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Nat Commun. 2018 Jun 11;9(1):2256. doi: 10.1038/s41467-018-04109-8.

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

Dadaev T1, Saunders EJ1, Newcombe PJ2, Anokian E1, Leongamornlert DA1,3, Brook MN1, Cieza-Borrella C1, Mijuskovic M1, Wakerell S1, Olama AAA4,5, Schumacher FR6,7, Berndt SI8, Benlloch S1,4, Ahmed M1, Goh C1, Sheng X9, Zhang Z9, Muir K10,11, Govindasami K1, Lophatananon A10,11, Stevens VL12, Gapstur SM12, Carter BD12, Tangen CM13, Goodman P13, Thompson IM Jr14, Batra J15,16, Chambers S17,18, Moya L15,16, Clements J15,16, Horvath L19,20, Tilley W21, Risbridger G22,23, Gronberg H24, Aly M24,25, Nordström T24,26, Pharoah P4,27, Pashayan N27,28, Schleutker J29,30, Tammela TLJ31, Sipeky C29, Auvinen A32, Albanes D8, Weinstein S8, Wolk A33, Hakansson N33, West C34, Dunning AM27, Burnet N35, Mucci L36, Giovannucci E36, Andriole G37, Cussenot O38,39, Cancel-Tassin G38,39, Koutros S8, Freeman LEB8, Sorensen KD40,41, Orntoft TF40,41, Borre M41,42, Maehle L43, Grindedal EM43, Neal DE44,45,46, Donovan JL47, Hamdy FC46,48, Martin RM47,49,50, Travis RC51, Key TJ51, Hamilton RJ52, Fleshner NE52, Finelli A52, Ingles SA9, Stern MC9, Rosenstein B53,54, Kerns S55, Ostrer H56, Lu YJ57, Zhang HW58, Feng N59, Mao X57, Guo X60,61, Wang G62, Sun Z61, Giles GG63,64, Southey MC65, MacInnis RJ63,64, FitzGerald LM64,66, Kibel AS67, Drake BF37, Vega A68, Gómez-Caamaño A69, Fachal L4,68, Szulkin R70,71, Eklund M24, Kogevinas M72,73,74,75, Llorca J73,76, Castaño-Vinyals G72,73,74,75, Penney KL77, Stampfer M77, Park JY78, Sellers TA78, Lin HY79, Stanford JL80,81, Cybulski C82, Wokolorczyk D82, Lubinski J82, Ostrander EA83, Geybels MS80, Nordestgaard BG84,85, Nielsen SF84,85, Weisher M85, Bisbjerg R86, Røder MA87, Iversen P84,87, Brenner H88,89,90, Cuk K88, Holleczek B91, Maier C92, Luedeke M92, Schnoeller T93, Kim J94, Logothetis CJ94, John EM95,96, Teixeira MR97,98, Paulo P97, Cardoso M97, Neuhausen SL99, Steele L99, Ding YC99, De Ruyck K100, De Meerleer G100, Ost P101, Razack A102, Lim J102, Teo SH103, Lin DW80,104, Newcomb LF80,104, Lessel D105, Gamulin M106, Kulis T107, Kaneva R108, Usmani N109,110, Slavov C111, Mitev V108, Parliament M109,110, Singhal S109, Claessens F112, Joniau S113, Van den Broeck T112,113, Larkin S114, Townsend PA115, Aukim-Hastie C116, Gago-Dominguez M117,118, Castelao JE119, Martinez ME120, Roobol MJ121, Jenster G121, van Schaik RHN122, Menegaux F123, Truong T123, Koudou YA123, Xu J124, Khaw KT125, Cannon-Albright L126,127, Pandha H116, Michael A116, Kierzek A116, Thibodeau SN128, McDonnell SK129, Schaid DJ129, Lindstrom S130, Turman C131, Ma J77, Hunter DJ131, Riboli E132, Siddiq A133, Canzian F134, Kolonel LN135, Le Marchand L135, Hoover RN8, Machiela MJ8, Kraft P131; PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium, Freedman M136, Wiklund F24, Chanock S8, Henderson BE9, Easton DF4,27, Haiman CA9, Eeles RA1,137, Conti DV9, Kote-Jarai Z138.

