Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci

Fredrick R. Schumacher; Ali Amin Al Olama; Sonja I. Berndt; Sara Benlloch; Mahbubl Ahmed; Edward J. Saunders; Tokhir Dadaev; Daniel Leongamornlert; Ezequiel Anokian; Clara Cieza-Borrella; Chee Goh; Mark N. Brook; Xin Sheng; Laura Fachal; Joe Dennis; Jonathan Tyrer; Kenneth Muir; Artitaya Lophatananon; Victoria L. Stevens; Susan M. Gapstur; Brian D. Carter; Catherine M. Tangen; Phyllis J. Goodman; Ian M. Thompson; Jyotsna Batra; Suzanne Chambers; Leire Moya; Judith Clements; Lisa Horvath; Wayne Tilley; Gail P. Risbridger; Henrik Gronberg; Markus Aly; Tobias Nordström; Paul Pharoah; Nora Pashayan; Johanna Schleutker; Teuvo L.J. Tammela; Csilla Sipeky; Anssi Auvinen; Demetrius Albanes; Stephanie Weinstein; Alicja Wolk; Niclas Håkansson; Catharine M.L. West; Alison M. Dunning; Neil Burnet; Lorelei A. Mucci; Edward Giovannucci; Gerald L. Andriole; Olivier Cussenot; Géraldine Cancel-Tassin; Stella Koutros; Laura E. Beane Freeman; Karina Dalsgaard Sorensen; Torben Falck Orntoft; Michael Borre; Lovise Maehle; Eli Marie Grindedal; David E. Neal; Jenny L. Donovan; Freddie C. Hamdy; Richard M. Martin; Ruth C. Travis; Tim J. Key; Robert J. Hamilton; Neil E. Fleshner; Antonio Finelli; Sue Ann Ingles; Mariana C. Stern; Barry S. Rosenstein; Sarah L. Kerns; Harry Ostrer; Yong Jie Lu; Hong Wei Zhang; Ninghan Feng; Xueying Mao; Xin Guo; Guomin Wang; Zan Sun; Graham G. Giles; Melissa C. Southey; Robert J. MacInnis; Liesel M. Fitzgerald; Adam S. Kibel; Bettina F. Drake; Ana Vega; Antonio Gómez-Caamaño; Robert Szulkin; Martin Eklund; Manolis Kogevinas; Javier Llorca; Gemma Castaño-Vinyals; Kathryn L. Penney; Meir Stampfer; Jong Y. Park; Thomas A. Sellers; Hui Yi Lin; Janet L. Stanford; Cezary Cybulski; Dominika Wokolorczyk; Jan Lubinski; Elaine A. Ostrander; Milan S. Geybels; Børge G. Nordestgaard; Sune F. Nielsen; Maren Weischer; Rasmus Bisbjerg; Martin Andreas Røder; Peter Iversen; Hermann Brenner; Katarina Cuk; Bernd Holleczek; Christiane Maier; Manuel Luedeke; Thomas Schnoeller; Jeri Kim; Christopher J. Logothetis; Esther M. John; Manuel R. Teixeira; Paula Paulo; Marta Cardoso; Susan L. Neuhausen; Linda Steele; Yuan Chun Ding; Kim De Ruyck; Gert De Meerleer; Piet Ost; Azad Razack; Jasmine Lim; Soo Hwang Teo; Daniel W. Lin; Lisa F. Newcomb; Davor Lessel; Marija Gamulin; Tomislav Kulis; Radka Kaneva; Nawaid Usmani; Sandeep Singhal; Chavdar Slavov; Vanio Mitev; Matthew Parliament; Frank Claessens; Steven Joniau; Thomas Van Den Broeck; Samantha Larkin; Paul A. Townsend; Claire Aukim-Hastie; Manuela Gago Dominguez; Jose Esteban Castelao; Maria Elena Martinez; Monique J. Roobol; Guido Jenster; Ron H.N. Van Schaik; Florence Menegaux; Thérèse Truong; Yves Akoli Koudou; Jianfeng Xu; Kay Tee Khaw; Lisa Cannon-Albright; Hardev Pandha; Agnieszka Michael; Stephen N. Thibodeau; Shannon K. McDonnell; Daniel J. Schaid; Sara Lindstrom; Constance Turman; Jing Ma; David J. Hunter; Elio Riboli; Afshan Siddiq; Federico Canzian; Laurence N. Kolonel; Loic Le Marchand; Robert N. Hoover; Mitchell J. Machiela; Zuxi Cui; Peter Kraft; Christopher I. Amos; David V. Conti; Douglas F. Easton; Fredrik Wiklund; Stephen J. Chanock; Brian E. Henderson; Zsofia Kote-Jarai; Christopher A. Haiman; Rosalind A. Eeles

