Ludmila Prokunina-Olsson, Oscar Florez-Vargas, Michael G Levin, Diptavo Dutta, Charles E Breeze, Lauren M Hurwitz, Wusheng Yan, Philippe Lamy, Brenen W Papenberg, Kevin Wang, Chia-Han Lee, Roger L Milne, Jian Gu, Caroline Y Um, Vijai Joseph, Helena Furberg, Florence Le Calvez-Kelm, Adriana Lori, Parichoy Pal Choudhury, Nina Afshar, Manolis Kogevinas, Kenneth Offit, Sita H Vermeulen, Evangelina López de Maturana, Demetrius Albanes, Mark P Purdue, Victoria K Cortessis, Margaret R Karagas, Charles Kooperberg, Marc Bjurlin, Deborah A Tadesse, Steven C Moore, Wen-Yi Huang, Christopher A Haiman, Mariana C Stern, A Heather Eliassen, Lorelei A Mucci, Katja K Aben, Tessel E Galesloot, UROMOL Consortium, Anurag Verma, Soichiro Yoshino, Keiko Hikino, Chikashi Terao, Thorunn Rafnar, Koichi Matsuda, Taro Shuin, Montserrat Garcia-Closas, Francisco X Real, Lambertus A Kiemeney, Stephen J Chanock, Núria Malats, Debra T Silverman, Lars Dyrskjot, Nathaniel Rothman, Scott M Damrauer, Stella Koutros, Jeffrey S Damrauer
Bladder cancer is the ninth most common cancer worldwide, caused by genetic and environmental risk factors. Here, we report the findings of a multi-population meta-analysis of genome-wide association studies, including 32,470 individuals with and 1,753,462 without bladder cancer. We identify 70 independent risk loci, of which 43 are novel. Using a 70-marker polygenic risk score (HR = 1.63 per standard deviation), we increase the area under the curve from 0.71 (baseline risk model) to 0.75. Integrative analyses reveal the enrichment of the associated variants within accessible chromatin regions, and of the prioritized genes within pathways for xenobiotic metabolism and smoking behavior. Specifically, we show that the 15q25.1 variant rs71581744-ACCCC/A co-localizes with tissue-specific CHRNA3 expression, modulates mRNA stability, and associates with risk of muscle-invasive bladder cancer among current smokers. Together, these findings substantially expand the known genetic architecture of bladder cancer risk and highlight the germline regulation of smoking behavior as a mechanism driving bladder cancer susceptibility.