Author information

1
The Institute of Cancer Research, London, SW7 3RP, UK.
2
MRC Biostatistics Unit, University of Cambridge, Robinson Way, Cambridge, CB2 0SR, UK.
3
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
4
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, CB1 8RN, UK.
5
Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0QQ, UK.
6
Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, 44106-7219, USA.
7
Seidman Cancer Center, University Hospitals, Cleveland, OH, 44106, USA.
8
Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, 20892, USA.
9
Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, 90015, USA.
10
Institute of Population Health, University of Manchester, Manchester, M13 9PL, UK.
11
Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK.
12
Epidemiology Research Program, American Cancer Society, 250 Williams Street, Atlanta, GA, 30303, USA.
13
SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
14
CHRISTUS Santa Rosa Hospital - Medical Center, San Antonio, TX, 78229, USA.
15
Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, QLD, 4059, Australia.
16
Translational Research Institute, Brisbane, QLD, 4102, Australia.
17
Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, 4222, Australia.
18
Cancer Council Queensland, Fortitude Valley, QLD, 4006, Australia.
19
Chris O'Brien Lifehouse (COBLH), Camperdown, Sydney, NSW, 2010, Australia.
20
Garvan Institute of Medical Research, Sydney, NSW, 2010, Australia.
21
Dame Roma Mitchell Cancer Research Centre, University of Adelaide, Adelaide, SA, 5005, Australia.
22
Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia.
23
Prostate Cancer Translational Research Program, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia.
24
Department of Medical Epidemiology and Biostatistics, Karolinska Institute, SE-171 77, Stockholm, Sweden.
25
Department of Molecular Medicine and Surgery, Karolinska Institutet, and Department of Urology, Karolinska University Hospital, 171 76, Stockholm, Sweden.
26
Department of Clinical Sciences at Danderyd Hospital, Karolinska Institutet, 182 88, Stockholm, Sweden.
27
Centre for Cancer Genetic Epidemiology, Department of Oncology, Strangeways Laboratory, University of Cambridge, Cambridge, CB1 8RN, UK.
28
Department of Applied Health Research, University College London, London, WC1E 7HB, UK.
29
Institute of Biomedicine, University of Turku, FI-20014, Turku, Finland.
30
Tyks Microbiology and Genetics, Department of Medical Genetics, Turku University Hospital, 20521, Turku, Finland.
31
Department of Urology, Tampere University Hospital, University of Tampere, Kalevantie 4, FI-33014, Tampere, Finland.
32
Department of Epidemiology, School of Health Sciences, University of Tampere, FI-33014, Tampere, Finland.
33
Division of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, SE-171 77, Stockholm, Sweden.
34
Division 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.
35
University of Cambridge Department of Oncology, Oncology Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB1 8RN, UK.
36
Department of Epidemiology, Harvard School of Public Health, Boston, MA, 02115, USA.
37
Washington University School of Medicine, St. Louis, MO, 63110, USA.
38
GRC N°5 ONCOTYPE-URO, UPMC Univ Paris 06, Tenon Hospital, F-75020, Paris, France.
39
CeRePP, Tenon Hospital, F-75020, Paris, France.
40
Department of Molecular Medicine, Aarhus University Hospital, 8200, Aarhus N, Denmark.
41
Department of Clinical Medicine, Aarhus University, 8200, Aarhus N, Denmark.
42
Department of Urology, Aarhus University Hospital, 8200, Aarhus N, Denmark.
43
Department of Medical Genetics, Oslo University Hospital, 0424, Oslo, Norway.
