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 JM
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
Kote-Jarai, ZSofia
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 LJ
Nordestgaard, Børge G
Key, Tim J
Travis, Ruth C
Neal, David E
Donovan, Jenny L
Hamdy, Freddie C
Pashayan, Nora
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
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
Publication Date
2016-04-07Journal Title
Nature Communications
ISSN
2041-1723
Publisher
Nature Publishing Group
Volume
7
Number
10979
Language
English
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Gusev, A., Shi, H., Kichaev, G., Pomerantz, M., Li, F., Long, H. W., Ingles, S. A., et al. (2016). Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation. Nature Communications, 7 (10979)https://doi.org/10.1038/ncomms10979
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.
Keywords
biological sciences, cancer, genetics
Sponsorship
This work was supported by NIH fellowship F32 GM106584 (AG), NIH grants R01 MH101244(A.G.), R01 CA188392 (B.P.), U01 CA194393(B.P.), R01 GM107427 (M.L.F.), R01 CA193910 (M.L.F./M.P.) and Prostate Cancer Foundation Challenge Award (M.L.F./M.P.). This study makes use of data generated by the Wellcome Trust Case Control Consortium and the Wellcome Trust Sanger Institute. A full list of the investigators who contributed to the generation of the Wellcome Trust Case Control Consortium data is available on www.wtccc.org.uk. Funding for the Wellcome Trust Case Control Consortium project was provided by the Wellcome Trust under award 076113. This study makes use of data generated by the UK10K Consortium. A full list of the investigators who contributed to the generation of the data is available online (http://www.UK10K.org). The PRACTICAL consortium was supported by the following grants: European Commission's Seventh Framework Programme grant agreement n° 223175 (HEALTH-F2-2009-223175), Cancer Research UK Grants C5047/A7357, C1287/A10118, C5047/A3354, C5047/A10692, C16913/A6135 and The National Institute of Health (NIH) Cancer Post-Cancer GWAS initiative Grant: no. 1 U19 CA 148537-01 (the GAME-ON initiative); Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007 and C5047/A10692), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112—the GAME-ON initiative), the Department of Defense (W81XWH-10-1-0341), A Linneus Centre (Contract ID 70867902), Swedish Research Council (grant no K2010-70X-20430-04-3), the Swedish Cancer Foundation (grant no 09-0677), grants RO1CA056678, RO1CA082664 and RO1CA092579 from the US National Cancer Institute, National Institutes of Health; US National Cancer Institute (R01CA72818); support from The National Health and Medical Research Council, Australia (126402, 209057, 251533, 396414, 450104, 504700, 504702, 504715, 623204, 940394 and 614296); NIH grants CA63464, CA54281 and CA098758; US National Cancer Institute (R01CA128813, PI: J.Y. Park); Bulgarian National Science Fund, Ministry of Education and Science (contract DOO-119/2009; DUNK01/2–2009; DFNI-B01/28/2012); Cancer Research UK grants [C8197/A10123] and [C8197/A10865]; grant code G0500966/75466; NIHR Health Technology Assessment Programme (projects 96/20/06 and 96/20/99); Cancer Research UK grant number C522/A8649, Medical Research Council of England grant number G0500966, ID 75466 and The NCRI, UK; The US Dept of Defense award W81XWH-04-1-0280; Australia Project Grant [390130, 1009458] and Enabling Grant [614296 to APCB]; the Prostate Cancer Foundation of Australia (Project Grant [PG7] and Research infrastructure grant [to APCB]); NIH grant R01 CA092447; Vanderbilt-Ingram Cancer Center (P30 CA68485); Cancer Research UK [C490/A10124] and supported by the UK National Institute for Health Research Biomedical Research Centre at the University of Cambridge; Competitive Research Funding of the Tampere University Hospital (9N069 and X51003); Award Number P30CA042014 from the National Cancer Institute.
Funder references
MRC (G0500966)
National Cancer Institute (NCI) (R01CA128978)
National Cancer Institute (NCI) (U19CA148537)
National Cancer Institute (NCI) (U19CA148065)
MEDICAL RESEARCH COUNCIL (MR/N003284/1)
MRC (G0401527)
EC FP7 CP (223175)
Cancer Research UK (CRUK-A10710)
Cancer Research UK (CRUK-A12014)
Cancer Research UK (CRUK-A10118)
Cancer Research UK (A10123)
Cancer Research UK (A8649)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1038/ncomms10979
This record's URL: https://www.repository.cam.ac.uk/handle/1810/256968
Rights
Attribution 4.0 International, Attribution 4.0 International, Attribution 4.0 International
Recommended or similar items
The following licence files are associated with this item: