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

Authors: Tokhir Dadaev, Edward J. Saunders, Paul J. Newcombe, Ezequiel Anokian, Daniel Leongamornlert, Mark N. Brook, Clara Cieza-Borrella, Martina Mijušković, Sarah Wakerell, Ali Amin Al Olama, Fredrick R. Schumacher, Sonja I. Berndt, Sara Benlloch, Mahbubl Ahmed, Chee Goh, Xin Sheng, Zhuo Zhang, Kenneth Muir, Koveela Govindasami, Artitaya Lophatananon, Victoria L. Stevens, Susan M. Gapstur, Brian D. Carter, Catherine M. Tangen, Phyllis J. Goodman, Ian M. Thompson, Jyotsna Batra, Suzanne K. Chambers, Leire Moya, Judith A. Clements, Lisa G. Horvath, Wayne D. Tilley, Gail P. Risbridger, Henrik Grönberg, Markus Aly, Tobias Nordström, Paul D.P. Pharoah, Nora Pashayan, Johanna Schleutker, Teuvo L.J. Tammela, Csilla Sipeky, Anssi Auvinen, Demetrius Albanes, Stephanie J. Weinstein, Alicja Wolk, Niclas Håkansson, Catharine West, Alison M. Dunning, N.G. Burnet, Lorelei A. Mucci, Edward Giovannucci, Gerald L. Andriole, Olivier Cussenot, Géraldine Cancel‐Tassin, Stella Koutros, Laura E. Beane Freeman, Karina D. Sørensen, Torben F. Ørntoft, Michael Borre, Lovise Mæhle, Eli Marie Grindedal, David E. Neal, Jenny Donovan, Freddie C. Hamdy, Richard M. Martin, Ruth C. Travis, Timothy J. Key, Robert J. Hamilton, Neil E. Fleshner, Antonio Finelli, Sue A. Ingles, Mariana C. Stern, Barry S. Rosenstein, Sarah L. Kerns, Harry Ostrer, Yong‐Jie Lu, Hong-Wei Zhang, Ninghan Feng, Xueying Mao, Xin Guo, Guomin Wang, Zan Sun, Graham G. Giles, Melissa C. Southey, Robert J. MacInnis, Liesel M. FitzGerald, Adam S. Kibel, Bettina F. Drake, Ana Vega, Antonio Gómez‐Caamaño, Laura Fachal, Robert Szulkin, Martin Eklund, Manolis Kogevinas, Javier Llorca, Gemma Castaño‐Vinyals, Kathryn L. Penney, Meir J. Stampfer, Jong Y. Park, Thomas A. Sellers, Hui‐Yi Lin, Janet L. Stanford, Cezary Cybulski, Dominika Wokołorczyk, Jan Lubiński, Elaine A. Ostrander, Milan S. Geybels, Børge G. Nordestgaard, Sune F. Nielsen, Maren Weisher, Rasmus Bisbjerg, Martin Andreas Røder, Peter Iversen, Hermann Brenner, Katarina Ćuk, Bernd Holleczek, Christiane Maier, Manuel Luedeke, Thomas Schnoeller, Jeri Kim, Christopher J. Logothetis, Esther M. John, Manuel R. Teixeira, Paula Paulo, Marta Cardoso, Susan L. Neuhausen, Linda Steele, Yuan Chun Ding, Kim De Ruyck, Gert De Meerleer, Piet Ost, Azad Hassan Abdul Razack, Jasmine Lim, Soo‐Hwang Teo, Daniel W. Lin, Lisa F. Newcomb, Davor Lessel, Marija Gamulin, Tomislav Kuliš, Radka Kaneva, Nawaid Usmani, Chavdar Slavov, Vanio Mitev, Matthew Parliament, Sandeep K. Singhal, Frank Claessens, Steven Joniau, Thomas Van den Broeck, Samantha Larkin, Paul A. Townsend, Claire Aukim-Hastie, Manuela