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; Bogdan Pasaniuc

doi:10.1038/ncomms10979

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 TrueloveShelley 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, Bogdan Pasaniuc

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	10979
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms10979
State	Published - 7 Apr 2016
Externally published	Yes

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Gusev, A., Shi, H., Kichaev, G., Pomerantz, M., Li, F., Long, H. W., Ingles, S. A., Kittles, R. A., Strom, S. S., Rybicki, B. A., Nemesure, B., Isaacs, W. B., Zheng, W., Pettaway, C. A., Yeboah, E. D., Tettey, Y., Biritwum, R. B., Adjei, A. A., Tay, E., ... Pasaniuc, B. (2016). Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation. Nature Communications, 7, Article 10979. https://doi.org/10.1038/ncomms10979

@article{779be18e198c443d85037f38d2ea48b7,

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

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.",

author = "Alexander Gusev and Huwenbo Shi and Gleb Kichaev and Mark Pomerantz and Fugen Li and Long, {Henry W.} and Ingles, {Sue A.} and Kittles, {Rick A.} and Strom, {Sara S.} and Rybicki, {Benjamin A.} and Barbara Nemesure and Isaacs, {William B.} and Wei Zheng and Pettaway, {Curtis A.} and Yeboah, {Edward D.} and Yao Tettey and Biritwum, {Richard B.} and Adjei, {Andrew A.} and Evelyn Tay and Ann Truelove and Shelley Niwa and Chokkalingam, {Anand P.} and John, {Esther M.} and Murphy, {Adam B.} and Signorello, {Lisa B.} and John Carpten and Leske, {M. Cristina} and Wu, {Suh Yuh} and Hennis, {Anslem J.M.} and Christine Neslund-Dudas and Hsing, {Ann W.} and Lisa Chu and Goodman, {Phyllis J.} and Klein, {Eric A.} and Witte, {John S.} and Graham Casey and Sam Kaggwa and Cook, {Michael B.} and Stram, {Daniel O.} and Blot, {William J.} and Eeles, {Rosalind A.} and Douglas Easton and Zsofia Kote-Jarai and {Al Olama}, {Ali Amin} and Sara Benlloch and Kenneth Muir and Giles, {Graham G.} and Southey, {Melissa C.} and Fitzgerald, {Liesel M.} and Henrik Gronberg and Fredrik Wiklund and Markus Aly and Henderson, {Brian E.} and Johanna Schleutker and Tiina Wahlfors and Tammela, {Teuvo L.J.} and Nordestgaard, {B{\o}rge G.} and Key, {Tim J.} and Travis, {Ruth C.} and Neal, {David E.} and Donovan, {Jenny L.} and Hamdy, {Freddie C.} and Paul Pharoah and Nora Pashayan and Khaw, {Kay Tee} and Stanford, {Janet L.} and Thibodeau, {Stephen N.} and McDonnell, {Shannon K.} and Schaid, {Daniel J.} and Christiane Maier and Walther Vogel and Manuel Luedeke and Kathleen Herkommer and Kibel, {Adam S.} and Cezary Cybulski and Dominika Wokolorczyk and Wojciech Kluzniak and Lisa Cannon-Albright and Craig Teerlink and Hermann Brenner and Dieffenbach, {Aida K.} and Volker Arndt and Park, {Jong Y.} and Sellers, {Thomas A.} and Lin, {Hui Yi} and Chavdar Slavov and Radka Kaneva and Vanio Mitev and Jyotsna Batra and Amanda Spurdle and Clements, {Judith A.} and Teixeira, {Manuel R.} and Hardev Pandha and Agnieszka Michael and Paula Paulo and Sofia Maia and Andrzej Kierzek and Conti, {David V.} and Demetrius Albanes and Christine Berg and Berndt, {Sonja I.} and Daniele Campa and Crawford, {E. David} and Diver, {W. Ryan} and Gapstur, {Susan M.} and Gaziano, {J. Michael} and Edward Giovannucci and Robert Hoover and Hunter, {David J.} and Mattias Johansson and Peter Kraft and {Le Marchand}, Loic and Sara Lindstr{\"o}m and Carmen Navarro and Kim Overvad and Elio Riboli and Afshan Siddiq and Stevens, {Victoria L.} and Dimitrios Trichopoulos and Paolo Vineis and Meredith Yeager and Gosia Trynka and Soumya Raychaudhuri and Schumacher, {Frederick R.} and Price, {Alkes L.} and Freedman, {Matthew L.} and Haiman, {Christopher A.} and Bogdan Pasaniuc",