doi:10.1038/s41588-018-0142-8

Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci

Fredrick R. Schumacher, Ali Amin Al Olama, Sonja I. Berndt, Sara Benlloch, Mahbubl Ahmed, Edward J. Saunders, Tokhir Dadaev, Daniel Leongamornlert, Ezequiel Anokian, Clara Cieza-Borrella, Chee Goh, Mark N. Brook, Xin Sheng, Laura Fachal, Joe Dennis, Jonathan Tyrer, Kenneth Muir, Artitaya Lophatananon, Victoria L. Stevens, Susan M. GapsturBrian D. Carter, Catherine M. Tangen, Phyllis J. Goodman, Ian M. Thompson, Jyotsna Batra, Suzanne Chambers, Leire Moya, Judith Clements, Lisa Horvath, Wayne Tilley, Gail P. Risbridger, Henrik Gronberg, Markus Aly, Tobias Nordström, Paul Pharoah, Nora Pashayan, Johanna Schleutker, Teuvo L.J. Tammela, Csilla Sipeky, Anssi Auvinen, Demetrius Albanes, Stephanie Weinstein, Alicja Wolk, Niclas Håkansson, Catharine M.L. West, Alison M. Dunning, Neil Burnet, Lorelei A. Mucci, Edward Giovannucci, Gerald L. Andriole, Olivier Cussenot, Géraldine Cancel-Tassin, Stella Koutros, Laura E. Beane Freeman, Karina Dalsgaard Sorensen, Torben Falck Orntoft, Michael Borre, Lovise Maehle, Eli Marie Grindedal, David E. Neal, Jenny L. Donovan, Freddie C. Hamdy, Richard M. Martin, Ruth C. Travis, Tim J. Key, Robert J. Hamilton, Neil E. Fleshner, Antonio Finelli, Sue Ann Ingles, Mariana C. Stern, Barry S. Rosenstein, Sarah L. Kerns, Harry Ostrer, Yong Jie Lu, Hong Wei Zhang, Ninghan Feng, Xueying Mao, Xin Guo, Guomin Wang, Zan Sun, Graham G. Giles, Melissa C. Southey, Robert J. MacInnis, Liesel M. Fitzgerald, Adam S. Kibel, Bettina F. Drake, Ana Vega, Antonio Gómez-Caamaño, Robert Szulkin, Martin Eklund, Manolis Kogevinas, Javier Llorca, Gemma Castaño-Vinyals, Kathryn L. Penney, Meir Stampfer, Jong Y. Park, Thomas A. Sellers, Hui Yi Lin, Janet L. Stanford, Cezary Cybulski, Dominika Wokolorczyk, Jan Lubinski, Elaine A. Ostrander, Milan S. Geybels, Børge G. Nordestgaard, Sune F. Nielsen, Maren Weischer, Rasmus Bisbjerg, Martin Andreas Røder, Peter Iversen, Hermann Brenner, Katarina Cuk, Bernd Holleczek, Christiane Maier, Manuel Luedeke, Thomas Schnoeller, Jeri Kim, Christopher J. Logothetis, Esther M. John, Manuel R. Teixeira, Paula Paulo, Marta Cardoso, Susan L. Neuhausen, Linda Steele, Yuan Chun Ding, Kim De Ruyck, Gert De Meerleer, Piet Ost, Azad Razack, Jasmine Lim, Soo Hwang Teo, Daniel W. Lin, Lisa F. Newcomb, Davor Lessel, Marija Gamulin, Tomislav Kulis, Radka Kaneva, Nawaid Usmani, Sandeep Singhal, Chavdar Slavov, Vanio Mitev, Matthew Parliament, Frank Claessens, Steven Joniau, Thomas Van Den Broeck, Samantha Larkin, Paul A. Townsend, Claire Aukim-Hastie, Manuela Gago Dominguez, Jose Esteban Castelao, Maria Elena Martinez, Monique J. Roobol, Guido Jenster, Ron H.N. Van Schaik, Florence Menegaux, Thérèse Truong, Yves Akoli Koudou, Jianfeng Xu, Kay Tee Khaw, Lisa Cannon-Albright, Hardev Pandha, Agnieszka Michael, Stephen N. Thibodeau, Shannon K. McDonnell, Daniel J. Schaid, Sara Lindstrom, Constance Turman, Jing Ma, David J. Hunter, Elio Riboli, Afshan Siddiq, Federico Canzian, Laurence N. Kolonel, Loic Le Marchand, Robert N. Hoover, Mitchell J. Machiela, Zuxi Cui, Peter Kraft, Christopher I. Amos, David V. Conti, Douglas F. Easton, Fredrik Wiklund, Stephen J. Chanock, Brian E. Henderson, Zsofia Kote-Jarai, Christopher A. Haiman, Rosalind A. Eeles

