scholarly journals Detecting Gene-Environment Interaction for Maternal Exposures Using Case-Parent Trios Ascertained Through a Case With Non-Syndromic Orofacial Cleft

2021 ◽  
Vol 9 ◽  
Author(s):  
Wanying Zhang ◽  
Sowmya Venkataraghavan ◽  
Jacqueline B. Hetmanski ◽  
Elizabeth J. Leslie ◽  
Mary L. Marazita ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Ethnic Groups ◽  
Cleft Lip ◽  
Meta Analysis ◽  
Orofacial Cleft ◽  
Multivitamin Supplementation ◽  
Suggestive Evidence ◽  
Gene Environment ◽  
Genome Wide ◽  
Racial Ethnic

Two large studies of case–parent trios ascertained through a proband with a non-syndromic orofacial cleft (OFC, which includes cleft lip and palate, cleft lip alone, or cleft palate alone) were used to test for possible gene–environment (G × E) interaction between genome-wide markers (both observed and imputed) and self-reported maternal exposure to smoking, alcohol consumption, and multivitamin supplementation during pregnancy. The parent studies were as follows: GENEVA, which included 1,939 case–parent trios recruited largely through treatment centers in Europe, the United States, and Asia, and 1,443 case–parent trios from the Pittsburgh Orofacial Cleft Study (POFC) also ascertained through a proband with an OFC including three major racial/ethnic groups (European, Asian, and Latin American). Exposure rates to these environmental risk factors (maternal smoking, alcohol consumption, and multivitamin supplementation) varied across studies and among racial/ethnic groups, creating substantial differences in power to detect G × E interaction, but the trio design should minimize spurious results due to population stratification. The GENEVA and POFC studies were analyzed separately, and a meta-analysis was conducted across both studies to test for G × E interaction using the 2 df test of gene and G × E interaction and the 1 df test for G × E interaction alone. The 2 df test confirmed effects for several recognized risk genes, suggesting modest G × E effects. This analysis did reveal suggestive evidence for G × Vitamin interaction for CASP9 on 1p36 located about 3 Mb from PAX7, a recognized risk gene. Several regions gave suggestive evidence of G × E interaction in the 1 df test. For example, for G × Smoking interaction, the 1 df test suggested markers in MUSK on 9q31.3 from meta-analysis. Markers near SLCO3A1 also showed suggestive evidence in the 1 df test for G × Alcohol interaction, and rs41117 near RETREG1 (a.k.a. FAM134B) also gave suggestive significance in the meta-analysis of the 1 df test for G × Vitamin interaction. While it remains quite difficult to obtain definitive evidence for G × E interaction in genome-wide studies, perhaps due to small effect sizes of individual genes combined with low exposure rates, this analysis of two large case–parent trio studies argues for considering possible G × E interaction in any comprehensive study of complex and heterogeneous disorders such as OFC.

scholarly journals Effect of polygenic risk scores on depression in childhood trauma

2014 ◽  
Vol 205 (2) ◽  
pp. 113-119 ◽  
Author(s):  
Wouter J. Peyrot ◽  
Yuri Milaneschi ◽  
Abdel Abdellaoui ◽  
Patrick F. Sullivan ◽  
Jouke J. Hottenga ◽  
...  
Keyword(s):  
Childhood Trauma ◽  
Meta Analysis ◽  
Genetic Effect ◽  
Risk Scores ◽  
Environment Interaction ◽  
Polygenic Risk ◽  
Gene Environment Interaction ◽  
Gene Environment ◽  
Genome Wide ◽  
Direct Genetic Effect

BackgroundResearch on gene×environment interaction in major depressive disorder (MDD) has thus far primarily focused on candidate genes, although genetic effects are known to be polygenic.AimsTo test whether the effect of polygenic risk scores on MDD is moderated by childhood trauma.MethodThe study sample consisted of 1645 participants with a DSM-IV diagnosis of MDD and 340 screened controls from The Netherlands. Chronic or remitted episodes (severe MDD) were present in 956 participants. The occurrence of childhood trauma was assessed with the Childhood Trauma Interview and the polygenic risk scores were based on genome-wide meta-analysis results from the Psychiatric Genomics Consortium.ResultsThe polygenic risk scores and childhood trauma independently affected MDD risk, and evidence was found for interaction as departure from both multiplicativity and additivity, indicating that the effect of polygenic risk scores on depression is increased in the presence of childhood trauma. The interaction effects were similar in predicting all MDD risk and severe MDD risk, and explained a proportion of variation in MDD risk comparable to the polygenic risk scores themselves.ConclusionsThe interaction effect found between polygenic risk scores and childhood trauma implies that (1) studies on direct genetic effect on MDD gain power by focusing on individuals exposed to childhood trauma, and that (2) individuals with both high polygenic risk scores and exposure to childhood trauma are particularly at risk for developing MDD.

