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

      research-article
      1 , 1 , 2 , 1 , 1 , 3 , 1 , 1 , 1 , 1 , 4 , 5 , 6 , 7 , 8 , 1 , 4 , 1 , 1 , 9 , 9 , 10 , 11 , 1 , 10 , 11 , 12 , 12 , 12 , 13 , 13 , 14 , 15 , 16 , 17 , 18 , 15 , 16 , 15 , 16 , 19 , 20 , 21 , 22 , 23 , 24 , 24 , 25 , 24 , 26 , 4 , 27 , 27 , 28 , 29 , 30 , 31 , 29 , 32 , 8 , 8 , 33 , 33 , 34 , 27 , 35 , 36 , 36 , 37 , 38 , 39 , 38 , 39 , 8 , 8 , 40 , 41 , 40 , 41 , 41 , 42 , 43 , 43 , 44 , 45 , 46 , 47 , 46 , 48 , 47 , 49 , 50 , 51 , 51 , 52 , 52 , 52 , 9 , 9 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 57 , 60 , 61 , 62 , 61 , 63 , 64 , 65 , 63 , 64 , 64 , 66 , 67 , 37 , 68 , 69 , 4 , 68 , 70 , 71 , 24 , 72 , 73 , 74 , 75 , 73 , 76 , 72 , 73 , 74 , 75 , 77 , 77 , 78 , 78 , 79 , 80 , 81 , 82 , 82 , 82 , 83 , 80 , 84 , 85 , 84 , 85 , 85 , 86 , 87 , 84 , 87 , 88 , 89 , 90 , 88 , 91 , 92 , 92 , 93 , 94 , 94 , 95 , 96 , 97 , 98 , 97 , 97 , 99 , 99 , 99 , 100 , 100 , 101 , 102 , 102 , 103 , 80 , 104 , 80 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 108 , 109 , 110 , 109 , 112 , 113 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 121 , 122 , 123 , 123 , 123 , 124 , 125 , 126 , 127 , 116 , 116 , 116 , 128 , 129 , 129 , 130 , 131 , 77 , 131 , 132 , 133 , 134 , 135 , 135 , 8 , 8 , 131 , The PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium, 136 , 24 , 8 , 9 , 4 , 27 , 9 , 1 , 137 , 9 , 1 ,
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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.

          Abstract

          Prostate cancer (PrCa) involves a large heritable genetic component. Here, the authors perform multivariate fine-mapping of known PrCa GWAS loci, identifying variants enriched for biological function, explaining more familial relative risk, and with potential application in clinical risk profiling.

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          Most cited references75

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          • Abstract: found
          • Article: found
          Is Open Access

          An Integrated Encyclopedia of DNA Elements in the Human Genome

          Summary The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure, and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall the project provides new insights into the organization and regulation of our genes and genome, and an expansive resource of functional annotations for biomedical research.
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            A general framework for estimating the relative pathogenicity of human genetic variants

            Our capacity to sequence human genomes has exceeded our ability to interpret genetic variation. Current genomic annotations tend to exploit a single information type (e.g. conservation) and/or are restricted in scope (e.g. to missense changes). Here, we describe Combined Annotation Dependent Depletion (CADD), a framework that objectively integrates many diverse annotations into a single, quantitative score. We implement CADD as a support vector machine trained to differentiate 14.7 million high-frequency human derived alleles from 14.7 million simulated variants. We pre-compute “C-scores” for all 8.6 billion possible human single nucleotide variants and enable scoring of short insertions/deletions. C-scores correlate with allelic diversity, annotations of functionality, pathogenicity, disease severity, experimentally measured regulatory effects, and complex trait associations, and highly rank known pathogenic variants within individual genomes. The ability of CADD to prioritize functional, deleterious, and pathogenic variants across many functional categories, effect sizes and genetic architectures is unmatched by any current annotation.
