largely from GWAS) can be used to guide the design of these new studies by selecting cases, controls, or families who are most likely to harbor undiscovered risk alleles. We show that genetic risk prediction can select unrelated cases from large cohorts who are enriched for unknown risk factors, or multiply-affected families that are more likely to harbor high-penetrance risk alleles. We derive the frequency of an undiscovered risk allele in selected cases and controls, and show how this relates to the variance explained by the risk score, the disease prevalence and the population frequency of the risk allele. We also describe a new method for informing the design of sequencing studies using genetic risk prediction in large partially-genotyped families using an extension of the Inside-Outside algorithm for inference on trees. We explore several study design scenarios using both simulated and real data, and show that in many cases genetic risk prediction can provide significant increases in power to detect low-frequency and rare risk alleles. The same approach can also be used to aid discovery of non-genetic risk factors, suggesting possible future utility of genetic risk prediction in conventional epidemiology. Software implementing the methods in this paper is available in the R package Mangrove.

Analysis of autosomal genes reveals gene-sex interactions and higher total genetic risk in men with systemic lupus erythematosus.

PubMed

Hughes, Travis; Adler, Adam; Merrill, Joan T; Kelly, Jennifer A; Kaufman, Kenneth M; Williams, Adrienne; Langefeld, Carl D; Gilkeson, Gary S; Sanchez, Elena; Martin, Javier; Boackle, Susan A; Stevens, Anne M; Alarcón, Graciela S; Niewold, Timothy B; Brown, Elizabeth E; Kimberly, Robert P; Edberg, Jeffrey C; Ramsey-Goldman, Rosalind; Petri, Michelle; Reveille, John D; Criswell, Lindsey A; Vilá, Luis M; Jacob, Chaim O; Gaffney, Patrick M; Moser, Kathy L; Vyse, Timothy J; Alarcón-Riquelme, Marta E; James, Judith A; Tsao, Betty P; Scofield, R Hal; Harley, John B; Richardson, Bruce C; Sawalha, Amr H

2012-05-01

Systemic lupus erythematosus (SLE) is a sexually dimorphic autoimmune disease which is more common in women, but affected men often experience a more severe disease. The genetic basis of sexual dimorphism in SLE is not clearly defined. A study was undertaken to examine sex-specific genetic effects among SLE susceptibility loci. A total of 18 autosomal genetic susceptibility loci for SLE were genotyped in a large set of patients with SLE and controls of European descent, consisting of 5932 female and 1495 male samples. Sex-specific genetic association analyses were performed. The sex-gene interaction was further validated using parametric and non-parametric methods. Aggregate differences in sex-specific genetic risk were examined by calculating a cumulative genetic risk score for SLE in each individual and comparing the average genetic risk between male and female patients. A significantly higher cumulative genetic risk for SLE was observed in men than in women. (P=4.52x10-8) A significant sex-gene interaction was seen primarily in the human leucocyte antigen (HLA) region but also in IRF5, whereby men with SLE possess a significantly higher frequency of risk alleles than women. The genetic effect observed in KIAA1542 is specific to women with SLE and does not seem to have a role in men. The data indicate that men require a higher cumulative genetic load than women to develop SLE. These observations suggest that sex bias in autoimmunity could be influenced by autosomal genetic susceptibility loci.

Comparison of coronary heart disease genetic assessment with conventional cardiovascular risk assessment in primary care: reflections on a feasibility study.

PubMed

Qureshi, Nadeem; Kai, Joe; Middlemass, Jo; Dhiman, Paula; Cross-Bardell, Laura; Acharya, Jayshree; Li, Ka Wan; Humphries, Steve E; Standen, Penelope J

2015-11-01

This study assesses the feasibility of collecting genetic samples and self-reported outcome measures after cardiovascular risk assessment, and presenting the genetic test results to participants. Coronary heart disease (CHD) genetic tests are increasingly available through direct-to-consumer marketing, but their potential clinical impact on cardiovascular risk assessment is unclear. Observational study in 10 British general practices in Central England. A total of 320 individuals, who had completed conventional cardiovascular risk assessment, were offered CHD genetic test, with follow-up outcome questionnaire at eight months for lifestyle change and State-Trait Anxiety. A total of 119 (37%) participants returned genetic test specimens, with over a third reporting family history of CHD in a specified relative; 79 (66.4%) were categorized above-average risk on conventional cardiovascular risk assessment, 65 of whom (82.3%) were only average risk on genetic assessment. The dietary fat questionnaire was poorly completed while study participation was not associated with increased anxiety (mean increase in anxiety score=2.1; 95% CI -0.1-4.3; P=0.06). As a feasibility study, over a third of individuals offered genetic testing in primary care, as part of CVD risk assessment, took up the offer. Although intervention did not appear to increase anxiety, this needs further evaluation. To improve generalizability and effect size, future studies should actively engage individuals from wider socio-economic backgrounds who may not have already contemplated lifestyle change. The current research suggests general practitioners will face the clinical challenge of patients presenting with direct-to-consumer genetic results that are inconsistent with conventional cardiovascular risk assessment.

Genetically at-risk status and individual agency. A qualitative study on asymptomatic women living with genetic risk of breast/ovarian cancer.

PubMed

Caiata-Zufferey, Maria

2015-05-01

For the last 20 years, genetic tests have allowed unaffected women to determine whether they are predisposed to developing breast/ovarian cancer due to BRCA1/2 gene mutations. In the event of adverse results, women receive a specific label associated with a set of medical recommendations: the genetically at-risk status. This qualitative study adopted a life-course perspective to understand the impact of this status on women's agency. Following a grounded theory design, retrospective biographical interviews were conducted in Switzerland between 2011 and 2013 with 32 unaffected women at risk of developing genetic breast/ovarian cancer and aware of their predisposition for at least three years. The results show that the genetically at-risk status conveys an invitation to transform health into a project, i.e., into a set of planned activities realized in collaboration with the medical system in order to reduce the risk of developing cancer. This health project shapes women's agency in three ways: it enhances, constrains and questions it, thus creating a sense of disorientation about what is considered rational and appropriate in terms of genetic risk management. Based on these findings, the paper concludes by stressing the paradoxes of the genetically at-risk status and the limits of the medical system in managing women designated with it. The paper also suggests that because of the disorientation intrinsic to their situation, genetically at-risk women have to reflexively construct their own health project from a range of available options in ways that are coherent and viable for themselves and their significant others. This process of reflexive construction may be called legitimation. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cancer Risk Information Sharing: The Experience of Individuals Receiving Genetic Counseling for BRCA1/2 Mutations

PubMed Central

Chopra, Ishveen; Kelly, Kimberly M.

2017-01-01

Genetic counseling and testing for familial cancer is a unique context for the communication of risk information in the family. This study utilized a theoretical framework based on the family systems perspective to understand intra-familial cancer risk communication patterns in the Ashkenazi Jewish population. Individuals (n=120) at an elevated risk for BRCA1/2 mutations were included. Change in communication patterns over time was assessed using McNemar tests. Associations with communication patterns were assessed with multivariable logistic regression. Overall, the proportion of participants encouraged by others significantly (P<0.001) increased from pre- to post-genetic counseling. A higher proportion of participants were encouraged by female family members compared to male family members. Participants who were older, had no personal history of cancer, and had a higher cancer risk perception were more likely to be encouraged by others for genetic testing. Participant’s intent to encourage family members for genetic testing from pre-counseling to post-receipt of genetic test results decreased by 16.7%. Participants who had no personal history of cancer and had informative test results for a BRCA1/2 mutation were more likely to encourage other family members for genetic testing. In addition, qualitative findings suggested that closeness among family members, concern for family, especially future generations, and cognizance about cancer risk facilitates information sharing and encouragement for genetic testing. Our findings indicate that intra-familial cancer risk communication varies with structure of family relationships, where genetic counseling played an important role in improving intra-familial cancer risk communication. PMID:28112991

A Primer on the Genetics of Comorbid Eating Disorders and Substance Use Disorders.

PubMed

Munn-Chernoff, Melissa A; Baker, Jessica H

2016-03-01

Eating disorders (EDs) and substance use disorders (SUDs) frequently co-occur; however, the reasons for this are unclear. We review the current literature on genetic risk for EDs and SUDs, as well as preliminary findings exploring whether these classes of disorders have overlapping genetic risk. Overall, genetic factors contribute to individual differences in liability to multiple EDs and SUDs. Although initial family studies concluded that no shared familial (which includes genetic) risk between EDs and SUDs exists, twin studies suggest a moderate proportion of shared variance is attributable to overlapping genetic factors, particularly for those EDs characterized by binge eating and/or inappropriate compensatory behaviours. No adoption or molecular genetic studies have examined shared genetic risk between these classes of disorders. Research investigating binge eating and inappropriate compensatory behaviours using emerging statistical genetic methods, as well as examining gene-environment interplay, will provide important clues into the aetiology of comorbid EDs and SUDs. Copyright © 2015 John Wiley & Sons, Ltd and Eating Disorders Association.

Parents' perceptions of autism spectrum disorder etiology and recurrence risk and effects of their perceptions on family planning: Recommendations for genetic counselors.

PubMed

Selkirk, Christina G; McCarthy Veach, Patricia; Lian, Fengqin; Schimmenti, Lisa; LeRoy, Bonnie S

2009-10-01

Knowledge about the etiology of Autism Spectrum Disorders (ASDs) is increasing, but causes remain elusive for most cases. Genetic counselors are positioned to help families that have children with ASDs despite uncertainty regarding etiology. To determine how genetic counselors might best provide services, an anonymous survey was conducted with 255 parents whose children were diagnosed on the autism spectrum. Questions concerned: 1) their perceptions of ASD cause(s) and 2) recurrence risk, 3) whether perceived risk affected family planning decisions, 4) whether parents had received genetic services, and 5) how genetic counselors might assist families. The most prevalent perceived cause was genetic influences (72.6%). Most parents' recurrence risk perceptions were inaccurately high and significantly affected family planning. Only 10% had seen a genetic professional related to an ASD. Parents provided several suggestions for genetic counselor best practices. Findings indicate the importance of genetic counselor awareness of parent perceptions in order to best help families who have children with ASDs.

Lack of gene-diuretic interactions on the risk of incident gout: the Nurses' Health Study and Health Professionals Follow-up Study.

PubMed

Bao, Ying; Curhan, Gary; Merriman, Tony; Plenge, Robert; Kraft, Peter; Choi, Hyon K

2015-07-01

Diuretic-induced gout might occur only among those with a genetic predisposition to hyperuricaemia, as suggested by a recent study with 108 self-reported gout cases. We examined the role of urate genes on the risk of diuretic-induced incident gout in 6850 women from the Nurses' Health Study (NHS) and in 4223 men from the Health Professionals Follow-up Study (HPFS). Two published genetic risk scores (GRSs) were calculated using urate-associated single-nucleotide polymorphisms for 8 (GRS8) and 29 genes (GRS29). Our analyses included 727 and 354 confirmed incident gout cases in HPFS and NHS, respectively. The multivariate relative risk (RR) for diuretic use was 2.20 and 1.69 among those with GRS8 < and ≥ the median (p for interaction=0.27). The corresponding RRs using GRS29 were 2.19 and 1.88 (p for interaction=0.40). The lack of interaction persisted in NHS (all p values >0.20) and in our analyses limited to those with hypertension in both cohorts. SLC22A11 (OAT4) showed a significant interaction only among women but in the opposite direction to the recent study. In these large prospective studies, individuals with a genetic predisposition for hyperuricaemia are not at a higher risk of developing diuretic-induced gout than those without. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Aquaculture: Incorporating risk assessment and risk management into public policies on genetically modified finfish and shellfish

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

Hallerman, E.M.; Kapuscinski, A.R.

Genetically modified finfish and shellfish pose economic benefits to aquaculture, but also pose ecological and genetic risks to ecosystems receiving such organisms. Realization of benefits with minimization of risks posed by a new technology can be addressed through the processes of risk assessment and risk management. Public policies adopted by individual countries will reflect differences in the outocme of risk assessment and risk management processes resulting from differences among the receiving ecosystems and sets of human values at issue. A number of countries and international institutions have begun development of policies for oversight of genetically modified aquatic organisms. In themore » United States, a working group commissioned by the U.S. Department of Agriculture incorporated risk assessment and risk management principles into draft performance standards for safely conducting research with genetically modified finfish and shellfish. The performance standards address research with a broad range of aquatic GMO`s and compliance is intended to be voluntary. In contrast, the Canadian policy mandates adherence to specified guidelines for experiments with transgenic aquatic organisms; establishment as national policy is expended soon.« less

Heart Disease in Women: Unappreciated Challenges, GPER as a New Target.

