@article{bb8c66d664144456b849217f3f6dde30,
title = "Gene-lifestyle interactions in the genomics of human complex traits",
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.",
author = "{the CHARGE Gene-Lifestyle Interactions Working Group} and Vincent Laville and Timothy Majarian and Sung, {Yun J.} and Karen Schwander and Feitosa, {Mary F.} and Chasman, {Daniel I.} and Bentley, {Amy R.} and Rotimi, {Charles N.} and Cupples, {L. Adrienne} and {de Vries}, {Paul S.} and Brown, {Michael R.} and Morrison, {Alanna C.} and Kraja, {Aldi T.} and Mike Province and Gu, {C. Charles} and Gauderman, {W. James} and Vincent Laville and Timothy Majarian and Sung, {Yun J.} and Karen Schwander and Feitosa, {Mary F.} and Bentley, {Amy R.} and Rotimi, {Charles N.} and Cupples, {L. Adrienne} and {de Vries}, {Paul S.} and Brown, {Michael R.} and Morrison, {Alanna C.} and Kraja, {Aldi T.} and Mike Province and Gu, {C. Charles} and Gauderman, {W. James} and Rao, {D. C.} and Manning, {Alisa K.} and Hugues Aschard and Rao, {D. C.} and Manning, {Alisa K.} and Hugues Aschard",
note = "Funding Information: We warmly thank all the past and present members of the Gene Lifestyle Interaction Working Group. The various Gene-Lifestyle Interaction projects, including this summary project, are largely supported by a grant from the U.S. National Heart, Lung, and Blood Institute (NHLBI), the National Institutes of Health, R01HL118305. This work was also supported by the INCEPTION project (PIA/ANR-16-CONV-0005). This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. PSV was supported by American Heart Association grant number 18CDA34110116. YJS was supported by the K25HL121091 award from NHLBI. JG was partly supported by the P01CA196569 grant from the National Institutes of Health. Full set of study-specific funding sources and acknowledgments were included in the separate publications [–]. Funding Information: We warmly thank all the past and present members of the Gene Lifestyle Interaction Working Group. The various Gene-Lifestyle Interaction projects, including this summary project, are largely supported by a grant from the U.S. National Heart, Lung, and Blood Institute (NHLBI), the National Institutes of Health, R01HL118305. This work was also supported by the INCEPTION project (PIA/ANR-16-CONV-0005). This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. PSV was supported by American Heart Association grant number 18CDA34110116. YJS was supported by the K25HL121091 award from NHLBI. JG was partly supported by the P01CA196569 grant from the National Institutes of Health. Full set of study-specific funding sources and acknowledgments were included in the separate publications [7 –11]. Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = jun,
doi = "10.1038/s41431-022-01045-6",
language = "English",
volume = "30",
pages = "730--739",
journal = "European Journal of Human Genetics",
issn = "1018-4813",
number = "6",
}