Mays Cancer Center

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

410 Scopus citations

Abstract

Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.0 × 10^-8) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10^-9; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10^-9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa ¹ .

Original language	English (US)
Pages (from-to)	928-936
Number of pages	9
Journal	Nature Genetics
Volume	50
Issue number	7
DOIs	https://doi.org/10.1038/s41588-018-0142-8
State	Published - Jul 1 2018

ASJC Scopus subject areas

Genetics

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10.1038/s41588-018-0142-8

Cite this

Schumacher, F. R., Al Olama, A. A., Berndt, S. I., Benlloch, S., Ahmed, M., Saunders, E. J., Dadaev, T., Leongamornlert, D., Anokian, E., Cieza-Borrella, C., Goh, C., Brook, M. N., Sheng, X., Fachal, L., Dennis, J., Tyrer, J., Muir, K., Lophatananon, A., Stevens, V. L., ... Eeles, R. A. (2018). Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci. Nature Genetics, 50(7), 928-936. https://doi.org/10.1038/s41588-018-0142-8

Schumacher, FR, Al Olama, AA, Berndt, SI, Benlloch, S, Ahmed, M, Saunders, EJ, Dadaev, T, Leongamornlert, D, Anokian, E, Cieza-Borrella, C, Goh, C, Brook, MN, Sheng, X, Fachal, L, Dennis, J, Tyrer, J, Muir, K, Lophatananon, A, Stevens, VL, Gapstur, SM, Carter, BD, Tangen, CM, Goodman, PJ, Thompson, IM, Batra, J, Chambers, S, Moya, L, Clements, J, Horvath, L, Tilley, W, Risbridger, GP, Gronberg, H, Aly, M, Nordström, T, Pharoah, P, Pashayan, N, Schleutker, J, Tammela, TLJ, Sipeky, C, Auvinen, A, Albanes, D, Weinstein, S, Wolk, A, Håkansson, N, West, CML, Dunning, AM, Burnet, N, Mucci, LA, Giovannucci, E, Andriole, GL, Cussenot, O, Cancel-Tassin, G, Koutros, S, Beane Freeman, LE, Sorensen, KD, Orntoft, TF, Borre, M, Maehle, L, Grindedal, EM, Neal, DE, Donovan, JL, Hamdy, FC, Martin, RM, Travis, RC, Key, TJ, Hamilton, RJ, Fleshner, NE, Finelli, A, Ingles, SA, Stern, MC, Rosenstein, BS, Kerns, SL, Ostrer, H, Lu, YJ, Zhang, HW, Feng, N, Mao, X, Guo, X, Wang, G, Sun, Z, Giles, GG, Southey, MC, MacInnis, RJ, Fitzgerald, LM, Kibel, AS, Drake, BF, Vega, A, Gómez-Caamaño, A, Szulkin, R, Eklund, M, Kogevinas, M, Llorca, J, Castaño-Vinyals, G, Penney, KL, Stampfer, M, Park, JY, Sellers, TA, Lin, HY, Stanford, JL, Cybulski, C, Wokolorczyk, D, Lubinski, J, Ostrander, EA, Geybels, MS, Nordestgaard, BG, Nielsen, SF, Weischer, M, Bisbjerg, R, Røder, MA, Iversen, P, Brenner, H, Cuk, K, Holleczek, B, Maier, C, Luedeke, M, Schnoeller, T, Kim, J, Logothetis, CJ, John, EM, Teixeira, MR, Paulo, P, Cardoso, M, Neuhausen, SL, Steele, L, Ding, YC, De Ruyck, K, De Meerleer, G, Ost, P, Razack, A, Lim, J, Teo, SH, Lin, DW, Newcomb, LF, Lessel, D, Gamulin, M, Kulis, T, Kaneva, R, Usmani, N, Singhal, S, Slavov, C, Mitev, V, Parliament, M, Claessens, F, Joniau, S, Van Den Broeck, T, Larkin, S, Townsend, PA, Aukim-Hastie, C, Dominguez, MG, Castelao, JE, Martinez, ME, Roobol, MJ, Jenster, G, Van Schaik, RHN, Menegaux, F, Truong, T, Koudou, YA, Xu, J, Khaw, KT, Cannon-Albright, L, Pandha, H, Michael, A, Thibodeau, SN, McDonnell, SK, Schaid, DJ, Lindstrom, S, Turman, C, Ma, J, Hunter, DJ, Riboli, E, Siddiq, A, Canzian, F, Kolonel, LN, Le Marchand, L, Hoover, RN, Machiela, MJ, Cui, Z, Kraft, P, Amos, CI, Conti, DV, Easton, DF, Wiklund, F, Chanock, SJ, Henderson, BE, Kote-Jarai, Z, Haiman, CA & Eeles, RA 2018, 'Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci', Nature Genetics, vol. 50, no. 7, pp. 928-936. https://doi.org/10.1038/s41588-018-0142-8

