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.

127,582 European ancestry females