Faculty, Staff and Student Publications
Publication Date
6-1-2022
Journal
European Journal of Human Genetics
Abstract
The role and biological significance of gene-environment interactions in human traits and diseases remain poorly understood. To address these questions, the CHARGE Gene-Lifestyle Interactions Working Group conducted series of genome-wide interaction studies (GWIS) involving up to 610,475 individuals across four ancestries for three lipids and four blood pressure traits, while accounting for interaction effects with drinking and smoking exposures. Here we used GWIS summary statistics from these studies to decipher potential differences in genetic associations and G×E interactions across phenotype-exposure-ancestry combinations, and to derive insights on the potential mechanistic underlying G×E through in-silico functional analyses. Our analyses show first that interaction effects likely contribute to the commonly reported ancestry-specific genetic effect in complex traits, and second, that some phenotype-exposures pairs are more likely to benefit from a greater detection power when accounting for interactions. It also highlighted modest correlation between marginal and interaction effects, providing material for future methodological development and biological discussions. We also estimated contributions to phenotypic variance, including in particular the genetic heritability conditional on the exposure, and heritability partitioned across a range of functional annotations and cell types. In these analyses, we found multiple instances of potential heterogeneity of functional partitions between exposed and unexposed individuals, providing new evidence for likely exposure-specific genetic pathways. Finally, along this work, we identified potential biases in methods used to jointly meta-analyze genetic and interaction effects. We performed simulations to characterize these limitations and to provide the community with guidelines for future G×E studies.
Keywords
Epistasis, Genetic, Gene-Environment Interaction, Genome-Wide Association Study, Genomics, Humans, Life Style, Multifactorial Inheritance, Phenotype, Genetics research, High-throughput screening, Medical genomics
DOI
10.1038/s41431-022-01045-6
PMID
35314805
PMCID
PMC9178041
PubMedCentral® Posted Date
3-22-2022
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Biological Phenomena, Cell Phenomena, and Immunity Commons, Medical Genetics Commons, Public Health Commons