Excess weight accounts for up to 60% of endometrial cancer (EC) cases, yet the genetic mechanisms linking excess adiposity to carcinogenesis remain poorly understood. GWAS of BMI obscure genetic variation in fat distribution - a sexually dimorphic and metabolically distinct aspect of adiposity.
To address this, we applied Genomic Structural Equation Modelling (GenomicSEM) to construct sex-specific latent adiposity factors from six traits across ~2 million Europeans: BMI, waist-hip ratio, body fat percentage and visceral, abdominal subcutaneous and gluteofemoral adipose tissue levels. The latent-factor GWAS identified 262 female- and 230 male-specific loci, with 27 and 18, respectively, undetected in single-trait analyses. Although overall architecture was largely shared between sexes (rg = 0.96) with comparable SNP-based heritability, 11% of lead variants displayed significant sex-dimorphic effects, revealing subtle biological divergence.
Leveraging the female-specific adiposity factor and the largest EC GWAS (17,278 cases; 289,180 controls), we identified 26 adiposity–EC pleiotropic loci, 16 novel to EC. GWAS-by-subtraction decomposed EC risk into two orthogonal genetic components: an adiposity-mediated pathway accounting for 14.6 % of genetic risk and an adiposity-independent pathway explaining 85.4 %. Critically, this decomposition reveals that obesity's strong epidemiological association with EC predominantly reflects environmental influences rather than shared genetic risk.
Mediation modelling identified 45 variants exerting indirect effects via adiposity, highlighting insulin–leptin signalling with enrichment for GLP-1 pathway genes (PCSK1, LEP, CTNNB1). In contrast, 133 variants acted directly on EC through hormonal and transcriptional regulators (HNF1B, CYP19A1, KLF5). Several loci exhibited dual or opposing effects, exposing complex pleiotropy linking metabolic dysfunction to tumour biology. Fine-mapping prioritised high-confidence candidate causal variants, with functional integration underway.
Collectively, these findings delineate a core hormonal pathway underpinning endometrial carcinogenesis and show that excess adiposity adds biological and environmental complexity, pinpointing insulin–leptin and GLP-1 signalling as tractable targets for functional validation.