scholarly journals Evidence of gene–environment interaction for the IRF6 gene and maternal multivitamin supplementation in controlling the risk of cleft lip with/without cleft palate

2010 ◽  
Vol 128 (4) ◽  
pp. 401-410 ◽  
Author(s):  
Tao Wu ◽  
Kung Yee Liang ◽  
Jacqueline B. Hetmanski ◽  
Ingo Ruczinski ◽  
Margaret Daniele Fallin ◽  
...  
Keyword(s):  
Cleft Palate ◽  
Cleft Lip ◽  
Environment Interaction ◽  
Multivitamin Supplementation ◽  
Gene Environment Interaction ◽  
Irf6 Gene ◽  
Gene Environment

scholarly journals Re-analysis of a Genome-Wide Gene-By-Environment Interaction Study of Case Parent Trios, Adjusted for Population Stratification

2021 ◽  
Vol 11 ◽  
Author(s):  
Pulindu Ratnasekera ◽  
Brad McNeney
Keyword(s):  
East Asian ◽  
Environment Interaction ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Multivitamin Supplementation ◽  
Gene Environment ◽  
Genome Wide ◽  
A Genome ◽  
The Impact ◽  
East Asian Ancestry

We investigate the impact of confounding on the results of a genome-wide association analysis by Beaty et al., which identified multiple single nucleotide polymorphisms that appeared to modify the effect of maternal smoking, alcohol consumption, or multivitamin supplementation on risk of cleft palate. The study sample of case-parent trios was primarily of European and East Asian ancestry, and the distribution of all three exposures differed by ancestral group. Such differences raise the possibility that confounders, rather than the exposures, are the risk modifiers and hence that the inference of gene-environment (G×E) interaction may be spurious. Our analyses generally confirmed the result of Beaty et al. and suggest the interaction G×E is driven by the European trios, whereas the East Asian trios were less informative.

scholarly journals A Genome-wide Association and Admixture Mapping Study of Bronchodilator Drug Response in African Americans with Asthma

2017 ◽  
Author(s):  
Melissa L. Spear ◽  
Donglei Hu ◽  
Maria Pino-Yanes ◽  
Scott Huntsman ◽  
Anton S. M. Sonnenberg ◽  
...  
Keyword(s):  
African Americans ◽  
Genetic Variants ◽  
Drug Response ◽  
Meta Analysis ◽  
Genome Wide ◽  
A Genome ◽  
Children With Asthma ◽  
American Children ◽  
Racial Ethnic ◽  
Shared Genetic

AbstractBackgroundShort-acting B2-adrenergic receptor agonists (SABAs) are the most commonly prescribed asthma medications worldwide. Response to SABAs is measured as bronchodilator drug response (BDR), which varies among racial/ethnic groups in the U.S 1, 2. However, the genetic variation that contributes to BDR is largely undefined in African Americans with asthma3ObjectiveTo identify genetic variants that may contribute to differences in BDR in African Americans with asthma.MethodsWe performed a genome-wide association study of BDR in 949 African American children with asthma, genotyped with the Axiom World Array 4 (Affymetrix, Santa Clara, CA) followed by imputation using 1000 Genomes phase 3 genotypes. We used linear regression models adjusting for age, sex, body mass index and genetic ancestry to test for an association between BDR and genotype at single nucleotide polymorphisms (SNPs). To increase power and distinguish between shared vs. population-specific associations with BDR in children with asthma, we performed a meta-analysis across 949 African Americans and 1,830 Latinos (Total=2,779). Lastly, we performed genome-wide admixture mapping to identify regions whereby local African or European ancestry is associated with BDR in African Americans. Two additional populations of 416 Latinos and 1,325 African Americans were used to replicate significant associations.ResultsWe identified a population-specific association with an intergenic SNP on chromosome 9q21 that was significantly associated with BDR (rs73650726, p=7.69 × 10−9). A trans-ethnic meta-analysis across African Americans and Latinos identified three additional SNPs within the intron of PRKG1 that were significantly associated with BDR (rs7903366, rs7070958, and rs7081864, p≤5 × 10−8).ConclusionsOur findings indicate that both population specific and shared genetic variation contributes to differences in BDR in minority children with asthma, and that the genetic underpinnings of BDR may differ between racial/ethnic groups.Key messagesA GWAS for BDR in African American children with asthma identified an intergenic population specific variant at 9q21 to be associated with increased bronchodilator drug response (BDR).A meta-analysis of GWAS across African Americans and Latinos identified shared genetic variants at 10q21 in the intron of PRKG1 to be associated with differences in BDR.Further genetic studies need to be performed in diverse populations to identify the full set of genetic variants that contribute to BDR.