PubMed

Feldman, Ross D

2016-05-18

Heart disease in women remains underappreciated, underdiagnosed and undertreated. Further, although we are starting to understand some of the social and behavioral determinants for this, the biological basis for the increased rate of rise in atherosclerosis risk in women after menopause remains very poorly understand. In this review we will outline the scope of the clinical issues related to heart disease in women, the emerging findings regarding the biological basis underlying the increased prevalence of atherosclerotic risk factors in postmenopausal women (vs. men) and the role of the G protein-coupled estrogen receptor (GPER) and its genetic regulation as a determinant of these sex-specific risks. GPER is a recently appreciated GPCR that mediates the rapid effects of estrogen and aldosterone. Recent studies have identified that GPER activation regulates both blood pressure. We have shown that regulation of GPER function via expression of a hypofunctional GPER genetic variant is an important determinant of blood pressure and risk of hypertension in women. Further, our most recent studies have identified that GPER activation is an important regulator of low density lipoprotein (LDL) receptor metabolism and that expression of the hypofunctional GPER genetic variant is an important contributor to the development of hypercholesterolemia in women. GPER appears to be an important determinant of the two major risk factors for coronary artery disease-blood pressure and LDL cholesterol. Further, the importance of this mechanism appears to be greater in women. Thus, the appreciation of the role of GPER function as a determinant of the progression of atherosclerotic disease may be important both in our understanding of cardiometabolic function but also in opening the way to greater appreciation of the sex-specific regulation of atherosclerotic risk factors.

A multiple mediator analysis approach to quantify the effects of the ADH1B and ALDH2 genes on hepatocellular carcinoma risk.

PubMed

Shih, Stephannie; Huang, Yen-Tsung; Yang, Hwai-I

2018-06-01

Previous work suggested a genetic component affecting the risk of hepatocellular carcinoma (HCC) and mediation analyses have elucidated potential indirect pathways of these genetic effects. Specifically, the effects of alcohol dehydrogenase (ADH1B) and aldehyde dehydrogenase (ALDH2) genes on HCC risk vary based on alcohol consumption habits. However, alcohol consumption may not be the only mediator in the identified pathway: factors related to alcohol consumption may contribute to the same indirect pathway. Thus, we developed a multimediator model to quantify the genetic effects on HCC risk through sequential dichotomous mediators under the counterfactual framework. Our method provided a closed form formula for the mediation effects through different indirect paths, which requires no assumption for the rarity of outcome. In simulation studies of a finite sample, we presented the utility of the method with the variance of the effects estimated using the delta method and bootstrapping. We applied our method to data from participants in Taiwan (580 cases and 3,207 controls) and quantified the mediation effects of single nucleotide polymorphisms (SNPs) in the ADH1B and ALDH2 genes on HCC through alcohol consumption (yes/no) and high alanine transaminase (ALT) levels (greater than or equal to 45 U/L or below 45 U/L). Assuming a dominant risk model, we identified that the SNPs' effects through alcohol consumption is more significant than through ALT levels on HCC risk. This new method provides insight to the magnitude of various casual mechanisms as a closed form solution and can be readily applied in other genomic studies. © 2018 WILEY PERIODICALS, INC.

Personality and divorce: a genetic analysis.

PubMed

Jocklin, V; McGue, M; Lykken, D T

1996-08-01

M. McGue and D.T. Lykken (1992) found that divorce risk was, to a substantial degree, genetically mediated; prior research has identified numerous social and psychological factors that affect divorce risk (G.C. Kitson, K.B. Barbi, & M.J. Roach, 1985). The present study attempted to link these domains by examining the extent to which genetic influences on one such psychological factor, personality, explain divorce risk heritability. A sample of adult twins from the Minnesota Twin Registry completed a marital history questionnaire and the Multidimensional Personality Questionnaire (A. Tellegen, 1982). Positive Emotionality and Negative Emotionality factors were positively related to divorce risk, whereas Constraint was negatively related. In women and men, respectively, 30% and 42% of the heritability of divorce risk consisted of genetic factors affecting personality and divorce risk correlated largely as a result of these common genetic influences.

Influence of race/ethnicity on genetic counseling and testing for hereditary breast and ovarian cancer.

PubMed

Forman, Andrea D; Hall, Michael J

2009-01-01

Risk assessment coupled with genetic counseling and testing for the cancer predisposition genes BRCA1 and BRCA2 (BRCA1/2) has become an integral element of comprehensive patient evaluation and cancer risk management in the United States for individuals meeting high-risk criteria for hereditary breast and ovarian cancer (HBOC). For mutation carriers, several options for risk modification have achieved substantial reductions in future cancer risk. However, several recent studies have shown lower rates of BRCA1/2 counseling and testing among minority populations. Here, we explore the role of race/ethnicity in cancer risk assessment, genetic counseling and genetic testing for HBOC and the BRCA1/2 cancer predisposition genes. Barriers to genetic services related to race/ethnicity and underserved populations, including socioeconomic barriers (e.g., time, access, geographic, language/cultural, awareness, cost) and psychosocial barriers (e.g., medical mistrust, perceived disadvantages to genetic services), as well as additional barriers to care once mutation carriers are identified, will be reviewed.

Interactive effect of STAT6 and IL13 gene polymorphisms on eczema status: results from a longitudinal and a cross-sectional study

PubMed Central

2013-01-01

Background Eczema is a prevalent skin disease that is mainly characterized by systemic deviation of immune response and defective epidermal barrier. Th2 cytokines, such as IL-13 and transcription factor STAT6 are key elements in the inflammatory response that characterize allergic disorders, including eczema. Previous genetic association studies showed inconsistent results for the association of single nucleotide polymorphisms (SNPs) with eczema. Our aim was to investigate whether SNPs in IL13 and STAT6 genes, which share a biological pathway, have an interactive effect on eczema risk. Methods Data from two independent population-based studies were analyzed, namely the Isle of Wight birth cohort study (IOW; n = 1,456) and for the purpose of replication the Swansea PAPA (Poblogaeth Asthma Prifysgol Abertawe; n = 1,445) cross-sectional study. Log-binomial regressions were applied to (i) account for the interaction between IL13 (rs20541) and STAT6 (rs1059513) polymorphisms and (ii) estimate the combined effect, in terms of risk ratios (RRs), of both risk factors on the risk of eczema. Results Under a dominant genetic model, the interaction term [IL13 (rs20541) × STAT6 (rs1059513)] was statistically significant in both studies (IOW: adjusted Pinteraction = 0.046; PAPA: Pinteraction = 0.037). The assessment of the combined effect associated with having risk genotypes in both SNPs yielded a 1.52-fold increased risk of eczema in the IOW study (95% confidence interval (CI): 1.05 – 2.20; P = 0.028) and a 2.01-fold higher risk of eczema (95% CI: 1.29 – 3.12; P = 0.002) in the PAPA study population. Conclusions Our study adds to the current knowledge of genetic susceptibility by demonstrating for the first time an interactive effect between SNPs in IL13 (rs20541) and STAT6 (rs1059513) on the occurrence of eczema in two independent samples. Findings of this report further support the emerging evidence that points toward the existence of genetic effects that occur via complex networks involving gene-gene interactions (epistasis). PMID:23815671

MTHFR genetic polymorphisms may contribute to the risk of chronic myelogenous leukemia in adults: a meta-analysis of 12 genetic association studies.

PubMed

Li, Bin; Zhang, Jian; Wang, Lei; Li, Yan; Jin, Juping; Ai, Limei; Li, Chong; Li, Zhe; Mao, Shudan

2014-05-01

Chronic myelogenous leukemia (CML) is a complex disease with a genetic basis. The genetic association studies (GASs) that have investigated the association between adult CML and 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms have produced contradictory and inconclusive results. The aim of this meta-analysis is to provide a relatively comprehensive assessment of the association of these polymorphisms with adult CML risk. A literature search for eligible GAS published before September 15, 2013 was conducted in PubMed, Embase, Web of Science, Cochrane Library, and China National Knowledge Infrastructure (CNKI) databases. Pooled odds ratios (ORs) with their corresponding 95% confidence intervals (95% CIs) were used to evaluate the strength of the association under a fixed or random effect model according to heterogeneity test results. All analyses were performed using the Stata software, version 12.0. Twelve case-control studies were included in this meta-analysis with a total of 932 CML patients and 3,465 healthy controls. For MTHFR C677T (dbSNP: rs1801133, C>T), though the pooled ORs were not significant in the overall population, all the ORs greater than 1 suggested an increased risk of CML for carriers of the risk allele. However, stratified analysis based on genotyping method revealed a significant association in the PCR-restriction fragment length polymorphism (RFLP) subgroup, possibly as a result of heterogeneity. For MTHFR A1298C (dbSNP: rs1801131, A>C), the combined results showed that carriers of the C allele may be associated with a decreased risk of adult CML. Stratified analysis showed that the magnitude of this effect was especially significant among Asians, indicating ethnicity differences in adult CML susceptibility. This meta-analysis shows that the C allele of MTHFR A1298C may be associated with a decreased risk in adult CML, especially among Asians, while MTHFR C677T may not be associated with adult CML risk. However, the development of adult CML may be the result of gene-gene and gene-environment interactions, which should be considered in future individual GAS and subsequent meta-analyses.

Characteristics associated with genetic counseling referral and BRCA1/2 testing among women in a large integrated health system.

PubMed

Bellcross, Cecelia A; Peipins, Lucy A; McCarty, Frances A; Rodriguez, Juan L; Hawkins, Nikki A; Hensley Alford, Sharon; Leadbetter, Steven

2015-01-01

Evidence shows underutilization of cancer genetics services. To explore the reasons behind this underutilization, this study evaluated characteristics of women who were referred for genetic counseling and/or had undergone BRCA1/2 testing. An ovarian cancer risk perception study stratified 16,720 eligible women from the Henry Ford Health System into average-, elevated-, and high-risk groups based on family history. We randomly selected 3,307 subjects and interviewed 2,524 of them (76.3% response rate). Among the average-, elevated-, and high-risk groups, 2.3, 10.1, and 20.2%, respectively, reported genetic counseling referrals, and 0.8, 3.3, and 9.5%, respectively, reported having undergone BRCA testing. Personal breast cancer history, high risk, and perceived ovarian cancer risk were associated with both referral and testing. Discussion of family history with a doctor predicted counseling referral, whereas belief that family history influenced risk was the strongest BRCA testing predictor. Women perceiving their cancer risk as much higher than other women their age were twice as likely (95% confidence interval: 2.0-9.6) to report genetic counseling referral. In a health system with ready access to cancer genetic counseling and BRCA testing, women who were at high risk underutilized these services. There were strong associations between perceived ovarian cancer risk and genetic counseling referral, and between a belief that family history influenced risk and BRCA testing.

Quantifying introgression risk with realistic population genetics.

PubMed

Ghosh, Atiyo; Meirmans, Patrick G; Haccou, Patsy

2012-12-07

Introgression is the permanent incorporation of genes from the genome of one population into another. This can have severe consequences, such as extinction of endemic species, or the spread of transgenes. Quantification of the risk of introgression is an important component of genetically modified crop regulation. Most theoretical introgression studies aimed at such quantification disregard one or more of the most important factors concerning introgression: realistic genetical mechanisms, repeated invasions and stochasticity. In addition, the use of linkage as a risk mitigation strategy has not been studied properly yet with genetic introgression models. Current genetic introgression studies fail to take repeated invasions and demographic stochasticity into account properly, and use incorrect measures of introgression risk that can be manipulated by arbitrary choices. In this study, we present proper methods for risk quantification that overcome these difficulties. We generalize a probabilistic risk measure, the so-called hazard rate of introgression, for application to introgression models with complex genetics and small natural population sizes. We illustrate the method by studying the effects of linkage and recombination on transgene introgression risk at different population sizes.