Gago-Domínguez, Jose E. Castelao, Marı́a Elena Martı́nez, Monique J. Roobol, Guido Jenster, Ron H. N. van Schaik, F. Ménégaux, Thérèse Truong, Yves Akoli Koudou, Jianfeng Xu, Kay‐Tee Khaw, Lisa Cannon‐Albright, Hardev Pandha, Agnieszka Michael, Andrzej Kierzek, Stephen N. Thibodeau, Shannon K. McDonnell, Daniel J. Schaid, Sara Lindström, Constance Turman, Jing Ma, David J. Hunter, Elio Ríboli, Afshan Siddiq, Federico Canzian, Laurence N. Kolonel, Loı̈c Le Marchand, Robert N. Hoover, Mitchell J. Machiela, Peter Kraft, Margaret Cook, Alison Thwaites, Michelle Guy, Ian Whitmore, Angela Morgan, Cyril Fisher, Steve Hazel, Naomi Livni, Amanda B. Spurdle, Srilakshmi Srinivasan, Mary-Anne Kedda, Joanne F. Aitken, Robert A. Gardiner, Vanessa M. Hayes, Lisa M. Butler, Renea A. Taylor, Trina Yeadon, Allison Eckert, Pâmela Saunders, Anne-Maree Haynes, Melissa Papargiris, Paula Kujala, Kirsi Talala, Teemu Murtola, Kimmo Taari, David P. Dearnaley, Gill Barnett, Søren M. Bentzen, Rebecca Elliott, Hardeep Ranu, Belynda Hicks, Aurélie Vogt, Amy Hutchinson, Angela Cox, Michael Davis, Paul Brown, Anne George, Gemma Marsden, J. Athene Lane, Sarah J. Lewis, Clare Berry, Girish S. Kulkarni, Ants Toi, Andrew Evans, Alexandre R. Zlotta, Theodorus van der Kwast, Takashi Imai, Shiro Saito, Jacek Marzec, Guangwen Cao, Ji Lin, Jin Ling, Meiling Li, Shan‐Chao Zhao, Guoping Ren, Yongwei Yu, Yudong Wu, Ji Wu, Bo Zhou, Yangling Zhang, Jie Li, Weiyang He, Jianming Guo, John Pedersen, John L. Hopper, Roger L. Milne, Aleksandra Klim, Ana M. Carballo, Ramón Lobato-Busto, Paula Peleteiro, Patricia Calvo, Miguel Aguado, José Manuel Ruiz-Dominguez, Lluís Cecchini, Lourdes Mengual, Antonio Alcaraz, Mariona Bustamante, Esther Gràcia‐Lavedan, Trinidad Dierssen-Sotos, Inés Gómez‐Acebo, Julio M. Pow‐Sang, Hyun Park, Babu Zachariah, Wojciech Kluźniak, Suzanne Kolb, Peter Klarskov, Christa Stegmaier, Walther Vogel, Kathleen Herkommer, Philipp Bohnert, Sofia Maia, María P. Silva, Sofie De Langhe, Hubert Thierens, Meng H. Tan, Aik T. Ong, Željko Kaštelan, Elenko Popov, Darina Kachakova, A. Mitkova, Aleksandrina Vlahova, Tihomir Dikov, S. Christova, Ángel Carracedo, C. Bangma, Fritz H. Schröder, Sylvie Cénée, Brigitte Trétarre, Xavier Rébillard, Claire Mulot, Marie Sanchez, Jan Adolfsson, Pär Stattin, Jan-Erik Johansson, Carin Cavalli-Bjoerkman, Ami Karlsson, Michael Broms, Huihai Wu, Lori S. Tillmans, Shaun M. Riska, Matthew L. Freedman, Fredrik Wiklund, Stephen J. Chanock, Brian E. Henderson, Douglas F. Easton, Christopher A. Haiman, Rosalind A. Eeles, David V. Conti, Zsofia Kote‐Jarai - Nature Communications 2018 cited by 113

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.