Abstract P530: Pleiotropic Effects on Blood Pressure Traits Using Genome-wide Analysis of Gene-alcohol Interactions

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Aldi T Kraja ◽  
Mary F Feitosa ◽  
Daniel Chasman ◽  
Yun J Sung ◽  
Thomas W Winkler ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Alcohol Consumption ◽  
Meta Analysis ◽  
Left Ventricular ◽  
European Ancestry ◽  
The Novel ◽  
Gxe Interaction ◽  
Genome Wide ◽  
Gxe Interactions ◽  
Interaction Approach

We tested for pleiotropy in European ancestry subjects (N>90K) via GWAS of systolic and diastolic blood pressure (BP), mean arterial pressure, and pulse pressure, using gene (G)-alcohol consumption (E) interactions. The approach was a correlated meta-analysis (PMCID-PMC3773990) that combined simultaneously the 4 BP traits genome-wide GxE interactions summary meta-P values. This approach adjusts for correlations among single traits at the genomic level. A variant was considered pleiotropic when the overall correlated meta-analysis yielded P ≤5E-08 and GxE meta- P ≤E-04 for at least two single traits. The novel pleiotropic variants localize in eight loci. TTLL7 (1p31.1) is a tubulin modifier. DYRK3 (1q32.1) is a transcription regulator. MAPKAPK2 (1q32.1) is a stress-activated serine/threonine-protein kinase involved in cytokine production especially for TNF , IL6 and phosphorylates (among others) LSP1 , identified in our GWAS GxE study for individual BP traits. FSTL5 (4q32.2) is annotated as calcium ion binding . A locus at 11q13.1 includes SNX32 , EFEMP2, and FOSL1 . FOSL1 variants may regulate expression of SNX32 . EFEMP2 is implicated in blood coagulation. CATSPER2 (15q15.3) is a cation channel. CCDC151 (19p13.2) is an outer dynein arm assembly. The functions of two other loci (17q22 and 18q22.3) are unknown. We also identified 4 pleiotropic loci ( SGK223 , TNKS , GATA4 , FTO ) that were found significant at our GxE meta-GWAS of single traits in 572K multi-ancestry individuals. In addition, we detected 24 pleiotropic BP-known loci. Some of these genes relate to alcohol consumption (e.g., BLK , GATA4 , FTO ). TNKS , MAPKAPK2 and FSTL5 interact with the Wnt/β-catenin signaling pathway, which contributes to hypertension. Several pleiotropic variants showed features of regulation by locating at promoter and enhancer histone marks, at DNAse, at proteins binding sites and being eQTL. The 36 novel and BP-known loci comprising 86 significant genes were enriched for Hypertension , Cardiac arrhythmias , Myocardial infarction , Atrial fibrillation, and Left ventricular hypertrophy . Our correlated meta-analysis of GxE interaction approach identified novel pleiotropic loci and validated known BP loci, thus providing insights into the mechanisms of hypertension.

scholarly journals Functional validity, role, and implications of heavy alcohol consumption genetic loci

2020 ◽  
Vol 6 (3) ◽  
pp. eaay5034 ◽  
Author(s):  
Andrew Thompson ◽  
James Cook ◽  
Hélène Choquet ◽  
Eric Jorgenson ◽  
Jie Yin ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Disease Risk ◽  
Meta Analysis ◽  
Population Level ◽  
Model Organisms ◽  
High Alcohol ◽  
Genetic Loci ◽  
High Alcohol Consumption ◽  
Genome Wide ◽  
Heavy Alcohol Consumption