Quantifying introgression risk with realistic population genetics

PubMed Central

Ghosh, Atiyo; Meirmans, Patrick G.; Haccou, Patsy

2012-01-01

Introgression is the permanent incorporation of genes from the genome of one population into another. This can have severe consequences, such as extinction of endemic species, or the spread of transgenes. Quantification of the risk of introgression is an important component of genetically modified crop regulation. Most theoretical introgression studies aimed at such quantification disregard one or more of the most important factors concerning introgression: realistic genetical mechanisms, repeated invasions and stochasticity. In addition, the use of linkage as a risk mitigation strategy has not been studied properly yet with genetic introgression models. Current genetic introgression studies fail to take repeated invasions and demographic stochasticity into account properly, and use incorrect measures of introgression risk that can be manipulated by arbitrary choices. In this study, we present proper methods for risk quantification that overcome these difficulties. We generalize a probabilistic risk measure, the so-called hazard rate of introgression, for application to introgression models with complex genetics and small natural population sizes. We illustrate the method by studying the effects of linkage and recombination on transgene introgression risk at different population sizes. PMID:23055068

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

PubMed Central

Wiseman, Frances K.; Al-Janabi, Tamara; Hardy, John; Karmiloff-Smith, Annette; Nizetic, Dean; Tybulewicz, Victor L. J.; Fisher, Elizabeth M. C.; Strydom, André

2015-01-01

Down syndrome, which arises in individuals carrying an extra copy of chromosome 21, is associated with a greatly increased risk of early-onset Alzheimer disease. It is thought that this risk is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP) — an Alzheimer disease risk factor — although the possession of extra copies of other chromosome 21 genes may also play a part. Further study of the mechanisms underlying the development of Alzheimer disease in people with Down syndrome could provide insights into the mechanisms that cause dementia in the general population. PMID:26243569

Genetic susceptibility to type 2 diabetes and obesity: follow-up of findings from genome-wide association studies.

PubMed

Basile, Kevin J; Johnson, Matthew E; Xia, Qianghua; Grant, Struan F A

2014-01-01

Elucidating the underlying genetic variations influencing various complex diseases is one of the major challenges currently facing clinical genetic research. Although these variations are often difficult to uncover, approaches such as genome-wide association studies (GWASs) have been successful at finding statistically significant associations between specific genomic loci and disease susceptibility. GWAS has been especially successful in elucidating genetic variants that influence type 2 diabetes (T2D) and obesity/body mass index (BMI). Specifically, several GWASs have confirmed that a variant in transcription factor 7-like 2 (TCF7L2) confers risk for T2D, while a variant in fat mass and obesity-associated protein (FTO) confers risk for obesity/BMI; indeed both of these signals are considered the most statistically associated loci discovered for these respective traits to date. The discovery of these two key loci in this context has been invaluable for providing novel insight into mechanisms of heritability and disease pathogenesis. As follow-up studies of TCF7L2 and FTO have typically lead the way in how to follow up a GWAS discovery, we outline what has been learned from such investigations and how they have implications for the myriad of other loci that have been subsequently reported in this disease context.

Exome Sequencing in an Admixed Isolated Population Indicates NFXL1 Variants Confer a Risk for Specific Language Impairment

PubMed Central

Villanueva, Pía; Nudel, Ron; Hoischen, Alexander; Fernández, María Angélica; Simpson, Nuala H.; Gilissen, Christian; Reader, Rose H.; Jara, Lillian; Echeverry, Maria Magdalena; Francks, Clyde; Baird, Gillian; Conti-Ramsden, Gina; O’Hare, Anne; Bolton, Patrick F.; Hennessy, Elizabeth R.; Palomino, Hernán; Carvajal-Carmona, Luis; Veltman, Joris A.; Cazier, Jean-Baptiste; De Barbieri, Zulema

2015-01-01

Children affected by Specific Language Impairment (SLI) fail to acquire age appropriate language skills despite adequate intelligence and opportunity. SLI is highly heritable, but the understanding of underlying genetic mechanisms has proved challenging. In this study, we use molecular genetic techniques to investigate an admixed isolated founder population from the Robinson Crusoe Island (Chile), who are affected by a high incidence of SLI, increasing the power to discover contributory genetic factors. We utilize exome sequencing in selected individuals from this population to identify eight coding variants that are of putative significance. We then apply association analyses across the wider population to highlight a single rare coding variant (rs144169475, Minor Allele Frequency of 4.1% in admixed South American populations) in the NFXL1 gene that confers a nonsynonymous change (N150K) and is significantly associated with language impairment in the Robinson Crusoe population (p = 2.04 × 10–4, 8 variants tested). Subsequent sequencing of NFXL1 in 117 UK SLI cases identified four individuals with heterozygous variants predicted to be of functional consequence. We conclude that coding variants within NFXL1 confer an increased risk of SLI within a complex genetic model. PMID:25781923

Gene–environment interactions: key to unraveling the mystery of Parkinson’s disease

PubMed Central

Gao, Hui-Ming; Hong, Jau-shyong

2011-01-01

Parkinson’s disease (PD) is the second most common neurodegenerative disease. The gradual, irreversible loss of dopamine neurons in the substantia nigra isthe signature lesion of PD. Clinical symptoms of PD become apparent when 50–60% of nigral dopamine neurons are lost. PD progresses insidiously for 5–7 years (preclinical period) and then continues to worsen even under the symptomatic treatment. To determine what triggers the disease onset and what drives the chronic, self-propelling neurodegenerative process becomes critical and urgent, since lack of such knowledge impedes the discovery of effective treatments to retard PD progression. At present, available therapeutics only temporarily relieve PD symptoms. While the identification of causative gene defects in familial PD uncovers important genetic influences in this disease, the majority of PD cases are sporadic and idiopathic. The current consensus suggests that PD develops from multiple risk factors including aging, genetic predisposition, and environmental exposure. Here, we briefly review research on the genetic and environmental causes of PD. We also summarize very recent genome-wide association studies on risk gene polymorphisms in the emergence of PD. We highlight the new converging evidence on gene-environment interplay in the development of PD with an emphasis on newly developed multiple-hit PD models involving both genetic lesions and environmental triggers. PMID:21439347

Estimating the mode of inheritance in genetic association studies of qualitative traits based on the degree of dominance index

PubMed Central

2011-01-01

Background The biological justification for the choice of the genetic mode in genetic association studies (GAS) is seldom available. Then, the mode of inheritance is approximated by investigating a number of non-orthogonal genetic contrasts making the interpretation of results difficult. Methods We propose to define the mode of inheritance by the significance of the deviance of the co-dominant contrast and the degree of dominance (h), which is a function of two orthogonal contrasts (the co-dominant and additive). Non-dominance exists when the co-dominant contrast is non-significant and, hence, the risk effect of heterozygotes lies in the middle of the risk of the two homozygotes. Otherwise, dominance (including over- and under-dominance) is present and the direction of dominance depends on the value of h. Results Simulations show that h may capture the real mode of inheritance and it is affected by deviations from Hardy-Weinberg equilibrium (HWE). In addition, power for detecting significance of h when the study conforms to HWE rule increases with the degree of dominance and to some extent is related to the mutant allele frequency. Conclusion The introduction of the degree of dominance provides useful insights into the mode of inheritance in GAS. PMID:22188898

The etiology of essential tremor: Genes versus environment.

PubMed

Hopfner, Franziska; Helmich, Rick C

2018-01-01

Essential tremor (ET) is characterized by bilateral upper limb action tremor. Here we review the pathophysiology (cerebral mechanisms) and etiology (genetic and environmental risk factors) of ET. We reviewed the literature (until June 2017) by searching PubMed for relevant papers. The pathophysiology of ET involves oscillatory activity in the cortico-olivo-cerebello-thalamic circuit, evidenced by electrophysiological and metabolic imaging. Possible underlying mechanisms include GABA-ergic dysfunction, cerebellar neurodegeneration, olivary dysfunction, or a combination. Genetic studies have examined affected ET families (linkage studies and whole-exome sequencing studies). These studies revealed several chromosomal regions and genes associated with ET, but the findings have not been replicated across different ET families. Genetic studies also assessed the sporadic occurrence of ET using genome wide genotyping of single nucleotide polymorphisms (SNP's) and candidate gene studies. Several SNP's are associated with ET, and this has been replicated across different cohorts. Interestingly, some of the involved genes are linked to the cerebellum and inferior olive. Environmental studies point to an association between ET and beta-carboline alkaloids (such as harmane), which have been found in the cerebellum. Genetic and environmental risk factors may influence cerebellar and/or olivary function, resulting in abnormal cortico-olivo-cerebello-thalamic activity, and ultimately ET. Copyright © 2017 Elsevier Ltd. All rights reserved.

A Qualitative Inquiry of the Financial Concerns of Couples Opting to Use Preimplantation Genetic Diagnosis to Prevent the Transmission of Known Genetic Disorders

PubMed Central

Drazba, Kathryn T.; Kelley, Michele A.; Hershberger, Patricia E.

2013-01-01

Preimplantation genetic diagnosis (PGD) is an innovative prenatal testing option because the determination of whether a genetic disorder or chromosomal abnormality is evident occurs prior to pregnancy. However, PGD is not covered financially under the majority of private and public health insurance institutions in the United States, leaving couples to decide whether PGD is financially feasible. The aim of this qualitative study was to understand the role of finances in the decision-making process among couples who were actively considering PGD. In-depth, semi-structured interviews were completed with 18 genetic high-risk couples (36 individual partners). Grounded theory guided the analysis, whereby three themes emerged: 1) Cost is salient, 2) Emotions surrounding affordability, and 3) Financial burden and sacrifice. Ultimately, couples determined that the opportunity to avoid passing on a genetic disorder to a future child was paramount to the cost of PGD, but expressed financial concerns and recognized financial access as a major barrier to PGD utilization. PMID:23949612

MHC class II is an important genetic risk factor for canine systemic lupus erythematosus (SLE)-related disease: implications for reproductive success.

PubMed

Wilbe, M; Andersson, G

2012-01-01

Major histocompatibility complex (MHC) class II genes are important genetic risk factors for development of immune-mediated diseases in mammals. Recently, the dog (Canis lupus familiaris) has emerged as a useful model organism to identify critical MHC class II genotypes that contribute to development of these diseases. Therefore, a study aimed to evaluate a potential genetic association between the dog leukocyte antigen (DLA) class II region and an immune-mediated disease complex in dogs of the Nova Scotia duck tolling retriever breed was performed. We show that DLA is one of several genetic risk factors for this disease complex and that homozygosity of the risk haplotype is disadvantageous. Importantly, the disease is complex and has many genetic risk factors and therefore we cannot provide recommendations for breeders exclusively on the basis of genetic testing for DLA class II genotype. © 2012 Blackwell Verlag GmbH.

Epidemiology and RAPD-PCR typing of thermophilic campylobacters from children under five years and chickens in Morogoro Municipality, Tanzania.

PubMed

Chuma, Idrissa S; Nonga, Hezron E; Mdegela, Robinson H; Kazwala, Rudovick R

2016-11-21

Campylobacter species are gram negative and flagellated bacteria under the genus Campylobacter, family Campylobacteriaceae. These pathogens cause zoonotic infections among human and animal populations. This study was undertaken between December 2006 and May 2007 to determine prevalence, risk factors and genetic diversity of thermophilic Campylobacter isolates from children less than 5 years and chickens in Morogoro Municipality, Tanzania. The Skirrow's protocol was used for isolation and identification of Campylobacter from 268 human stool specimens and 419 chicken cloacal swabs. Patient biodata and risk factors associated with human infection were also collected. Genetic diversity of Campylobacter isolates was determined by a RAPD-PCR technique using OPA 11 primer (5'-CAA TCG CCG T-3'). Phylogenetic analysis and band pattern comparison were done by Bionumerics software and visual inspection. Stool samples from 268 children and 419 cloacal swabs from chickens were analyzed. Prevalence of thermophilic Campylobacters in children was 19% with higher isolation frequency (p = 0.046) in males (23.5%) than females (13.8%). Campylobacter jejuni (78.4%) was more isolated (p = 0.000) than C. coli (19.6%) and 2% were unidentified isolates. In chickens, the prevalence was 42.5% with higher isolation rate (p = 0.000) of C. jejuni (87%) than C. coli (13%). Campylobacters were more frequently recovered (p = 0.000) from indigenous/ local chickens (75.0%) followed by cockerels (52.2%), broilers (50.0%) and lowest in layers (22.7%). Keeping chickens without other domestic animals concurrently (p = 0.000), chicken types (p = 0.000) and flock size (p = 0.007) were risk factors for infection in chickens. One hundred and fifty two (152) thermophillic Campylobacter isolates were genotyped by RAPD-PCR of which 114 were C. jejuni (74 from chickens and 40 humans) and 38 C. coli (28 from chickens and 10 humans). Comparison of Campylobacter isolates from children and chickens revealed high diversity with only 6.1% of C. jejuni and 5.3% of C. coli being 100% genetically similar. This study has recorded high prevalence of thermophilic Campylobacter in children less than 5 years and chickens in Morogoro municipality. The observed genetic similarity among few C. jejuni and C. coli isolates from children and chicken suggests existence of cross transmission of these pathogens between children under 5 years and chickens.

Considerations for Using Genetic and Epigenetic Information in Occupational Health Risk Assessment and Standard Setting

PubMed Central

Schulte, P. A.; Whittaker, C.; Curran, C. P.

