Sex-specific dissection of adiposity genetics reveals distinct pathways to endometrial cancer risk

Abstract Excess adiposity accounts for up to 60% of endometrial cancer cases, yet the mechanisms linking adiposity to carcinogenesis and the relevance of sex-specific adiposity genetics to disease risk have been largely unexplored. Using genomic structural equation modelling of six adiposity genome-wide association studies (GWAS), we perform the first sex-stratified adiposity common factor GWAS model, combining data from 2 million people. We identified sex differences in adiposity genetic effects and identified a fourfold larger female-specific causal genetic component relative to males. Female adiposity genetics converged on hormone-responsive and oncogenic pathways directly implicated in endometrial carcinogenesis, a specificity confirmed by stronger female adiposity genetic effects on endometrial cancer but not other hormone-related cancers. Cross-trait analysis identified 26 loci jointly associated with female adiposity and endometrial cancer, including 16 previously unreported loci. GWAS-by-subtraction revealed that only 14.1% of the genetic variance in endometrial cancer is shared with adiposity, with the remainder reflecting adiposity-independent mechanisms captured by established endometrial cancer loci. The adiposity-mediated component converged on insulin-leptin adipocyte signalling and on imprinted and pluripotency-associated developmental pathways, linked by shared nodes such as PTPN11 and PPARG . These findings recast the obesity-endometrial cancer relationship from an epidemiological observation into a mechanistically partitioned genetic programme, and underscores the importance of sex-stratified approaches to resolving how adiposity genetics contributes to disease susceptibility.