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.
| Original language | English (US) |
|---|---|
| Article number | 2256 |
| Journal | Nature communications |
| Volume | 9 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 1 2018 |
ASJC Scopus subject areas
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology
- General Physics and Astronomy
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In: Nature communications, Vol. 9, No. 1, 2256, 01.12.2018.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants
AU - Dadaev, Tokhir
AU - Saunders, Edward J.
AU - Newcombe, Paul J.
AU - Anokian, Ezequiel
AU - Leongamornlert, Daniel A.
AU - Brook, Mark N.
AU - Cieza-Borrella, Clara
AU - Mijuskovic, Martina
AU - Wakerell, Sarah
AU - Olama, Ali Amin Al
AU - Schumacher, Fredrick R.
AU - Berndt, Sonja I.
AU - Benlloch, Sara
AU - Ahmed, Mahbubl
AU - Goh, Chee
AU - Sheng, Xin
AU - Zhang, Zhuo
AU - Muir, Kenneth
AU - Govindasami, Koveela
AU - Lophatananon, Artitaya
AU - Stevens, Victoria L.
AU - Gapstur, Susan M.
AU - Carter, Brian D.
AU - Tangen, Catherine M.
AU - Goodman, Phyllis
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
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 - Hakansson, Niclas
AU - West, Catharine
AU - Dunning, Alison M.
AU - Burnet, Neil
AU - Mucci, Lorelei
AU - Giovannucci, Edward
AU - Andriole, Gerald
AU - Cussenot, Olivier
AU - Cancel-Tassin, Géraldine
AU - Koutros, Stella
AU - Freeman, Laura E.Beane
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
AU - Kerns, Sarah
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 - Fachal, Laura
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 - Weisher, 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 - Slavov, Chavdar
AU - Mitev, Vanio
AU - Parliament, Matthew
AU - Singhal, Sandeep
AU - Claessens, Frank
AU - Joniau, Steven
AU - Van Den Broeck, Thomas
AU - Larkin, Samantha
AU - Townsend, Paul A.
AU - Aukim-Hastie, Claire
AU - Gago-Dominguez, Manuela
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 - Kierzek, Andrzej
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 - Kraft, Peter
AU - Cook, Margaret
AU - Thwaites, Alison
AU - Guy, Michelle
AU - Whitmore, Ian
AU - Morgan, Angela
AU - Fisher, Cyril
AU - Hazel, Steve
AU - Livni, Naomi
AU - Spurdle, Amanda
AU - Srinivasan, Srilakshmi
AU - Kedda, Mary Anne
AU - Aitken, Joanne
AU - Gardiner, Robert
AU - Hayes, Vanessa
AU - Butler, Lisa
AU - Taylor, Renea
AU - Yeadon, Trina
AU - Eckert, Allison
AU - Saunders, Pamela
AU - Haynes, Anne Maree
AU - Papargiris, Melissa
AU - Kujala, Paula
AU - Talala, Kirsi
AU - Murtola, Teemu
AU - Taari, Kimmo
AU - Dearnaley, David
AU - Barnett, Gill
AU - Bentzen, Søren
AU - Elliott, Rebecca
AU - Ranu, Hardeep
AU - Hicks, Belynda
AU - Vogt, Aurelie
AU - Hutchinson, Amy
AU - Cox, Angela
AU - Davis, Michael
AU - Brown, Paul
AU - George, Anne
AU - Marsden, Gemma
AU - Lane, Athene
AU - Lewis, Sarah J.
AU - Berry, Clare
AU - Kulkarni, Girish S.
AU - Toi, Ants
AU - Evans, Andrew
AU - Zlotta, Alexandre R.
AU - Van Der Kwast, Theodorus H.
AU - Imai, Takashi
AU - Saito, Shiro
AU - Marzec, Jacek
AU - Cao, Guangwen
AU - Lin, Ji
AU - Ling, Jin
AU - Li, Meiling
AU - Zhao, Shan Chao
AU - Ren, Guoping
AU - Yu, Yongwei
AU - Wu, Yudong
AU - Wu, Ji
AU - Zhou, Bo
AU - Zhang, Yangling
AU - Li, Jie
AU - He, Weiyang
AU - Guo, Jianming
AU - Pedersen, John
AU - Hopper, John L.
AU - Milne, Roger
AU - Klim, Aleksandra
AU - Carballo, Ana
AU - Lobato-Busto, Ramón
AU - Peleteiro, Paula
AU - Calvo, Patricia
AU - Aguado, Miguel
AU - Ruiz-Dominguez, José Manuel
AU - Cecchini, Lluís
AU - Mengual, Lourdes
AU - Alcaraz, Antonio
AU - Bustamante, Mariona
AU - Gracia-Lavedan, Esther
AU - Dierssen-Sotos, Trinidad
AU - Gomez-Acebo, Ines
AU - Pow-Sang, Julio
AU - Park, Hyun
AU - Zachariah, Babu
AU - Kluzniak, Wojciech
AU - Kolb, Suzanne
AU - Klarskov, Peter
AU - Stegmaier, Christa
AU - Vogel, Walther
AU - Herkommer, Kathleen
AU - Bohnert, Philipp
AU - Maia, Sofia
AU - Silva, Maria P.
AU - De Langhe, Sofie
AU - Thierens, Hubert
AU - Tan, Meng H.
AU - Ong, Aik T.
AU - Kastelan, Zeljko
AU - Popov, Elenko
AU - Kachakova, Darina
AU - Mitkova, Atanaska
AU - Vlahova, Aleksandrina
AU - Dikov, Tihomir
AU - Christova, Svetlana
AU - Carracedo, Angel
AU - Bangma, Christopher
AU - Schroder, F. H.
AU - Cenee, Sylvie
AU - Tretarre, Brigitte
AU - Rebillard, Xavier
AU - Mulot, Claire
AU - Sanchez, Marie
AU - Adolfsson, Jan
AU - Stattin, Par
AU - Johansson, Jan Erik
AU - Cavalli-Bjoerkman, Carin
AU - Karlsson, Ami
AU - Broms, Michael
AU - Wu, Huihai
AU - Tillmans, Lori
AU - Riska, Shaun
AU - Freedman, Matthew
AU - Wiklund, Fredrik
AU - Chanock, Stephen
AU - Henderson, Brian E.
AU - Easton, Douglas F.
AU - Haiman, Christopher A.
AU - Eeles, Rosalind A.
AU - Conti, David V.
AU - Kote-Jarai, Zsofia
N1 - Publisher Copyright: © 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85048420948&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85048420948&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-04109-8
DO - 10.1038/s41467-018-04109-8
M3 - Article
C2 - 29892050
AN - SCOPUS:85048420948
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2256
ER -