Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation
Authors: Gusev Alexander , Shi Huwenbo , Kichaev Gleb , Pomerantz Mark , Li Fugen , Long Henry W. , Ingles Sue A. , Kittles Rick A. , Strom Sara S. , Rybicki Benjamin A. , Nemesure Barbara , Isaacs William B. , Zheng Wei , Pettaway Curtis A. , Yeboah Edward D. , Tettey Yao , Biritwum Richard B. , Adjei Andrew A. , Tay Evelyn , Truelove Ann , Niwa Shelley , Chokkalingam Anand P. , John Esther M. , Murphy Adam B. , Signorello Lisa B. , Carpten John , Leske M. Cristina , Wu Suh-Yuh , Hennis Anslem J. M. , Neslund-Dudas Christine , Hsing Ann W. , Chu Lisa , Goodman Phyllis J. , Klein Eric A. , Witte John S. , Casey Graham , Kaggwa Sam , Cook Michael B. , Stram Daniel O. , Blot William J. , Eeles Rosalind A. , Easton Douglas , Kote-Jarai ZSofia , Al Olama Ali Amin , Benlloch Sara , Muir Kenneth , Giles Graham G. , Southey Melissa C. , Fitzgerald Liesel M. , Gronberg Henrik , Wiklund Fredrik , Aly Markus , Henderson Brian E. , Schleutker Johanna , Wahlfors Tiina , Tammela Teuvo L. J. , Nordestgaard Børge G. , Key Tim J. , Travis Ruth C. , Neal David E. , Donovan Jenny L. , Hamdy Freddie C. , Pharoah Paul , Pashayan Nora , Khaw Kay-Tee , Stanford Janet L. , Thibodeau Stephen N. , McDonnell Shannon K. , Schaid Daniel J. , Maier Christiane , Vogel Walther , Luedeke Manuel , Herkommer Kathleen , Kibel Adam S. , Cybulski Cezary , Wokolorczyk Dominika , Kluzniak Wojciech , Cannon-Albright Lisa , Teerlink Craig , Brenner Hermann , Dieffenbach Aida K. , Arndt Volker , Park Jong Y. , Sellers Thomas A. , Lin Hui-Yi , Slavov Chavdar , Kaneva Radka , Mitev Vanio , Batra Jyotsna , Spurdle Amanda , Clements Judith A. , Teixeira Manuel R. , Pandha Hardev , Michael Agnieszka , Paulo Paula , Maia Sofia , Kierzek Andrzej ,   The PRACTICAL consortium, Cook Margaret , Guy Michelle , Govindasami Koveela , Leongamornlert Daniel , Sawyer Emma J. , Wilkinson Rosemary , Saunders Edward J. , Tymrakiewicz Malgorzata , Dadaev Tokhir , Morgan Angela , Fisher Cyril , Hazel Steve , Livni Naomi , Lophatananon Artitaya , Pedersen John , Hopper John L. , Adolfson Jan , Stattin Paer , Johansson Jan-Erik , Cavalli-Bjoerkman Carin , Karlsson Ami , Broms Michael , Auvinen Anssi , Kujala Paula , Maeaettaenen Liisa , Murtola Teemu , Taari Kimmo , Weischer Maren , Nielsen Sune F. , Klarskov Peter , Roder Andreas , Iversen Peter , Wallinder Hans , Gustafsson Sven , Cox Angela , Brown Paul , George Anne , Marsden Gemma , Lane Athene , Davis Michael , Zheng Wei , Signorello Lisa B. , Blot William J. , Tillmans Lori , Riska Shaun , Wang Liang , Rinckleb Antje , Lubiski Jan , Stegmaier Christa , Pow-Sang Julio , Park Hyun , Radlein Selina , Rincon Maria , Haley James , Zachariah Babu , Kachakova Darina , Popov Elenko , Mitkova Atanaska , Vlahova Aleksandrina , Dikov Tihomir , Christova Svetlana , Heathcote Peter , Wood Glenn , Malone Greg , Saunders Pamela , Eckert Allison , Yeadon Trina , Kerr Kris , Collins Angus , Turner Megan , Srinivasan Srilakshmi , Kedda Mary-Anne , Alexander Kimberly , Omara Tracy , Wu Huihai , Henrique Rui , Pinto Pedro , Santos Joana , Barros-Silva Joao , Conti David V. , Albanes Demetrius , Berg Christine , Berndt Sonja I. , Campa Daniele , Crawford E. David , Diver W. Ryan , Gapstur Susan M. , Gaziano J. Michael , Giovannucci Edward , Hoover Robert , Hunter David J. , Johansson Mattias , Kraft Peter , Le Marchand Loic , Lindström Sara , Navarro Carmen , Overvad Kim , Riboli Elio , Siddiq Afshan , Stevens Victoria L. , Trichopoulos Dimitrios , Vineis Paolo , Yeager Meredith , Trynka Gosia , Raychaudhuri Soumya , Schumacher Frederick R. , Price Alkes L. , Freedman Matthew L. , Haiman Christopher A. , Pasaniuc Bogdan 
Published: April 2016

AbstractAlthough 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.