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

Tokhir Dadaev, Edward J. Saunders, Paul J. Newcombe, Ezequiel Anokian, Daniel A. Leongamornlert, Mark N. Brook, Clara Cieza-Borrella, Martina Mijuskovic, 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 Goodman, Ian M. Thompson, Jyotsna Batra, Suzanne Chambers, Leire Moya, Judith Clements, Lisa Horvath, Wayne Tilley, Gail Risbridger, Henrik Gronberg, Markus Aly, Tobias Nordström, Paul Pharoah, Nora Pashayan, Johanna Schleutker, Teuvo L. J. Tammela, Csilla Sipeky, Anssi Auvinen, Demetrius Albanes, Stephanie Weinstein, Alicja Wolk, Niclas Hakansson, Catharine West, Alison M. Dunning, Neil Burnet, Lorelei Mucci, Edward Giovannucci, Gerald Andriole, Olivier Cussenot, Géraldine Cancel-Tassin, Stella Koutros, Laura E. Beane Freeman, Karina Dalsgaard Sorensen, Torben Falck Orntoft, Michael Borre, Lovise Maehle, Eli Marie Grindedal, David E. Neal, Jenny L. Donovan, Freddie C. Hamdy, Richard M. Martin, Ruth C. Travis, Tim J. Key, Robert J. Hamilton, Neil E. Fleshner, Antonio Finelli, Sue Ann Ingles, Mariana C. Stern, Barry Rosenstein, Sarah 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 Stampfer, Jong Y. Park, Thomas A. Sellers, Hui-Yi Lin, Janet L. Stanford, Cezary Cybulski, Dominika Wokolorczyk, Jan Lubinski, Elaine A. Ostrander, Milan S. Geybels, Børge G. Nordestgaard, Sune F. Nielsen, Maren Weisher, Rasmus Bisbjerg, Martin Andreas Røder, Peter Iversen, Hermann Brenner, Katarina Cuk, 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 Ruyck, Gert Meerleer, Piet Ost, Azad Razack, Jasmine Lim, Soo-Hwang Teo, Daniel W. Lin, Lisa F. Newcomb, Davor Lessel, Marija Gamulin, Tomislav Kulis, Radka Kaneva, Nawaid Usmani, Chavdar Slavov, Vanio Mitev, Matthew Parliament, Sandeep Singhal, Frank Claessens, Steven Joniau, Thomas Broeck, Samantha Larkin, Paul A. Townsend, Claire Aukim-Hastie, Manuela Gago-Dominguez, Jose Esteban Castelao, Maria Elena Martinez, Monique J. Roobol, Guido Jenster, Ron H. N. 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 Marchand, Robert N. Hoover, Mitchell J. Machiela, Peter Kraft, Matthew Freedman, Fredrik Wiklund, Stephen Chanock, Brian E. Henderson, Douglas F. Easton, Christopher A. Haiman, Rosalind A. Eeles, David V. Conti and Zsofia Kote-Jarai ()
Additional contact information
Tokhir Dadaev: The Institute of Cancer Research
Edward J. Saunders: The Institute of Cancer Research
Paul J. Newcombe: University of Cambridge
Ezequiel Anokian: The Institute of Cancer Research
Daniel A. Leongamornlert: The Institute of Cancer Research
Mark N. Brook: The Institute of Cancer Research
Clara Cieza-Borrella: The Institute of Cancer Research
Martina Mijuskovic: The Institute of Cancer Research
Sarah Wakerell: The Institute of Cancer Research
Ali Amin Al Olama: University of Cambridge
Fredrick R. Schumacher: Case Western Reserve University
Sonja I. Berndt: National Cancer Institute, NIH
Sara Benlloch: The Institute of Cancer Research
Mahbubl Ahmed: The Institute of Cancer Research
Chee Goh: The Institute of Cancer Research
Xin Sheng: University of Southern California/Norris Comprehensive Cancer Center
Zhuo Zhang: University of Southern California/Norris Comprehensive Cancer Center
Kenneth Muir: University of Manchester
Koveela Govindasami: The Institute of Cancer Research
Artitaya Lophatananon: University of Manchester
Victoria L. Stevens: American Cancer Society
Susan M. Gapstur: American Cancer Society
Brian D. Carter: American Cancer Society
Catherine M. Tangen: Fred Hutchinson Cancer Research Center
Phyllis Goodman: Fred Hutchinson Cancer Research Center
Ian M. Thompson: CHRISTUS Santa Rosa Hospital - Medical Center
Jyotsna Batra: Queensland University of Technology
Suzanne Chambers: Griffith University
Leire Moya: Queensland University of Technology
Judith Clements: Queensland University of Technology
Lisa Horvath: Chris O’Brien Lifehouse (COBLH), Camperdown
Wayne Tilley: University of Adelaide