2015-01-01

Risk assessment forms the basis for both occupational health decision-making and the development of occupational exposure limits (OELs). Although genetic and epigenetic data have not been widely used in risk assessment and ultimately, standard setting, it is possible to envision such uses. A growing body of literature demonstrates that genetic and epigenetic factors condition biological responses to occupational and environmental hazards or serve as targets of them. This presentation addresses the considerations for using genetic and epigenetic information in risk assessments, provides guidance on using this information within the classic risk assessment paradigm, and describes a framework to organize thinking about such uses. The framework is a 4 × 4 matrix involving the risk assessment functions (hazard identification, dose-response modeling, exposure assessment, and risk characterization) on one axis and inherited and acquired genetic and epigenetic data on the other axis. The cells in the matrix identify how genetic and epigenetic data can be used for each risk assessment function. Generally, genetic and epigenetic data might be used as endpoints in hazard identification, as indicators of exposure, as effect modifiers in exposure assessment and dose-response modeling, as descriptors of mode of action, and to characterize toxicity pathways. Vast amounts of genetic and epigenetic data may be generated by high-throughput technologies. These data can be useful for assessing variability and reducing uncertainty in extrapolations, and they may serve as the foundation upon which identification of biological perturbations would lead to a new paradigm of toxicity pathway-based risk assessments. PMID:26583908

Sperm quality but not relatedness predicts sperm competition success in threespine sticklebacks (Gasterosteus aculeatus).

PubMed

Mehlis, Marion; Rahn, Anna K; Bakker, Theo C M

2015-04-26

Mating between close relatives often leads to a reduction of an individual's fitness, due to an increased expression of deleterious alleles. Thus, in many animal taxa pre- as well as postcopulatory inbreeding avoidance mechanisms have evolved. An increased risk of inbreeding and hence a loss of genetic variation may occur during founder events as in most cases only few individuals establish a new population. The threespine stickleback (Gasterosteus aculeatus) is a small externally fertilizing fish species subject to strong sperm competition. Sticklebacks inhabit both marine and freshwater environments and anadromous populations have repeatedly established new genetically less diverse freshwater populations. Previous studies showed that anadromous sticklebacks strongly suffer from inbreeding depression and when given the choice females prefer to mate with unrelated males. The present study aimed to address whether there exists a postcopulatory inbreeding avoidance mechanism solely based on sperm-egg interactions in sperm competition experiments. We used F1 individuals that originated either from a large, genetically heterogeneous anadromous population or from a small, genetically less diverse freshwater population. For each population, eggs of two different females were in vitro fertilized by the same two males' sperm in a paired study design. In the main experiment one male was the female's full-sib brother and in the control experiment all individuals were unrelated. The results revealed that fertilization success was independent of relatedness in both populations suggesting a general lack of a postcopulatory inbreeding avoidance mechanism. Instead, male quality (i.e. sperm morphology) predicted paternity success during competitive fertilization trials. In sticklebacks, there is no evidence for postcopulatory inbreeding avoidance. Sperm morphology predicted paternity instead, thus sperm quality traits are under strong sexual selection, presumably driven by the high risk of sperm competition under natural conditions.

Association between KCNJ11 gene polymorphisms and risk of type 2 diabetes mellitus in East Asian populations: a meta-analysis in 42,573 individuals.

PubMed

Yang, Lijuan; Zhou, Xianghai; Luo, Yingying; Sun, Xiuqin; Tang, Yong; Guo, Wulan; Han, Xueyao; Ji, Linong

2012-01-01

A number of studies have been performed to identify the association between potassium inwardly-rectifying channel, subfamily J, member 11 (KCNJ11) gene and type 2 diabetes mellitus (T2DM) in East Asian populations, with inconsistent results. The main aim of this work was to evaluate more precisely the genetic influence of KCNJ11 on T2DM in East Asian populations by means of a meta-analysis. We identified 20 articles for qualitative analysis and 16 were eligible for quantitative analysis (meta-analysis) by database searching up to May 2010. The association was assessed under different genetic models, and the pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. The allelic and genotypic contrast demonstrated that the association between KCNJ11 and T2DM was significant for rs5210. However, not all results for rs5215 and rs5218 showed significant associations. For rs5219, the combined ORs (95% CIs) for allelic contrast, dominant and recessive models contrast (with allelic frequency and genotypic distribution data) were 1.139 (1.093-1.188), 1.177 (1.099-1.259) and 1.207 (1.094-1.332), respectively (random effect model). The analysis on the most completely adjusted ORs (95% CIs) by the covariates of rs5219 all presented significant associations under different genetic models. Population-stratified analysis (Korean, Japanese and Chinese) and sensitivity analysis verified the significant results. Cumulative meta-analysis including publication time and sample size illustrated the exaggerated genetic effect in the earliest studies. Heterogeneity and publication bias were assessed. Our study verified that single nucleotide polymorphisms (SNPs) of KCNJ11 gene were significantly associated with the risk of T2DM in East Asian populations.

A common 16p11.2 inversion underlies the joint susceptibility to asthma and obesity.

PubMed

González, Juan R; Cáceres, Alejandro; Esko, Tonu; Cuscó, Ivon; Puig, Marta; Esnaola, Mikel; Reina, Judith; Siroux, Valerie; Bouzigon, Emmanuelle; Nadif, Rachel; Reinmaa, Eva; Milani, Lili; Bustamante, Mariona; Jarvis, Deborah; Antó, Josep M; Sunyer, Jordi; Demenais, Florence; Kogevinas, Manolis; Metspalu, Andres; Cáceres, Mario; Pérez-Jurado, Luis A

2014-03-06

The prevalence of asthma and obesity is increasing worldwide, and obesity is a well-documented risk factor for asthma. The mechanisms underlying this association and parallel time trends remain largely unknown but genetic factors may be involved. Here, we report on a common ~0.45 Mb genomic inversion at 16p11.2 that can be accurately genotyped via SNP array data. We show that the inversion allele protects against the joint occurrence of asthma and obesity in five large independent studies (combined sample size of 317 cases and 543 controls drawn from a total of 5,809 samples; combined OR = 0.48, p = 5.5 × 10(-6)). Allele frequencies show remarkable worldwide population stratification, ranging from 10% in East Africa to 49% in Northern Europe, consistent with discordant and extreme genetic drifts or adaptive selections after human migration out of Africa. Inversion alleles strongly correlate with expression levels of neighboring genes, especially TUFM (p = 3.0 × 10(-40)) that encodes a mitochondrial protein regulator of energy balance and inhibitor of type 1 interferon, and other candidates for asthma (IL27) and obesity (APOB48R and SH2B1). Therefore, by affecting gene expression, the ~0.45 Mb 16p11.2 inversion provides a genetic basis for the joint susceptibility to asthma and obesity, with a population attributable risk of 39.7%. Differential mitochondrial function and basal energy balance of inversion alleles might also underlie the potential selection signature that led to their uneven distribution in world populations. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

CRHR1 genotypes, neural circuits and the diathesis for anxiety and depression.

PubMed

Rogers, J; Raveendran, M; Fawcett, G L; Fox, A S; Shelton, S E; Oler, J A; Cheverud, J; Muzny, D M; Gibbs, R A; Davidson, R J; Kalin, N H

2013-06-01

The corticotrophin-releasing hormone (CRH) system integrates the stress response and is associated with stress-related psychopathology. Previous reports have identified interactions between childhood trauma and sequence variation in the CRH receptor 1 gene (CRHR1) that increase risk for affective disorders. However, the underlying mechanisms that connect variation in CRHR1 to psychopathology are unknown. To explore potential mechanisms, we used a validated rhesus macaque model to investigate association between genetic variation in CRHR1, anxious temperament (AT) and brain metabolic activity. In young rhesus monkeys, AT is analogous to the childhood risk phenotype that predicts the development of human anxiety and depressive disorders. Regional brain metabolism was assessed with (18)F-labeled fluoro-2-deoxyglucose (FDG) positron emission tomography in 236 young, normally reared macaques that were also characterized for AT. We show that single nucleotide polymorphisms (SNPs) affecting exon 6 of CRHR1 influence both AT and metabolic activity in the anterior hippocampus and amygdala, components of the neural circuit underlying AT. We also find evidence for association between SNPs in CRHR1 and metabolism in the intraparietal sulcus and precuneus. These translational data suggest that genetic variation in CRHR1 affects the risk for affective disorders by influencing the function of the neural circuit underlying AT and that differences in gene expression or the protein sequence involving exon 6 may be important. These results suggest that variation in CRHR1 may influence brain function before any childhood adversity and may be a diathesis for the interaction between CRHR1 genotypes and childhood trauma reported to affect human psychopathology.

Circulating interleukin-10 levels and human papilloma virus and Epstein-Barr virus-associated cancers: evidence from a Mendelian randomization meta-analysis based on 11,170 subjects.

PubMed

Qu, Kai; Pang, Qing; Lin, Ting; Zhang, Li; Gu, Mingliang; Niu, Wenquan; Liu, Chang; Zhang, Ming

2016-01-01

Recent studies have showed interleukin 10 (IL-10) is a critical cytokine that determines antiviral immune response and is related to virus-associated cancers. However, whether genetically elevated circulating IL-10 levels are associated with the risk of human papilloma virus and Epstein-Barr virus-associated cancers (HEACs) is still unclear. Mendelian randomization method was implemented to meta-analyze available observational studies by employing IL-10 three variants (-592C>A, -819C>T, and -1082A>G) as instruments. A total of 24 articles encompassing 11,170 subjects were ultimately eligible for the meta-analysis. Overall, there was a significant association between IL-10 promoter variant -1082A>G and HEACs under allelic and dominant models (both P<0.01). Subgroup analysis by cancer type indicated that the risk estimate of -1082A>G was significant for nasopharyngeal cancer under allelic, homozygous genotypic and dominant models (all P<0.001). Moreover by ethnicity, carriers of -1082G allele had a 74% increased risk for nasopharyngeal cancer in Asians under dominant model (odds ratio [OR] =1.737; 95% confidence interval [CI]: 1.280-2.358; P<0.001). In further Mendelian randomization analysis, the predicted OR for 10 pg/mL increment in IL-10 levels was 1.14 (95% CI: 1.01-16.99) in HEACs. Our findings provided strong evidence for a critical role of genetically elevated circulating IL-10 levels in the development of HEACs, especially in Asian population and for nasopharyngeal cancer.

Arsenic accumulation in rice: Consequences of rice genotypes and management practices to reduce human health risk.

PubMed

Islam, Shofiqul; Rahman, Mohammad Mahmudur; Islam, M R; Naidu, Ravi

2016-11-01

Rice is an essential staple food and feeds over half of the world's population. Consumption of rice has increased from limited intake in Western countries some 50years ago to major dietary intake now. Rice consumption represents a major route for inorganic arsenic (As) exposure in many countries, especially for people with a large proportion of rice in their daily diet as much as 60%. Rice plants are more efficient in assimilating As into its grains than other cereal crops and the accumulation may also adversely affect the quality of rice and their nutrition. Rice is generally grown as a lowland crop in flooded soils under reducing conditions. Under these conditions the bioavailability of As is greatly enhanced leading to excessive As bioaccumulation compared to that under oxidizing upland conditions. Inorganic As species are carcinogenic to humans and even at low levels in the diet pose a considerable risk to humans. There is a substantial genetic variation among the rice genotypes in grain-As accumulation as well as speciation. Identifying the extent of genetic variation in grain-As concentration and speciation of As compounds are crucial to determining the rice varieties which accumulate low inorganic As. Varietal selection, irrigation water management, use of fertilizer and soil amendments, cooking practices etc. play a vital role in reducing As exposure from rice grains. In the meantime assessing the bioavailability of As from rice is crucial to understanding human health exposure and reducing the risk. Copyright © 2016 Elsevier Ltd. All rights reserved.

Childhood socioeconomic status and longitudinal patterns of alcohol problems: Variation across etiological pathways in genetic risk.

PubMed

Barr, Peter B; Silberg, Judy; Dick, Danielle M; Maes, Hermine H

2018-05-14

Childhood socioeconomic status (SES) is an important aspect of early life environment associated with later life health/health behaviors, including alcohol misuse. However, alcohol misuse is modestly heritable and involves differing etiological pathways. Externalizing disorders show significant genetic overlap with substance use, suggesting an impulsivity pathway to alcohol misuse. Alcohol misuse also overlaps with internalizing disorders, suggesting alcohol is used to cope. These differing pathways could lead to different patterns over time and/or differential susceptibility to environmental conditions, such as childhood SES. We examine whether: 1) genetic risk for externalizing and internalizing disorders influence trajectories of alcohol problems across adolescence to adulthood, 2) childhood SES alters genetic risk these disorders on trajectories of alcohol problems, and 3) these patterns are consistent across sex. We find modest evidence of gene-environment interaction. Higher childhood SES increases the risk of alcohol problems in late adolescence/early adulthood, while lower childhood SES increases the risk of alcohol problems in later adulthood, but only among males at greater genetic risk of externalizing disorders. Females from lower SES families with higher genetic risk of internalizing or externalizing disorders have greater risk of developing alcohol problems. Copyright © 2018 Elsevier Ltd. All rights reserved.

