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A new Approach to Identify Gene-Environment Interactions and Reveal New Biological Insight in Complex traits.

ABSTRACT: There is a long-standing debate about the magnitude of the contribution of gene-environment interactions to phenotypic variations of complex traits owing to the low statistical power and few reported interactions to date. To address this issue, the CHARGE Gene-Lifestyle Interactions Working Group has been spearheading efforts to investigate G×E in large and diverse samples through meta-analysis. Here, we present a powerful new approach to screen for interactions across the genome, an approach that shares substantial similarity to the Mendelian randomization framework. We identified and confirmed 5 loci (6 independent signals) interacting with either cigarette smoking or alcohol consumption for serum lipids, and empirically demonstrated that interaction and mediation are the major contributors to genetic effect size heterogeneity across populations. The estimated lower bound of the interaction and environmentally mediated contribution ranges from 1.76% to 14.05% of SNP heritability of serum lipids in Cross-Population data. Our study improves the understanding of the genetic architecture and environmental contributions to complex traits.

SUBMITTER: Zhu X

PROVIDER: S-EPMC10602131 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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A new Approach to Identify Gene-Environment Interactions and Reveal New Biological Insight in Complex traits.

Zhu Xiaofeng X Yang Yihe Y Lorincz-Comi Noah N Li Gen G Bentley Amy A de Vries Paul S PS Brown Michael M Morrison Alanna C AC Rotimi Charles C James Gauderman W W Rao D C DC Aschard Hugues H

Research square 20231005

There is a long-standing debate about the magnitude of the contribution of gene-environment interactions to phenotypic variations of complex traits owing to the low statistical power and few reported interactions to date. To address this issue, the CHARGE Gene-Lifestyle Interactions Working Group has been spearheading efforts to investigate G×E in large and diverse samples through meta-analysis. Here, we present a powerful new approach to screen for interactions across the genome, an approach th ...[more]

PMID: 37886448

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Project description:Mitochondrial function requires the coordinated expression of dozens of gene products from the mitochondrial genome and hundreds from the nuclear genomes. The systems that emerge from these interactions convert the food we eat and the oxygen we breathe into energy for life, while regulating a wide range of other cellular processes. These facts beg the question of whether the gene-by-gene interactions (G x G) that enable mitochondrial function are distinct from the gene-by-environment interactions (G x E) that fuel mitochondrial activity. We examine this question using a Drosophila model of mitonuclear interactions in which experimental combinations of mtDNA and nuclear chromosomes generate pairs of mitonuclear genotypes to test for epistatic interactions (G x G). These mitonuclear genotypes are then exposed to altered dietary or oxygen environments to test for G x E interactions. We use development time to assess dietary effects, and genome wide RNAseq analyses to assess hypoxic effects on transcription, which can be partitioned in to mito, nuclear, and environmental (G x G x E) contributions to these complex traits. We find that mitonuclear epistasis is universal, and that dietary and hypoxic treatments alter the epistatic interactions. We further show that the transcriptional response to alternative mitonuclear interactions has significant overlap with the transcriptional response to alternative oxygen environments. Gene coexpression analyses suggest that these shared genes are more central in networks of gene interactions, implying some functional overlap between epistasis and genotype by environment interactions. These results are discussed in the context of evolutionary fitness, the genetic basis of complex traits, and the challenge of achieving precision in personalized medicine. © 2018 The Authors. IUBMB Life published by Wiley Periodicals, Inc. on behalf of International Union of Biochemistry and Molecular Biology, 70(12):1275-1288, 2018.

Dataset Information

A new Approach to Identify Gene-Environment Interactions and Reveal New Biological Insight in Complex traits.

Publications

A new Approach to Identify Gene-Environment Interactions and Reveal New Biological Insight in Complex traits.

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