Genome-wide Interaction Studies by the CHARGE Gene-Lifestyle Interactions Working Group: what we have learned and what is coming next.

The Gene-Lifestyle Interactions Working Group has recently conducted series of multi-ancestry genome-wide association screenings (GWAS) involving up to 610,475 individuals for three lipids (total triglyceride, high-density lipoprotein, and low-density lipoprotein), and four blood pressure traits (diastolic blood pressure, systolic blood pressure, mean arterial pressure, and pulse pressure) while accounting for potential interaction effect with drinking and smoking exposures. These GWAS reported both a 1 degree-of-freedom (df) test of gene-by-exposure (GxE) interaction, and a 2 df test of main genetic effect and interaction effect. Here we synthetized these results and generated a number of cross-studies statistics, providing a global perspective on this unique initiative, and suggesting guidelines for future GxE studies. We first summarized the signals identified across all phenotype-exposure pairs and ancestries considered, highlighting similarity and specificity of gene-environment interaction effects across phenotypes and ancestries. We then performed several follow-up analyses using genome-wide summary statistics, focusing in particular on multi-SNPs approaches and the relationship between interactions effect and marginal genetic effect. Those analyses identified new associations and demonstrated potential alternatives approaches for future GxE screenings. Finally, we explored differences in heritability conditional on the exposures considered. Our work provides new evidence for the potential implication of exposure-specific pathway, and opening new path for future gene-environment association studies.