Abstract
PURPOSE: This study aims to identify specific genotypes within the UK Biobank (UKB) cohort contributing to a genetic predisposition for bladder cancer (UBC). It highlighted the impact of environmental exposures and the broader role of certain genes in UBC development, offering a comprehensive understanding of the genetic basis for UBC susceptibility. EXPERIMENTAL DESIGN: Leveraging the rich data from the UKB- a longitudinal study involving participants across the UK-the primary outcome was the presence of UBC, determined using ICD-10 and ICD-9 codes. The study employed rigorous Genome-Wide Association Study (GWAS) protocols, Phenome-Wide Association (PheWAS) frameworks, and gene-level pleiotropy analyses. Quality control measures were applied, such as single-nucleotide polymorphisms (SNP) missingness and minor allele frequency thresholds. Polygenic Risk Score (PRS) evaluations were also conducted based on the Mavaddat score using UKB's high-density genome-wide SNP dataset. RESULTS: Our GWAS identified significant associations between UBC risk and genetic variants, notably in the PSCA and TERT genes. The UGT1A polymorphism was found to be protective against UBC, particularly in heavy smokers. The PheWAS framework linked UBC-predisposition polymorphisms to other conditions, such as prostate cancer. CONCLUSIONS: Our GWAS identified significant associations between UBC risk and genetic variants across loci, including PSCA, TERT, TACC3 and TMEM129. The protective effect of the UGT1A variant against UBC, especially concerning tobacco exposure, suggests the potential for genetic-based preventive strategies in UBC management.Patient summary In our study of a large group from the United Kingdom (UK), we explored genetic factors that might increase the likelihood of developing UBC. We discovered that certain genetic changes offer protection against UBC, particularly in individuals exposed to tobacco smoke. Understanding these genetic factors could improve strategies for preventing and treating UBC.