44
Department of Oncology, Addenbrooke's Hospital, University of Cambridge, Cambridge, CB2 0QQ, UK.
45
Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, CB2 0RE, UK.
46
Nuffield Department of Surgical Sciences, University of Oxford, Oxford, OX1 2JD, UK.
47
School of Social and Community Medicine, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS, UK.
48
Faculty of Medical Science, John Radcliffe Hospital, University of Oxford, Oxford, OX1 2JD, UK.
49
Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, UK.
50
National Institute for Health Research (NIHR) Biomedical Research Centre, University of Bristol, Bristol, BS8 1TH, UK.
51
Cancer Epidemiology, Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, UK.
52
Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, ON, M5G 2M9, Canada.
53
Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
54
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029-5674, USA.
55
Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY, 14620, USA.
56
Professor of Pathology and Pediatrics, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
57
Centre for Molecular Oncology, Barts Cancer Institute, John Vane Science Centre, Queen Mary University of London, London, EC1M 6BQ, UK.
58
Second Military Medical University, Shanghai, 200433, P. R. China.
59
Wuxi Second Hospital, Nanjing Medical University, Wuxi, Jiangzhu, 214003, China.
60
Department of Urology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, 200032, China.
61
The People's Hospital of Liaoning Province and The People's Hospital of China Medical University, Shenyang, 110001, China.
62
Department of Urology, Zhongshan Hospital, Fudan University Medical College, Shanghai, 200032, China.
63
Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, VIC, 3004, Australia.
64
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, 3010, Australia.
65
Precision Medicine, School and Clinical Sciences at Monash Health, Monash University, Clayton, VIC, 3168, Australia.
66
Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, 7000, Australia.
67
Division of Urologic Surgery, Brigham and Womens Hospital, Boston, MA, 02115, USA.
68
Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica, CIBERER, IDIS, Santiago de Compostela, 15706, Spain.
69
Department of Radiation Oncology, Complexo Hospitalario Universitario de Santiago, SERGAS, 15706, Santiago de Compostela, Spain.
70
Division of Family Medicine, Department of Neurobiology, Care Science and Society, Karolinska Institutet, Huddinge, SE-171 77, Stockholm, Sweden.
71
Scandinavian Development Services, 182 33, Danderyd, Sweden.
72
Centre for Research in Environmental Epidemiology (CREAL), Barcelona Institute for Global Health (ISGlobal), 08003, Barcelona, Spain.
73
CIBER Epidemiología y Salud Pública (CIBERESP), 28029, Madrid, Spain.
74
IMIM (Hospital del Mar Research Institute), 08003, Barcelona, Spain.
75
Universitat Pompeu Fabra (UPF), 08002, Barcelona, Spain.
76
University of Cantabria-IDIVAL, 39005, Santander, Spain.
77
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, MA, 02184, USA.
78
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, 33612, USA.
79
School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA.
80
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109-1024, USA.
81
Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, 98195, USA.
82
International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, 70-115, Szczecin, Poland.
83
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
84
Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.
85
Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, 2200, Copenhagen, Denmark.
86
Department of Urology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, 2200, Copenhagen, Denmark.
87
Copenhagen Prostate Cancer Center, Department of Urology, Rigshospitalet, Copenhagen University Hospital, DK-2730, Herlev, Denmark.
88
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), D-69120, Heidelberg, Germany.
89
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), D-69120, Heidelberg, Germany.
90
Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), 69120, Heidelberg, Germany.
91
Saarland Cancer Registry, 66119, Saarbrücken, Germany.
92
Institute for Human Genetics, University Hospital Ulm, 89075, Ulm, Germany.
93
Department of Urology, University Hospital Ulm, 89075, Ulm, Germany.
94
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
95
Cancer Prevention Institute of California, Fremont, CA, 94538, USA.
96
Department of Health Research & Policy (Epidemiology) and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, 94305-5101, USA.
