Genome-Wide Association Studies and Meta-Analyses for Congenital Heart Defects

Introduction: Sulfonylureas are a commonly-used class of diabetes medication that can prolong the QT-interval, which is a leading cause of drug withdrawals from the market given the possible risk of life-threatening arrhythmias. Previously, we conducted a meta-analysis of genome-wide association studies of sulfonylurea-genetic interactions on QT interval among 9 European-ancestry (EA) cohorts using cross-sectional data, with null results. To improve our power to identify novel drug-gene interactions, we have included repeated measures of medication use and QT interval and expanded our study to include several additional cohorts, including African-American (AA) and Hispanic-ancestry (HA) cohorts with a high prevalence of sulfonylurea use. To identify potentially differential effects on cardiac depolarization and repolarization, we have also added two phenotypes - the JT and QRS intervals, which together comprise the QT interval. Hypothesis: The use of repeated measures and expansion of our meta-analysis to include diverse ancestry populations will allow us to identify novel pharmacogenomic interactions for sulfonylureas on the ECG phenotypes QT, JT, and QRS. Methods: Cohorts with unrelated individuals used generalized estimating equations to estimate interactions; cohorts with related individuals used mixed effect models clustered on family. For each ECG phenotype (QT, JT, QRS), we conducted ancestry-specific (EA, AA, HA) inverse variance weighted meta-analyses using standard errors based on the t-distribution to correct for small sample inflation in the test statistic. Ancestry-specific summary estimates were combined using MANTRA, an analytic method that accounts for differences in local linkage disequilibrium between ethnic groups. Results: Our study included 65,997 participants from 21 cohorts, including 4,020 (6%) sulfonylurea users, a substantial increase from the 26,986 participants and 846 sulfonylureas users in the previous meta-analysis. Preliminary ancestry-specific meta-analyses have identified genome-wide significant associations (P < 5х10–8) for each ECG phenotype, and analyses with MANTRA are in progress. Conclusions: In the setting of the largest collection of pharmacogenomic studies to date, we used repeated measurements and leveraged diverse ancestry populations to identify new pharmacogenomic loci for ECG traits associated with cardiovascular risk.

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Meta-analyses of genome wide association studies in lines of laying hens divergently selected for feather pecking using imputed sequence level genotypes

BMC Genetics ◽

10.1186/s12863-020-00920-9 ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Clemens Falker-Gieske ◽

Hanna Iffland ◽

Siegfried Preuß ◽

Werner Bessei ◽

Cord Drögemüller ◽

...

Keyword(s):

Brain Structure ◽

Laying Hens ◽

Association Studies ◽

Gene Set Enrichment Analysis ◽

Genome Wide Association ◽

Economic Losses ◽

Genome Wide Association Studies ◽

Feather Pecking ◽

Genome Wide ◽

Meta Analyses

Abstract Background Feather pecking (FP) is damaging behavior in laying hens leading to global economic losses in the layer industry and massive impairments of animal welfare. The objective of the study was to discover genetic variants and affected genes that lead to FP behavior. To achieve that we imputed low-density genotypes from two different populations of layers divergently selected for FP to sequence level by performing whole genome sequencing on founder and half-sib individuals. In order to decipher the genetic structure of FP, genome wide association studies and meta-analyses of two resource populations were carried out by focusing on the traits ‘feather pecks delivered’ (FPD) and the ‘posterior probability of a hen to belong to the extreme feather pecking subgroup’ (pEFP). Results In this meta-analysis, we discovered numerous genes that are affected by polymorphisms significantly associated with the trait FPD. Among them SPATS2L, ZEB2, KCHN8, and MRPL13 which have been previously connected to psychiatric disorders with the latter two being responsive to nicotine treatment. Gene set enrichment analysis revealed that phosphatidylinositol signaling is affected by genes identified in the GWAS and that the Golgi apparatus as well as brain structure may be involved in the development of a FP phenotype. Further, we were able to validate a previously discovered QTL for the trait pEFP on GGA1, which contains variants affecting NIPA1, KIAA1211L, AFF3, and TSGA10. Conclusions We provide evidence for the involvement of numerous genes in the propensity to exhibit FP behavior that could aid in the selection against this unwanted trait. Furthermore, we identified variants that are involved in phosphatidylinositol signaling, Golgi metabolism and cell structure and therefore propose changes in brain structure to be an influential factor in FP, as already described in human neuropsychiatric disorders.

