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
- Physics and Astronomy(all)
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
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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.
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AU - Giovannucci, Edward
AU - Andriole, Gerald
AU - Cussenot, Olivier
AU - Cancel-Tassin, Géraldine
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AU - Freeman, Laura E.Beane
AU - Sorensen, Karina Dalsgaard
AU - Orntoft, Torben Falck
AU - Borre, Michael
AU - Maehle, Lovise
AU - Grindedal, Eli Marie
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AU - Kulis, Tomislav
AU - Kaneva, Radka
AU - Usmani, Nawaid
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AU - Gago-Dominguez, Manuela
AU - Castelao, Jose Esteban
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AU - Van Schaik, Ron H.N.
AU - Menegaux, Florence
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AU - Cannon-Albright, Lisa
AU - Pandha, Hardev
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AU - Kierzek, Andrzej
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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
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AU - Whitmore, Ian
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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
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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 - Funding Information: 15Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, QLD 4059, Australia. 16Translational Research Institute, Brisbane, QLD 4102, Australia. 17Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD 4222, Australia. 18Cancer Council Queensland, Fortitude Valley, QLD 4006, Australia. Funding Information: 19Chris O’Brien Lifehouse (COBLH), Camperdown, Sydney, NSW 2010, Australia. 20Garvan Institute of Medical Research, Sydney, NSW 2010, Australia. 21Dame Roma Mitchell Cancer Research Centre, University of Adelaide, Adelaide, SA 5005, Australia. 22Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia. 23Prostate Cancer Translational Research Program, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. 24Department of Medical Epidemiology and Biostatistics, Karolinska Institute, SE-171 77 Stockholm, Sweden. 25Department of Molecular Medicine and Surgery, Karolinska Institutet, and Department of Urology, Karolinska University Hospital, 171 76 Stockholm, Sweden. 26Department of Clinical Sciences at Danderyd Hospital, Karolinska Institutet, 182 88 Stockholm, Sweden. 27Centre for Cancer Genetic Epidemiology, Department of Oncology, Strangeways Laboratory, University of Cambridge, Cambridge CB1 8RN, UK. 28Department of Applied Health Research, University College London, London WC1E 7HB, UK. 29Institute of Biomedicine, University of Turku, FI-20014 Turku, Finland. 30Tyks Microbiology and Genetics, Department of Medical Genetics, Turku University Hospital, 20521 Turku, Finland. 31Department of Urology, Tampere University Hospital, University of Tampere, Kalevantie 4, FI-33014 Tampere, Finland. 32Department of Epidemiology, School of Health Sciences, University of Tampere, FI-33014 Tampere, Finland. 33Division of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden. 34Division of Cancer Sciences, Manchester Academic Health Science Centre, Radiotherapy Related Research, Manchester NIHR Biomedical Research Centre, The Christie Hospital NHS Foundation Trust, University of Manchester, Manchester M13 9PL, UK. 35University of Cambridge Department of Oncology, Oncology Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB1 8RN, UK. 36Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA. 37Washington University School of Medicine, St. Louis, MO 63110, USA. 38GRC N°5 ONCOTYPE-URO, UPMC Univ Paris 06, Tenon Hospital, F-75020 Paris, France. 39CeRePP, Tenon Hospital, F-75020 Paris, France. 40Department of Molecular Medicine, Aarhus University Hospital, 8200 Aarhus N, Denmark. 41Department of Clinical Medicine, Aarhus University, 8200 Aarhus N, Denmark. 42Department of Urology, Aarhus University Hospital, 8200 Aarhus N, Denmark. 43Department of Medical Genetics, Oslo University Hospital, 0424 Oslo, Norway. 44Department of Oncology, Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 0QQ, UK. 45Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, UK. 46Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX1 2JD, UK. 47School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol BS8 2PS, UK. 48Faculty of Medical Science, John Radcliffe Hospital, University of Oxford, Oxford OX1 2JD, UK. 49Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK. 50National Institute for Health Research (NIHR) Biomedical Research Centre, University of Bristol, Bristol BS8 1TH, UK. 51Cancer Epidemiology, Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK. 52Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, ON M5G 2M9, Canada. 53Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. 54Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029-5674, USA. 55Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY 14620, USA. 56Professor of Pathology and Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461, USA. 57Centre for Molecular Oncology, Barts Cancer Institute, John Vane Science Centre, Queen Mary University of London, London EC1M 6BQ, UK. 58Second Military Medical University, Shanghai 200433, P. R. China. 59Wuxi Second Hospital, Nanjing Medical University, Wuxi, Jiangzhu 214003, China. 60Department of Urology, The First Affiliated Hospital, Chongqing Medical University, Chongqing 200032, China. 61The People’s Hospital of Liaoning Province and The People’s Hospital of China Medical University, Shenyang 110001, China. 62Department of Urology, Zhongshan Hospital, Fudan University Medical College, Shanghai 200032, China. 63Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, VIC 3004, Australia. 64Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3010, Australia. 65Precision Medicine, School and Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia. 66Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7000, Australia. 67Division of Urologic Surgery, Brigham and Womens Hospital, Boston, MA 02115, USA. 68Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica, CIBERER, IDIS, Santiago de Compostela 15706, Spain. 69Department of Radiation Oncology, Complexo Hospitalario Universitario de Santiago, SERGAS, 15706 Santiago de Compostela, Spain. 70Division of Family Medicine, Department of Neurobiology, Care Science and Society, Karolinska Institutet, Huddinge, SE-171 77 Stockholm, Sweden. 71Scandinavian Development Services, 182 33 Danderyd, Sweden. 72Centre for Research in Environmental Epidemiology (CREAL), Barcelona Institute for Global Health (ISGlobal), 08003 Barcelona, Spain. 73CIBER Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain. 74IMIM (Hospital del Mar Research Institute), 08003 Barcelona, Spain. 75Universitat Pompeu Fabra (UPF), 08002 Barcelona, Spain. 76University of Cantabria-IDIVAL, 39005 Santander, Spain. 77Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital/Harvard Medical School, Boston, MA 02184, USA. 78Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL 33612, USA. 79School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA. 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 -