Hitting the mark or falling short with nanotechnology regulation?

PubMed

Ludlow, Karinne; Bowman, Diana M; Kirk, Dwayne D

2009-11-01

Regulation of all new technology ebbs and flows between periods of under- and over-regulation, often dependant on the viewpoint of the observer and the underlying objectives of the particular regulation. As illustrated by genetic modification (GM) applications, defining what constitutes appropriate regulation for a rapidly evolving technology can be difficult. Drawing upon the lessons of GM, we argue that nanotechnology will go through similar periods of inappropriate regulation. As with GM, future regulatory responses to nanotechnology will be shaped by perceptions of risk and willingness to accept varying levels of risk. With varying responses between jurisdictions appearing inevitable, we argue that the timing and type of regulation adopted for nanotechnology, and its appropriateness, will be crucial to its commercial success.

The association between carbohydrate-rich foods and risk of cardiovascular disease is not modified by genetic susceptibility to dyslipidemia as determined by 80 validated variants.

PubMed

Sonestedt, Emily; Hellstrand, Sophie; Schulz, Christina-Alexandra; Wallström, Peter; Drake, Isabel; Ericson, Ulrika; Gullberg, Bo; Hedblad, Bo; Orho-Melander, Marju

2015-01-01

It is still unclear whether carbohydrate consumption is associated with cardiovascular disease (CVD) risk. Genetic susceptibility might modify the associations between dietary intakes and disease risk. The aim was to examine the association between the consumption of carbohydrate-rich foods (vegetables, fruits and berries, juice, potatoes, whole grains, refined grains, cookies and cakes, sugar and sweets, and sugar-sweetened beverages) and the risk of incident ischemic CVD (iCVD; coronary events and ischemic stroke), and whether these associations differ depending on genetic susceptibility to dyslipidemia. Among 26,445 individuals (44-74 years; 62% females) from the Malmö Diet and Cancer Study cohort, 2,921 experienced an iCVD event during a mean follow-up time of 14 years. At baseline, dietary data were collected using a modified diet history method, and clinical risk factors were measured in 4,535 subjects. We combined 80 validated genetic variants associated with triglycerides and HDL-C or LDL-C, into genetic risk scores and examined the interactions between dietary intakes and genetic risk scores on the incidence of iCVD. Subjects in the highest intake quintile for whole grains had a 13% (95% CI: 3-23%; p-trend: 0.002) lower risk for iCVD compared to the lowest quintile. A higher consumption of foods rich in added sugar (sugar and sweets, and sugar-sweetened beverages) had a significant cross-sectional association with higher triglyceride concentrations and lower HDL-C concentrations. A stronger positive association between a high consumption of sugar and sweets on iCVD risk was observed among those with low genetic risk score for triglycerides (p-interaction=0.05). In this prospective cohort study that examined food sources of carbohydrates, individuals with a high consumption of whole grains had a decreased risk of iCVD. No convincing evidence of an interaction between genetic susceptibility for dyslipidemia, measured as genetic risk scores of dyslipidemia-associated variants, and the consumption of carbohydrate-rich foods on iCVD risk was observed.

The effect of communicating the genetic risk of cardiometabolic disorders on motivation and actual engagement in preventative lifestyle modification and clinical outcome: a systematic review and meta-analysis of randomised controlled trials.

PubMed

Li, Sherly X; Ye, Zheng; Whelan, Kevin; Truby, Helen

2016-09-01

Genetic risk prediction of chronic conditions including obesity, diabetes and CVD currently has limited predictive power but its potential to engage healthy behaviour change has been of immense research interest. We aimed to understand whether the latter is indeed true by conducting a systematic review and meta-analysis investigating whether genetic risk communication affects motivation and actual behaviour change towards preventative lifestyle modification. We included all randomised controlled trials (RCT) since 2003 investigating the impact of genetic risk communication on health behaviour to prevent cardiometabolic disease, without restrictions on age, duration of intervention or language. We conducted random-effects meta-analyses for perceived motivation for behaviour change and clinical changes (weight loss) and a narrative analysis for other outcomes. Within the thirteen studies reviewed, five were vignette studies (hypothetical RCT) and seven were clinical RCT. There was no consistent effect of genetic risk on actual motivation for weight loss, perceived motivation for dietary change (control v. genetic risk group standardised mean difference (smd) -0·15; 95 % CI -1·03, 0·73, P=0·74) or actual change in dietary behaviour. Similar results were observed for actual weight loss (control v. high genetic risk SMD 0·29 kg; 95 % CI -0·74, 1·31, P=0·58). This review found no clear or consistent evidence that genetic risk communication alone either raises motivation or translates into actual change in dietary intake or physical activity to reduce the risk of cardiometabolic disorders in adults. Of thirteen studies, eight were at high or unclear risk of bias. Additional larger-scale, high-quality clinical RCT are warranted.

Breast Cancer

MedlinePlus

... a genetic counselor, who can review your family health history. A genetic counselor can also discuss the benefits, risks and limitations of genetic testing to assist you with shared decision-making. Risk ...

Adaptation prevents the extinction of Chlamydomonas reinhardtii under toxic beryllium

PubMed Central

Baselga-Cervera, Beatriz; Costas, Eduardo; Bustillo-Avendaño, Estéfano

2016-01-01

The current biodiversity crisis represents a historic challenge for natural communities: the environmental rate of change exceeds the population’s adaptation capability. Integrating both ecological and evolutionary responses is necessary to make reliable predictions regarding the loss of biodiversity. The race against extinction from an eco-evolutionary perspective is gaining importance in ecological risk assessment. Here, we performed a classical study of population dynamics—a fluctuation analysis—and evaluated the results from an adaption perspective. Fluctuation analysis, widely used with microorganisms, is an effective empirical procedure to study adaptation under strong selective pressure because it incorporates the factors that influence demographic, genetic and environmental changes. The adaptation of phytoplankton to beryllium (Be) is of interest because human activities are increasing the concentration of Be in freshwater reserves; therefore, predicting the effects of human-induced pollutants is necessary for proper risk assessment. The fluctuation analysis was performed with phytoplankton, specifically, the freshwater microalgae Chlamydomonas reinhardtii, under acute Be exposure. High doses of Be led to massive microalgae death; however, by conducting a fluctuation analysis experiment, we found that C. reinhardtii was able to adapt to 33 mg/l of Be due to pre-existing genetic variability. The rescuing adapting genotype presented a mutation rate of 9.61 × 10−6 and a frequency of 10.42 resistant cells per million wild-type cells. The genetic adaptation pathway that was experimentally obtained agreed with the theoretical models of evolutionary rescue (ER). Furthermore, the rescuing genotype presented phenotypic and physiologic differences from the wild-type genotype, was 25% smaller than the Be-resistant genotype and presented a lower fitness and quantum yield performance. The abrupt distinctions between the wild-type and the Be-resistant genotype suggest a pleiotropic effect mediated by an advantageous mutation; however, no sequencing confirmation was performed. PMID:27019784

Risk and reproductive decisions: British Pakistani couples’ responses to genetic counselling

PubMed Central

Shaw, Alison

2011-01-01

How far does ethnicity/culture/religion mediate couples’ responses to genetic risk? This paper examines the responses of 51 British Pakistani couples referred to a genetics clinic in southern England to counselling about recurrence risks for genetic problems in children. It is based on fieldwork conducted between 2000 and 2004 that combined participant observation of genetics consultations with interviews in respondents’ homes. Interviews were conducted with 62 adults in connection with these 51 cases, of which 32 were followed through two or more clinical consultations and 12 through more than one pregnancy. Risk responses were categorized as: taking the risk; postponing; exploring risk management or dismissing the risk as irrelevant to current circumstances. Responses were cross-referenced for associations with the severity of the condition, number of affected and unaffected children, availability of a prenatal test, age, gender, and migration history. I found that most couples were initially risk-takers who already had an unaffected child or children. Couples caring for living children with severe conditions were more likely to postpone. However, the risk responses of 15 couples changed over time, most towards and some away from risk management, reflecting changes in couples’ appreciation of the severity of the condition and their subsequent reproductive experiences. The study highlights the diversity and dynamism of responses within one ethnic group and challenges stereotypes about cultural and religious responses to genetic risk. PMID:21641705

Counterpoint: implementing population genetic screening for Lynch Syndrome among newly diagnosed colorectal cancer patients--will the ends justify the means?

PubMed

Hall, Michael J

2010-05-01

Inherited mutations in 1 of 4 known mismatch repair genes (MLH1, MSH2, MSH6, PMS2) are associated with various cancer risks collectively referred to as Lynch syndrome. Roughly 3 of every 100 new colorectal cancers (CRCs) have an underlying Lynch mutation. Tumor-based screening for Lynch among all patients with newly diagnosed CRC could theoretically improve the ability to identify Lynch and prevent cancer among at-risk family members, but the patient-level and social implications of this approach must be carefully considered before adopting this strategy. Poorly addressed issues include the role/timing of informed consent for testing, access and cost barriers associated with genetic counseling and DNA testing, psychosocial burdens to the thousands of middle-aged and elderly patients with CRC coping with surgical and chemotherapy treatments and poor prognosis, the need for providers to warn third-party relatives of risk for Lynch syndrome, limited effectiveness of screening, and the cost burden to society when poor DNA testing uptake, test limitations, and modest screening compliance are considered. Diverse barriers to the success of a population-based Lynch screening program in the United States remain (e.g., clinical resource needs, financial limitations, clinical expertise gaps, educational deficits). Data supporting clinical efficacy (feasibility) and effectiveness (real-life performance) are critical before important policy changes are adopted, especially where issues of hereditary cancer risk and genetic privacy are involved.

A Genetically Informed Study of the Processes Underlying the Association Between Parental Marital Instability and Offspring Adjustment

PubMed Central

D’Onofrio, Brian M.; Turkheimer, Eric; Emery, Robert E.; Heath, Andrew C.; Madden, Pamela A.; Slutske, Wendy S.; Martin, Nicholas G.

2010-01-01

Parental divorce is associated with problematic offspring adjustment, but the relation may be due to shared genetic or environmental factors. One way to test for these confounds is to study offspring of twins discordant for divorce. The current analyses used this design to separate the mechanisms responsible for the association between parental divorce, experienced either before or after the age of 16, and offspring well-being. The results were consistent with a causal role of divorce in earlier initiation of sexual intercourse and emotional difficulties, in addition to a greater probability of educational problems, depressed mood, and suicidal ideation. In contrast, the increased risk for cohabitation and earlier initiation of drug use was explained by selection factors, including genetic confounds. PMID:16756440

Electrophysiological Endophenotypes for Schizophrenia

PubMed Central

Owens, Emily; Bachman, Peter; Glahn, David C; Bearden, Carrie E

2016-01-01

Endophenotypes are quantitative, heritable traits that may help to elucidate the pathophysiologic mechanisms underlying complex disease syndromes, such as schizophrenia. They can be assessed at numerous levels of analysis; here, we review electrophysiological endophenotypes that have shown promise in helping us understand schizophrenia from a more mechanistic point of view. For each endophenotype, we describe typical experimental procedures, reliability, heritability, and reported gene and neurobiological associations. We discuss recent findings regarding the genetic architecture of specific electrophysiological endophenotypes, as well as converging evidence from EEG studies implicating disrupted balance of glutamatergic signaling and GABA-ergic inhibition in the pathophysiology of schizophrenia. We conclude that refining the measurement of electrophysiological endophenotypes, expanding genetic association studies, and integrating datasets are important next steps for understanding the mechanisms that connect identified genetic risk loci for schizophrenia to the disease phenotype. PMID:26954597

The effect of direct-to-consumer genetic tests on anticipated affect and health-seeking behaviors: a pilot survey.