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Genetic polymorphisms and lung cancer risk: Evidence from meta-analyses and genome-wide association studies

Lung Cancer ◽

10.1016/j.lungcan.2017.08.026 ◽

2017 ◽

Vol 113 ◽

pp. 18-29 ◽

Cited By ~ 13

Author(s):

Caiyang Liu ◽

Huijie Cui ◽

Dongqing Gu ◽

Min Zhang ◽

Yanfei Fang ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Risk ◽

Genetic Polymorphisms ◽

Lung Cancer Risk ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Meta Analyses

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Abstract P142: Meta-analyses Of Genome-wide Association Studies Accounting For Gene-psychosocial Factor Interactions Identify Novel Loci For Blood Pressure Traits

Circulation ◽

10.1161/circ.141.suppl_1.p142 ◽

2020 ◽

Vol 141 (Suppl_1) ◽

Author(s):

Myriam Fornage ◽

Daokun Sun ◽

Melissa A Richard ◽

Solomon K Musani ◽

Yun Ju Sung ◽

...

Keyword(s):

Blood Pressure ◽

Psychosocial Factors ◽

Social Factors ◽

Association Studies ◽

Psychosocial Factor ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

The Novel ◽

Genome Wide ◽

Meta Analyses

Background: Genome-wide association studies (GWAS) have identified hundreds of genetic loci for blood pressure (BP) traits and advanced our understanding of BP regulation and hypertension etiology. Psychological and social factors are known to influence BP and risk of cardiovascular diseases. Accounting for psychosocial factors may help identify BP loci and extend our knowledge of its genetic architecture. Methods: To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptomatology, trait anxiety, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. Results: In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response ( PLCL2 ), synaptic function and neurotransmission ( LIN7A, PFIA2 ), as well as genes previously implicated in neuropsychiatric or stress-related disorders ( FSTL5, CHODL ). Conclusion: These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.

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Identification of a novelFGFRL1MicroRNA target site polymorphism for bone mineral density in meta-analyses of genome-wide association studies

Human Molecular Genetics ◽

10.1093/hmg/ddv144 ◽

2015 ◽

Vol 24 (16) ◽

pp. 4710-4727 ◽

Cited By ~ 14

Author(s):

Tianhua Niu ◽

Ning Liu ◽

Ming Zhao ◽

Guie Xie ◽

Lei Zhang ◽

...

Keyword(s):

Bone Mineral Density ◽

Bone Mineral ◽

Association Studies ◽

Target Site ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Mineral Density ◽

Genome Wide ◽

Meta Analyses

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A meta-analysis of genome-wide association studies of asthma in Puerto Ricans

European Respiratory Journal ◽

10.1183/13993003.01505-2016 ◽

2017 ◽

Vol 49 (5) ◽

pp. 1601505 ◽

Cited By ~ 30

Author(s):

Qi Yan ◽

John Brehm ◽

Maria Pino-Yanes ◽

Erick Forno ◽

Jerome Lin ◽

...

Keyword(s):

Puerto Ricans ◽

Association Studies ◽

Meta Analysis ◽

Linkage Disequilibrium Block ◽

Genome Wide Association ◽

Health Study ◽

Genome Wide Association Studies ◽

Genome Wide ◽

The Usa ◽

Meta Analyses

Puerto Ricans are disproportionately affected with asthma in the USA. In this study, we aim to identify genetic variants that confer susceptibility to asthma in Puerto Ricans.We conducted a meta-analysis of genome-wide association studies (GWAS) of asthma in Puerto Ricans, including participants from: the Genetics of Asthma in Latino Americans (GALA) I-II, the Hartford–Puerto Rico Study and the Hispanic Community Health Study. Moreover, we examined whether susceptibility loci identified in previous meta-analyses of GWAS are associated with asthma in Puerto Ricans.The only locus to achieve genome-wide significance was chromosome 17q21, as evidenced by our top single nucleotide polymorphism (SNP), rs907092 (OR 0.71, p=1.2×10−12) at IKZF3. Similar to results in non-Puerto Ricans, SNPs in genes in the same linkage disequilibrium block as IKZF3 (e.g. ZPBP2, ORMDL3 and GSDMB) were significantly associated with asthma in Puerto Ricans. With regard to results from a meta-analysis in Europeans, we replicated findings for rs2305480 at GSDMB, but not for SNPs in any other genes. On the other hand, we replicated results from a meta-analysis of North American populations for SNPs at IL1RL1, TSLP and GSDMB but not for IL33.Our findings suggest that common variants on chromosome 17q21 have the greatest effects on asthma in Puerto Ricans.

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