Abstract
Bladder cancer (BCa) is a common cancer worldwide and is often linked with obesity-related comorbidities, but little is known about the underlying genetic mechanisms. To investigate these mechanisms, we used various quantitative tools, including conditional quantile-quantile (Q-Q) plots, conditional false discovery rate (cFDR), and conjunctional conditional false discovery rate (ccFDR), to explore the pleiotropic enrichment of risk loci between BCa and obesity-related traits. We also performed an expression quantitative trait locus (eQTL) analysis to assess the relationship between shared risk loci and gene expression. Finally, we conducted functional annotation using Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) analysis. Our findings indicated that there was successive enrichment for a range of obesity-related traits, including body fat percentage, body mass index, fasting insulin, type 2 diabetes mellitus, fasting glucose, high-density lipoprotein cholesterol, total triglycerides, and waist-to-hip ratio. Using the tools mentioned above, we identified 18 significant SNPs and 18 closely related genes (cFDR<0.01) under the condition of 8 obesity-related traits. The SNPs included rs143004880, rs73301337, rs10798572, rs11594929, rs17019138, rs2877, rs149795948, rs142509736, rs12727575, rs1571277, rs12131828, rs635634, rs76895963, rs118081211, rs7044247, rs138895564, rs4135275, and rs148023060. Additionally, we identified 15 novel loci using ccFDR, including rs143004880, rs73301337, rs10798572, rs11594929, rs17019138, rs2877, rs142509736, rs1571277, rs635634, rs76895963, rs12131828, rs118081211, rs7044247, rs138895564, and rs4135275. Of the 2 significant loci that modify gene expression, rs12131828 and rs635634 were identified. The functional annotation indicated that the conditional risk genes mainly participated in the regulation of gene silencing. Our study provided evidence of pleiotropic enrichment between BCa and 8 obesity-related traits, and we identified potential genetic mechanisms underlying this relationship. These findings may help in developing targeted clinical treatments for BCa.