@article{20cd01dc0494406f94cf20ccc10fee00,

title = "Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci",

abstract = "Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.0 × 10-8) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10-9; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10-9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa 1 .",

author = "Schumacher, {Fredrick R.} and {Al Olama}, {Ali Amin} and Berndt, {Sonja I.} and Sara Benlloch and Mahbubl Ahmed and Saunders, {Edward J.} and Tokhir Dadaev and Daniel Leongamornlert and Ezequiel Anokian and Clara Cieza-Borrella and Chee Goh and Brook, {Mark N.} and Xin Sheng and Laura Fachal and Joe Dennis and Jonathan Tyrer and Kenneth Muir and Artitaya Lophatananon and Stevens, {Victoria L.} and Gapstur, {Susan M.} and Carter, {Brian D.} and Tangen, {Catherine M.} and Goodman, {Phyllis J.} and Thompson, {Ian M.} and Jyotsna Batra and Suzanne Chambers and Leire Moya and Judith Clements and Lisa Horvath and Wayne Tilley and Risbridger, {Gail P.} and Henrik Gronberg and Markus Aly and Tobias Nordstr{\"o}m and Paul Pharoah and Nora Pashayan and Johanna Schleutker and Tammela, {Teuvo L.J.} and Csilla Sipeky and Anssi Auvinen and Demetrius Albanes and Stephanie Weinstein and Alicja Wolk and Niclas H{\aa}kansson and West, {Catharine M.L.} and Dunning, {Alison M.} and Neil Burnet and Mucci, {Lorelei A.} and Edward Giovannucci and Andriole, {Gerald L.} and Olivier Cussenot and G{\'e}raldine Cancel-Tassin and Stella Koutros and {Beane Freeman}, {Laura E.} and Sorensen, {Karina Dalsgaard} and Orntoft, {Torben Falck} and Michael Borre and Lovise Maehle and Grindedal, {Eli Marie} and Neal, {David E.} and Donovan, {Jenny L.} and Hamdy, {Freddie C.} and Martin, {Richard M.} and Travis, {Ruth C.} and Key, {Tim J.} and Hamilton, {Robert J.} and Fleshner, {Neil E.} and Antonio Finelli and Ingles, {Sue Ann} and Stern, {Mariana C.} and Rosenstein, {Barry S.} and Kerns, {Sarah L.} and Harry Ostrer and Lu, {Yong Jie} and Zhang, {Hong Wei} and Ninghan Feng and Xueying Mao and Xin Guo and Guomin Wang and Zan Sun and Giles, {Graham G.} and Southey, {Melissa C.} and MacInnis, {Robert J.} and Fitzgerald, {Liesel M.} and Kibel, {Adam S.