High alcohol consumption is a risk factor for morbidity and mortality, yet few genetic loci have been robustly associated with alcohol intake. Here, we use U.K. Biobank (n = 125,249) and GERA (n = 47,967) datasets to determine genetic factors associated with extreme population-level alcohol consumption and examine the functional validity of outcomes using model organisms and in silico techniques. We identified six loci attaining genome-wide significant association with alcohol consumption after meta-analysis and meeting our criteria for replication: ADH1B (lead SNP: rs1229984), KLB (rs13130794), BTF3P13 (rs144198753), GCKR (rs1260326), SLC39A8 (rs13107325), and DRD2 (rs11214609). A conserved role in phenotypic responses to alcohol was observed for all genetic targets available for investigation (ADH1B, GCKR, SLC39A8, and KLB) in Caenorhabditis elegans. Evidence of causal links to lung cancer, and shared genetic architecture with gout and hypertension was also found. These findings offer insight into genes, pathways, and relationships for disease risk associated with high alcohol consumption.

scholarly journals Cardiovascular Outcomes of Antidiabetes Medications by Race/Ethnicity: a systematic review and meta-analysis

2020 ◽  
Author(s):  
Xiaoling Cai ◽  
Sam Dagogo-Jack ◽  
Chu Lin ◽  
Wenjia Yang ◽  
Linong Ji
Keyword(s):  
Type 2 Diabetes ◽  
Cardiovascular Risk ◽  
Risk Reduction ◽  
Ethnic Groups ◽  
Meta Analysis ◽  
Cardiovascular Outcomes ◽  
Control Treatment ◽  
Cardiovascular Risk Reduction ◽  
Racial Ethnic

Abstract Background: The consistency of cardiovascular risk reduction by antidiabetes medications across racial and ethnic groups remains unclear. The aim of this study was to analyze racial/ethnic patterns in the results of cardiovascular outcomes trials of antidiabetes medications in people with type 2 diabetes.Method: PubMed and Cochrane library databases were searched from the inception dates to December 2019. Cardiovascular outcome trials in type 2 diabetes that randomized participants to active or control treatment and reported results by race/ethnic groups or region were included.Results: A total of 16 studies were included in this meta-analysis. Among White participants, active antidiabetes medication, compared with control treatment, significantly decreased the composite cardiovascular outcomes (OR=0.90, 95% CI 0.86-0.94, p<0.05). Among Asian participants, active antidiabetes medication, compared with control treatment, also significantly decreased the composite cardiovascular outcomes (OR=0.82, 95%CI 0.76-0.90, p<0.05). Among Black participants (OR=0.96, 95% CI 0.69-1.32, p=0.79) and subjects from other groups (mostly Hispanics or Pacific Islanders) (OR=0.92, 95% CI 0.81-1.04, p=0.16), active anti-diabetes medication resulted in nominal but non-significant decreases in the composite cardiovascular outcomes, compared with the control treatment.Conclusions: Antidiabetes drugs demonstrated cardiovascular safety in people with type 2 diabetes from all racial/ethnic groups studied, but achieved significant composite cardiovascular risk reduction only in White and Asian participants, perhaps due to differences in sample size and power.

scholarly journals Susceptibility variants for rheumatoid arthritis in the TRAF1-C5 and 6q23 loci: a meta-analysis

2009 ◽  
Vol 69 (3) ◽  
pp. 561-566 ◽  
Author(s):  
Nikolaos A Patsopoulos ◽  
John P A Ioannidis
Keyword(s):  
Rheumatoid Arthritis ◽  
Association Studies ◽  
Meta Analysis ◽  
Statistical Significance ◽  
Genome Wide Association Studies ◽  
Gene Environment ◽  
Genome Wide ◽  
Study Heterogeneity ◽  
Meta Analyses ◽  
Citrullinated Peptide

BackgroundGenome-wide association studies have proposed susceptibility variants for rheumatoid arthritis in the TRAF1-C5 locus and 6q23 region. Furthermore, additional independent studies have investigated the same or highly linked polymorphisms in the same regions.ObjectiveTo carry out a meta-analysis of the available evidence for the association of polymorphisms in the TRAF1-C5 locus and 6q23 region with rheumatoid arthritis.MethodsData were synthesised for four polymorphisms: rs3761847 (n=13 datasets) and rs2900180 (n=9 datasets) in the TRAF1-C5 locus, and rs10499194 (n=5 datasets) and rs6920220 (n=7 datasets) in the 6q23 region. Meta-analyses for subgroups defined by anti-cyclic citrullinated peptide (anti-CCP) and rheumatoid factor (RF) status were also performed.ResultsThe polymorphism rs6920220 reached genome-wide statistical significance with p=7.9×10−17 and an allelic odds ratio of 1.24 (95% CI 1.18 to 1.30) and no between-study heterogeneity (I2=0%). The risk was significantly stronger in patients with anti-CCP antibodies and in patients with RF. The other three variants showed large between-study heterogeneity across datasets (I2 range 74–82%); rs10499194 was nominally statistically significant after exclusion of the discovery data. Two variants had genome-wide statistical significance in subgroups defined by the presence of RF (rs3761847 and rs6920220) or anti-CCP (rs6920220).ConclusionsGenetic markers in the 6q23 region and TRAF1-C5 are associated with rheumatoid arthritis, in particular with positive anti-CCP and RF profile. With the exception of rs6920220, which shows highly consistent results, other proposed markers have high between-study heterogeneity that may reflect unrecognised phenotypic or genetic variability (eg, gene environment interactions) within rheumatoid arthritis. Furthermore, these markers may not be the true causative loci but rather be in linkage disequilibrium with the true ones.