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              • Article: not found

              Bayes Factors

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                Author and article information

                Contributors
                zsofia.kote-jarai@icr.ac.uk
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                11 June 2018
                11 June 2018
                2018
                : 9
                : 2256
                Affiliations
                [1 ]ISNI 0000 0001 1271 4623, GRID grid.18886.3f, The Institute of Cancer Research, ; London, SW7 3RP UK
                [2 ]ISNI 0000000121885934, GRID grid.5335.0, MRC Biostatistics Unit, , University of Cambridge, ; Robinson Way, Cambridge, CB2 0SR UK
                [3 ]ISNI 0000 0004 0606 5382, GRID grid.10306.34, Cancer Genome Project, , Wellcome Trust Sanger Institute, ; Hinxton, Cambridge CB10 1SA UK
                [4 ]ISNI 0000000121885934, GRID grid.5335.0, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Strangeways Research Laboratory, , University of Cambridge, ; Cambridge, CB1 8RN UK
                [5 ]ISNI 0000000121885934, GRID grid.5335.0, Department of Clinical Neurosciences, , University of Cambridge, ; Cambridge, CB2 0QQ UK
                [6 ]ISNI 0000 0001 2164 3847, GRID grid.67105.35, Department of Population and Quantitative Health Sciences, , Case Western Reserve University, ; Cleveland, OH 44106-7219 USA
                [7 ]ISNI 0000 0004 0452 4020, GRID grid.241104.2, Seidman Cancer Center, , University Hospitals, ; Cleveland, OH 44106 USA
                [8 ]ISNI 0000 0004 0483 9129, GRID grid.417768.b, Division of Cancer Epidemiology and Genetics, , National Cancer Institute, NIH, ; Bethesda, MD 20892 USA
                [9 ]ISNI 0000 0001 2156 6853, GRID grid.42505.36, Department of Preventive Medicine, Keck School of Medicine, , University of Southern California/Norris Comprehensive Cancer Center, ; Los Angeles, CA 90015 USA
                [10 ]ISNI 0000000121662407, GRID grid.5379.8, Institute of Population Health, , University of Manchester, ; Manchester, M13 9PL UK
                [11 ]ISNI 0000 0000 8809 1613, GRID grid.7372.1, Warwick Medical School, , University of Warwick, ; Coventry, CV4 7AL UK
                [12 ]ISNI 0000 0004 0371 6485, GRID grid.422418.9, Epidemiology Research Program, , American Cancer Society, ; 250 Williams Street, Atlanta, GA 30303 USA
                [13 ]ISNI 0000 0001 2180 1622, GRID grid.270240.3, SWOG Statistical Center, , Fred Hutchinson Cancer Research Center, ; Seattle, WA 98109 USA
                [14 ]GRID grid.430467.2, CHRISTUS Santa Rosa Hospital - Medical Center, ; San Antonio, TX 78229 USA
                [15 ]ISNI 0000000089150953, GRID grid.1024.7, 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 ]ISNI 0000 0004 0437 5432, GRID grid.1022.1, Menzies Health Institute Queensland, , Griffith University, ; Gold Coast, QLD 4222 Australia
                [18 ]ISNI 0000 0000 9761 7912, GRID grid.430282.f, Cancer Council Queensland, ; Fortitude Valley, QLD 4006 Australia
                [19 ]GRID grid.419783.0, Chris O’Brien Lifehouse (COBLH), Camperdown, ; Sydney, NSW 2010 Australia
                [20 ]ISNI 0000 0000 9983 6924, GRID grid.415306.5, Garvan Institute of Medical Research, ; Sydney, NSW 2010 Australia
                [21 ]ISNI 0000 0004 1936 7304, GRID grid.1010.0, Dame Roma Mitchell Cancer Research Centre, , University of Adelaide, ; Adelaide, SA 5005 Australia
                [22 ]ISNI 0000 0004 1936 7857, GRID grid.1002.3, Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, , Monash University, ; Melbourne, VIC 3800 Australia
                [23 ]ISNI 0000000403978434, GRID grid.1055.1, Prostate Cancer Translational Research Program, Cancer Research Division, , Peter MacCallum Cancer Centre, ; Melbourne, VIC 3000 Australia
                [24 ]ISNI 0000 0004 1937 0626, GRID grid.4714.6, Department of Medical Epidemiology and Biostatistics, , Karolinska Institute, ; SE-171 77 Stockholm, Sweden
