The University of Southampton
University of Southampton Institutional Repository

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

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

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 PrCa1.

1061-4036
928–936
Schumacher, Fredrick R.
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Al Olama, Ali Amin
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Ahmed, Mahbubl
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Saunders, Edward J.
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Dadaev, Tokhir
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Sheng, Xin
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Fachal, Laura
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Dennis, Joe
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Tyrer, Jonathan
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Muir, Kenneth
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Lophatananon, Artitaya
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Stevens, Victoria L.
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Thompson, Ian M.
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Batra, Jyotsna
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Chambers, Suzanne
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Moya, Leire
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Horvath, Lisa
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Tilley, Wayne
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Gronberg, Henrik
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Lu, Yong Jie
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Wang, Guomin
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Giles, Graham G.
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Southey, Melissa C.
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MacInnis, Robert J.
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FitzGerald, Liesel M.
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Gómez-Caamaño, Antonio
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de Ruyck, Kim
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Lophatananon, Artitaya
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Horvath, Lisa
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Tilley, Wayne
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Gronberg, Henrik
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Aly, Markus
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Nordström, Tobias
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Schleutker, Johanna
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Tammela, Teuvo L.J.
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Holleczek, Bernd
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van Den Broeck, Thomas
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Martinez, Maria Elena
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van Schaik, Ron H.N.
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Wiklund, Fredrik
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Chanock, Stephen J.
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Kote-Jarai, Zsofia
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Haiman, Christopher A.
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Eeles, Rosalind A.
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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, 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, 928–936. (doi:10.1038/s41588-018-0142-8).

Record type: Letter

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 PrCa1.

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Accepted/In Press date: 5 April 2018
e-pub ahead of print date: 11 June 2018
Published date: July 2018

Identifiers

Local EPrints ID: 424826
URI: https://eprints.soton.ac.uk/id/eprint/424826
ISSN: 1061-4036
PURE UUID: e9c28141-68f6-420f-878f-6a6d4f8477f1

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Date deposited: 05 Oct 2018 11:48
Last modified: 05 Oct 2018 11:48

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Contributors

Author: Fredrick R. Schumacher
Author: Ali Amin Al Olama
Author: Sonja I. Berndt
Author: Sara Benlloch
Author: Mahbubl Ahmed
Author: Edward J. Saunders
Author: Tokhir Dadaev
Author: Daniel Leongamornlert
Author: Ezequiel Anokian
Author: Clara Cieza-Borrella
Author: Chee Goh
Author: Mark N. Brook
Author: Xin Sheng
Author: Laura Fachal
Author: Joe Dennis
Author: Jonathan Tyrer
Author: Kenneth Muir
Author: Artitaya Lophatananon
Author: Victoria L. Stevens
Author: Susan M. Gapstur
Author: Brian D. Carter
Author: Catherine M. Tangen
Author: Phyllis J. Goodman
Author: Ian M. Thompson
Author: Jyotsna Batra
Author: Suzanne Chambers
Author: Leire Moya
Author: Judith Clements
Author: Lisa Horvath
Author: Wayne Tilley
Author: Gail P. Risbridger
Author: Henrik Gronberg
Author: Markus Aly
Author: Tobias Nordström
Author: Paul Pharoah
Author: Nora Pashayan
Author: Johanna Schleutker
Author: Teuvo L.J. Tammela
Author: Csilla Sipeky
Author: Anssi Auvinen
Author: Demetrius Albanes
Author: Stephanie Weinstein
Author: Alicja Wolk
Author: Niclas Håkansson
Author: Catharine M.L. West
Author: Alison M. Dunning
Author: Neil Burnet
Author: Lorelei A. Mucci
Author: Edward Giovannucci
Author: Gerald L. Andriole
Author: Olivier Cussenot
Author: Géraldine Cancel-Tassin
Author: Stella Koutros
Author: Laura E. Beane Freeman
Author: Karina Dalsgaard Sorensen
Author: Torben Falck Orntoft
Author: Michael Borre
Author: Lovise Maehle
Author: Eli Marie Grindedal
Author: David E. Neal
Author: Jenny L. Donovan
Author: Freddie C. Hamdy
Author: Richard M. Martin
Author: Ruth C. Travis
Author: Tim J. Key
Author: Robert J. Hamilton
Author: Neil E. Fleshner
Author: Antonio Finelli
Author: Sue Ann Ingles
Author: Mariana C. Stern
Author: Barry S. Rosenstein
Author: Sarah L. Kerns
Author: Harry Ostrer
Author: Yong Jie Lu
Author: Hong Wei Zhang
Author: Ninghan Feng
Author: Xueying Mao
Author: Xin Guo
Author: Guomin Wang
Author: Zan Sun
Author: Graham G. Giles
Author: Melissa C. Southey
Author: Robert J. MacInnis
Author: Liesel M. FitzGerald
Author: Adam S. Kibel
Author: Bettina F. Drake
Author: Ana Vega
Author: Antonio Gómez-Caamaño
Author: Robert Szulkin
Author: Martin Eklund
Author: Manolis Kogevinas
Author: Javier Llorca
Author: Gemma Castaño-Vinyals
Author: Kathryn L. Penney
Author: Meir Stampfer
Author: Jong Y. Park
Author: Thomas A. Sellers
Author: Hui Yi Lin
Author: Janet L. Stanford
Author: Cezary Cybulski
Author: Dominika Wokolorczyk
Author: Jan Lubinski
Author: Elaine A. Ostrander
Author: Milan S. Geybels
Author: Børge G. Nordestgaard
Author: Sune F. Nielsen
Author: Maren Weischer
Author: Rasmus Bisbjerg
Author: Martin Andreas Røder
Author: Peter Iversen
Author: Hermann Brenner
Author: Katarina Cuk
Author: Bernd Holleczek
Author: Christiane Maier
Author: Manuel Luedeke
Author: Thomas Schnoeller
Author: Jeri Kim
Author: Christopher J. Logothetis
Author: Esther M. John
Author: Manuel R. Teixeira
Author: Paula Paulo
Author: Marta Cardoso
Author: Susan L. Neuhausen
Author: Linda Steele
Author: Yuan Chun Ding
Author: Kim de Ruyck
Author: Gert de Meerleer
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