Large scale phenotype imputation and in vivo functional validation implicate ADAMTS14 as a novel adiposity gene - Supplementary data

Obesity remains an unmet global health burden. Detrimental anatomical distribution of body fat is a major driver of obesity-mediated mortality risk and is demonstrably heritable. However, our understanding of the full genetic contribution to human adiposity is incomplete, as few studies measure adiposity directly. To address this, we imputed DXA adiposity phenotypes in UK Biobank from the 5,000 directly measured participants onto the rest of the cohort, greatly increasing our discovery power. GWAS on these imputed phenotypes in over 390,000 participants yielded hundreds of novel associations, six of which were replicated in independent DXA cohorts. The leading causal gene candidate, ADAMTS14, was further investigated in a mouse knockout model. Concordant with the GWAS data, the Adamts14–/– mice exhibited reduced adiposity and weight-gain under obesogenic conditions, alongside an improved metabolic rate and health. Phenotypic imputation at scale has offered deeper biological insights into the genetics of human adiposity that could lead to novel therapeutic targets.