Cross-ancestry analysis identifies genes associated with obesity risk and protection

Gene discoveries in obesity have largely been based on European cohorts, leading to an ancestral bias, that limits their generalizability across populations. We performed a gene-based rare variant association study of 721,941 individuals and identified 116 novel BMI-associated genes with consistent effects across ancestries, including 50 risk-conferring and 66 protective genes against obesity. Protective genes such as DCUN1D3 and NEUROD6 had effect sizes comparable to high-risk genes such as MC4R and BSN , and nearly twice that of known protective genes such as GPR75 , which, along with five other genes, showed strong European bias. Notably, 82 of the 116 genes showed functional relevance to obesity including adiposity, energy homeostasis, and glucose metabolism. While polygenic risks or an obesogenic lifestyle amplified the effect of 15 genes on BMI, including the combination of low physical activity and MACROD1 , 23 genes including VIRMA , AQP3 , and PML retained protective effects even at high polygenic scores. Our findings provide further insights into the genetic basis of obesity that is conserved across ancestries and their interactions with obesogenic factors.