                [25 ]ISNI 0000 0000 9241 5705, GRID grid.24381.3c, Department of Molecular Medicine and Surgery, Karolinska Institutet, and Department of Urology, , Karolinska University Hospital, ; 171 76 Stockholm, Sweden
                [26 ]ISNI 0000 0004 1937 0626, GRID grid.4714.6, Department of Clinical Sciences at Danderyd Hospital, , Karolinska Institutet, ; 182 88 Stockholm, Sweden
                [27 ]ISNI 0000000121885934, GRID grid.5335.0, Centre for Cancer Genetic Epidemiology, Department of Oncology, Strangeways Laboratory, , University of Cambridge, ; Cambridge, CB1 8RN UK
                [28 ]ISNI 0000000121901201, GRID grid.83440.3b, Department of Applied Health Research, , University College London, ; London, WC1E 7HB UK
                [29 ]ISNI 0000 0001 2097 1371, GRID grid.1374.1, Institute of Biomedicine, , University of Turku, ; FI-20014 Turku, Finland
                [30 ]ISNI 0000 0004 0628 215X, GRID grid.410552.7, Tyks Microbiology and Genetics, Department of Medical Genetics, , Turku University Hospital, ; 20521 Turku, Finland
                [31 ]ISNI 0000 0001 2314 6254, GRID grid.5509.9, Department of Urology, Tampere University Hospital, , University of Tampere, ; Kalevantie 4, FI-33014 Tampere, Finland
                [32 ]ISNI 0000 0001 2314 6254, GRID grid.5509.9, Department of Epidemiology, School of Health Sciences, , University of Tampere, ; FI-33014 Tampere, Finland
                [33 ]ISNI 0000 0004 1937 0626, GRID grid.4714.6, Division of Nutritional Epidemiology, Institute of Environmental Medicine, , Karolinska Institutet, ; SE-171 77 Stockholm, Sweden
                [34 ]ISNI 0000000121662407, GRID grid.5379.8, 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 ]ISNI 0000 0004 0383 8386, GRID grid.24029.3d, University of Cambridge Department of Oncology, Oncology Centre, , Cambridge University Hospitals NHS Foundation Trust, ; Cambridge, CB1 8RN UK
                [36 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Epidemiology, , Harvard School of Public Health, ; Boston, MA 02115 USA
                [37 ]ISNI 0000 0001 2355 7002, GRID grid.4367.6, Washington University School of Medicine, ; St. Louis, MO 63110 USA
                [38 ]ISNI 0000 0001 2259 4338, GRID grid.413483.9, GRC N°5 ONCOTYPE-URO, UPMC Univ Paris 06, , Tenon Hospital, ; F-75020 Paris, France
                [39 ]ISNI 0000 0001 2259 4338, GRID grid.413483.9, CeRePP, , Tenon Hospital, ; F-75020 Paris, France
                [40 ]ISNI 0000 0004 0512 597X, GRID grid.154185.c, Department of Molecular Medicine, , Aarhus University Hospital, ; 8200 Aarhus N, Denmark
                [41 ]ISNI 0000 0001 1956 2722, GRID grid.7048.b, Department of Clinical Medicine, , Aarhus University, ; 8200 Aarhus N, Denmark
                [42 ]ISNI 0000 0004 0512 597X, GRID grid.154185.c, Department of Urology, , Aarhus University Hospital, ; 8200 Aarhus N, Denmark
                [43 ]ISNI 0000 0004 0389 8485, GRID grid.55325.34, Department of Medical Genetics, , Oslo University Hospital, ; 0424 Oslo, Norway
                [44 ]ISNI 0000000121885934, GRID grid.5335.0, Department of Oncology, Addenbrooke’s Hospital, , University of Cambridge, ; Cambridge, CB2 0QQ UK
                [45 ]ISNI 0000000121885934, GRID grid.5335.0, Cancer Research UK Cambridge Research Institute, , Li Ka Shing Centre, ; Cambridge, CB2 0RE UK
                [46 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, Nuffield Department of Surgical Sciences, , University of Oxford, ; Oxford, OX1 2JD UK
                [47 ]ISNI 0000 0004 1936 7603, GRID grid.5337.2, School of Social and Community Medicine, , University of Bristol, ; Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS UK
                [48 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, Faculty of Medical Science, John Radcliffe Hospital, , University of Oxford, ; Oxford, OX1 2JD UK
                [49 ]ISNI 0000 0004 1936 7603, GRID grid.5337.2, Medical Research Council (MRC) Integrative Epidemiology Unit, , University of Bristol, ; Bristol, BS8 2BN UK
