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

A. Gusev,Huwenbo Shi,Gleb Kichaev,M. Pomerantz,Fugen Li,Henry W. Long,S. Ingles,R. Kittles,S. Strom,B. Rybicki,B. Nemesure,W. Isaacs,Wei Zheng,C. Pettaway,E. Yeboah,Y. Tettey,R. Biritwum,A. Adjei,E. Tay,A. Truelove,S. Niwa,A. Chokkalingam,E. John,Adam B. Murphy,L. Signorello,J. Carpten,M. Leske,Suh-yuh Wu,A. Hennis,C. Neslund-Dudas,A. Hsing,L. Chu,P. Goodman,E. Klein,J. Witte,G. Casey,S. Kaggwa,Michael B. Cook,D. Stram,William J Blot,R. Eeles,D. Easton,Z. Kote-Jarai,A. A. Al Olama,S. Benlloch,K. Muir,G. Giles,M. Southey,L. FitzGerald,H. Gronberg,F. Wiklund,M. Aly,B. Henderson,J. Schleutker,Tiina Wahlfors,T. Tammela,B. Nordestgaard,T. Key,R. Travis,D. Neal,J. Donovan,F. Hamdy,P. Pharoah,N. Pashayan,K. Khaw,J. Stanford,S. Thibodeau,S. McDonnell,D. Schaid,C. Maier,W. Vogel,Manuel Luedeke,K. Herkommer,A. Kibel,C. Cybulski,D. Wokołorczyk,W. Kluźniak,L. Cannon-Albright,C. Teerlink,H. Brenner,A. K. Dieffenbach,V. Arndt,Jong Y. Park,T. Sellers,Hui-Yi Lin,C. Slavov,R. Kaneva,V. Mitev,J. Batra,A. Spurdle,J. Clements,M. Teixeira,H. Pandha,A. Michael,P. Paulo,S. Maia,A. Kierzek,Margaret R. Cook,M. Guy,K. Govindasami,D. Leongamornlert,E. Sawyer,R. Wilkinson,E. Saunders,M. Tymrakiewicz,Tokhir Dadaev,A. Morgan,C. Fisher,Steve Hazel,N. Livni,A. Lophatananon,J. Pedersen,J. Hopper,J. Adolfson,P. Stattin,J. Johansson,Carin Cavalli-Bjoerkman,Ami Karlsson,Michael Broms,Anssi Auvinen,P. Kujala,Liisa Maeaettaenen,T. Murtola,K. Taari,Maren Weischer,S. F. Nielsen,P. Klarskov,A. Røder,P. Iversen,H. Wallinder,Sven-Åke Gustafsson,A. Cox,Paul Brown,A. George,G. Marsden,A. Lane,Michael Davis,Wei Zheng,L. Signorello,William J Blot,Lori S Tillmans,S. Riska,Liang Wang,A. Rinckleb,Jan Lubiski,C. Stegmaier,J. Pow‐Sang,Hyun Y Park,S. Radlein,Maria Rincon,James Haley,B. Zachariah,D. Kachakova,E. Popov,A. Mitkova,Aleksandrina Vlahova,T. Dikov,S. Christova,P. Heathcote,G. Wood,G. Malone,P. Saunders,A. Eckert,T. Yeadon,K. Kerr,A. Collins,M. Turner,Srilakshmi Srinivasan,M. Kedda,Kimberly E Alexander,Tracy Omara,Huihai Wu,R. Henrique,P. Pinto,Joana C Santos,J. Barros-Silva,D. Conti,D. Albanes,C. Berg,S. Berndt,D. Campa,E. Crawford,W. Diver,S. Gapstur,J. Gaziano,E. Giovannucci,R. Hoover,D. Hunter,M. Johansson,P. Kraft,L. Le Marchand,S. Lindström,C. Navarro,K. Overvad,E. Riboli,A. Siddiq,V. Stevens,D. Trichopoulos,P. Vineis,M. Yeager,G. Trynka,S. Raychaudhuri,F. Schumacher,A. Price,M. Freedman,C. Haiman,B. Pasaniuc

Published 2016 in Nature Communications

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. Over one hundred loci have been identified to be associated with the familial risk of prostate cancer but the functional effects are poorly understood. Here the authors use single-nucleotide variant and epigentic data to show an underlying genetic architecture marked by histone modification.

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