A genome-wide interaction analysis of tricyclic/tetracyclic antidepressants and RR and QT intervals: a pharmacogenomics study from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium

AbstractChlorthalidone (CTD) is more potent than hydrochlorothiazide (HCTZ) in reducing blood pressure (BP) in hypertensive patients, though both are plagued with BP response variability. However, there is a void in the literature regarding the genetic determinants contributing to the variability observed in BP response to CTD. We performed a discovery genome wide association analysis of BP response post CTD treatment in African Americans (AA) and European Americans (EA) from the Pharmacogenomic Evaluation of Antihypertensive Responses-2 (PEAR-2) study and replication in an independent cohort of AA and EA treated with HCTZ from the PEAR study, followed by a race specific meta-analysis of the two studies. Successfully replicated SNPs were further validated in beta-blocker treated participants from PEAR-2 and PEAR for opposite direction of association. The replicated and validated signals were further evaluated by protein-protein interaction network analysis. An intronic SNP rs79237970 in the WDR92 (eQTL for PPP3R1) was significantly associated with better DBP response to CTD (p = 5.76 × 10−6, β = −15.75) in the AA cohort. This SNP further replicated in PEAR (p = 0.00046, β = −9.815) with a genome wide significant meta-analysis p-value of 8.49 × 10−9. This variant was further validated for opposite association in two β-blockers treated cohorts from PEAR-2 metoprolol (p = 9.9 × 10−3, β = 7.47) and PEAR atenolol (p = 0.04, β = 4.36) for association with DBP. Studies have implicated WDR92 in coronary artery damage. PPP3R1 is the regulatory subunit of the calcineurin complex. Use of calcineurin inhibitors is associated with HTN. Studies have also shown polymorphisms in PPP3R1 to be associated with ventricular hypertrophy in AA hypertensive patients. Protein-protein interaction analysis further identified important hypertension related pathways such as inositol phosphate-mediated signaling and calcineurin-NFAT signaling cascade as important biological process associated with PPP3R1 which further strengthen the potential importance of this signal. These data collectively suggest that WDR92 and PPP3R1 are novel candidates that may help explain the genetic underpinnings of BP response of thiazide and thiazide-like diuretics and help identify the patients better suited for thiazide and thiazide-like diuretics compared to β-blockers for improved BP management. This may further help advance personalized approaches to antihypertensive therapy.

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Epistatic Effects on Abdominal Fat Content in Chickens: Results from a Genome-Wide SNP-SNP Interaction Analysis

PLoS ONE ◽

10.1371/journal.pone.0081520 ◽

2013 ◽

Vol 8 (12) ◽

pp. e81520 ◽

Cited By ~ 10

Author(s):

Fangge Li ◽

Guo Hu ◽

Hui Zhang ◽

Shouzhi Wang ◽

Zhipeng Wang ◽

...

Keyword(s):

Interaction Analysis ◽

Abdominal Fat ◽

Fat Content ◽

Epistatic Effects ◽

Genome Wide ◽

A Genome ◽

Snp Interaction

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Genome-wide Studies of Verbal Declarative Memory in Nondemented Older People: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium

Biological Psychiatry ◽

10.1016/j.biopsych.2014.08.027 ◽

2015 ◽

Vol 77 (8) ◽

pp. 749-763 ◽

Cited By ~ 40

Author(s):

Stéphanie Debette ◽

Carla A. Ibrahim Verbaas ◽

Jan Bressler ◽

Maaike Schuur ◽

Albert Smith ◽

...

Keyword(s):

Older People ◽

Declarative Memory ◽

Aging Research ◽

Genomic Epidemiology ◽

Genome Wide

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A sex-stratified genome-wide association study of tuberculosis using a multi-ethnic genotyping array

10.1101/405571 ◽

2018 ◽

Cited By ~ 2

Author(s):

Haiko Schurz ◽

Craig J Kinnear ◽

Chris Gignoux ◽

Genevieve Wojcik ◽

Paul D van Helden ◽

...

Keyword(s):

Association Study ◽

X Chromosome ◽

Complex Disease ◽

Genome Wide Association Study ◽

Interaction Analysis ◽

Genome Wide Association ◽

Genotyping Array ◽

Association Testing ◽

Genome Wide ◽

A Genome

AbstractTuberculosis (TB), caused by Mycobacterium tuberculosis, is a complex disease with a known human genetic component. Males seem to be more affected than females and in most countries the TB notification rate is twice as high in males as in females. While socio-economic status, behaviour and sex hormones influence the male bias they do not fully account for it. Males have only one copy of the X chromosome, while diploid females are subject to X chromosome inactivation. In addition, the X chromosome codes for many immune-related genes, supporting the hypothesis that X-linked genes could contribute to TB susceptibility in a sex-biased manner. We report the first TB susceptibility genome-wide association study (GWAS) with a specific focus on sex-stratified autosomal analysis and the X chromosome. Individuals from an admixed South African population were genotyped using the Illumina Multi Ethnic Genotyping Array, specifically designed as a suitable platform for diverse and admixed populations. Association testing was done on the autosome and X chromosome in a sex stratified and combined manner. SNP association testing was not statistically significant using a stringent cut-off for significance but revealed likely candidate genes that warrant further investigation. A genome wide interaction analysis detected 16 significant interactions. Finally, the results highlight the importance of sex-stratified analysis as strong sex-specific effects were identified on both the autosome and X chromosome.