                [50 ]ISNI 0000 0004 1936 7603, GRID grid.5337.2, National Institute for Health Research (NIHR) Biomedical Research Centre, , University of Bristol, ; Bristol, BS8 1TH UK
                [51 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, Cancer Epidemiology, Nuffield Department of Population Health, , University of Oxford, ; Oxford, OX3 7LF UK
                [52 ]ISNI 0000 0001 2150 066X, GRID grid.415224.4, Department of Surgical Oncology, , Princess Margaret Cancer Centre, ; Toronto, ON M5G 2M9 Canada
                [53 ]ISNI 0000 0001 0670 2351, GRID grid.59734.3c, Department of Radiation Oncology, , Icahn School of Medicine at Mount Sinai, ; New York, NY 10029 USA
                [54 ]ISNI 0000 0001 0670 2351, GRID grid.59734.3c, Department of Genetics and Genomic Sciences, , Icahn School of Medicine at Mount Sinai, ; New York, NY 10029-5674 USA
                [55 ]ISNI 0000 0004 1936 9166, GRID grid.412750.5, Department of Radiation Oncology, , University of Rochester Medical Center, ; Rochester, NY 14620 USA
                [56 ]ISNI 0000000121791997, GRID grid.251993.5, Professor of Pathology and Pediatrics, , Albert Einstein College of Medicine, ; Bronx, NY 10461 USA
                [57 ]ISNI 0000 0001 2171 1133, GRID grid.4868.2, Centre for Molecular Oncology, Barts Cancer Institute, John Vane Science Centre, , Queen Mary University of London, ; London, EC1M 6BQ UK
                [58 ]ISNI 0000 0004 0369 1660, GRID grid.73113.37, Second Military Medical University, ; Shanghai, 200433 P. R. China
                [59 ]ISNI 0000 0000 9255 8984, GRID grid.89957.3a, Wuxi Second Hospital, , Nanjing Medical University, ; Wuxi, Jiangzhu 214003 China
                [60 ]ISNI 0000 0000 8653 0555, GRID grid.203458.8, Department of Urology, The First Affiliated Hospital, , Chongqing Medical University, ; Chongqing, 200032 China
                [61 ]ISNI 0000 0004 1757 9522, GRID grid.452816.c, The People’s Hospital of Liaoning Province and The People’s Hospital of China Medical University, ; Shenyang, 110001 China
                [62 ]ISNI 0000 0001 0125 2443, GRID grid.8547.e, Department of Urology, Zhongshan Hospital, , Fudan University Medical College, ; Shanghai, 200032 China
                [63 ]ISNI 0000 0001 1482 3639, GRID grid.3263.4, Cancer Epidemiology & Intelligence Division, , Cancer Council Victoria, ; Melbourne, VIC 3004 Australia
                [64 ]ISNI 0000 0001 2179 088X, GRID grid.1008.9, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, , The University of Melbourne, ; Melbourne, VIC 3010 Australia
                [65 ]ISNI 0000 0004 1936 7857, GRID grid.1002.3, Precision Medicine, School and Clinical Sciences at Monash Health, , Monash University, ; Clayton, VIC 3168 Australia
                [66 ]ISNI 0000 0004 1936 826X, GRID grid.1009.8, Menzies Institute for Medical Research, , University of Tasmania, ; Hobart, TAS 7000 Australia
                [67 ]ISNI 0000 0004 0378 8294, GRID grid.62560.37, 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 ]ISNI 0000 0000 8816 6945, GRID grid.411048.8, Department of Radiation Oncology, , Complexo Hospitalario Universitario de Santiago, SERGAS, ; 15706 Santiago de Compostela, Spain
                [70 ]ISNI 0000 0004 1937 0626, GRID grid.4714.6, 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 ]ISNI 0000 0004 1763 3517, GRID grid.434607.2, Centre for Research in Environmental Epidemiology (CREAL), , Barcelona Institute for Global Health (ISGlobal), ; 08003 Barcelona, Spain
                [73 ]ISNI 0000 0000 9314 1427, GRID grid.413448.e, CIBER Epidemiología y Salud Pública (CIBERESP), ; 28029 Madrid, Spain
                [74 ]ISNI 0000 0004 1767 8811, GRID grid.411142.3, IMIM (Hospital del Mar Research Institute), ; 08003 Barcelona, Spain
                [75 ]ISNI 0000 0001 2172 2676, GRID grid.5612.0, Universitat Pompeu Fabra (UPF), ; 08002 Barcelona, Spain
                [76 ]ISNI 0000 0004 1770 272X, GRID grid.7821.c, University of Cantabria-IDIVAL, ; 39005 Santander, Spain
                [77 ]ISNI 0000 0004 0378 8294, GRID grid.62560.37, Channing Division of Network Medicine, Department of Medicine, , Brigham and Women’s Hospital/Harvard Medical School, ; Boston, MA 02184 USA