} and Drake, {Bettina F.} and Ana Vega and Antonio G{\'o}mez-Caama{\~n}o and Robert Szulkin and Martin Eklund and Manolis Kogevinas and Javier Llorca and Gemma Casta{\~n}o-Vinyals and Penney, {Kathryn L.} and Meir Stampfer and Park, {Jong Y.} and Sellers, {Thomas A.} and Lin, {Hui Yi} and Stanford, {Janet L.} and Cezary Cybulski and Dominika Wokolorczyk and Jan Lubinski and Ostrander, {Elaine A.} and Geybels, {Milan S.} and Nordestgaard, {B{\o}rge G.} and Nielsen, {Sune F.} and Maren Weischer and Rasmus Bisbjerg and R{\o}der, {Martin Andreas} and Peter Iversen and Hermann Brenner and Katarina Cuk and Bernd Holleczek and Christiane Maier and Manuel Luedeke and Thomas Schnoeller and Jeri Kim and Logothetis, {Christopher J.} and John, {Esther M.} and Teixeira, {Manuel R.} and Paula Paulo and Marta Cardoso and Neuhausen, {Susan L.} and Linda Steele and Ding, {Yuan Chun} and {De Ruyck}, Kim and {De Meerleer}, Gert and Piet Ost and Azad Razack and Jasmine Lim and Teo, {Soo Hwang} and Lin, {Daniel W.} and Newcomb, {Lisa F.} and Davor Lessel and Marija Gamulin and Tomislav Kulis and Radka Kaneva and Nawaid Usmani and Sandeep Singhal and Chavdar Slavov and Vanio Mitev and Matthew Parliament and Frank Claessens and Steven Joniau and {Van Den Broeck}, Thomas and Samantha Larkin and Townsend, {Paul A.} and Claire Aukim-Hastie and Dominguez, {Manuela Gago} and Castelao, {Jose Esteban} and Martinez, {Maria Elena} and Roobol, {Monique J.} and Guido Jenster and {Van Schaik}, {Ron H.N.} and Florence Menegaux and Th{\'e}r{\`e}se Truong and Koudou, {Yves Akoli} and Jianfeng Xu and Khaw, {Kay Tee} and Lisa Cannon-Albright and Hardev Pandha and Agnieszka Michael and Thibodeau, {Stephen N.} and McDonnell, {Shannon K.} and Schaid, {Daniel J.} and Sara Lindstrom and Constance Turman and Jing Ma and Hunter, {David J.} and Elio Riboli and Afshan Siddiq and Federico Canzian and Kolonel, {Laurence N.} and {Le Marchand}, Loic and Hoover, {Robert N.} and Machiela, {Mitchell J.} and Zuxi Cui and Peter Kraft and Amos, {Christopher I.} and Conti, {David V.} and Easton, {Douglas F.} and Fredrik Wiklund and Chanock, {Stephen J.} and Henderson, {Brian E.} and Zsofia Kote-Jarai and Haiman, {Christopher A.} and Eeles, {Rosalind A.}",

