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

Schumacher, Fredrick R., Al Olama, Ali Amin, Berndt, Sonja I., Benlloch, Sara, Ahmed, Mahbubl, Saunders, Edward J., Dadaev, Tokhir, Leongamornlert, Daniel, Anokian, Ezequiel, Cieza-Borrella, Clara et al, Goh, Chee, Brook, Mark N., Sheng, Xin, Fachal, Laura, Dennis, Joe, Tyrer, Jonathan, Muir, Kenneth, Lophatananon, Artitaya, Stevens, Victoria L., Gapstur, Susan M., Carter, Brian D., Tangen, Catherine M., Goodman, Phyllis J., Thompson, Ian M., Batra, Jyotsna, Chambers, Suzanne, Moya, Leire, Clements, Judith, Horvath, Lisa, Tilley, Wayne, Risbridger, Gail P., Gronberg, Henrik, Aly, Markus, Nordström, Tobias, Pharoah, Paul, Pashayan, Nora, Schleutker, Johanna, Tammela, Teuvo L. J., Sipeky, Csilla, Auvinen, Anssi, Albanes, Demetrius, Weinstein, Stephanie, Wolk, Alicja, Håkansson, Niclas, West, Catharine M. L., Dunning, Alison M., Burnet, Neil, Mucci, Lorelei A., Giovannucci, Edward, Andriole, Gerald L., Cussenot, Olivier, Cancel-Tassin, Géraldine, Koutros, Stella, Beane Freeman, Laura E., Sorensen, Karina Dalsgaard, Orntoft, Torben Falck, Borre, Michael, Maehle, Lovise, Grindedal, Eli Marie, Neal, David E., Donovan, Jenny L., Hamdy, Freddie C., Martin, Richard M., Travis, Ruth C., Key, Tim J., Hamilton, Robert J., Fleshner, Neil E., Finelli, Antonio, Ingles, Sue Ann, Stern, Mariana C., Rosenstein, Barry S., Kerns, Sarah L., Ostrer, Harry, Lu, Yong-Jie, Zhang, Hong-Wei, Feng, Ninghan, Mao, Xueying, Guo, Xin, Wang, Guomin, Sun, Zan, Giles, Graham G., Southey, Melissa C., MacInnis, Robert J., FitzGerald, Liesel M., Kibel, Adam S., Drake, Bettina F., Vega, Ana, Gómez-Caamaño, Antonio, Szulkin, Robert, Eklund, Martin, Kogevinas, Manolis, Llorca, Javier, Castaño-Vinyals, Gemma, Penney, Kathryn L., Stampfer, Meir, Park, Jong Y., Sellers, Thomas A., Lin, Hui-Yi, Stanford, Janet L., Cybulski, Cezary, Wokolorczyk, Dominika, Lubinski, Jan, Ostrander, Elaine A., Geybels, Milan S., Nordestgaard, Børge G., Nielsen, Sune F., Weischer, Maren, Bisbjerg, Rasmus, Røder, Martin Andreas, Iversen, Peter, Brenner, Hermann, Cuk, Katarina, Holleczek, Bernd, Maier, Christiane, Luedeke, Manuel, Schnoeller, Thomas, Kim, Jeri, Logothetis, Christopher J., John, Esther M., Teixeira, Manuel R., Paulo, Paula, Cardoso, Marta, Neuhausen, Susan L., Steele, Linda, Ding, Yuan Chun, De Ruyck, Kim, De Meerleer, Gert, Ost, Piet, Razack, Azad, Lim, Jasmine, Teo, Soo-Hwang, Lin, Daniel W., Newcomb, Lisa F., Lessel, Davor, Gamulin, Marija, Kulis, Tomislav, Kaneva, Radka, Usmani, Nawaid, Singhal, Sandeep, Slavov, Chavdar, Mitev, Vanio, Parliament, Matthew, Claessens, Frank, Joniau, Steven, Van den Broeck, Thomas, Larkin, Samantha, Townsend, Paul A., Aukim-Hastie, Claire, Dominguez, Manuela Gago, Castelao, Jose Esteban, Martinez, Maria Elena, Roobol, Monique J., Jenster, Guido, van Schaik, Ron H. N., Menegaux, Florence, Truong, Thérèse, Koudou, Yves Akoli, Xu, Jianfeng, Khaw, Kay-Tee, Cannon-Albright, Lisa, Pandha, Hardev, Michael, Agnieszka, Thibodeau, Stephen N., McDonnell, Shannon K., Schaid, Daniel J., Lindstrom, Sara, Turman, Constance, Ma, Jing, Hunter, David J., Riboli, Elio, Siddiq, Afshan, Canzian, Federico, Kolonel, Laurence N., Le Marchand, Loic, Hoover, Robert N., Machiela, Mitchell J., Cui, Zuxi, Kraft, Peter, Amos, Christopher I., Conti, David V., Easton, Douglas F., Wiklund, Fredrik, Chanock, Stephen J., Henderson, Brian E., Kote-Jarai, Zsofia, Haiman, Christopher A. and Eeles, Rosalind A. (2018) Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci Nature Genetics, 50 (7). pp. 928-936.

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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.