Gail Risbridger: Monash University
Henrik Gronberg: Karolinska Institute
Markus Aly: Karolinska Institute
Tobias Nordström: Karolinska Institute
Paul Pharoah: University of Cambridge
Nora Pashayan: University of Cambridge
Johanna Schleutker: University of Turku
Teuvo L. J. Tammela: University of Tampere
Csilla Sipeky: University of Turku
Anssi Auvinen: University of Tampere
Demetrius Albanes: National Cancer Institute, NIH
Stephanie Weinstein: National Cancer Institute, NIH
Alicja Wolk: Karolinska Institutet
Niclas Hakansson: Karolinska Institutet
Catharine West: University of Manchester
Alison M. Dunning: University of Cambridge
Neil Burnet: Cambridge University Hospitals NHS Foundation Trust
Lorelei Mucci: Harvard School of Public Health
Edward Giovannucci: Harvard School of Public Health
Gerald Andriole: Washington University School of Medicine
Olivier Cussenot: Tenon Hospital
Géraldine Cancel-Tassin: Tenon Hospital
Stella Koutros: National Cancer Institute, NIH
Laura E. Beane Freeman: National Cancer Institute, NIH
Karina Dalsgaard Sorensen: Aarhus University Hospital
Torben Falck Orntoft: Aarhus University Hospital
Michael Borre: Aarhus University
Lovise Maehle: Oslo University Hospital
Eli Marie Grindedal: Oslo University Hospital
David E. Neal: University of Cambridge
Jenny L. Donovan: University of Bristol
Freddie C. Hamdy: University of Oxford
Richard M. Martin: University of Bristol
Ruth C. Travis: University of Oxford
Tim J. Key: University of Oxford
Robert J. Hamilton: Princess Margaret Cancer Centre
Neil E. Fleshner: Princess Margaret Cancer Centre
Antonio Finelli: Princess Margaret Cancer Centre
Sue Ann Ingles: University of Southern California/Norris Comprehensive Cancer Center
Mariana C. Stern: University of Southern California/Norris Comprehensive Cancer Center
Barry Rosenstein: Icahn School of Medicine at Mount Sinai
Sarah Kerns: University of Rochester Medical Center
Harry Ostrer: Albert Einstein College of Medicine
Yong-Jie Lu: Queen Mary University of London
Hong-Wei Zhang: Second Military Medical University
Ninghan Feng: Nanjing Medical University
Xueying Mao: Queen Mary University of London
Xin Guo: Chongqing Medical University
Guomin Wang: Fudan University Medical College
Zan Sun: The People’s Hospital of Liaoning Province and The People’s Hospital of China Medical University
Graham G. Giles: Cancer Council Victoria
Melissa C. Southey: Monash University
Robert J. MacInnis: Cancer Council Victoria
Liesel M. FitzGerald: The University of Melbourne
Adam S. Kibel: Brigham and Womens Hospital
Bettina F. Drake: Washington University School of Medicine
Ana Vega: IDIS
Antonio Gómez-Caamaño: Complexo Hospitalario Universitario de Santiago, SERGAS
Laura Fachal: University of Cambridge
Robert Szulkin: Karolinska Institutet
Martin Eklund: Karolinska Institute
Manolis Kogevinas: Barcelona Institute for Global Health (ISGlobal)
Javier Llorca: CIBER Epidemiología y Salud Pública (CIBERESP)
Gemma Castaño-Vinyals: Barcelona Institute for Global Health (ISGlobal)
Kathryn L. Penney: Brigham and Women’s Hospital/Harvard Medical School
Meir Stampfer: Brigham and Women’s Hospital/Harvard Medical School
Jong Y. Park: Moffitt Cancer Center
Thomas A. Sellers: Moffitt Cancer Center
Hui-Yi Lin: Louisiana State University Health Sciences Center
Janet L. Stanford: Fred Hutchinson Cancer Research Center
Cezary Cybulski: Pomeranian Medical University
Dominika Wokolorczyk: Pomeranian Medical University
Jan Lubinski: Pomeranian Medical University
Elaine A. Ostrander: National Institutes of Health
Milan S. Geybels: Fred Hutchinson Cancer Research Center
Børge G. Nordestgaard: University of Copenhagen
Sune F. Nielsen: University of Copenhagen
Maren Weisher: Copenhagen University Hospital
Rasmus Bisbjerg: Copenhagen University Hospital
Martin Andreas Røder: Copenhagen University Hospital
Peter Iversen: University of Copenhagen
Hermann Brenner: German Cancer Research Center (DKFZ)
