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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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1 The Institute of Cancer Research, London, UK
2 MRC Biostatistics Unit, University of Cambridge, Cambridge, UK
3 The Institute of Cancer Research, London, UK; Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK
4 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK; Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
5 Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA; Seidman Cancer Center, University Hospitals, Cleveland, OH, USA
6 Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA
7 The Institute of Cancer Research, London, UK; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK
8 Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA
9 Institute of Population Health, University of Manchester, Manchester, UK; Warwick Medical School, University of Warwick, Coventry, UK
10 Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA
11 SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
12 CHRISTUS Santa Rosa Hospital - Medical Center, San Antonio, TX, USA
13 Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Science, Queensland University of Technology, Brisbane, QLD, Australia; Translational Research Institute, Brisbane, QLD, Australia
14 Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, Australia; Cancer Council Queensland, Fortitude Valley, QLD, Australia
15 Chris O’Brien Lifehouse (COBLH), Camperdown, Sydney, NSW, Australia; Garvan Institute of Medical Research, Sydney, NSW, Australia
16 Dame Roma Mitchell Cancer Research Centre, University of Adelaide, Adelaide, SA, Australia
17 Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia; Prostate Cancer Translational Research Program, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
18 Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
19 Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, and Department of Urology, Karolinska University Hospital, Stockholm, Sweden
20 Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden; Department of Clinical Sciences at Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden
21 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK; Centre for Cancer Genetic Epidemiology, Department of Oncology, Strangeways Laboratory, University of Cambridge, Cambridge, UK
22 Centre for Cancer Genetic Epidemiology, Department of Oncology, Strangeways Laboratory, University of Cambridge, Cambridge, UK; Department of Applied Health Research, University College London, London, UK
23 Institute of Biomedicine, University of Turku, Turku, Finland; Tyks Microbiology and Genetics, Department of Medical Genetics, Turku University Hospital, Turku, Finland
24 Department of Urology, Tampere University Hospital, University of Tampere, Tampere, Finland
25 Institute of Biomedicine, University of Turku, Turku, Finland
26 Department of Epidemiology, School of Health Sciences, University of Tampere, Tampere, Finland
27 Division of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
28 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, UK
29 Centre for Cancer Genetic Epidemiology, Department of Oncology, Strangeways Laboratory, University of Cambridge, Cambridge, UK
30 University of Cambridge Department of Oncology, Oncology Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
31 Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA
32 Washington University School of Medicine, St. Louis, MO, USA
33 GRC N°5 ONCOTYPE-URO, UPMC Univ Paris 06, Tenon Hospital, Paris, France; CeRePP, Tenon Hospital, Paris, France
34 Department of Molecular Medicine, Aarhus University Hospital, Aarhus N, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark
35 Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark; Department of Urology, Aarhus University Hospital, Aarhus N, Denmark
36 Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
37 Department of Oncology, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK; Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK; Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
38 School of Social and Community Medicine, University of Bristol, Bristol, UK
39 Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK; Faculty of Medical Science, John Radcliffe Hospital, University of Oxford, Oxford, UK
40 School of Social and Community Medicine, University of Bristol, Bristol, UK; Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK; National Institute for Health Research (NIHR) Biomedical Research Centre, University of Bristol, Bristol, UK
41 Cancer Epidemiology, Nuffield Department of Population Health, University of Oxford, Oxford, UK
42 Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada
43 Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
44 Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY, USA
45 Professor of Pathology and Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA
46 Centre for Molecular Oncology, Barts Cancer Institute, John Vane Science Centre, Queen Mary University of London, London, UK
47 Second Military Medical University, Shanghai, P. R. China
48 Wuxi Second Hospital, Nanjing Medical University, Wuxi, Jiangzhu, China
49 Department of Urology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China; The People’s Hospital of Liaoning Province and The People’s Hospital of China Medical University, Shenyang, China
50 Department of Urology, Zhongshan Hospital, Fudan University Medical College, Shanghai, China
51 The People’s Hospital of Liaoning Province and The People’s Hospital of China Medical University, Shenyang, China