                [78 ]ISNI 0000 0000 9891 5233, GRID grid.468198.a, Department of Cancer Epidemiology, , Moffitt Cancer Center, ; Tampa, FL 33612 USA
                [79 ]ISNI 0000 0000 8954 1233, GRID grid.279863.1, School of Public Health, , Louisiana State University Health Sciences Center, ; New Orleans, LA 70112 USA
                [80 ]ISNI 0000 0001 2180 1622, GRID grid.270240.3, Division of Public Health Sciences, , Fred Hutchinson Cancer Research Center, ; Seattle, WA 98109-1024 USA
                [81 ]ISNI 0000000122986657, GRID grid.34477.33, Department of Epidemiology, School of Public Health, , University of Washington, ; Seattle, WA 98195 USA
                [82 ]ISNI 0000 0001 1411 4349, GRID grid.107950.a, International Hereditary Cancer Center, Department of Genetics and Pathology, , Pomeranian Medical University, ; 70-115 Szczecin, Poland
                [83 ]ISNI 0000 0001 2297 5165, GRID grid.94365.3d, National Human Genome Research Institute, , National Institutes of Health, ; Bethesda, MD 20892 USA
                [84 ]ISNI 0000 0001 0674 042X, GRID grid.5254.6, Faculty of Health and Medical Sciences, , University of Copenhagen, ; 2200 Copenhagen, Denmark
                [85 ]ISNI 0000 0004 0646 7373, GRID grid.4973.9, Department of Clinical Biochemistry, Herlev and Gentofte Hospital, , Copenhagen University Hospital, ; Herlev, 2200 Copenhagen, Denmark
                [86 ]ISNI 0000 0004 0646 7373, GRID grid.4973.9, Department of Urology, Herlev and Gentofte Hospital, , Copenhagen University Hospital, ; Herlev, 2200 Copenhagen, Denmark
                [87 ]ISNI 0000 0004 0646 7373, GRID grid.4973.9, Copenhagen Prostate Cancer Center, Department of Urology, Rigshospitalet, , Copenhagen University Hospital, ; DK-2730 Herlev, Denmark
                [88 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, Division of Clinical Epidemiology and Aging Research, , German Cancer Research Center (DKFZ), ; D-69120 Heidelberg, Germany
                [89 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, German Cancer Consortium (DKTK), , German Cancer Research Center (DKFZ), ; D-69120 Heidelberg, Germany
                [90 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, Division of Preventive Oncology, , German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), ; 69120 Heidelberg, Germany
                [91 ]GRID grid.482902.5, Saarland Cancer Registry, ; 66119 Saarbrücken, Germany
                [92 ]GRID grid.410712.1, Institute for Human Genetics, , University Hospital Ulm, ; 89075 Ulm, Germany
                [93 ]GRID grid.410712.1, Department of Urology, , University Hospital Ulm, ; 89075 Ulm, Germany
                [94 ]ISNI 0000 0001 2291 4776, GRID grid.240145.6, Department of Genitourinary Medical Oncology, , The University of Texas MD Anderson Cancer Center, ; Houston, TX 77030 USA
                [95 ]ISNI 0000 0004 0498 8300, GRID grid.280669.3, Cancer Prevention Institute of California, ; Fremont, CA 94538 USA
                [96 ]ISNI 0000000419368956, GRID grid.168010.e, Department of Health Research & Policy (Epidemiology) and Stanford Cancer Institute, , Stanford University School of Medicine, ; Stanford, CA 94305-5101 USA
                [97 ]ISNI 0000 0004 0631 0608, GRID grid.418711.a, Department of Genetics, , Portuguese Oncology Institute of Porto, ; 4200-072 Porto, Portugal
                [98 ]ISNI 0000 0001 1503 7226, GRID grid.5808.5, Biomedical Sciences Institute (ICBAS), , University of Porto, ; 4050-313 Porto, Portugal
                [99 ]ISNI 0000 0004 0421 8357, GRID grid.410425.6, 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 ]ISNI 0000 0004 0626 3303, GRID grid.410566.0, Department of Radiotherapy, , Ghent University Hospital, ; B-9000 Gent, Belgium
                [102 ]ISNI 0000 0001 2308 5949, GRID grid.10347.31, Department of Surgery, Faculty of Medicine, , University of Malaya, ; 50603 Kuala Lumpur, Malaysia