note = "Funding Information: We pay tribute to Brian Henderson for his vision and leadership; he was a driving force behind the OncoArray project and he unfortunately passed away before seeing its fruition. We also thank the individuals who participated in these studies enabling this work. Genotyping of the OncoArray was funded by the US National Institutes of Health (NIH) (U19 CA 148537 for the ELLIPSE project and X01HG007492 to the Center for Inherited Disease Research (CIDR) under contract no. HHSN268201200008I. Additional analytical support was provided by NIH NCI U01 CA188392 (to F.R.S.). Funding for the iCOGS infrastructure came from the European Community's Seventh Framework Programme under grant agreement no. 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, and C8197/A16565), the NIH (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), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. This work was supported by the Canadian Institutes of Health Research; the European Commission's Seventh Framework Programme grant agreement no. 223175 (HEALTH-F2-2009-223175); Cancer Research UK grants C5047/A7357, C1287/A10118, C1287/A16563, C5047/A3354, C5047/A10692, and C16913/A6135; and NIH Cancer Post-Cancer GWAS initiative grant no. 1 U19 CA 148537-01 (the GAME-ON initiative). Funding Information: We also thank the following for funding support: the Institute of Cancer Research and the Everyman Campaign, the Prostate Cancer Research Foundation, Prostate Research Campaign UK (now Prostate Action), the Orchid Cancer Appeal, the National Cancer Research Network UK, and the National Cancer Research Institute (NCRI) UK. We are grateful for the support of NIHR funding to the NIHR Biomedical Research Centre at the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust. Funding Information: PEGASUS was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH. A full description of funding and acknowledgements can be found in the Supplementary Note. Funding Information: The Prostate Cancer Program of Cancer Council Victoria also acknowledges grant support from the National Health and Medical Research Council, Australia (126402, 209057, 251533, 396414, 450104, 504700, 504702, 504715, 623204, 940394, and 614296), VicHealth, Cancer Council Victoria, the Prostate Cancer Foundation of Australia, the Whitten Foundation, PricewaterhouseCoopers, and Tattersall{\textquoteright}s. E.A.O., D.M.K., and E.M.K. acknowledge the Intramural Program of the National Human Genome Research Institute for support. The BPC3 was supported by the NIH, National Cancer Institute (cooperative agreements U01-CA98233 to D.J.H., U01-CA98710 to S.M.G., U01-CA98216 to E.R., and U01-CA98758 to B.E.H., and the Intramural Research Program of the NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics). The CAPS GWAS study was supported by the Swedish Cancer Foundation (grant nos. 09-0677, 11-484, and 12-823), the Cancer Risk Prediction Center (CRisP; http:// ki.se/en/meb/crisp/), a Linneus Centre grant (contract ID 70867902) financed by the Swedish Research Council, and the Swedish Research Council (grant nos. K2010-70X-20430-04-3, and 2014-2269). Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = jul,

day = "1",

doi = "10.1038/s41588-018-0142-8",

language = "English (US)",

volume = "50",

pages = "928--936",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "7",

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TY - JOUR

T1 - Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci

AU - Schumacher, Fredrick R.

AU - Al Olama, Ali Amin

AU - Berndt, Sonja I.

AU - Benlloch, Sara

AU - Ahmed, Mahbubl

AU - Saunders, Edward J.

AU - Dadaev, Tokhir

AU - Leongamornlert, Daniel

AU - Anokian, Ezequiel

AU - Cieza-Borrella, Clara

AU - Goh, Chee

AU - Brook, Mark N.

AU - Sheng, Xin

AU - Fachal, Laura

AU - Dennis, Joe

AU - Tyrer, Jonathan

AU - Muir, Kenneth

AU - Lophatananon, Artitaya

AU - Stevens, Victoria L.

AU - Gapstur, Susan M.

AU - Carter, Brian D.

AU - Tangen, Catherine M.

AU - Goodman, Phyllis J.

AU - Thompson, Ian M.

AU - Batra, Jyotsna

AU - Chambers, Suzanne

AU - Moya, Leire

AU - Clements, Judith

AU - Horvath, Lisa

AU - Tilley, Wayne

AU - Risbridger, Gail P.

AU - Gronberg, Henrik

AU - Aly, Markus

AU - Nordström, Tobias

AU - Pharoah, Paul

AU - Pashayan, Nora

AU - Schleutker, Johanna

AU - Tammela, Teuvo L.J.

AU - Sipeky, Csilla

AU - Auvinen, Anssi

AU - Albanes, Demetrius

AU - Weinstein, Stephanie

AU - Wolk, Alicja

AU - Håkansson, Niclas

AU - West, Catharine M.L.

AU - Dunning, Alison M.

AU - Burnet, Neil

AU - Mucci, Lorelei A.

AU - Giovannucci, Edward

AU - Andriole, Gerald L.

AU - Cussenot, Olivier

AU - Cancel-Tassin, Géraldine

AU - Koutros, Stella

AU - Beane Freeman, Laura E.