PubMed

Bansback, Nick; Sizto, Sonia; Guh, Daphne; Anis, Aslam H

2012-10-01

Numerous websites offer direct-to-consumer (DTC) genetic testing, yet it is unknown how individuals will react to genetic risk profiles online. The objective of this study was to determine the feasibility of using a web-based survey and conjoint methods to elicit individuals' interpretations of genetic risk profiles by their anticipated worry/anxiousness and health-seeking behaviors. A web-based survey was developed using conjoint methods. Each survey presented 12 hypothetical genetic risk profiles describing genetic test results for four diseases. Test results were characterized by the type of disease (eight diseases), individual risk (five levels), and research confidence (three levels). After each profile, four questions were asked regarding anticipated worry and health-seeking behaviors. Probabilities of response outcomes based on attribute levels were estimated from logistic regression models, adjusting for covariates. Overall, 319 participants (69%) completed 3828 unique genetic risk profiles. Across all profiles, most participants anticipated making doctor's appointments (63%), lifestyle changes (57%), and accessing screening (57%); 40% anticipated feeling more worried and anxious. Higher levels of disease risk were significantly associated with affirmative responses. Conjoint methods may be used to elicit reactions to genetic information online. Preliminary results suggest that genetic information may increase worry/anxiousness and health-seeking behaviors among consumers of DTC tests. Further research is planned to determine the appropriateness of these affects and behaviors.

Genetic Risk Score of NOS Gene Variants Associated with Myocardial Infarction Correlates with Coronary Incidence across Europe

PubMed Central

Carreras-Torres, Robert; Kundu, Suman; Zanetti, Daniela; Esteban, Esther

2014-01-01

Coronary artery disease (CAD) mortality and morbidity is present in the European continent in a four-fold gradient across populations, from the South (Spain and France) with the lowest CAD mortality, towards the North (Finland and UK). This observed gradient has not been fully explained by classical or single genetic risk factors, resulting in some cases in the so called Southern European or Mediterranean paradox. Here we approached population genetic risk estimates using genetic risk scores (GRS) constructed with single nucleotide polymorphisms (SNP) from nitric oxide synthases (NOS) genes. These SNPs appeared to be associated with myocardial infarction (MI) in 2165 cases and 2153 controls. The GRSs were computed in 34 general European populations. Although the contribution of these GRS was lower than 1% between cases and controls, the mean GRS per population was positively correlated with coronary incidence explaining 65–85% of the variation among populations (67% in women and 86% in men). This large contribution to CAD incidence variation among populations might be a result of colinearity with several other common genetic and environmental factors. These results are not consistent with the cardiovascular Mediterranean paradox for genetics and support a CAD genetic architecture mainly based on combinations of common genetic polymorphisms. Population genetic risk scores is a promising approach in public health interventions to develop lifestyle programs and prevent intermediate risk factors in certain subpopulations with specific genetic predisposition. PMID:24806096

Coronary artery disease in Bangladesh: A review

PubMed Central

Islam, A.K.M. Monwarul; Majumder, A.A.S.

2013-01-01

Coronary artery disease (CAD) is an increasingly important medical and public health problem, and is the leading cause of mortality in Bangladesh. Like other South Asians, Bangladeshis are unduly prone to develop CAD, which is often premature in onset, follows a rapidly progressive course and angiographically more severe. The underlying pathophysiology is poorly understood. Genetic predisposition, high prevalence of metabolic syndrome and conventional risk factors play important role. Lifestyle related factors, including poor dietary habits, excess saturated and trans fat, high salt intake, and low-level physical activity may be important as well. Some novel risk factors, including hypovitaminosis D, arsenic contamination in water and food-stuff, particulate matter air pollution may play unique role. At the advent of the new millennium, we know little about our real situation. Largescale epidemiological, genetic and clinical researches are needed to explore the different aspects of CAD in Bangladesh. PMID:23993003

Asthma phenotypes in childhood.

PubMed

Reddy, Monica B; Covar, Ronina A

2016-04-01

This review describes the literature over the past 18 months that evaluated childhood asthma phenotypes, highlighting the key aspects of these studies, and comparing these studies to previous ones in this area. Recent studies on asthma phenotypes have identified new phenotypes on the basis of statistical analyses (using cluster analysis and latent class analysis methodology) and have evaluated the outcomes and associated risk factors of previously established early childhood asthma phenotypes that are based on asthma onset and patterns of wheezing illness. There have also been investigations focusing on immunologic, physiologic, and genetic correlates of various phenotypes, as well as identification of subphenotypes of severe childhood asthma. Childhood asthma remains a heterogeneous condition, and investigations into these various presentations, risk factors, and outcomes are important since they can offer therapeutic and prognostic relevance. Further investigation into the immunopathology and genetic basis underlying childhood phenotypes is important so therapy can be tailored accordingly.

Blood type gene locus has no influence on ACE association with Alzheimer's disease.

PubMed

Braae, Anne; Medway, Christopher; Carrasquillo, Minerva; Younkin, Steven; Kehoe, Patrick G; Morgan, Kevin

2015-04-01

The ABO blood group locus was recently found to contribute independently and via interactions with angiotensin-converting enzyme (ACE) gene variation to plasma levels of ACE. Variation in ACE has previously been not only implicated as individually conferring susceptibility for Alzheimer's disease (AD) but also proposed to confer risk via interactions with other as yet unknown genes. More recently, larger studies have not supported ACE as a risk factor for AD, whereas the role of ACE pathway in AD has come under increased levels of scrutiny with respect to various aspects of AD pathology and possible therapies. We explored the potential combined involvement of ABO and ACE variations in the genetic susceptibility of 2067 AD cases compared with 1376 nondemented elderly. Including the effects of ABO haplotype did not provide any evidence for the genetic association of ACE with AD. Copyright © 2015 Elsevier Inc. All rights reserved.

Velo-Cardio-Facial Syndrome

PubMed Central

Gothelf, Doron; Frisch, Amos; Michaelovsky, Elena; Weizman, Abraham; Shprintzen, Robert J.

2010-01-01

Velocardiofacial syndrome (VCFS) also known as DiGeorge, conotruncal anomaly face and Cayler syndromes is caused by a microdeletion in the long arm of chromosome 22. We review the history of the syndrome from the first clinical reports almost half a century ago to the current intriguing molecular findings associating genes from the microdeletion region and the physical and neuropsychiatric phenotype of the syndrome. Velocardiofacial syndrome has a wide spectrum of more than 200 physical manifestations including palate and cardiac anomalies. Yet, the most challenging manifestations of VCFS are the learning disabilities and neuropsychiatric disorders. As VCFS is relatively common and as up to one third of the subjects with VCFS develop schizophrenia like psychotic disorder the syndrome is the most commonly known genetic risk factor to schizophrenia. Identifying the genetic, cognitive and psychiatric risk factors for VCFS-schizophrenia is under the focus of intensive research. PMID:20111667

Copy number variations in patients with electrical status epilepticus in sleep.

PubMed

Kevelam, Sietske H G; Jansen, Floor E; Binsbergen, Ellen van; Braun, Kees P J; Verbeek, Nienke E; Lindhout, Dick; Poot, Martin; Brilstra, Eva H

2012-02-01

Electrical status epilepticus in sleep syndrome is the association of the electroencephalographic pattern and deficits in language or global cognitive function and behavioral problems. The etiology is often unknown, but genetic risk factors have been implicated. Array-based comparative genomic hybridization was used to identify copy number variations in 13 children with electrical status epilepticus in sleep syndrome to identify possible underlying risk factors. Seven copy number variations were detected in 4 of the 13 patients, which consisted of 6 novel gains and 1 loss, the recurrent 15q13.3 microdeletion. Two patients carried a probable pathogenic copy number variation containing a gene involved in the cholinergic pathway. Genetic aberrations in patients with electrical status epilepticus in sleep syndrome can provide an entry in the investigation of the etiology of electrical status epilepticus in sleep. However, further studies are needed to confirm our findings.

The fewer and the better: prioritization of populations for conservation under limited resources, a genetic study with Borderea pyrenaica (Dioscoreaceae) in the Pyrenean National Park.

PubMed

Segarra-Moragues, J G; Catalán, P

2010-03-01

Taxa considered under low International Union for the Conservation of Nature categories of extinction risk often represent cases of concern to conservation biology. Their high relative abundance precludes management of the entire range due to limited economical resources. Therefore, they require a cost-effective management plan. Borderea pyrenaica (Dioscoreaceae), an endemic plant of the Central Pyrenees and pre-Pyrenees, reaches the French side of the Central Pyrenees on its narrow northernmost boundary at Gavarnie (Parc National des Pyrenées, PNP, France), where it is protected as Vulnerable and considered a priority species. We have used nuclear microsatellite population genetic data to design a management strategy for the 11 populations of B. pyrenaica present in this area and to identify Relevant Genetic Units for its Conservation. The 18 SSR loci analysed identified 56 alleles, 24 of which fulfilled the rarity criterion for this set of populations. Genetic structuring of populations and representativity values derived from regression analyses of probabilities of loss of rare alleles together support differentiation of the B. pyrenaica populations into different management units. Estimates derived from G(ST) values indicate that five populations would adequately represent the 99.9% of the variation relative to most common alleles whereas calculations based on representativity values indicated that these five populations should equate the proportion 2:2:1 from the three different phylogeographical subdivisions of Gavarnie (Western, Eastern-1 and Eastern-2 ranges). This scheme would allow the preservation of 98.21% of the total B. pyrenaica alleles present in Gavarnie, according to the post glacial history of its populations. This conservation genetic approach could be applied to other low-extinction risk categories of extremely rare and subalpine plants in need of regulatory plans in European National Parks and Natural Reserves.

Non-alcoholic Fatty Liver Disease in Lean Subjects: Characteristics and Implications.

PubMed

Kumar, Ramesh; Mohan, Shantam

2017-09-28

Non-alcoholic fatty liver disease (NAFLD) is commonly diagnosed in obese subjects; however, it is not rare among lean individuals. Given the absence of traditional risk factors, it tends to remain under-recognised. The metabolic profiles of lean NAFLD patients are frequently comparable to those of obese NAFLD patients. Though results from several studies have been mixed, it has been generally revealed that lean subjects with NAFLD have minor insulin resistance compared to that in obese NAFLD. Several genetic variants are associated with NAFLD without insulin resistance. Some data suggest that the prevalence of steatohepatitis and advanced fibrosis do not differ significantly between lean and obese NAFLD; however, the former tend to have less severe disease at presentation. The underlying pathophysiology of lean NAFLD may be quite different. Genetic predispositions, fructose- and cholesterol-rich diet, visceral adiposity and dyslipidaemia have potential roles in the pathogenic underpinnings. Lean NAFLD may pose a risk for metabolic disturbances, cardiovascular morbidity or overall mortality. Secondary causes of hepatic steatosis are also needed to be ruled out in lean subjects with NAFLD. The effectiveness of various treatment modalities, such as exercise and pharmacotherapy, on lean NAFLD is not known. Weight loss is expected to help lean NAFLD patients who have visceral obesity. Further investigation is needed for many aspects of lean NAFLD, including mechanistic pathogenesis, risk assessment, natural history and therapeutic approach.

Non-alcoholic Fatty Liver Disease in Lean Subjects: Characteristics and Implications

PubMed Central

Kumar, Ramesh; Mohan, Shantam

2017-01-01

Abstract Non-alcoholic fatty liver disease (NAFLD) is commonly diagnosed in obese subjects; however, it is not rare among lean individuals. Given the absence of traditional risk factors, it tends to remain under-recognised. The metabolic profiles of lean NAFLD patients are frequently comparable to those of obese NAFLD patients. Though results from several studies have been mixed, it has been generally revealed that lean subjects with NAFLD have minor insulin resistance compared to that in obese NAFLD. Several genetic variants are associated with NAFLD without insulin resistance. Some data suggest that the prevalence of steatohepatitis and advanced fibrosis do not differ significantly between lean and obese NAFLD; however, the former tend to have less severe disease at presentation. The underlying pathophysiology of lean NAFLD may be quite different. Genetic predispositions, fructose- and cholesterol-rich diet, visceral adiposity and dyslipidaemia have potential roles in the pathogenic underpinnings. Lean NAFLD may pose a risk for metabolic disturbances, cardiovascular morbidity or overall mortality. Secondary causes of hepatic steatosis are also needed to be ruled out in lean subjects with NAFLD. The effectiveness of various treatment modalities, such as exercise and pharmacotherapy, on lean NAFLD is not known. Weight loss is expected to help lean NAFLD patients who have visceral obesity. Further investigation is needed for many aspects of lean NAFLD, including mechanistic pathogenesis, risk assessment, natural history and therapeutic approach. PMID:28936403

Conference summary: Navigating the Sea of Genomic Data, October 28-29, 2015.