97
Department of Genetics, Portuguese Oncology Institute of Porto, 4200-072, Porto, Portugal.
98
Biomedical Sciences Institute (ICBAS), University of Porto, 4050-313, Porto, Portugal.
99
Department of Population Sciences, Beckman Research Institute of the City of Hope, Duarte, CA, 91010, USA.
100
Ghent University, Faculty of Medicine and Health Sciences, Basic Medical Sciences, B-9000, Gent, Belgium.
101
Department of Radiotherapy, Ghent University Hospital, B-9000, Gent, Belgium.
102
Department of Surgery, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.
103
Cancer Research Malaysia (CRM), Outpatient Centre, Subang Jaya Medical Centre, 47500, Subang Jaya, Selangor, Malaysia.
104
Department of Urology, University of Washington, Seattle, WA, 98195, USA.
105
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, D-20246, Hamburg, Germany.
106
Division of Medical Oncology, Urogenital Unit, Department of Oncology at the University Hospital Centre Zagreb, Šalata 2, 10000, Zagreb, Croatia.
107
Department of Urology, University Hospital Center Zagreb, University of Zagreb School of Medicine, Šalata 2, 10000, Zagreb, Croatia.
108
Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University of Sofia, 1431, Sofia, Bulgaria.
109
Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, T6G 1Z2, Canada.
110
Division of Radiation Oncology, Cross Cancer Institute, Edmonton, AB, T6G 1Z2, Canada.
111
Department of Urology and Alexandrovska University Hospital, Medical University of Sofia, 1431, Sofia, Bulgaria.
112
Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, BE-3000, Leuven, Belgium.
113
Department of Urology, University Hospitals Leuven, BE-3000, Leuven, Belgium.
114
Southampton General Hospital, The University of Southampton, Southampton, SO16 6YD, UK.
115
Manchester Cancer Research Centre, Faculty of Biology Medicine & Health, Manchester Academic Health Science Centre, NIHR Manchester Biomedical Research Centre, Health Innovation Manchester, University of Manchester, Manchester, M13 9WL, UK.
116
The University of Surrey, Guildford, Surrey, GU2 7XH, UK.
117
Genomic Medicine Group, Galician Foundation of Genomic Medicine, Instituto de Investigacion Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, Servicio Galego de Saúde, SERGAS, 15706, Santiago de Compostela, Spain.
118
Moores Cancer Center, University of California San Diego, La Jolla, CA, 92037, USA.
119
Genetic Oncology Unit, CHUVI Hospital, Complexo Hospitalario Universitario de Vigo, Instituto de Investigación Biomédica Galicia Sur (IISGS), 36204, Vigo (Pontevedra), Spain.
120
Moores Cancer Center, Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, 92093-0012, USA.
121
Department of Urology, Erasmus University Medical Center, 3015 CE, Rotterdam, The Netherlands.
122
Department of Clinical Chemistry, Erasmus University Medical Center, 3015 CE, Rotterdam, The Netherlands.
123
Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, 94807, Villejuif Cédex, France.
124
Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, IL, 60201, USA.
125
Clinical Gerontology Unit, University of Cambridge, Cambridge, CB2 2QQ, UK.
126
Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA.
127
George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, 84148, USA.
128
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA.
129
Division of Biomedical Statistics & Informatics, Mayo Clinic, Rochester, MN, 55905, USA.
130
Department of Epidemiology, University of Washington, Seattle, WA, 98195, USA.
131
Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
132
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, SW7 2AZ, UK.
133
Genomics England, Queen Mary University of London, Dawson Hall, Charterhouse Square, London, EC1M 6BQ, UK.
134
Genomic Epidemiology Group, German Cancer Research Center (DKFZ), D-69120, Heidelberg, Germany.
135
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, 96813, USA.
136
Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
137
Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK.
138
The Institute of Cancer Research, London, SW7 3RP, UK. zsofia.kote-jarai@icr.ac.uk.

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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