AU - Sorensen, Karina Dalsgaard

AU - Orntoft, Torben Falck

AU - Borre, Michael

AU - Maehle, Lovise

AU - Grindedal, Eli Marie

AU - Neal, David E.

AU - Donovan, Jenny L.

AU - Hamdy, Freddie C.

AU - Martin, Richard M.

AU - Travis, Ruth C.

AU - Key, Tim J.

AU - Hamilton, Robert J.

AU - Fleshner, Neil E.

AU - Finelli, Antonio

AU - Ingles, Sue Ann

AU - Stern, Mariana C.

AU - Rosenstein, Barry S.

AU - Kerns, Sarah L.

AU - Ostrer, Harry

AU - Lu, Yong Jie

AU - Zhang, Hong Wei

AU - Feng, Ninghan

AU - Mao, Xueying

AU - Guo, Xin

AU - Wang, Guomin

AU - Sun, Zan

AU - Giles, Graham G.

AU - Southey, Melissa C.

AU - MacInnis, Robert J.

AU - Fitzgerald, Liesel M.

AU - Kibel, Adam S.

AU - Drake, Bettina F.

AU - Vega, Ana

AU - Gómez-Caamaño, Antonio

AU - Szulkin, Robert

AU - Eklund, Martin

AU - Kogevinas, Manolis

AU - Llorca, Javier

AU - Castaño-Vinyals, Gemma

AU - Penney, Kathryn L.

AU - Stampfer, Meir

AU - Park, Jong Y.

AU - Sellers, Thomas A.

AU - Lin, Hui Yi

AU - Stanford, Janet L.

AU - Cybulski, Cezary

AU - Wokolorczyk, Dominika

AU - Lubinski, Jan

AU - Ostrander, Elaine A.

AU - Geybels, Milan S.

AU - Nordestgaard, Børge G.

AU - Nielsen, Sune F.

AU - Weischer, Maren

AU - Bisbjerg, Rasmus

AU - Røder, Martin Andreas

AU - Iversen, Peter

AU - Brenner, Hermann

AU - Cuk, Katarina

AU - Holleczek, Bernd

AU - Maier, Christiane

AU - Luedeke, Manuel

AU - Schnoeller, Thomas

AU - Kim, Jeri

AU - Logothetis, Christopher J.

AU - John, Esther M.

AU - Teixeira, Manuel R.

AU - Paulo, Paula

AU - Cardoso, Marta

AU - Neuhausen, Susan L.

AU - Steele, Linda

AU - Ding, Yuan Chun

AU - De Ruyck, Kim

AU - De Meerleer, Gert

AU - Ost, Piet

AU - Razack, Azad

AU - Lim, Jasmine

AU - Teo, Soo Hwang

AU - Lin, Daniel W.

AU - Newcomb, Lisa F.

AU - Lessel, Davor

AU - Gamulin, Marija

AU - Kulis, Tomislav

AU - Kaneva, Radka

AU - Usmani, Nawaid

AU - Singhal, Sandeep

AU - Slavov, Chavdar

AU - Mitev, Vanio

AU - Parliament, Matthew

AU - Claessens, Frank

AU - Joniau, Steven

AU - Van Den Broeck, Thomas

AU - Larkin, Samantha

AU - Townsend, Paul A.

AU - Aukim-Hastie, Claire

AU - Dominguez, Manuela Gago

AU - Castelao, Jose Esteban

AU - Martinez, Maria Elena

AU - Roobol, Monique J.

AU - Jenster, Guido

AU - Van Schaik, Ron H.N.

AU - Menegaux, Florence

AU - Truong, Thérèse

AU - Koudou, Yves Akoli

AU - Xu, Jianfeng

AU - Khaw, Kay Tee

AU - Cannon-Albright, Lisa

AU - Pandha, Hardev

AU - Michael, Agnieszka

AU - Thibodeau, Stephen N.

AU - McDonnell, Shannon K.

AU - Schaid, Daniel J.

AU - Lindstrom, Sara

AU - Turman, Constance

AU - Ma, Jing

AU - Hunter, David J.

