Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

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Author(s)
Dadaev, Tokhir
Saunders, Edward J
Newcombe, Paul J
Anokian, Ezequiel
Leongamornlert, Daniel A
Brook, Mark N
Cieza-Borrella, Clara
Mijuskovic, Martina
Wakerell, Sarah
Al Olama, Ali Amin
Schumacher, Fredrick R
Berndt, Sonja I
Benlloch, Sara
Ahmed, Mahbubl
Goh, Chee
Sheng, Xin
Zhang, Zhuo
Muir, Kenneth
Govindasami, Koveela
Lophatananon, Artitaya
Stevens, Victoria L
Gapstur, Susan M
Carter, Brian D
Tangen, Catherine M
Goodman, Phyllis
Thompson, Ian M
Batra, Jyotsna
Chambers, Suzanne
Moya, Leire
Clements, Judith
Horvath, Lisa
Tilley, Wayne
Risbridger, Gail
Gronberg, Henrik
Aly, Markus
Nordstrom, Tobias
Pharoah, Paul
Pashayan, Nora
Schleutker, Johanna
Tammela, Teuvo LJ
Sipeky, Csilla
Auvinen, Anssi
Albanes, Demetrius
Weinstein, Stephanie
Wolk, Alicja
Hakansson, Niclas
West, Catharine
Dunning, Alison M
Burnet, Neil
Mucci, Lorelei
Giovannucci, Edward
Andriole, Gerald
Cussenot, Olivier
Cancel-Tassin, Geraldine
Koutros, Stella
Freeman, Laura E Beane
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
Kerns, Sarah
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
Gomez-Caamano, Antonio
Fachal, Laura
Szulkin, Robert
Eklund, Martin
Kogevinas, Manolis
Llorca, Javier
Castano-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, Borge G
Nielsen, Sune F
Weisher, Maren
Bisbjerg, Rasmus
Roder, 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
Slavov, Chavdar
Mitev, Vanio
Parliament, Matthew
Singhal, Sandeep
Claessens, Frank
Joniau, Steven
Van den Broeck, Thomas
Larkin, Samantha
Townsend, Paul A
Aukim-Hastie, Claire
Gago-Dominguez, Manuela
Castelao, Jose Esteban
Martinez, Maria Elena
Roobol, Monique J
Jenster, Guido
van Schaik, Ron HN
Menegaux, Florence
Truong, Therese
Koudou, Yves Akoli
Xu, Jianfeng
Khaw, Kay-Tee
Cannon-Albright, Lisa
Pandha, Hardev
Michael, Agnieszka
Kierzek, Andrzej
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
Kraft, Peter
Freedman, Matthew
Wiklund, Fredrik
Chanock, Stephen
Henderson, Brian E
Easton, Douglas F
Haiman, Christopher A
Eeles, Rosalind A
Conti, David V
Kote-Jarai, Zsofia
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2018
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Abstract

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.

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NATURE COMMUNICATIONS

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9

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This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Oncology and carcinogenesis

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