                [103 ]ISNI 0000 0004 0647 0388, GRID grid.415921.a, Cancer Research Malaysia (CRM), Outpatient Centre, , Subang Jaya Medical Centre, ; 47500 Subang Jaya, Selangor Malaysia
                [104 ]ISNI 0000000122986657, GRID grid.34477.33, Department of Urology, , University of Washington, ; Seattle, WA 98195 USA
                [105 ]ISNI 0000 0001 2180 3484, GRID grid.13648.38, Institute of Human Genetics, , University Medical Center Hamburg-Eppendorf, ; D-20246 Hamburg, Germany
                [106 ]ISNI 0000 0004 0397 9648, GRID grid.412688.1, Division of Medical Oncology, Urogenital Unit, , Department of Oncology at the University Hospital Centre Zagreb, ; Šalata 2, 10000 Zagreb, Croatia
                [107 ]ISNI 0000 0001 0657 4636, GRID grid.4808.4, Department of Urology, University Hospital Center Zagreb, , University of Zagreb School of Medicine, ; Šalata 2, 10000 Zagreb, Croatia
                [108 ]ISNI 0000 0004 0621 0092, GRID grid.410563.5, Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, , Medical University of Sofia, ; 1431 Sofia, Bulgaria
                [109 ]GRID grid.17089.37, Department of Oncology, Cross Cancer Institute, , University of Alberta, ; Edmonton, AB T6G 1Z2 Canada
                [110 ]GRID grid.17089.37, Division of Radiation Oncology, , Cross Cancer Institute, ; Edmonton, AB T6G 1Z2 Canada
                [111 ]ISNI 0000 0004 0621 0092, GRID grid.410563.5, Department of Urology and Alexandrovska University Hospital, , Medical University of Sofia, ; 1431 Sofia, Bulgaria
                [112 ]ISNI 0000 0001 0668 7884, GRID grid.5596.f, Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, , KU Leuven, ; BE-3000 Leuven, Belgium
                [113 ]ISNI 0000 0004 0626 3338, GRID grid.410569.f, Department of Urology, , University Hospitals Leuven, ; BE-3000 Leuven, Belgium
                [114 ]ISNI 0000 0004 1936 9297, GRID grid.5491.9, Southampton General Hospital, , The University of Southampton, ; Southampton, SO16 6YD UK
                [115 ]ISNI 0000000121662407, GRID grid.5379.8, 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 ]ISNI 0000 0004 0407 4824, GRID grid.5475.3, The University of Surrey, ; Guildford, Surrey GU2 7XH UK
                [117 ]ISNI 0000 0000 9403 4738, GRID grid.420359.9, 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 ]ISNI 0000 0001 2107 4242, GRID grid.266100.3, 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 ]ISNI 0000 0001 2107 4242, GRID grid.266100.3, Moores Cancer Center, Department of Family Medicine and Public Health, , University of California San Diego, ; La Jolla, CA 92093-0012 USA
                [121 ]ISNI 000000040459992X, GRID grid.5645.2, Department of Urology, , Erasmus University Medical Center, ; 3015 CE Rotterdam, The Netherlands
                [122 ]ISNI 000000040459992X, GRID grid.5645.2, Department of Clinical Chemistry, , Erasmus University Medical Center, ; 3015 CE Rotterdam, The Netherlands
                [123 ]ISNI 0000 0004 4910 6535, GRID grid.460789.4, Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, , University Paris-Saclay, ; 94807 Villejuif Cédex, France
                [124 ]ISNI 0000 0004 0400 4439, GRID grid.240372.0, Program for Personalized Cancer Care, , NorthShore University HealthSystem, ; Evanston, IL 60201 USA
                [125 ]ISNI 0000000121885934, GRID grid.5335.0, Clinical Gerontology Unit, , University of Cambridge, ; Cambridge, CB2 2QQ UK
                [126 ]ISNI 0000 0001 2193 0096, GRID grid.223827.e, Division of Genetic Epidemiology, Department of Medicine, , University of Utah School of Medicine, ; Salt Lake City, UT 84112 USA
                [127 ]GRID grid.413886.0, George E. Wahlen Department of Veterans Affairs Medical Center, ; Salt Lake City, UT 84148 USA
                [128 ]ISNI 0000 0004 0459 167X, GRID grid.66875.3a, Department of Laboratory Medicine and Pathology, , Mayo Clinic, ; Rochester, MN 55905 USA
                [129 ]ISNI 0000 0004 0459 167X, GRID grid.66875.3a, Division of Biomedical Statistics & Informatics, , Mayo Clinic, ; Rochester, MN 55905 USA