Katarina Cuk: German Cancer Research Center (DKFZ)
Bernd Holleczek: Saarland Cancer Registry
Christiane Maier: University Hospital Ulm
Manuel Luedeke: University Hospital Ulm
Thomas Schnoeller: University Hospital Ulm
Jeri Kim: The University of Texas MD Anderson Cancer Center
Christopher J. Logothetis: The University of Texas MD Anderson Cancer Center
Esther M. John: Cancer Prevention Institute of California
Manuel R. Teixeira: Portuguese Oncology Institute of Porto
Paula Paulo: Portuguese Oncology Institute of Porto
Marta Cardoso: Portuguese Oncology Institute of Porto
Susan L. Neuhausen: Beckman Research Institute of the City of Hope
Linda Steele: Beckman Research Institute of the City of Hope
Yuan Chun Ding: Beckman Research Institute of the City of Hope
Kim Ruyck: Basic Medical Sciences
Gert Meerleer: Basic Medical Sciences
Piet Ost: Ghent University Hospital
Azad Razack: University of Malaya
Jasmine Lim: University of Malaya
Soo-Hwang Teo: Subang Jaya Medical Centre
Daniel W. Lin: Fred Hutchinson Cancer Research Center
Lisa F. Newcomb: Fred Hutchinson Cancer Research Center
Davor Lessel: University Medical Center Hamburg-Eppendorf
Marija Gamulin: Department of Oncology at the University Hospital Centre Zagreb
Tomislav Kulis: University of Zagreb School of Medicine
Radka Kaneva: Medical University of Sofia
Nawaid Usmani: University of Alberta
Chavdar Slavov: Medical University of Sofia
Vanio Mitev: Medical University of Sofia
Matthew Parliament: University of Alberta
Sandeep Singhal: University of Alberta
Frank Claessens: KU Leuven
Steven Joniau: University Hospitals Leuven
Thomas Broeck: KU Leuven
Samantha Larkin: The University of Southampton
Paul A. Townsend: University of Manchester
Claire Aukim-Hastie: The University of Surrey
Manuela Gago-Dominguez: SERGAS
Jose Esteban Castelao: Instituto de Investigación Biomédica Galicia Sur (IISGS)
Maria Elena Martinez: University of California San Diego
Monique J. Roobol: Erasmus University Medical Center
Guido Jenster: Erasmus University Medical Center
Ron H. N. Schaik: Erasmus University Medical Center
Florence Menegaux: University Paris-Saclay
Thérèse Truong: University Paris-Saclay
Yves Akoli Koudou: University Paris-Saclay
Jianfeng Xu: NorthShore University HealthSystem
Kay-Tee Khaw: University of Cambridge
Lisa Cannon-Albright: University of Utah School of Medicine
Hardev Pandha: The University of Surrey
Agnieszka Michael: The University of Surrey
Andrzej Kierzek: The University of Surrey
Stephen N. Thibodeau: Mayo Clinic
Shannon K. McDonnell: Mayo Clinic
Daniel J. Schaid: Mayo Clinic
Sara Lindstrom: University of Washington
Constance Turman: Harvard T.H. Chan School of Public Health
Jing Ma: Brigham and Women’s Hospital/Harvard Medical School
David J. Hunter: Harvard T.H. Chan School of Public Health
Elio Riboli: Imperial College
Afshan Siddiq: Queen Mary University of London
Federico Canzian: German Cancer Research Center (DKFZ)
Laurence N. Kolonel: University of Hawaii Cancer Center
Loic Marchand: University of Hawaii Cancer Center
Robert N. Hoover: National Cancer Institute, NIH
Mitchell J. Machiela: National Cancer Institute, NIH
Peter Kraft: Harvard T.H. Chan School of Public Health
Matthew Freedman: Dana-Farber Cancer Institute
Fredrik Wiklund: Karolinska Institute
Stephen Chanock: National Cancer Institute, NIH
Brian E. Henderson: University of Southern California/Norris Comprehensive Cancer Center
Douglas F. Easton: University of Cambridge
Christopher A. Haiman: University of Southern California/Norris Comprehensive Cancer Center
Rosalind A. Eeles: The Institute of Cancer Research
David V. Conti: University of Southern California/Norris Comprehensive Cancer Center
Zsofia Kote-Jarai: The Institute of Cancer Research

Nature Communications, 2018, vol. 9, issue 1, 1-19

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04109-8

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