AU - Riboli, Elio

AU - Siddiq, Afshan

AU - Canzian, Federico

AU - Kolonel, Laurence N.

AU - Le Marchand, Loic

AU - Hoover, Robert N.

AU - Machiela, Mitchell J.

AU - Cui, Zuxi

AU - Kraft, Peter

AU - Amos, Christopher I.

AU - Conti, David V.

AU - Easton, Douglas F.

AU - Wiklund, Fredrik

AU - Chanock, Stephen J.

AU - Henderson, Brian E.

AU - Kote-Jarai, Zsofia

AU - Haiman, Christopher A.

AU - Eeles, Rosalind A.

N1 - Funding Information: We pay tribute to Brian Henderson for his vision and leadership; he was a driving force behind the OncoArray project and he unfortunately passed away before seeing its fruition. We also thank the individuals who participated in these studies enabling this work. Genotyping of the OncoArray was funded by the US National Institutes of Health (NIH) (U19 CA 148537 for the ELLIPSE project and X01HG007492 to the Center for Inherited Disease Research (CIDR) under contract no. HHSN268201200008I. Additional analytical support was provided by NIH NCI U01 CA188392 (to F.R.S.). Funding for the iCOGS infrastructure came from the European Community's Seventh Framework Programme under grant agreement no. 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, and C8197/A16565), the NIH (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), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. This work was supported by the Canadian Institutes of Health Research; the European Commission's Seventh Framework Programme grant agreement no. 223175 (HEALTH-F2-2009-223175); Cancer Research UK grants C5047/A7357, C1287/A10118, C1287/A16563, C5047/A3354, C5047/A10692, and C16913/A6135; and NIH Cancer Post-Cancer GWAS initiative grant no. 1 U19 CA 148537-01 (the GAME-ON initiative). Funding Information: We also thank the following for funding support: the Institute of Cancer Research and the Everyman Campaign, the Prostate Cancer Research Foundation, Prostate Research Campaign UK (now Prostate Action), the Orchid Cancer Appeal, the National Cancer Research Network UK, and the National Cancer Research Institute (NCRI) UK. We are grateful for the support of NIHR funding to the NIHR Biomedical Research Centre at the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust. Funding Information: PEGASUS was supported by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH. A full description of funding and acknowledgements can be found in the Supplementary Note. Funding Information: The Prostate Cancer Program of Cancer Council Victoria also acknowledges grant support from the National Health and Medical Research Council, Australia (126402, 209057, 251533, 396414, 450104, 504700, 504702, 504715, 623204, 940394, and 614296), VicHealth, Cancer Council Victoria, the Prostate Cancer Foundation of Australia, the Whitten Foundation, PricewaterhouseCoopers, and Tattersall’s. E.A.O., D.M.K., and E.M.K. acknowledge the Intramural Program of the National Human Genome Research Institute for support. The BPC3 was supported by the NIH, National Cancer Institute (cooperative agreements U01-CA98233 to D.J.H., U01-CA98710 to S.M.G., U01-CA98216 to E.R., and U01-CA98758 to B.E.H., and the Intramural Research Program of the NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics). The CAPS GWAS study was supported by the Swedish Cancer Foundation (grant nos. 09-0677, 11-484, and 12-823), the Cancer Risk Prediction Center (CRisP; http:// ki.se/en/meb/crisp/), a Linneus Centre grant (contract ID 70867902) financed by the Swedish Research Council, and the Swedish Research Council (grant nos. K2010-70X-20430-04-3, and 2014-2269). Publisher Copyright: © 2018 The Author(s).

PY - 2018/7/1

Y1 - 2018/7/1

N2 - Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.0 × 10-8) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10-9; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10-9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa 1 .

AB - Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.0 × 10-8) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10-9; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10-9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa 1 .

UR - http://www.scopus.com/inward/record.url?scp=85048333838&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85048333838&partnerID=8YFLogxK

U2 - 10.1038/s41588-018-0142-8

DO - 10.1038/s41588-018-0142-8

M3 - Article

C2 - 29892016

AN - SCOPUS:85048333838

SN - 1061-4036

VL - 50

SP - 928

EP - 936

JO - Nature Genetics

JF - Nature Genetics

IS - 7

ER -

Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci

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