52 Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, VIC, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia
53 Precision Medicine, School and Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia
54 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia; Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia
55 Division of Urologic Surgery, Brigham and Womens Hospital, Boston, MA, USA
56 Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica, CIBERER, IDIS, Santiago de Compostela, Spain
57 Department of Radiation Oncology, Complexo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain
58 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK; Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica, CIBERER, IDIS, Santiago de Compostela, Spain
59 Division of Family Medicine, Department of Neurobiology, Care Science and Society, Karolinska Institutet, Stockholm, Sweden; Scandinavian Development Services, Danderyd, Sweden
60 Centre for Research in Environmental Epidemiology (CREAL), Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain; CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; IMIM (Hospital del Mar Research Institute), Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain
61 CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; University of Cantabria-IDIVAL, Santander, Spain
62 Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital/Harvard Medical School, Boston, MA, USA
63 Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA
64 School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, USA
65 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA
66 International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
67 National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
68 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
69 Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark
70 Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark
71 Department of Urology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark
72 Copenhagen Prostate Cancer Center, Department of Urology, Rigshospitalet, Copenhagen University Hospital, Herlev, Denmark
73 Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Copenhagen Prostate Cancer Center, Department of Urology, Rigshospitalet, Copenhagen University Hospital, Herlev, Denmark
74 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
75 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
76 Saarland Cancer Registry, Saarbrücken, Germany
77 Institute for Human Genetics, University Hospital Ulm, Ulm, Germany
78 Department of Urology, University Hospital Ulm, Ulm, Germany
79 Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
80 Cancer Prevention Institute of California, Fremont, CA, USA; Department of Health Research & Policy (Epidemiology) and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA
81 Department of Genetics, Portuguese Oncology Institute of Porto, Porto, Portugal; Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal
82 Department of Genetics, Portuguese Oncology Institute of Porto, Porto, Portugal
83 Department of Population Sciences, Beckman Research Institute of the City of Hope, Duarte, CA, USA
84 Ghent University, Faculty of Medicine and Health Sciences, Basic Medical Sciences, Gent, Belgium
85 Department of Radiotherapy, Ghent University Hospital, Gent, Belgium
86 Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
87 Cancer Research Malaysia (CRM), Outpatient Centre, Subang Jaya Medical Centre, Subang Jaya, Selangor, Malaysia
88 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Urology, University of Washington, Seattle, WA, USA
89 Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
90 Division of Medical Oncology, Urogenital Unit, Department of Oncology at the University Hospital Centre Zagreb, Zagreb, Croatia
91 Department of Urology, University Hospital Center Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia
92 Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University of Sofia, Sofia, Bulgaria
93 Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada; Division of Radiation Oncology, Cross Cancer Institute, Edmonton, AB, Canada
94 Department of Urology and Alexandrovska University Hospital, Medical University of Sofia, Sofia, Bulgaria
95 Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada
96 Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
97 Department of Urology, University Hospitals Leuven, Leuven, Belgium
98 Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium; Department of Urology, University Hospitals Leuven, Leuven, Belgium
99 Southampton General Hospital, The University of Southampton, Southampton, UK
100 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, UK
101 The University of Surrey, Guildford, Surrey, UK
102 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, Santiago de Compostela, Spain; Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
103 Genetic Oncology Unit, CHUVI Hospital, Complexo Hospitalario Universitario de Vigo, Instituto de Investigación Biomédica Galicia Sur (IISGS), Vigo (Pontevedra), Spain
104 Moores Cancer Center, Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA
105 Department of Urology, Erasmus University Medical Center, Rotterdam, The Netherlands
106 Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands
107 Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif Cédex, France
108 Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, IL, USA
109 Clinical Gerontology Unit, University of Cambridge, Cambridge, UK
