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

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.