scholarly journals ALDH2 genotype modulates the association between alcohol consumption and AST/ALT ratio among middle-aged Japanese men: a genome-wide G × E interaction analysis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yoichi Sutoh ◽  
Tsuyoshi Hachiya ◽  
Yuji Suzuki ◽  
Shohei Komaki ◽  
Hideki Ohmomo ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Interaction Analysis ◽  
Meta Analysis ◽  
Drinking Behavior ◽  
Japanese Men ◽  
Genome Wide ◽  
A Genome ◽  
Alcohol Intolerance ◽  
Related Liver Disease ◽  
The Impact

Abstract Liver tests (LT), especially to measure AST, ALT and GGT levels, are widely used to evaluate the risk of alcohol-related liver disease (ALD). In this study, we investigated the potential genetic factors that modulate the association between LTs and alcohol consumption. We conducted a genome-wide interaction meta-analysis in 7856 Japanese subjects from Tohoku Medical Megabank Community-Based Cohort (TMM CommCohort) study recruited in 2013, and identified 2 loci (12q24 and 2p16) with genome-wide significance (P > 5 × 10–8). The significant variants in the 12q24 included rs671, a variant associated with alcohol intolerance and located at a coding exon of ALDH2. We found that the amount of alcohol consumption was associated with increased level AST/ALT ratio among the subjects with the rs671 GA genotype. The elevated AST/ALT ratio among subjects with moderate-to-high levels of drinking behavior and the rs671 GA genotype was due to decreased levels of ALT, which was not accompanied with significant differences in AST levels. Although the interaction effect was significant in both men and women, the effect was much larger in men. Our results suggest that the impact of alcohol consumption on LT varies according to the ALDH2 genotype, providing an insight for the accurate screening of ALD in drinkers with the rs671 GA genotype.

scholarly journals Haplotype and Haplotype-Environment Interaction Analysis Revealed Roles of SPRY2 for NSCL/P among Chinese Populations

2019 ◽  
Vol 16 (4) ◽  
pp. 557 ◽  
Author(s):  
Ren Zhou ◽  
Mengying Wang ◽  
Wenyong Li ◽  
Siyue Wang ◽  
Hongchen Zheng ◽  
...  
Keyword(s):  
Interaction Analysis ◽  
Genome Wide Association ◽  
Environment Interaction ◽  
Genome Wide Association Studies ◽  
Gene Effects ◽  
Multivitamin Supplementation ◽  
Chinese Populations ◽  
Gene Environment Interaction ◽  
Gene Environment ◽  
Genome Wide

Non-syndromic cleft lip with or without cleft palate (NSCL/P) is one of common birth defects in China, with genetic and environmental components contributing to the etiology. Genome wide association studies (GWASs) have identified SPRY1 and SPRY2 to be associated with NSCL/P among Chinese populations. This study aimed to further explore potential genetic effect and gene—environment interaction among SPRY genes based on haplotype analysis, using 806 Chinese case—parent NSCL/P trios drawn from an international consortium which conducted a genome-wide association study. After the process of quality control, 190 single nucleotide polymorphisms (SNPs) of SPRY genes were included for analyses. Haplotype and haplotype—environment interaction analyses were conducted in Population-Based Association Test (PBAT) software. A 2-SNP haplotype and three 3-SNP haplotypes showed a significant association with the risk of NSCL/P after Bonferroni correction (corrected significance level = 2.6 × 10−4). Moreover, haplotype—environment interaction analysis identified these haplotypes respectively showing statistically significant interactions with maternal multivitamin supplementation or maternal environmental tobacco smoke. This study showed SPRY2 to be associated with NSCL/P among the Chinese population through not only gene effects, but also a gene—environment interaction, highlighting the importance of considering environmental exposures in the genetic etiological study of NSCL/P.

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