110 Division of Genetic Epidemiology, Department of Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA; George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, USA
111 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
112 Division of Biomedical Statistics & Informatics, Mayo Clinic, Rochester, MN, USA
113 Department of Epidemiology, University of Washington, Seattle, WA, USA
114 Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
115 Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, UK
116 Genomics England, Queen Mary University of London, London, UK
117 Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
118 Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
119 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK
120 Molecular Cancer Epidemiology Laboratory, QIMR Berghofer Institute of Medical Research, Herston, QLD, Australia
121 School of Medicine, University of Queensland, Herston, QLD, Australia; Royal Brisbane & Women’s Hospital, Herston, QLD, Australia
122 The Kinghorn Cancer Centre (TKCC), Victoria, NSW, Australia
123 Prostate Cancer Research Group, South Australian Health & Medical Research Institute, Adelaide, SA, Australia
124 Department of Physiology, Biomedicine Discovery Institute, Cancer Program, Monash University, Melbourne, VIC, Australia
125 University of Adelaide, North Terrace, Adelaide, SA, Australia
126 Garvan Institute of Medical Research, Sydney, NSW, Australia; The Kinghorn Cancer Centre (TKCC), Victoria, NSW, Australia
127 Fimlab Laboratories, Tampere University Hospital, Tampere, Finland
128 Finnish Cancer Registry, Helsinki, Finland
129 Department of Urology, Tampere University Hospital, University of Tampere, Tampere, Finland; Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland
130 Department of Urology, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland
131 The Institute of Cancer Research, London, UK; Royal Marsden NHS Foundation Trust, London, UK
132 Division of Biostatistics and Bioinformatics, University of Maryland Greenebaum Cancer Center, and Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, USA
133 Cancer Genomics Research Laboratory (CGR), Division of Cancer Epidemiology and Genetics, FNLCR Leidos Biomedical Research, National Cancer Institute, Frederick, MD, USA
134 DNA Extraction and Staging Laboratory (DESL), Cancer Genomics Research Laboratory (CGR), Division of Cancer Epidemiology and Genetics, FNLCR Leidos Biomedical Research, National Cancer Institute, Frederick, MD, USA
135 Sheffield Institute for Nucleic Acids, University of Sheffield, Sheffield, UK
136 Cambridge Cancer Trials Centre, Cambridge Clinical Trials Unit - Cancer Theme, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
137 Department of Medical Imaging, University Health Network, Toronto, ON, Canada
138 Department of Pathology, University Health Network, Toronto, ON, Canada
139 Advanced Radiation Biology Research Program, Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan
140 Department of Urology, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
141 Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, China
142 Department of Pathology, The First Affiliated Hospital, Zhejiang University Medical College, Hangzhou, China
143 Department of Pathology, Changhai Hospital, The Second Military Medical University, Shanghai, China
144 Department of Urology, First Affiliated Hospital, Medical College, Zhengzhou University, Zhengzhou, China
145 Department of Urology, North Sichuan Medical College, Nanchong, China
146 Department of Nutrition Science, Shenyang Medical College, Shenyang, China
147 Department of Urology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, China
148 Tissupath Pty Ltd., Melbourne, VIC, Australia
149 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia
150 Department of Medical Physics, Complexo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain
151 Urology Department, Hospital Germans Trias I Pujol, Barcelona, Spain
152 IMIM (Hospital del Mar Research Institute), Barcelona, Spain
153 Laboratory and Department of Urology, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain; Centre de Recerca Biomèdica CELLEX, Barcelona, Spain
154 Department and Laboratory of Urology, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain
155 Centre for Research in Environmental Epidemiology (CREAL), Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain
156 Genitourinary Program, Moffitt Cancer Center, Tampa, FL, USA
157 Department of Urology, Klinikum rechts der Isar der Technischen Universitaet Muenchen, Munich, Germany
158 Department of General and Clinical Pathology and Alexandrovska University Hospital, Medical University, Sofia, Bulgaria
159 Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica, CIBERER, IDIS, Santiago de Compostela, Spain; Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia; Grupo de Medicina Xenómica, CIBERER, CIMUS, Universidad de Santiago de Compostela, Avenida de Barcelona, Santiago de Compostela, Spain
160 Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif Cédex, France; Paris-Sud University, UMRS 1018, Villejuif, France
161 Hérault Cancer Registry, Montpellier, France
162 Urology Department, Clinique Beau Soleil, Montpellier, France
163 INSERM U1147, Paris, France
164 Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; Swedish Agency for Health Technology Assessment and Assessment of Social Services, Stockholm, Sweden
165 Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden; Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
166 Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
167 Dana-Farber Cancer Institute, Boston, MA, USA