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

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Van Schaik, Florence Menegaux, 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 Lindstrom, Constance Turman, Jing Ma, David J. Hunter, Elio Riboli, Afshan Siddiq, Federico Canzian, Laurence N. Kolonel, Loic 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 Spurdle, Srilakshmi Srinivasan, Mary Anne Kedda, Joanne Aitken, Robert Gardiner, Vanessa Hayes, Lisa Butler, Renea Taylor, Trina Yeadon, Allison Eckert, Pamela Saunders, Anne Maree Haynes, Melissa Papargiris, Paula Kujala, Kirsi Talala, Teemu Murtola, Kimmo Taari, David Dearnaley, Gill Barnett, Søren Bentzen, Rebecca Elliott, Hardeep Ranu, Belynda Hicks, Aurelie Vogt, Amy Hutchinson, Angela Cox, Michael Davis, Paul Brown, Anne George, Gemma Marsden, Athene Lane, Sarah J. Lewis, Clare Berry, Girish S. Kulkarni, Ants Toi, Andrew Evans, Alexandre R. Zlotta, Theodorus H. 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 Milne, Aleksandra Klim, Ana Carballo, Ramón Lobato-Busto, Paula Peleteiro, Patricia Calvo, Miguel Aguado, José Manuel Ruiz-Dominguez, Lluís Cecchini, Lourdes Mengual, Antonio Alcaraz, Mariona Bustamante, Esther Gracia-Lavedan, Trinidad Dierssen-Sotos, Ines Gomez-Acebo, Julio Pow-Sang, Hyun Park, Babu Zachariah, Wojciech Kluzniak, Suzanne Kolb, Peter Klarskov, Christa Stegmaier, Walther Vogel, Kathleen Herkommer, Philipp Bohnert, Sofia Maia, Maria P. Silva, Sofie De Langhe, Hubert Thierens, Meng H. Tan, Aik T. Ong, Zeljko Kastelan, Elenko Popov, Darina Kachakova, Atanaska Mitkova, Aleksandrina Vlahova, Tihomir Dikov, Svetlana Christova, Angel Carracedo, Christopher Bangma, F. H. Schroder, Sylvie Cenee, Brigitte Tretarre, Xavier Rebillard, Claire Mulot, Marie Sanchez, Jan Adolfsson, Par Stattin, Jan Erik Johansson, Carin Cavalli-Bjoerkman, Ami Karlsson, Michael Broms, Huihai Wu, Lori Tillmans, Shaun Riska, Matthew Freedman, Fredrik Wiklund, Stephen Chanock, Brian E. Henderson, Douglas F. Easton, Christopher A. Haiman, Rosalind A. Eeles, David V. Conti, Zsofia Kote-Jarai

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.

Original languageEnglish
Article number2256
JournalNature Communications
Volume9
Issue number1
ISSN2041-1723
DOIs
Publication statusPublished - 2018

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