Genetic Impacts on Variability of Body Fat Distribution Uncover Gene-Environment and Gene-Gene Interactions

Body fat distribution is a strong predictor of cardiometabolic disease risk. Gene-environment and gene-gene interactions can affect body fat distribution, resulting in differential phenotypic variance across genotype groups that can be detected through variance quantitative trait loci (vQTLs). Using UK Biobank MRI data in conjunction with genetic data, we explored evidence for vQTLs for body fat distribution phenotypes aiming to uncover potential genetic interactions. We identified three vQTLs for liver fat distribution, including rs738408 ( PNPLA3 ), rs4293458 ( APOE ), and rs58542926 ( TM6SF2 ), and one vQTL region ( FTO ) for abdominal subcutaneous adipose tissue. To dissect putative gene-environment and gene-gene interactions underlying these signals, we identified multiple vQTL-environment interactions and one epistatic effect (rs58542926*rs429358) for liver fat. The vQTLs and interaction results were validated in multiple UK Biobank and external replication cohort datasets (Framingham Heart Study, All of Us, and TwinsUK), showing replication of the three liver vQTLs with the greatest reproducibility for vQTL rs738408. Our findings uncover vQTLs and underlying interaction effects on body fat distribution, especially liver fat, that may be useful for the development of precision medicine approaches.