                [130 ]ISNI 0000000122986657, GRID grid.34477.33, Department of Epidemiology, , University of Washington, ; Seattle, WA 98195 USA
                [131 ]ISNI 000000041936754X, GRID grid.38142.3c, Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, , Harvard T.H. Chan School of Public Health, ; Boston, MA 02115 USA
                [132 ]ISNI 0000 0001 2113 8111, GRID grid.7445.2, Department of Epidemiology and Biostatistics, School of Public Health, , Imperial College, ; London, SW7 2AZ UK
                [133 ]ISNI 0000 0001 2171 1133, GRID grid.4868.2, Genomics England, , Queen Mary University of London, ; Dawson Hall, Charterhouse Square, London, EC1M 6BQ UK
                [134 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, Genomic Epidemiology Group, , German Cancer Research Center (DKFZ), ; D-69120 Heidelberg, Germany
                [135 ]ISNI 0000 0001 2188 0957, GRID grid.410445.0, Epidemiology Program, , University of Hawaii Cancer Center, ; Honolulu, HI 96813 USA
                [136 ]ISNI 0000 0001 2106 9910, GRID grid.65499.37, Dana-Farber Cancer Institute, ; Boston, MA 02215 USA
                [137 ]ISNI 0000 0001 0304 893X, GRID grid.5072.0, Royal Marsden NHS Foundation Trust, ; London, SW3 6JJ UK
                [138 ]ISNI 0000 0001 2294 1395, GRID grid.1049.c, Molecular Cancer Epidemiology Laboratory, , QIMR Berghofer Institute of Medical Research, ; Herston, QLD 4006 Australia
                [139 ]ISNI 0000 0000 9320 7537, GRID grid.1003.2, School of Medicine, , University of Queensland, ; Herston, QLD 4006 Australia
                [140 ]ISNI 0000 0001 0688 4634, GRID grid.416100.2, Royal Brisbane & Women’s Hospital, ; Herston, QLD 4029 Australia
                [141 ]GRID grid.410697.d, The Kinghorn Cancer Centre (TKCC), ; Victoria, NSW 2010 Australia
                [142 ]GRID grid.430453.5, Prostate Cancer Research Group, , South Australian Health & Medical Research Institute, ; Adelaide, SA 5000 Australia
                [143 ]ISNI 0000 0004 1936 7857, GRID grid.1002.3, Department of Physiology, Biomedicine Discovery Institute, Cancer Program, , Monash University, ; Melbourne, VIC 3800 Australia
                [144 ]ISNI 0000 0004 1936 7304, GRID grid.1010.0, University of Adelaide, North Terrace, ; Adelaide, SA 5005 Australia
                [145 ]ISNI 0000 0004 0628 2985, GRID grid.412330.7, Fimlab Laboratories, , Tampere University Hospital, ; FI-33520 Tampere, Finland
                [146 ]ISNI 0000 0000 8634 0612, GRID grid.424339.b, Finnish Cancer Registry, ; FI-00130 Helsinki, Finland
                [147 ]ISNI 0000 0001 2314 6254, GRID grid.5509.9, Faculty of Medicine and Life Sciences, , University of Tampere, ; FI-33014 Tampere, Finland
                [148 ]ISNI 0000 0000 9950 5666, GRID grid.15485.3d, Department of Urology, , Helsinki University Central Hospital and University of Helsinki, ; FI-00014 Helsinki, Finland
                [149 ]ISNI 0000 0001 2175 4264, GRID grid.411024.2, 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 21201 USA
                [150 ]ISNI 0000 0004 1936 8075, GRID grid.48336.3a, Cancer Genomics Research Laboratory (CGR), Division of Cancer Epidemiology and Genetics, FNLCR Leidos Biomedical Research, , National Cancer Institute, ; Frederick, MD 21701 USA
                [151 ]ISNI 0000 0004 1936 8075, GRID grid.48336.3a, 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 21701 USA
                [152 ]ISNI 0000 0004 1936 9262, GRID grid.11835.3e, Sheffield Institute for Nucleic Acids, , University of Sheffield, ; Sheffield, S10 2TN UK
                [153 ]ISNI 0000 0004 0383 8386, GRID grid.24029.3d, Cambridge Cancer Trials Centre, Cambridge Clinical Trials Unit - Cancer Theme, , Cambridge University Hospitals NHS Foundation Trust, ; Cambridge, CB2 0QQ UK
                [154 ]ISNI 0000 0004 0474 0428, GRID grid.231844.8, Department of Medical Imaging, , University Health Network, ; Toronto, ON M5G 2C4 Canada
                [155 ]ISNI 0000 0004 0474 0428, GRID grid.231844.8, Department of Pathology, , University Health Network, ; Toronto, ON M5G 2C4 Canada
