Identifying gene-environment interactions (GxEs) contributing to human cardiometabolic disorders is challenging. Here we apply a reverse GxE candidate search by deriving candidate variants from promoter-enhancer interactions that respond to dietary fatty acid challenge through altered chromatin accessibility in human primary adipocytes. We then test all variants residing in the lipid-responsive open chromatin sites within adipocyte promoter-enhancer contacts for interaction effects between the genotype and dietary saturated fat intake on body mass index (BMI) in the UK Biobank. We discover 14 novel GxE variants in 12 lipid-responsive promoters, including well-known lipid genes (LIPE, CARM1, and PLIN2) and novel genes, such as LDB3, for which we provide further functional and integrative genomics evidence. We further identify 24 GxE variants in enhancers, totaling 38 new GxE variants for BMI in the UK Biobank, demonstrating that molecular genomics data produced in physiologically relevant contexts can discover new functional GxE mechanisms in humans.

Identifying gene-environment interactions (GxEs) contributing to human cardiometabolic disorders is challenging. Here we apply a reverse GxE candidate search by deriving candidate variants from promoter-enhancer interactions that respond to dietary fatty acid challenge through altered chromatin accessibility in human primary adipocytes. We then test all variants residing in the lipid-responsive open chromatin sites within adipocyte promoter-enhancer contacts for interaction effects between the genotype and dietary saturated fat intake on body mass index (BMI) in the UK Biobank. We discover 14 novel GxE variants in 12 lipid-responsive promoters, including well-known lipid genes (LIPE, CARM1, and PLIN2) and novel genes, such as LDB3, for which we provide further functional and integrative genomics evidence. We further identify 24 GxE variants in enhancers, totaling 38 new GxE variants for BMI in the UK Biobank, demonstrating that molecular genomics data produced in physiologically relevant contexts can discover new functional GxE mechanisms in humans.