Variance-quantitative trait loci enable systematic discovery of gene-environment interactions for cardiometabolic serum biomarkers

Gene-environment interactions (GEIs) represent the modification of genetic effects by environmental exposures and are critical for understanding disease and informing personalized medicine. GEIs often induce differential phenotypic variance across genotypes; these variance-quantitative trait loci (vQTLs) can be prioritized in a two-stage GEI detection strategy to greatly reduce the computational and statistical burden and enable testing of a broader range of exposures. We performed genome-wide vQTL analysis for 20 serum cardiometabolic biomarkers by multi-ancestry meta-analysis of 350,016 unrelated participants in the UK Biobank, identifying 182 independent locus-biomarker pairs (p < 4.5x10-9). Most vQTLs were concentrated in a small subset (4%) of loci with genome-wide significant main effects, and 44% replicated (p < 0.05) in the Women's Genome Health Study (N = 23,294). Next, we tested each vQTL for interaction across 2,380 exposures, identifying 846 significant GEIs (p < 2.4x10-7). Specific examples demonstrated interaction of triglyceride-associated variants with distinct body mass- versus body fat-related exposures as well as genotype-specific associations between alcohol consumption and liver stress at the ADH1B gene. Our catalog of vQTLs and GEIs is publicly available in an online portal.