                [156 ]ISNI 0000 0001 2181 8731, GRID grid.419638.1, Advanced Radiation Biology Research Program, Research Center for Charged Particle Therapy, , National Institute of Radiological Sciences, ; Chiba, 263-8555 Japan
                [157 ]GRID grid.416239.b, Department of Urology, , National Hospital Organization Tokyo Medical Center, ; Tokyo, 152-8902 Japan
                [158 ]GRID grid.416466.7, Department of Urology, , Nanfang Hospital, Southern Medical University, ; 510515 Guangzhou, China
                [159 ]ISNI 0000 0004 1759 700X, GRID grid.13402.34, Department of Pathology, The First Affiliated Hospital, , Zhejiang University Medical College, ; 310009 Hangzhou, China
                [160 ]ISNI 0000 0004 0369 1660, GRID grid.73113.37, Department of Pathology, Changhai Hospital, , The Second Military Medical University, ; 200433 Shanghai, China
                [161 ]ISNI 0000 0001 2189 3846, GRID grid.207374.5, Department of Urology, First Affiliated Hospital, Medical College, , Zhengzhou University, ; 450003 Zhengzhou, China
                [162 ]ISNI 0000 0004 1798 4472, GRID grid.449525.b, Department of Urology, , North Sichuan Medical College, ; 637000 Nanchong, China
                [163 ]ISNI 0000 0000 9549 5392, GRID grid.415680.e, Department of Nutrition Science, , Shenyang Medical College, ; 110034 Shenyang, China
                [164 ]Tissupath Pty Ltd., Melbourne, VIC 3122 Australia
                [165 ]ISNI 0000 0000 8816 6945, GRID grid.411048.8, Department of Medical Physics, , Complexo Hospitalario Universitario de Santiago, SERGAS, ; 15706 Santiago de Compostela, Spain
                [166 ]ISNI 0000 0004 1767 6330, GRID grid.411438.b, Urology Department, , Hospital Germans Trias I Pujol, ; 08916 Barcelona, Spain
                [167 ]ISNI 0000 0004 1937 0247, GRID grid.5841.8, Laboratory and Department of Urology, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), , Universitat de Barcelona, ; 08036 Barcelona, Spain
                [168 ]Centre de Recerca Biomèdica CELLEX, 08036 Barcelona, Spain
                [169 ]ISNI 0000 0004 1937 0247, GRID grid.5841.8, Department and Laboratory of Urology, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), , Universitat de Barcelona, ; 08036 Barcelona, Spain
                [170 ]ISNI 0000 0000 9891 5233, GRID grid.468198.a, Genitourinary Program, Moffitt Cancer Center, ; Tampa, FL 33612 USA
                [171 ]ISNI 0000 0004 0477 2438, GRID grid.15474.33, Department of Urology, , Klinikum rechts der Isar der Technischen Universitaet Muenchen, ; 81675 Munich, Germany
                [172 ]ISNI 0000 0004 0621 0092, GRID grid.410563.5, Department of General and Clinical Pathology and Alexandrovska University Hospital, , Medical University, ; 1431 Sofia, Bulgaria
                [173 ]ISNI 0000 0001 0619 1117, GRID grid.412125.1, Center of Excellence in Genomic Medicine Research, , King Abdulaziz University, ; Jeddah, 2252 3270 Saudi Arabia
                [174 ]ISNI 0000000109410645, GRID grid.11794.3a, Grupo de Medicina Xenómica, CIBERER, CIMUS, , Universidad de Santiago de Compostela, Avenida de Barcelona, ; 15782 Santiago de Compostela, Spain
                [175 ]ISNI 0000 0001 2171 2558, GRID grid.5842.b, Paris-Sud University, UMRS 1018, ; Cedex, 94807 Villejuif, France
                [176 ]Hérault Cancer Registry, Montpellier cedex 5, Montpellier, 34298 France
                [177 ]Urology Department, Clinique Beau Soleil, 34070 Montpellier, France
                [178 ]INSERM U1147, 75013 Paris, France
                [179 ]ISNI 0000 0004 1937 0626, GRID grid.4714.6, Department of Clinical Science, Intervention and Technology, , Karolinska Institutet, ; SE-171 77 Stockholm, Sweden
                [180 ]Swedish Agency for Health Technology Assessment and Assessment of Social Services, SE-102 33 Stockholm, Sweden
                [181 ]ISNI 0000 0001 1034 3451, GRID grid.12650.30, Department of Surgical and Perioperative Sciences, Urology and Andrology, , Umeå University, ; SE-901 85 Umeå, Sweden
                [182 ]ISNI 0000 0004 1936 9457, GRID grid.8993.b, