Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Dadaev, Tokhir and Saunders, Edward J. and Newcombe, Paul J. and Anokian, Ezequiel and Leongamornlert, Daniel A. and Brook, Mark N. and Cieza-Borrella, Clara and Mijuskovic, Martina and Wakerell, Sarah and Olama, Ali Amin Al and Schumacher, Fredrick R. and Berndt, Sonja I. and Benlloch, Sara and Ahmed, Mahbubl and Goh, Chee and Sheng, Xin and Zhang, Zhuo and Muir, Kenneth and Govindasami, Koveela and Lophatananon, Artitaya and Stevens, Victoria L. and Gapstur, Susan M. and Carter, Brian D. and Tangen, Catherine M. and Goodman, Phyllis and Thompson, Ian M. and Batra, Jyotsna and Chambers, Suzanne and Moya, Leire and Clements, Judith and Horvath, Lisa and Tilley, Wayne and Risbridger, Gail and Gronberg, Henrik and Aly, Markus and Nordström, Tobias and Pharoah, Paul and Pashayan, Nora and Schleutker, Johanna and Tammela, Teuvo L. J. and Sipeky, Csilla and Auvinen, Anssi and Albanes, Demetrius and Weinstein, Stephanie and Wolk, Alicja and Hakansson, Niclas and West, Catharine and Dunning, Alison M. and Burnet, Neil and Mucci, Lorelei and Giovannucci, Edward and Andriole, Gerald and Cussenot, Olivier and Cancel-Tassin, Géraldine and Koutros, Stella and Freeman, Laura E. Beane and Sorensen, Karina Dalsgaard and Orntoft, Torben Falck and Borre, Michael and Maehle, Lovise and Grindedal, Eli Marie and Neal, David E. and Donovan, Jenny L. and Hamdy, Freddie C. and Martin, Richard M. and Travis, Ruth C. and Key, Tim J. and Hamilton, Robert J. and Fleshner, Neil E. and Finelli, Antonio and Ingles, Sue Ann and Stern, Mariana C. and Rosenstein, Barry and Kerns, Sarah and Ostrer, Harry and Lu, Yong-Jie and Zhang, Hong-Wei and Feng, Ninghan and Mao, Xueying and Guo, Xin and Wang, Guomin and Sun, Zan and Giles, Graham G. and Southey, Melissa C. and MacInnis, Robert J. and FitzGerald, Liesel M. and Kibel, Adam S. and Drake, Bettina F. and Vega, Ana and Gómez-Caamaño, Antonio and Fachal, Laura and Szulkin, Robert and Eklund, Martin and Kogevinas, Manolis and Llorca, Javier and Castaño-Vinyals, Gemma and Penney, Kathryn L. and Stampfer, Meir and Park, Jong Y. and Sellers, Thomas A. and Lin, Hui-Yi and Stanford, Janet L. and Cybulski, Cezary and Wokolorczyk, Dominika and Lubinski, Jan and Ostrander, Elaine A. and Geybels, Milan S. and Nordestgaard, Børge G. and Nielsen, Sune F. and Weisher, Maren and Bisbjerg, Rasmus and Røder, Martin Andreas and Iversen, Peter and Brenner, Hermann and Cuk, Katarina and Holleczek, Bernd and Maier, Christiane and Luedeke, Manuel and Schnoeller, Thomas and Kim, Jeri and Logothetis, Christopher J. and John, Esther M. and Teixeira, Manuel R. and Paulo, Paula and Cardoso, Marta and Neuhausen, Susan L. and Steele, Linda and Ding, Yuan Chun and De Ruyck, Kim and De Meerleer, Gert and Ost, Piet and Razack, Azad and Lim, Jasmine and Teo, Soo-Hwang and Lin, Daniel W. and Newcomb, Lisa F. and Lessel, Davor and Gamulin, Marija and Kuliš, Tomislav and Kaneva, Radka and Usmani, Nawaid and Slavov, Chavdar and Mitev, Vanio and Parliament, Matthew and Singhal, Sandeep and Claessens, Frank and Joniau, Steven and Van den Broeck, Thomas and Larkin, Samantha and Townsend, Paul A. and Aukim-Hastie, Claire and Gago-Dominguez, Manuela and Castelao, Jose Esteban and Martinez, Maria Elena and Roobol, Monique J. and Jenster, Guido and van Schaik, Ron H. N. and Menegaux, Florence and Truong, Thérèse and Koudou, Yves Akoli and Xu, Jianfeng and Khaw, Kay-Tee and Cannon-Albright, Lisa and Pandha, Hardev and Michael, Agnieszka and Kierzek, Andrzej and Thibodeau, Stephen N. and McDonnell, Shannon K. and Schaid, Daniel J. and Lindstrom, Sara and Turman, Constance and Ma, Jing and Hunter, David J. and Riboli, Elio and Siddiq, Afshan and Canzian, Federico and Kolonel, Laurence N. and Le Marchand, Loic and Hoover, Robert N. and Machiela, Mitchell J. and Kraft, Peter and Freedman, Matthew and Wiklund, Fredrik and Chanock, Stephen and Henderson, Brian E. and Easton, Douglas F. and Haiman, Christopher A. and Eeles, Rosalind A. and Conti, David V. and Kote-Jarai, Zsofia (2018) Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants. Nature Communications, 9 (1). p. 2256. ISSN 2041-1723

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Abstract

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.

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