Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

Alexander Gusev (), Huwenbo Shi, Gleb Kichaev, Mark Pomerantz, Fugen Li, Henry W. Long, Sue A. Ingles, Rick A. Kittles, Sara S. Strom, Benjamin A. Rybicki, Barbara Nemesure, William B. Isaacs, Wei Zheng, Curtis A. Pettaway, Edward D. Yeboah, Yao Tettey, Richard B. Biritwum, Andrew A. Adjei, Evelyn Tay, Ann Truelove, Shelley Niwa, Anand P. Chokkalingam, Esther M. John, Adam B. Murphy, Lisa B. Signorello, John Carpten, M. Cristina Leske, Suh-Yuh Wu, Anslem J. M. Hennis, Christine Neslund-Dudas, Ann W. Hsing, Lisa Chu, Phyllis J. Goodman, Eric A. Klein, John S. Witte, Graham Casey, Sam Kaggwa, Michael B. Cook, Daniel O. Stram, William J. Blot, Rosalind A. Eeles, Douglas Easton, ZSofia Kote-Jarai, Ali Amin Al Olama, Sara Benlloch, Kenneth Muir, Graham G. Giles, Melissa C. Southey, Liesel M. Fitzgerald, Henrik Gronberg, Fredrik Wiklund, Markus Aly, Brian E. Henderson, Johanna Schleutker, Tiina Wahlfors, Teuvo L. J. Tammela, Børge G. Nordestgaard, Tim J. Key, Ruth C. Travis, David E. Neal, Jenny L. Donovan, Freddie C. Hamdy, Paul Pharoah, Nora Pashayan, Kay-Tee Khaw, Janet L. Stanford, Stephen N. Thibodeau, Shannon K. McDonnell, Daniel J. Schaid, Christiane Maier, Walther Vogel, Manuel Luedeke, Kathleen Herkommer, Adam S. Kibel, Cezary Cybulski, Dominika Wokolorczyk, Wojciech Kluzniak, Lisa Cannon-Albright, Craig Teerlink, Hermann Brenner, Aida K. Dieffenbach, Volker Arndt, Jong Y. Park, Thomas A. Sellers, Hui-Yi Lin, Chavdar Slavov, Radka Kaneva, Vanio Mitev, Jyotsna Batra, Amanda Spurdle, Judith A. Clements, Manuel R. Teixeira, Hardev Pandha, Agnieszka Michael, Paula Paulo, Sofia Maia, Andrzej Kierzek, David V. Conti, Demetrius Albanes, Christine Berg, Sonja I. Berndt, Daniele Campa, E. David Crawford, W. Ryan Diver, Susan M. Gapstur, J. Michael Gaziano, Edward Giovannucci, Robert Hoover, David J. Hunter, Mattias Johansson, Peter Kraft, Loic Le Marchand, Sara Lindström, Carmen Navarro, Kim Overvad, Elio Riboli, Afshan Siddiq, Victoria L. Stevens, Dimitrios Trichopoulos, Paolo Vineis, Meredith Yeager, Gosia Trynka, Soumya Raychaudhuri, Frederick R. Schumacher, Alkes L. Price, Matthew L. Freedman, Christopher A. Haiman and Bogdan Pasaniuc ()
Additional contact information
Alexander Gusev: Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health
Huwenbo Shi: University of California Los Angeles
Gleb Kichaev: University of California Los Angeles
Mark Pomerantz: Dana-Farber Cancer Institute and Harvard Medical School
Fugen Li: Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute
Henry W. Long: Dana-Farber Cancer Institute and Harvard Medical School
Sue A. Ingles: Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center
Rick A. Kittles: University of Arizona College of Medicine and University of Arizona Cancer Center
Sara S. Strom: University of Texas M.D. Anderson Cancer Center
Benjamin A. Rybicki: Henry Ford Hospital
Barbara Nemesure: Stony Brook University
William B. Isaacs: James Buchanan Brady Urological Institute, Johns Hopkins Hospital and Medical Institution
Wei Zheng: Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine
Curtis A. Pettaway: University of Texas M.D. Anderson Cancer Center
Edward D. Yeboah: Korle Bu Teaching Hospital
Yao Tettey: Korle Bu Teaching Hospital
Richard B. Biritwum: Korle Bu Teaching Hospital
Andrew A. Adjei: Korle Bu Teaching Hospital
Evelyn Tay: Korle Bu Teaching Hospital
Ann Truelove: Westat
Shelley Niwa: Westat
Anand P. Chokkalingam: School of Public Health, University of California
Esther M. John: Cancer Prevention Institute of California
Adam B. Murphy: Northwestern University
Lisa B. Signorello: Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health
John Carpten: The Translational Genomics Research Institute
M. Cristina Leske: Stony Brook University
Suh-Yuh Wu: Stony Brook University
Anslem J. M. Hennis: Stony Brook University
Christine Neslund-Dudas: Henry Ford Hospital
Ann W. Hsing: Cancer Prevention Institute of California
Lisa Chu: Cancer Prevention Institute of California
Phyllis J. Goodman: SWOG Statistical Center, Fred Hutchinson Cancer Research Center
Eric A. Klein: Glickman Urological & Kidney Institute, Cleveland Clinic
John S. Witte: University of California, San Francisco
Graham Casey: Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center
Sam Kaggwa: Makerere University College of Health Sciences
Michael B. Cook: National Cancer Institute
Daniel O. Stram: Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center
William J. Blot: Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine
Rosalind A. Eeles: The Institute of Cancer Research
Douglas Easton: Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Laboratory
ZSofia Kote-Jarai: The Institute of Cancer Research
Ali Amin Al Olama: Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Laboratory
Sara Benlloch: Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Laboratory
Kenneth Muir: Institute of Population Health, University of Manchester
Graham G. Giles: Cancer Epidemiology Centre, The Cancer Council Victoria
Melissa C. Southey: Genetic Epidemiology Laboratory, The University of Melbourne