note = "Funding Information: 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 theWellcome 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.",

year = "2016",

month = apr,

day = "7",

doi = "10.1038/ncomms10979",

language = "English",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

Gusev, A, Shi, H, Kichaev, G, Pomerantz, M, Li, F, Long, HW, Ingles, SA, Kittles, RA, Strom, SS, Rybicki, BA, Nemesure, B, Isaacs, WB, Zheng, W, Pettaway, CA, Yeboah, ED, Tettey, Y, Biritwum, RB, Adjei, AA, Tay, E, Truelove, A, Niwa, S, Chokkalingam, AP, John, EM, Murphy, AB, Signorello, LB, Carpten, J, Leske, MC, Wu, SY, Hennis, AJM, Neslund-Dudas, C, Hsing, AW, Chu, L, Goodman, PJ, Klein, EA, Witte, JS, Casey, G, Kaggwa, S, Cook, MB, Stram, DO, Blot, WJ, Eeles, RA, Easton, D, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Muir, K, Giles, GG, Southey, MC, Fitzgerald, LM, Gronberg, H, Wiklund, F, Aly, M, Henderson, BE, Schleutker, J, Wahlfors, T, Tammela, TLJ, Nordestgaard, BG, Key, TJ, Travis, RC, Neal, DE, Donovan, JL, Hamdy, FC, Pharoah, P, Pashayan, N, Khaw, KT, Stanford, JL, Thibodeau, SN, McDonnell, SK, Schaid, DJ, Maier, C, Vogel, W, Luedeke, M, Herkommer, K, Kibel, AS, Cybulski, C, Wokolorczyk, D, Kluzniak, W, Cannon-Albright, L, Teerlink, C, Brenner, H, Dieffenbach, AK, Arndt, V, Park, JY, Sellers, TA, Lin, HY, Slavov, C, Kaneva, R, Mitev, V, Batra, J, Spurdle, A, Clements, JA, Teixeira, MR, Pandha, H, Michael, A, Paulo, P, Maia, S, Kierzek, A, Conti, DV, Albanes, D, Berg, C, Berndt, SI, Campa, D, Crawford, ED, Diver, WR, Gapstur, SM, Gaziano, JM, Giovannucci, E, Hoover, R, Hunter, DJ, Johansson, M, Kraft, P, Le Marchand, L, Lindström, S, Navarro, C, Overvad, K, Riboli, E, Siddiq, A, Stevens, VL, Trichopoulos, D, Vineis, P, Yeager, M, Trynka, G, Raychaudhuri, S, Schumacher, FR, Price, AL, Freedman, ML, Haiman, CA & Pasaniuc, B 2016, 'Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation', Nature Communications, vol. 7, 10979. https://doi.org/10.1038/ncomms10979

TY - JOUR

T1 - Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

AU - Gusev, Alexander

AU - Shi, Huwenbo

AU - Kichaev, Gleb

AU - Pomerantz, Mark

AU - Li, Fugen

AU - Long, Henry W.

AU - Ingles, Sue A.

AU - Kittles, Rick A.

AU - Strom, Sara S.

AU - Rybicki, Benjamin A.

AU - Nemesure, Barbara

AU - Isaacs, William B.

AU - Zheng, Wei

AU - Pettaway, Curtis A.

AU - Yeboah, Edward D.

AU - Tettey, Yao

AU - Biritwum, Richard B.

AU - Adjei, Andrew A.

AU - Tay, Evelyn

AU - Truelove, Ann

AU - Niwa, Shelley

AU - Chokkalingam, Anand P.

AU - John, Esther M.