PubMed

Pihlstrom, Bruce L; Barnett, Michael L

2016-03-01

The rapid pace of biomedical discoveries in the past few years has resulted in substantial advances in our ability to diagnose, treat, and prevent a wide variety of diseases. The sequencing of the human genome offered the possibility of understanding the etiology, pathogenesis, and risk of developing disease from a genetic perspective and has resulted, for example, in the development of genomic-based diagnostic or risk-assessment tests for a number of medical and dental conditions. To assess the scientific evidence underlying such tests and determine whether they may be useful in clinical practice, practitioners need to have a basic understanding of the state-of-the-science of genomics and genetic testing. To assist practitioners in understanding the science of genomics, the American Dental Association and the Task Force on Design and Analysis in Oral Health Research co-sponsored a landmark conference, Navigating the Sea of Genomic Data, held October 28-29, 2015, at the American Dental Association headquarters building in Chicago, IL. The purpose of this conference was to review the basics of genomic science, promote sound design and analysis of genomic studies of oral diseases, and provide a basis or "framework" to guide practitioners in assessing new development in genomics and genetic tests for oral diseases. Presentations at this conference were made by 9 world-renowned scientists who discussed a wide range of topics involving genomic science, genetic testing for rare mendelian single gene disorders, and genetic testing for assessing the risk of experiencing common complex diseases. This article summarizes the key points and concepts presented by the speakers. It is essential for oral health care professionals to have a fundamental understanding of genomic science so that they can evaluate new advances in this field and the use of genetic testing for the benefit of their patients. Copyright © 2016 American Dental Association. Published by Elsevier Inc. All rights reserved.

Risk assessment in man and mouse.

PubMed

Balci, Fuat; Freestone, David; Gallistel, Charles R

2009-02-17

Human and mouse subjects tried to anticipate at which of 2 locations a reward would appear. On a randomly scheduled fraction of the trials, it appeared with a short latency at one location; on the complementary fraction, it appeared after a longer latency at the other location. Subjects of both species accurately assessed the exogenous uncertainty (the probability of a short versus a long trial) and the endogenous uncertainty (from the scalar variability in their estimates of an elapsed duration) to compute the optimal target latency for a switch from the short- to the long-latency location. The optimal latency was arrived at so rapidly that there was no reliably discernible improvement over trials. Under these nonverbal conditions, humans and mice accurately assess risks and behave nearly optimally. That this capacity is well-developed in the mouse opens up the possibility of a genetic approach to the neurobiological mechanisms underlying risk assessment.

Risk assessment in man and mouse

PubMed Central

Balci, Fuat; Freestone, David; Gallistel, Charles R.

2009-01-01

Human and mouse subjects tried to anticipate at which of 2 locations a reward would appear. On a randomly scheduled fraction of the trials, it appeared with a short latency at one location; on the complementary fraction, it appeared after a longer latency at the other location. Subjects of both species accurately assessed the exogenous uncertainty (the probability of a short versus a long trial) and the endogenous uncertainty (from the scalar variability in their estimates of an elapsed duration) to compute the optimal target latency for a switch from the short- to the long-latency location. The optimal latency was arrived at so rapidly that there was no reliably discernible improvement over trials. Under these nonverbal conditions, humans and mice accurately assess risks and behave nearly optimally. That this capacity is well-developed in the mouse opens up the possibility of a genetic approach to the neurobiological mechanisms underlying risk assessment. PMID:19188592

The impact of APOA5, APOB, APOC3 and ABCA1 gene polymorphisms on ischemic stroke: Evidence from a meta-analysis.

PubMed

Au, Anthony; Griffiths, Lyn R; Irene, Looi; Kooi, Cheah Wee; Wei, Loo Keat

2017-10-01

Genetic studies have been reported on the association between APOA5, APOB, APOC3 and ABCA1 gene polymorphisms and ischemic stroke, but results remain controversial. Hence, this meta-analysis aimed to infer the causal relationships of APOA5 (rs662799, rs3135506), APOB (rs693, rs1042031, rs1801701), APOC3 (rs4520, rs5128, rs2854116, rs2854117) and ABCA1 rs2230806 with ischemic stroke risk. A systematic review was performed for all the articles retrieved from multiple databases, up until March 2017. Data were extracted from all eligible studies, and meta-analysis was carried out using RevMan 5.3 and R package 3.2.1. The strength of association between each studied polymorphism and ischemic stroke risk was measured as odds ratios (ORs) and 95% confidence intervals (CIs), under fixed- and random-effect models. A total of 79 studies reporting on the association between the studied polymorphisms and ischemic stroke risk were identified. The pooled data indicated that all genetic models of APOA5 rs662799 (ORs = 1.23-1.43), allelic and over-dominant models of APOA5 rs3135506 (ORs = 1.77-1.97), APOB rs1801701 (ORs = 1.72-2.13) and APOB rs1042031 (ORs = 1.66-1.88) as well as dominant model of ABCA1 rs2230806 (OR = 1.31) were significantly associated with higher risk of ischemic stroke. However, no significant associations were observed between ischemic stroke and the other five polymorphisms, namely ApoB (rs693) and APOC3 (rs4520, rs5128, rs2854116 and rs2854117), under any genetic model. The present meta-analysis confirmed a significant association of APOA5 rs662799 CC, APOA5 rs3135506 CG, APOB rs1801701 GA, APOB rs1042031 GA and ABCA1 rs2230806 GG with increased risk of ischemic stroke. Copyright © 2017 Elsevier B.V. All rights reserved.

Genetic Determinants of Thrombin Generation and Their Relation to Venous Thrombosis: Results from the GAIT-2 Project

PubMed Central

Martin-Fernandez, Laura; Ziyatdinov, Andrey; Carrasco, Marina; Millon, Juan Antonio; Martinez-Perez, Angel; Vilalta, Noelia; Brunel, Helena; Font, Montserrat; Hamsten, Anders; Souto, Juan Carlos; Soria, José Manuel

2016-01-01

Background Venous thromboembolism (VTE) is a common disease where known genetic risk factors explain only a small portion of the genetic variance. Then, the analysis of intermediate phenotypes, such as thrombin generation assay, can be used to identify novel genetic risk factors that contribute to VTE. Objectives To investigate the genetic basis of distinct quantitative phenotypes of thrombin generation and its relationship to the risk of VTE. Patients/Methods Lag time, thrombin peak and endogenous thrombin potential (ETP) were measured in the families of the Genetic Analysis of Idiopathic Thrombophilia 2 (GAIT-2) Project. This sample consisted of 935 individuals in 35 extended families selected through a proband with idiopathic thrombophilia. We performed also genome wide association studies (GWAS) with thrombin generation phenotypes. Results The results showed that 67% of the variation in the risk of VTE is attributable to genetic factors. The heritabilities of lag time, thrombin peak and ETP were 49%, 54% and 52%, respectively. More importantly, we demonstrated also the existence of positive genetic correlations between thrombin peak or ETP and the risk of VTE. Moreover, the major genetic determinant of thrombin generation was the F2 gene. However, other suggestive signals were observed. Conclusions The thrombin generation phenotypes are strongly genetically determined. The thrombin peak and ETP are significantly genetically correlated with the risk of VTE. In addition, F2 was identified as a major determinant of thrombin generation. We reported suggestive signals that might increase our knowledge to explain the variability of this important phenotype. Validation and functional studies are required to confirm GWAS results. PMID:26784699

Patient compliance based on genetic medicine: a literature review.

PubMed

Schneider, Kai Insa; Schmidtke, Jörg

2014-01-01

For this literature review, medical literature data bases were searched for studies on patient compliance after genetic risk assessment. The review focused on conditions where secondary or tertiary preventive options exist, namely cancer syndromes (BRCA-related cancer, HNPCC/colon cancer), hemochromatosis, thrombophilia, smoking cessation, and obesity. As a counterpart, patient compliance was assessed regarding medication adherence and medical advice in some of the most epidemiologically important conditions (including high blood pressure, metabolic syndrome, and coronary heart disease) after receiving medical advice based on nongenetic risk information or a combination of genetic and nongenetic risk information. In the majority of studies based on genetic risk assessments, patients were confronted with predictive rather than diagnostic genetic profiles. Most of the studies started from a knowledge base around 10 years ago when DNA testing was at an early stage, limited in scope and specificity, and costly. The major result is that overall compliance of patients after receiving a high-risk estimate from genetic testing for a given condition is high. However, significant behavior change does not take place just because the analyte is "genetic." Many more factors play a role in the complex process of behavioral tuning. Without adequate counseling and guidance, patients may interpret risk estimates of predictive genetic testing with an increase in fear and anxiety.

The impact of direct-to-consumer marketing of cancer genetic testing on women according to their genetic risk.

PubMed

Lowery, Jan T; Byers, Tim; Axell, Lisen; Ku, Lisa; Jacobellis, Jillian

2008-12-01

To assess the impact of direct-to-consumer marketing for genetic testing among women of varying genetic risk for breast and ovarian cancer. Telephone surveys were conducted with 315 women in Denver, Colorado, one target audience for the Myriad BRACAnalysis ad campaign. Genetic risk was determined from personal and family history and grouped by probability of having a BRCA1/2 mutation (low <5%, moderate 5-<10%, high > or =10%). High-risk women were more knowledgeable about BRACAnalysis and more likely to recall the media ads than were low-risk women (60 vs. 39%, P < 0.01). After seeing the ads, about 40% of women were more interested in testing and about 10% expressed increased worry about developing breast or ovarian cancer. Women across all risk groups overstated the benefits and appropriateness of testing. An equal percentage of high- and low-risk women (51 and 60%) felt that they would benefit from genetic testing. The campaign effectively reached a large audience. Concern about breast cancer was not appreciably increased. A large percentage of low-risk women (not candidates for testing) expressed interest in testing, suggesting the campaign was too broad. A campaign targeted at high-risk women, who may benefit from testing might be preferred.

Improving adherence to healthy dietary patterns, genetic risk, and long term weight gain: gene-diet interaction analysis in two prospective cohort studies.

PubMed

Wang, Tiange; Heianza, Yoriko; Sun, Dianjianyi; Huang, Tao; Ma, Wenjie; Rimm, Eric B; Manson, JoAnn E; Hu, Frank B; Willett, Walter C; Qi, Lu

2018-01-10

To investigate whether improving adherence to healthy dietary patterns interacts with the genetic predisposition to obesity in relation to long term changes in body mass index and body weight. Prospective cohort study. Health professionals in the United States. 8828 women from the Nurses' Health Study and 5218 men from the Health Professionals Follow-up Study. Genetic predisposition score was calculated on the basis of 77 variants associated with body mass index. Dietary patterns were assessed by the Alternate Healthy Eating Index 2010 (AHEI-2010), Dietary Approach to Stop Hypertension (DASH), and Alternate Mediterranean Diet (AMED). Five repeated measurements of four year changes in body mass index and body weight over follow-up (1986 to 2006). During a 20 year follow-up, genetic association with change in body mass index was significantly attenuated with increasing adherence to the AHEI-2010 in the Nurses' Health Study (P=0.001 for interaction) and Health Professionals Follow-up Study (P=0.005 for interaction). In the combined cohorts, four year changes in body mass index per 10 risk allele increment were 0.07 (SE 0.02) among participants with decreased AHEI-2010 score and -0.01 (0.02) among those with increased AHEI-2010 score, corresponding to 0.16 (0.05) kg versus -0.02 (0.05) kg weight change every four years (P<0.001 for interaction). Viewed differently, changes in body mass index per 1 SD increment of AHEI-2010 score were -0.12 (0.01), -0.14 (0.01), and -0.18 (0.01) (weight change: -0.35 (0.03), -0.36 (0.04), and -0.50 (0.04) kg) among participants with low, intermediate, and high genetic risk, respectively. Similar interaction was also found for DASH but not for AMED. These data indicate that improving adherence to healthy dietary patterns could attenuate the genetic association with weight gain. Moreover, the beneficial effect of improved diet quality on weight management was particularly pronounced in people at high genetic risk for obesity. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Molecular mechanisms of the genetic risk factors in pathogenesis of Alzheimer disease.

PubMed

Kanatsu, Kunihiko; Tomita, Taisuke

2017-01-01

Alzheimer disease (AD) is a neurodegenerative disease characterized by the extensive deposition of senile plaques and neurofibrillary tangles. Until recently, only the APOE gene had been known as a genetic risk factor for late-onset AD (LOAD), which accounts for more than 95% of all AD cases. However, in addition to this well-established genetic risk factor, genome-wide association studies have identified several single nucleotide polymorphisms as genetic risk factors of LOAD, such as PICALM and BIN1 . In addition, whole genome sequencing and exome sequencing have identified rare variants associated with LOAD, including TREM2 . We review the recent findings related to the molecular mechanisms by which these genetic risk factors contribute to AD, and our perspectives regarding the etiology of AD for the development of therapeutic agents.

p16 gene silencing along with p53 single-nucleotide polymorphism and risk of esophageal cancer in Northeast India.

PubMed

Das, Mandakini; Sharma, Santanu Kumar; Sekhon, Gaganpreet Singh; Mahanta, Jagadish; Phukan, Rup Kumar; Jalan, Bimal Kumar

2017-05-01

The high incidence of esophageal cancer in Northeast India and the unique ethnic background and dietary habits provide a great opportunity to study the molecular genetics behind esophageal squamous cell carcinoma in this part of the region. We hypothesized that in addition to currently known environmental risk factors for esophageal cancer, genetic and epigenetic factors are also involved in esophageal carcinogenesis in Northeast India. Therefore, in this study, we explored the possible association between the two important G1 cell cycle regulatory genes p16 and p53 and environmental risk factors and risk of esophageal carcinogenesis. A total of 100 newly diagnosed esophageal cancer cases along with equal number of age-, sex-, and ethnicity-matched controls were included in this study. Methylation-specific polymerase chain reaction was used to determine the p16 promoter methylation status. Single-nucleotide polymorphism at codon 72 of p53 gene was assessed by the polymerase chain reaction-restriction fragment length polymorphism method. Aberrant methylation of p16 gene was seen in 81% of esophageal cancer cases. Hypermethylation of p16 gene was not found in healthy controls. p53 Pro/Pro genotype was found to be a risk genotype in Northeast India compared with Arg/Pro and Arg/Arg. p53 variant/polymorphism was significantly associated with esophageal cancer risk in the study population under all three genetic models, namely, dominant model (Arg/Pro + Pro/Pro vs Arg/Arg odds ratio = 2.25, confidence interval = 1.19-4.26; p = 0.012), recessive model (Arg/Arg + Arg/Pro vs Pro/Pro odds ratio = 2.35, confidence interval = 1.24-4.44; p = 0.008), and homozygous model (Pro/Pro vs Arg/Arg odds ratio = 3.33, confidence interval = 1.54-7.20; p = 0.002). However, p53 variant/polymorphism was not statistically associated with esophageal cancer risk under the heterozygous model (Pro/Pro vs Arg/Pro). In the case-only analysis based on p16 methylation, the p53 variant/polymorphism (Pro/Pro or Arg/Pro) showed significant association for esophageal cancer risk (odds ratio = 3.33, confidence interval = 1.54-7.20; p = 0.002). Gene-gene and gene-environment interaction using the case-only approach revealed a strong association between p16 methylation, p53 single-nucleotide polymorphism, and environmental factors and esophageal cancer risk. Cases with p16 methylation and p53 variant/polymorphism (Pro/Pro or Arg/Pro) along with both betel quid and tobacco chewing habit (odds ratio = 8.29, confidence interval = 1.14-60.23; p = 0.037) conferred eightfold increased risk toward esophageal cancer development. This study reveals a synergistic interaction between epigenetic, genetic, and environmental factors and risk of esophageal cancer in this high-incidence region of Northeast India. The inactivation of either p16 or p53 in a majority of esophageal cancer cases in this study suggests the possible crosstalk between the important cell cycle genes.

Risky communication: pitfalls in counseling about risk, and how to avoid them.

PubMed

O'Doherty, K; Suthers, G K

2007-08-01

A genetic counselor is often faced with the difficult task of conveying a set of complex and highly abstract factors associated with the client's risk of developing a familial disorder. The client is faced with the even more difficult task of making significant health-related decisions about an event which may or may not eventuate. Although there is a large corpus of research on this topic, much of the knowledge on risk communication is difficult to apply in a practical context. In this paper we draw together some insights on risk communication and decision-making under conditions of uncertainty, and apply them directly to the problem of communicating familial cancer risk. In particular, we focus on the distinction between individual risk and observed frequencies of adverse events, various framing effects, and contextualizing risk communication. We draw attention to some of the potential pitfalls in counseling about risk and offer avenues for circumventing them.

The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) consortium: A collaborative cognitive and neuroimaging genetics project.

PubMed

Blokland, Gabriëlla A M; Del Re, Elisabetta C; Mesholam-Gately, Raquelle I; Jovicich, Jorge; Trampush, Joey W; Keshavan, Matcheri S; DeLisi, Lynn E; Walters, James T R; Turner, Jessica A; Malhotra, Anil K; Lencz, Todd; Shenton, Martha E; Voineskos, Aristotle N; Rujescu, Dan; Giegling, Ina; Kahn, René S; Roffman, Joshua L; Holt, Daphne J; Ehrlich, Stefan; Kikinis, Zora; Dazzan, Paola; Murray, Robin M; Di Forti, Marta; Lee, Jimmy; Sim, Kang; Lam, Max; Wolthusen, Rick P F; de Zwarte, Sonja M C; Walton, Esther; Cosgrove, Donna; Kelly, Sinead; Maleki, Nasim; Osiecki, Lisa; Picchioni, Marco M; Bramon, Elvira; Russo, Manuela; David, Anthony S; Mondelli, Valeria; Reinders, Antje A T S; Falcone, M Aurora; Hartmann, Annette M; Konte, Bettina; Morris, Derek W; Gill, Michael; Corvin, Aiden P; Cahn, Wiepke; Ho, New Fei; Liu, Jian Jun; Keefe, Richard S E; Gollub, Randy L; Manoach, Dara S; Calhoun, Vince D; Schulz, S Charles; Sponheim, Scott R; Goff, Donald C; Buka, Stephen L; Cherkerzian, Sara; Thermenos, Heidi W; Kubicki, Marek; Nestor, Paul G; Dickie, Erin W; Vassos, Evangelos; Ciufolini, Simone; Reis Marques, Tiago; Crossley, Nicolas A; Purcell, Shaun M; Smoller, Jordan W; van Haren, Neeltje E M; Toulopoulou, Timothea; Donohoe, Gary; Goldstein, Jill M; Seidman, Larry J; McCarley, Robert W; Petryshen, Tracey L

2018-05-01

Schizophrenia has a large genetic component, and the pathways from genes to illness manifestation are beginning to be identified. The Genetics of Endophenotypes of Neurofunction to Understand Schizophrenia (GENUS) Consortium aims to clarify the role of genetic variation in brain abnormalities underlying schizophrenia. This article describes the GENUS Consortium sample collection. We identified existing samples collected for schizophrenia studies consisting of patients, controls, and/or individuals at familial high-risk (FHR) for schizophrenia. Samples had single nucleotide polymorphism (SNP) array data or genomic DNA, clinical and demographic data, and neuropsychological and/or brain magnetic resonance imaging (MRI) data. Data were subjected to quality control procedures at a central site. Sixteen research groups contributed data from 5199 psychosis patients, 4877 controls, and 725 FHR individuals. All participants have relevant demographic data and all patients have relevant clinical data. The sex ratio is 56.5% male and 43.5% female. Significant differences exist between diagnostic groups for premorbid and current IQ (both p<1×10 -10 ). Data from a diversity of neuropsychological tests are available for 92% of participants, and 30% have structural MRI scans (half also have diffusion-weighted MRI scans). SNP data are available for 76% of participants. The ancestry composition is 70% European, 20% East Asian, 7% African, and 3% other. The Consortium is investigating the genetic contribution to brain phenotypes in a schizophrenia sample collection of >10,000 participants. The breadth of data across clinical, genetic, neuropsychological, and MRI modalities provides an important opportunity for elucidating the genetic basis of neural processes underlying schizophrenia. Copyright © 2017 Elsevier B.V. All rights reserved.

Psychological opportunities and hazards in predictive genetic testing for cancer risk.

PubMed

Codori, A M

1997-03-01

Although the availability of genetic tests seems like an unequivocally favorable turn of events, they are, in fact, not without controversy. At the center of the controversy is a question regarding the risks and benefits of genetic testing. Many geneticists, ethicists, psychologists, and persons at risk for cancer are concerned about the potentially adverse psychological effects of genetic testing on tested persons and their families. In addition, the screening and interventions that are useful in the general population remain to be shown effective in those with high genetic cancer risk. Consequently, there have been calls for caution in moving genetic testing out of research laboratories and into commercial laboratories until their impact and the effectiveness of cancer prevention strategies can be studied. This article examines the arguments and data for and against this caution, citing examples related to hereditary nonpolyposis colon cancer and drawing upon literature on testing for other genetic diseases.

Atrial Fibrillation Genetic Risk and Ischemic Stroke Mechanisms.

PubMed

Lubitz, Steven A; Parsons, Owen E; Anderson, Christopher D; Benjamin, Emelia J; Malik, Rainer; Weng, Lu-Chen; Dichgans, Martin; Sudlow, Cathie L; Rothwell, Peter M; Rosand, Jonathan; Ellinor, Patrick T; Markus, Hugh S; Traylor, Matthew

2017-06-01

Atrial fibrillation (AF) is a leading cause of cardioembolic stroke, but the relationship between AF and noncardioembolic stroke subtypes are unclear. Because AF may be unrecognized, and because AF has a substantial genetic basis, we assessed for predisposition to AF across ischemic stroke subtypes. We examined associations between AF genetic risk and Trial of Org 10172 in Acute Stroke Treatment stroke subtypes in 2374 ambulatory individuals with ischemic stroke and 5175 without from the Wellcome Trust Case-Control Consortium 2 using logistic regression. We calculated AF genetic risk scores using single-nucleotide polymorphisms associated with AF in a previous independent analysis across a range of preselected significance thresholds. There were 460 (19.4%) individuals with cardioembolic stroke, 498 (21.0%) with large vessel, 474 (20.0%) with small vessel, and 814 (32.3%) individuals with strokes of undetermined cause. Most AF genetic risk scores were associated with stroke, with the strongest association ( P =6×10 - 4 ) attributed to scores of 944 single-nucleotide polymorphisms (each associated with AF at P <1×10 - 3 in a previous analysis). Associations between AF genetic risk and stroke were enriched in the cardioembolic stroke subset (strongest P =1.2×10 - 9 , 944 single-nucleotide polymorphism score). In contrast, AF genetic risk was not significantly associated with noncardioembolic stroke subtypes. Comprehensive AF genetic risk scores were specific for cardioembolic stroke. Incomplete workups and subtype misclassification may have limited the power to detect associations with strokes of undetermined pathogenesis. Future studies are warranted to determine whether AF genetic risk is a useful biomarker to enhance clinical discrimination of stroke pathogeneses. © 2017 American Heart Association, Inc.

Genetic variants primarily associated with type 2 diabetes are related to coronary artery disease risk

PubMed Central

Jansen, Henning; Loley, Christina; Lieb, Wolfgang; Pencina, Michael J; Nelson, Christopher P; Kathiresan, Sekar; Peloso, Gina M; Voight, Benjamin F; Reilly, Muredach P; Assimes, Themistocles L; Boerwinkle, Eric; Hengstenberg, Christian; Laaksonen, Reijo; McPherson, Ruth; Roberts, Robert; Thorsteinsdottir, Unnur; Peters, Annette; Gieger, Christian; Rawal, Rajesh; Thompson, John R; König, Inke R; Vasan, Ramachandran S; Erdmann, Jeanette; Samani, Nilesh J; Schunkert, Heribert

2015-01-01

Background The mechanisms underlying the association between diabetes and coronary artery disease (CAD) risk are unclear. We aimed to assess this association by studying genetic variants that have been shown to associate with type 2 diabetes (T2DM). If the association between diabetes and CAD is causal, we expected to observe an association of these variants with CAD as well. Methods and Results We studied all genetic variants currently known to be associated with T2DM at a genome-wide significant level (p<5*10−8) in CARDIoGRAM, a genome-wide data-set of CAD including 22,233 CAD cases and 64,762 controls. Out of the 44 published T2DM SNPs 10 were significantly associated with CAD in CARDIoGRAM (OR>1, p<0.05), more than expected by chance (p=5.0*10−5). Considering all 44 SNPs, the average CAD risk observed per individual T2DM risk allele was 1.0076 (95% confidence interval (CI), 0.9973–1.0180). Such average risk increase was significantly lower than the increase expected based on i) the published effects of the SNPs on T2DM risk and ii) the effect of T2DM on CAD risk as observed in the Framingham Heart Study, which suggested a risk of 1.067 per allele (p=7.2*10−10 vs. the observed effect). Studying two risk scores based on risk alleles of the diabetes SNPs, one score using individual level data in 9856 subjects, and the second score on average effects of reported beta-coefficients from the entire CARDIoGRAM data-set, we again observed a significant - yet smaller than expected - association with CAD. Conclusions Our data indicate that an association between type 2 diabetes related SNPs and CAD exists. However, the effects on CAD risk appear to be by far lower than what would be expected based on the effects of risk alleles on T2DM and the effect of T2DM on CAD in the epidemiological setting. PMID:26074316