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P1-019: Large-Scale Meta-Analysis of Genome-Wide Association Data on Delayed Recall Memory Performance: The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium

Alzheimer s & Dementia ◽

10.1016/j.jalz.2016.06.766 ◽

2016 ◽

Vol 12 ◽

pp. P406-P407

Author(s):

Muralidharan Sargurupremraj ◽

Claudia L. Satizabal ◽

Jan Bressler ◽

Ganesh Chauhan ◽

Thomas H. Mosley ◽

...

Keyword(s):

Large Scale ◽

Memory Performance ◽

Meta Analysis ◽

Genome Wide Association ◽

Aging Research ◽

Delayed Recall ◽

Genomic Epidemiology ◽

Genome Wide ◽

Recall Memory ◽

Association Data

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Large-Scale, Genome-Wide Gene-Diet Interaction Testing for HbA1c Using Derived Dietary Patterns in the UK Biobank

Current Developments in Nutrition ◽

10.1093/cdn/nzaa058_038 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1280-1280

Author(s):

Kenneth Westerman ◽

Ye Chen ◽

Han Chen ◽

Jose Florez ◽

Joanne Cole ◽

...

Keyword(s):

Principal Components ◽

Dietary Patterns ◽

Genetic Variants ◽

Interaction Analysis ◽

European Ancestry ◽

Uk Biobank ◽

Genome Wide ◽

A Genome ◽

Gene Level ◽

The Uk

Abstract Objectives Gene-diet interaction analysis can inform the development of precision nutrition for diabetes by uncovering genetic variants whose effects on glycemic traits vary across dietary behaviors. However, due to noise in dietary datasets and the low statistical power inherent in interaction analysis, there is a lack of confident, well-replicated gene-diet interactions for glycemic traits. Emerging computationally-efficient software tools have made it feasible to conduct well-powered, genome-wide interaction analysis in hundreds of thousands of individuals. Here, our objective was to conduct a genome-wide gene-diet interaction analysis for glycated hemoglobin (HbA1c; a measure of hyperglycemia), leveraging the large sample size of the UK Biobank cohort and data-driven dietary patterns to discover genetic variants whose effect is modulated by diet. Methods Food frequency questionnaires were previously used to derive empirical dietary patterns using principal components analysis (FFQ-PCs) in the UK Biobank. FFQ-PCs were used in genome-wide interaction analysis for HbA1c levels in unrelated, non-diabetic individuals of European ancestry (N = 331,610), adjusting for age, sex, and 10 genetic principal components. P-values were calculated for both the interaction (P-int) and a joint test (significance of the variant-HbA1c association combining the main and interaction effects) and the MAGMA tool was used to calculate gene-level enrichment statistics. Results Preliminary results from the first two FFQ-PCs confirmed known genetic loci for HbA1c using the joint test, such as at G6PC2 and GCK. Though no interaction tests reached genome-wide significance, suggestive signals (P-int < 1e-5) emerged at the variant level (including one near TPSD1, which codes for a tryptase and has been linked to red blood cell traits) and the gene level (such as for GTF3C2, which has previously been shown to interact with sleep in impacting lipid traits). Conclusions We have conducted the largest genome-wide study of gene-diet interactions for glycemic traits to-date and identified regions in the genome whose effect on HbA1c may be modulated by dietary intake, suggesting that this approach has the potential to reveal new insights into the genetics of glycemic traits and inform individualized dietary guidelines for diabetes prevention and management. Funding Sources NHLBI.

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

Scientific Reports ◽

10.1038/s41598-020-73263-1 ◽

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.

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A multi-ancestry genome-wide study incorporating gene–smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure

Human Molecular Genetics ◽

10.1093/hmg/ddz070 ◽

2019 ◽

Vol 28 (15) ◽

pp. 2615-2633 ◽

Cited By ~ 8

Author(s):

Yun Ju Sung ◽

Lisa de las Fuentes ◽

Thomas W Winkler ◽

Daniel I Chasman ◽

Amy R Bentley ◽

...

Keyword(s):

Mean Arterial Pressure ◽

Arterial Pressure ◽

Pulse Pressure ◽

Contractile Function ◽

Interaction Analysis ◽

Collecting Duct ◽

Lifestyle Factors ◽

Genome Wide ◽

A Genome ◽

Smoking Interaction

Abstract Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene–smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene–smoking interaction analysis and 38 were newly identified (P < 5 × 10−8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.

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