Item Type:	Article
Divisions :	Faculty of Health and Medical Sciences > School of Biosciences and Medicine
Authors :	Name Email ORCID Schumacher, Fredrick R. Al Olama, Ali Amin Berndt, Sonja I. Benlloch, Sara Ahmed, Mahbubl Saunders, Edward J. Dadaev, Tokhir Leongamornlert, Daniel Anokian, Ezequiel Cieza-Borrella, Clara Goh, Chee Brook, Mark N. Sheng, Xin Fachal, Laura Dennis, Joe Tyrer, Jonathan Muir, Kenneth Lophatananon, Artitaya Stevens, Victoria L. Gapstur, Susan M. Carter, Brian D. Tangen, Catherine M. Goodman, Phyllis J. Thompson, Ian M. Batra, Jyotsna Chambers, Suzanne Moya, Leire Clements, Judith Horvath, Lisa Tilley, Wayne Risbridger, Gail P. Gronberg, Henrik Aly, Markus Nordström, Tobias Pharoah, Paul Pashayan, Nora Schleutker, Johanna Tammela, Teuvo L. J. Sipeky, Csilla Auvinen, Anssi Albanes, Demetrius Weinstein, Stephanie Wolk, Alicja Håkansson, Niclas West, Catharine M. L. Dunning, Alison M. Burnet, Neil Mucci, Lorelei A. Giovannucci, Edward Andriole, Gerald L. Cussenot, Olivier Cancel-Tassin, Géraldine Koutros, Stella Beane Freeman, Laura E. Sorensen, Karina Dalsgaard Orntoft, Torben Falck Borre, Michael Maehle, Lovise Grindedal, Eli Marie Neal, David E. Donovan, Jenny L. Hamdy, Freddie C. Martin, Richard M. Travis, Ruth C. Key, Tim J. Hamilton, Robert J. Fleshner, Neil E. Finelli, Antonio Ingles, Sue Ann Stern, Mariana C. Rosenstein, Barry S. Kerns, Sarah L. Ostrer, Harry Lu, Yong-Jie Zhang, Hong-Wei Feng, Ninghan Mao, Xueying Guo, Xin Wang, Guomin Sun, Zan Giles, Graham G. Southey, Melissa C. MacInnis, Robert J. FitzGerald, Liesel M. Kibel, Adam S. Drake, Bettina F. Vega, Ana Gómez-Caamaño, Antonio Szulkin, Robert Eklund, Martin Kogevinas, Manolis Llorca, Javier Castaño-Vinyals, Gemma Penney, Kathryn L. Stampfer, Meir Park, Jong Y. Sellers, Thomas A. Lin, Hui-Yi Stanford, Janet L. Cybulski, Cezary Wokolorczyk, Dominika Lubinski, Jan Ostrander, Elaine A. Geybels, Milan S. Nordestgaard, Børge G. Nielsen, Sune F. Weischer, Maren Bisbjerg, Rasmus Røder, Martin Andreas Iversen, Peter Brenner, Hermann Cuk, Katarina Holleczek, Bernd Maier, Christiane Luedeke, Manuel Schnoeller, Thomas Kim, Jeri Logothetis, Christopher J. John, Esther M. Teixeira, Manuel R. Paulo, Paula Cardoso, Marta Neuhausen, Susan L. Steele, Linda Ding, Yuan Chun De Ruyck, Kim De Meerleer, Gert Ost, Piet Razack, Azad Lim, Jasmine Teo, Soo-Hwang Lin, Daniel W. Newcomb, Lisa F. Lessel, Davor Gamulin, Marija Kulis, Tomislav Kaneva, Radka Usmani, Nawaid Singhal, Sandeep Slavov, Chavdar Mitev, Vanio Parliament, Matthew Claessens, Frank Joniau, Steven Van den Broeck, Thomas Larkin, Samantha Townsend, Paul A. Aukim-Hastie, Claire Dominguez, Manuela Gago Castelao, Jose Esteban Martinez, Maria Elena Roobol, Monique J. Jenster, Guido van Schaik, Ron H. N. Menegaux, Florence Truong, Thérèse Koudou, Yves Akoli Xu, Jianfeng Khaw, Kay-Tee Cannon-Albright, Lisa Pandha, Hardev H.Pandha@surrey.ac.uk Michael, Agnieszka A.Michael@surrey.ac.uk Thibodeau, Stephen N. McDonnell, Shannon K. Schaid, Daniel J. Lindstrom, Sara Turman, Constance Ma, Jing Hunter, David J. Riboli, Elio Siddiq, Afshan Canzian, Federico Kolonel, Laurence N. Le Marchand, Loic Hoover, Robert N. Machiela, Mitchell J. Cui, Zuxi Kraft, Peter Amos, Christopher I. Conti, David V. Easton, Douglas F. Wiklund, Fredrik Chanock, Stephen J. Henderson, Brian E. Kote-Jarai, Zsofia Haiman, Christopher A. Eeles, Rosalind A.
Date :	11 June 2018
DOI :	10.1038/s41588-018-0142-8
Copyright Disclaimer :	© 2018 Nature America Inc., part of Springer Nature. All rights reserved.
Uncontrolled Keywords :	Epidemiology; Genetic association study; Prostate cancer
Depositing User :	Clive Harris
Date Deposited :	09 Jul 2018 08:38
Last Modified :	09 Jul 2018 08:38
URI:	http://epubs.surrey.ac.uk/id/eprint/848669

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