Parekh, Sneha, Calaway, Adam, Davis, Laura, Ponsky, Lee, Abbosh, Philip, Bigalli, Alberto Castro, Uzzo, Robert, Sindhani, Mohit, Kutikov, Alexander, Correa, Andres, and Bukavina, Laura
Bladder cancer, the most prevalent urological malignancy worldwide, accounts for a staggering 600,000 new cases annually. Its etiology is complex and multifactorial, influenced by various risk factors. Recent advances in genomic research, particularly genome-wide association studies (GWAS), have led to the discovery of new single nucleotide polymorphisms (SNPs) and associations in diverse cohorts. GWASs have proven to be a powerful tool for identifying links between genetic variants and SNPs. Additionally, phenome-wide association studies (PheWAS) have explored associations between specific genetic variants and a wide range of phenotypes, enabling the identification of genetic variants associated not only with bladder cancer but also with other diseases and traits that may share genetic risk factors. Our study, conducted using data from the UK Biobank's prospective cohort, aims to combine the findings from GWAS and PheWAS to identify both epidemiological and genetic risk factors associated with bladder cancer. 375,981 healthy individuals and 5,090 bladder cancer patients analyzed. Genotype calling, quality control, and imputation processes;previously described. Generic risk variants, like;single nucleotide polymorphisms (SNPs), selected based on conventional genome-wide significance thresholds (p<5×10-6) and specific criteria (MAF >0.01 and r 2 <0.001 for LD). Functional GWAS analysis using FUMA;performed to annotate GWAS results, prioritize genes,assess chromatic interaction mapping and tissue enrichment.To explore association between bladder cancer and other phenotypes, PheWas (phenome-wide association studies) associations conducted using GLM function in R. Covariates like sex, smoking, age, alcohol consumption, air pollution exposure, daily traffic intensity, dietary habits, and workplace exposure were included in all associations. Logistic regression models with log-transformed odds ratios;used for binary dependent variables. Statistical inferences relied on two-sided tests at significance level of 0.05, unless specified differently. The analysis done;using SAS software v.9.4 (SAS Institute, Cary, NC) and R v.3.6.0 software. Our study identified;SNPs;associated with increased bladdercancer risk, including variants in;PSCA;TMEM129;TERT;LYNX1-SLURP2;LSP1, and;HIPK1;(Fig1A). Protective associations for bladder cancer with SNPs within;UGTA1, THEM6, RAPGEF5, LY6K, LY6D, LNCOC1, JRK, and CLPTML;(Figure1A,B). Gene prioritization using FUMA and tissue mapping with chromatin interaction analysis revealed 9 lead SNPs across 8 genomic risk loci, with exonic SNPs exhibiting highest Combined Annotation Dependent Depletion;(CADD) scores indicating deleteriousness (Figure1C,D). Additionally, gene set enrichment analysis of common SNPs uncovered significant associations with biological processes like;Flavonoid & Xenobiotic Glucuronidation and Glucuronosyltransferase, closely linked to bladdercancer (Fig1E). PheWAS analysis revealed four phenotypes linked to bladder cancer risk, including prostate cancer (rs2242652), seborrheic keratosis and skin conditions (rs2242652), and BPH (rs31489) (Figure1F). Regression analysis for modifiable risk factors;demonstrated significant associations with bladder cancer susceptibility for BMI, heavy smoking, and male sex. Conversely, alcohol intake 3-4 drinks/week is protective. The study sheds light on various relevant SNPs and novel associations among germline mutations in bladder cancer, which have not been previously reported. Through further functional analysis, we discovered germline variants associated with glucuronosyltransferase activity, providing supporting evidence of toxin metabolism and its impact on bladder cancer risk. Additionally, our PheWAS analysis revealed co-associations with prostate cancer, prostatic hyperplasia, and dermatologic conditions linked to specific SNPs.Furthermore, our study reaffirmed well-known risk factors associated with bladder cancer, including sex and smoking, while also highlighting the protective effect of moderate alcohol consumption in the context of carcinogenesis.These findings have the potential to offer valuable insights into common pathways underlying bladder cancer, inform screening recommendations, and identify potential therapeutic targets for the disease. [ABSTRACT FROM AUTHOR]