Investigating the shared genetic architecture between adiposity measures and obesity-related cancers

Fat distribution patterns are increasingly linked to obesity-related cancers; however, their shared genetic determinants remain unclear. To identify shared genetic architecture between adiposity measures and obesity-related cancers. Utilizing large-scale summary statistics from genome-wide association study, we conducted genome-wide cross trait analyses of nine adiposity measures [body mass index (BMI), waist-to-hip (WTH) ratio, waist-to-hip ratio adjusted for BMI, arm fat ratio, trunk fat ratio, leg fat ratio, abdominal subcutaneous adipose tissue, gluteofemoral adipose tissue, and visceral adipose tissue] in five obesity-related cancers (colorectal cancer, esophageal adenocarcinoma, breast cancer, endometrial cancer, and ovarian cancer) to characterize their shared genetic architecture, biological pathways, and causal relationships. Cross-trait analyses revealed extensive genomic correlations between adiposity measures and obesity-related cancers. Pleiotropic analysis identified 464 pleiotropic loci and 409 unique candidate pleiotropic genes, 128 of which replicated in the transcriptome-wide association studies analysis. Gene-level analysis revealed potential shared biological mechanisms involving the brain-derived neurotrophic factor signaling pathway, WNT/β-catenin signaling, and adipogenesis, whereas TWAS revealed their predominant expression in the digestive, nervous, and adipose tissues. Mendelian randomization analysis showed stronger associations between genetically increased BMI, WTH, and obesity-related cancers than other body fat distributions. Our study demonstrates that pleiotropic genetic determinants between adiposity and obesity-related cancers are widely distributed across the genome, reinforcing the hypothesis that adiposity increases cancer risk and revealing potential molecular pathways that may contribute to both adiposity and cancer development.