Discovering pure gene-environment interactions in blood pressure genome-wide association studies data: a two-step approach incorporating new statistics

Abstract Gene-environment correlations can bias associations between genetic variants and complex traits in genome-wide association studies (GWASs). Here, we control for geographic sources of gene-environment correlation in GWASs on 56 complex traits (N = 69,772–271,457). Controlling for geographic region significantly decreases heritability signals for SES-related traits, most strongly for educational attainment and income, indicating that socio-economic differences between regions induce gene-environment correlations that become part of the polygenic signal. For most other complex traits investigated, genetic correlations with educational attainment and income are significantly reduced, most significantly for traits related to BMI, sedentary behavior, and substance use. Controlling for current address has greater impact on the polygenic signal than birth place, suggesting both active and passive sources of gene-environment correlations. Our results show that societal sources of social stratification that extend beyond families introduce regional-level gene-environment correlations that affect GWAS results.

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Geographic Confounding in Genome-Wide Association Studies

10.1101/2021.03.18.435971 ◽

2021 ◽

Author(s):

Abdel Abdellaoui ◽

Karin J.H. Verweij ◽

Michel G. Nivard

Keyword(s):

Educational Attainment ◽

Social Stratification ◽

Complex Traits ◽

Association Studies ◽

Genetic Correlations ◽

Geographic Region ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Gene Environment ◽

Genome Wide

Gene-environment correlations can bias associations between genetic variants and complex traits in genome-wide association studies (GWASs). Here, we control for geographic sources of gene-environment correlation in GWASs on 56 complex traits (N=69,772-271,457). Controlling for geographic region significantly decreases heritability signals for SES-related traits, most strongly for educational attainment and income, indicating that socio-economic differences between regions induce gene-environment correlations that become part of the polygenic signal. For most other complex traits investigated, genetic correlations with educational attainment and income are significantly reduced, most significantly for traits related to BMI, sedentary behavior, and substance use. Controlling for current address has greater impact on the polygenic signal than birth place, suggesting both active and passive sources of gene-environment correlations. Our results show that societal sources of social stratification that extend beyond families introduce regional-level gene-environment correlations that affect GWAS results.

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Blood Pressure Genome-Wide Association Studies, Missing Heritability, and Omnigenics

Circulation Cardiovascular Genetics ◽

10.1161/circgenetics.117.001943 ◽

2017 ◽

Vol 10 (5) ◽

Cited By ~ 2

Author(s):

Brian J. Morris

Keyword(s):

Blood Pressure ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Missing Heritability ◽

Genome Wide

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Identification of Phosphorylation Associated SNPs for Blood Pressure, Coronary Artery Disease and Stroke from Genome-wide Association Studies

Current Molecular Medicine ◽

10.2174/1566524019666190828151540 ◽

2019 ◽

Vol 19 (10) ◽

pp. 731-738

Author(s):

Xingchen Wang ◽

Xingbo Mo ◽

Huan Zhang ◽

Yonghong Zhang ◽

Yueping Shen

Keyword(s):

Blood Pressure ◽

Coronary Artery Disease ◽

Coronary Artery ◽

Cardiovascular Diseases ◽

Association Studies ◽

Serum Levels ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Artery Disease

Purpose: Phosphorylation-related SNP (phosSNP) is a non-synonymous SNP that might influence protein phosphorylation status. The aim of this study was to assess the effect of phosSNPs on blood pressure (BP), coronary artery disease (CAD) and ischemic stroke (IS). Methods: We examined the association of phosSNPs with BP, CAD and IS in shared data from genome-wide association studies (GWAS) and tested if the disease loci were enriched with phosSNPs. Furthermore, we performed quantitative trait locus analysis to find out if the identified phosSNPs have impacts on gene expression, protein and metabolite levels. Results: We found numerous phosSNPs for systolic BP (count=148), diastolic BP (count=206), CAD (count=20) and IS (count=4). The most significant phosSNPs for SBP, DBP, CAD and IS were rs1801131 in MTHFR, rs3184504 in SH2B3, rs35212307 in WDR12 and rs3184504 in SH2B3, respectively. Our analyses revealed that the associated SNPs identified by the original GWAS were significantly enriched with phosSNPs and many well-known genes predisposing to cardiovascular diseases contain significant phosSNPs. We found that BP, CAD and IS shared for phosSNPs in loci that contain functional genes involve in cardiovascular diseases, e.g., rs11556924 (ZC3HC1), rs1971819 (ICA1L), rs3184504 (SH2B3), rs3739998 (JCAD), rs903160 (SMG6). Four phosSNPs in ADAMTS7 were significantly associated with CAD, including the known functional SNP rs3825807. Moreover, the identified phosSNPs seemed to have the potential to affect transcription regulation and serum levels of numerous cardiovascular diseases-related proteins and metabolites. Conclusion: The findings suggested that phosSNPs may play important roles in BP regulation and the pathological mechanisms of CAD and IS.

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Two-Stage Procedures for the Identification of Gene × Environment and Gene × Gene Interactions in Genome-Wide Association Studies

Statistical Approaches to Gene X Environment Interactions for Complex Phenotypes ◽

10.7551/mitpress/9780262034685.003.0002 ◽

2016 ◽

Author(s):

Charles Kooperberg ◽

James Y. Dai ◽

Li Hsu

Keyword(s):

Association Studies ◽

Gene Interaction ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Two Stage ◽

Genetic Studies ◽

Gene Environment ◽

Genome Wide ◽

Sequencing Studies ◽

Generation Sequencing

Genome-wide association studies and next generation sequencing studies offer us an unprecedented opportunity to study the genetic etiology of diseases and other traits. Over the last few years, many replicated associations between SNPs and traits have been published. It is of particular interest to identify how genes may interact with environmental factors and other genes. In this chapter, we show that a two-stage approach, where in the first stage SNPs are screened for their potential to be involved in interactions, and interactions are then tested only among SNPs that pass the screening can greatly enhance power for detecting gene-environment and gene-gene interaction in large genetic studies compared to the tests without screening.

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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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