Liesel M. Fitzgerald: Cancer Epidemiology Centre, The Cancer Council Victoria
Henrik Gronberg: Karolinska Institute
Fredrik Wiklund: Karolinska Institute
Markus Aly: Karolinska Institute
Brian E. Henderson: Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center
Johanna Schleutker: University of Turku
Tiina Wahlfors: BioMediTech, University of Tampere and FimLab Laboratories
Teuvo L. J. Tammela: Tampere University Hospital and Medical School, University of Tampere
Børge G. Nordestgaard: Herlev Hospital, Copenhagen University Hospital
Tim J. Key: Cancer Epidemiology
Ruth C. Travis: Cancer Epidemiology
David E. Neal: University of Cambridge, Addenbrooke's Hospital
Jenny L. Donovan: School of Social and Community Medicine, University of Bristol, Canynge Hall
Freddie C. Hamdy: Section for Epidemiology, Aarhus University
Paul Pharoah: Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Laboratory
Nora Pashayan: Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Laboratory
Kay-Tee Khaw: Clinical Gerontology Unit, University of Cambridge
Janet L. Stanford: Fred Hutchinson Cancer Research Center
Stephen N. Thibodeau: Mayo Clinic
Shannon K. McDonnell: Mayo Clinic
Daniel J. Schaid: Mayo Clinic
Christiane Maier: Institute of Human Genetics, University Hospital Ulm
Walther Vogel: Institute of Human Genetics, University Hospital Ulm
Manuel Luedeke: University Hospital Ulm
Kathleen Herkommer: Klinikum rechts der Isar der Technischen Universitaet Muenchen
Adam S. Kibel: Brigham and Womens Hospital, Dana-Farber Cancer Institute
Cezary Cybulski: International Hereditary Cancer Center, Pomeranian Medical University
Dominika Wokolorczyk: International Hereditary Cancer Center, Pomeranian Medical University
Wojciech Kluzniak: International Hereditary Cancer Center, Pomeranian Medical University
Lisa Cannon-Albright: University of Utah School of Medicine
Craig Teerlink: University of Utah School of Medicine
Hermann Brenner: German Cancer Research Center (DKFZ)
Aida K. Dieffenbach: German Cancer Research Center (DKFZ)
Volker Arndt: German Cancer Research Center (DKFZ)
Jong Y. Park: Moffitt Cancer Center
Thomas A. Sellers: Moffitt Cancer Center
Hui-Yi Lin: Biostatistics Program, Moffitt Cancer Center
Chavdar Slavov: Medical University
Radka Kaneva: Molecular Medicine Center, Medical University
Vanio Mitev: Molecular Medicine Center, Medical University
Jyotsna Batra: Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology
Amanda Spurdle: Molecular Cancer Epidemiology Laboratory, Queensland Institute of Medical Research
Judith A. Clements: Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology
Manuel R. Teixeira: Portuguese Oncology Institute
Hardev Pandha: The University of Surrey
Agnieszka Michael: The University of Surrey
Paula Paulo: Portuguese Oncology Institute
Sofia Maia: Portuguese Oncology Institute
Andrzej Kierzek: The University of Surrey
David V. Conti: Norris Cancer Center, University of Southern California Keck School of Medicine
Demetrius Albanes: Nutritional Epidemiology Branch, National Cancer Institute, US National Institute of Health
Christine Berg: Johns Hopkins Medicine
Sonja I. Berndt: National Cancer Institute
Daniele Campa: Genomic Epidemiology Group, German Cancer Research Center (DKFZ)
E. David Crawford: Urologic Oncology, University of Colorado at Denver Health Sciences Center
W. Ryan Diver: Epidemiology Research Program, American Cancer Society
Susan M. Gapstur: Epidemiology Research Program, American Cancer Society
J. Michael Gaziano: Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health
Edward Giovannucci: Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health
Robert Hoover: National Cancer Institute
David J. Hunter: Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health
Mattias Johansson: International Agency for Research on Cancer
Peter Kraft: Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health
Loic Le Marchand: Epidemiology Program, University of Hawaii Cancer Center
Sara Lindström: Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health
Carmen Navarro: Regional Health Authority
Kim Overvad: Johns Hopkins Medicine
Elio Riboli: School of Public Health, Imperial College London
Afshan Siddiq: School of Public Health, Imperial College London
Victoria L. Stevens: Epidemiology Research Program, American Cancer Society
Dimitrios Trichopoulos: Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health
Paolo Vineis: HuGeF Foundation
Meredith Yeager: National Cancer Institute
Gosia Trynka: Brigham and Women's Hospital and Harvard Medical School
Soumya Raychaudhuri: Broad Institute of Harvard and MIT
Frederick R. Schumacher: Norris Cancer Center, University of Southern California Keck School of Medicine
Alkes L. Price: Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health
Matthew L. Freedman: Broad Institute of Harvard and MIT
Christopher A. Haiman: Norris Cancer Center, University of Southern California Keck School of Medicine
Bogdan Pasaniuc: University of California Los Angeles

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.

Date: 2016
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DOI: 10.1038/ncomms10979

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