AU - Murphy, Adam B.

AU - Signorello, Lisa B.

AU - Carpten, John

AU - Leske, M. Cristina

AU - Wu, Suh Yuh

AU - Hennis, Anslem J.M.

AU - Neslund-Dudas, Christine

AU - Hsing, Ann W.

AU - Chu, Lisa

AU - Goodman, Phyllis J.

AU - Klein, Eric A.

AU - Witte, John S.

AU - Casey, Graham

AU - Kaggwa, Sam

AU - Cook, Michael B.

AU - Stram, Daniel O.

AU - Blot, William J.

AU - Eeles, Rosalind A.

AU - Easton, Douglas

AU - Kote-Jarai, Zsofia

AU - Al Olama, Ali Amin

AU - Benlloch, Sara

AU - Muir, Kenneth

AU - Giles, Graham G.

AU - Southey, Melissa C.

AU - Fitzgerald, Liesel M.

AU - Gronberg, Henrik

AU - Wiklund, Fredrik

AU - Aly, Markus

AU - Henderson, Brian E.

AU - Schleutker, Johanna

AU - Wahlfors, Tiina

AU - Tammela, Teuvo L.J.

AU - Nordestgaard, Børge G.

AU - Key, Tim J.

AU - Travis, Ruth C.

AU - Neal, David E.

AU - Donovan, Jenny L.

AU - Hamdy, Freddie C.

AU - Pharoah, Paul

AU - Pashayan, Nora

AU - Khaw, Kay Tee

AU - Stanford, Janet L.

AU - Thibodeau, Stephen N.

AU - McDonnell, Shannon K.

AU - Schaid, Daniel J.

AU - Maier, Christiane

AU - Vogel, Walther

AU - Luedeke, Manuel

AU - Herkommer, Kathleen

AU - Kibel, Adam S.

AU - Cybulski, Cezary

AU - Wokolorczyk, Dominika

AU - Kluzniak, Wojciech

AU - Cannon-Albright, Lisa

AU - Teerlink, Craig

AU - Brenner, Hermann

AU - Dieffenbach, Aida K.

AU - Arndt, Volker

AU - Park, Jong Y.

AU - Sellers, Thomas A.

AU - Lin, Hui Yi

AU - Slavov, Chavdar

AU - Kaneva, Radka

AU - Mitev, Vanio

AU - Batra, Jyotsna

AU - Spurdle, Amanda

AU - Clements, Judith A.

AU - Teixeira, Manuel R.

AU - Pandha, Hardev

AU - Michael, Agnieszka

AU - Paulo, Paula

AU - Maia, Sofia

AU - Kierzek, Andrzej

AU - Conti, David V.

AU - Albanes, Demetrius

AU - Berg, Christine

AU - Berndt, Sonja I.

AU - Campa, Daniele

AU - Crawford, E. David

AU - Diver, W. Ryan

AU - Gapstur, Susan M.

AU - Gaziano, J. Michael

AU - Giovannucci, Edward

AU - Hoover, Robert

AU - Hunter, David J.

AU - Johansson, Mattias

AU - Kraft, Peter

AU - Le Marchand, Loic

AU - Lindström, Sara

AU - Navarro, Carmen

AU - Overvad, Kim

AU - Riboli, Elio

AU - Siddiq, Afshan

AU - Stevens, Victoria L.

AU - Trichopoulos, Dimitrios

AU - Vineis, Paolo

AU - Yeager, Meredith

AU - Trynka, Gosia

AU - Raychaudhuri, Soumya

AU - Schumacher, Frederick R.

AU - Price, Alkes L.

AU - Freedman, Matthew L.

AU - Haiman, Christopher A.

AU - Pasaniuc, Bogdan

N1 - Funding Information: 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 theWellcome 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.

PY - 2016/4/7

Y1 - 2016/4/7

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84963635486&partnerID=8YFLogxK

U2 - 10.1038/ncomms10979

DO - 10.1038/ncomms10979

M3 - Article

C2 - 27052111

AN - SCOPUS:84963635486

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 10979

ER -

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

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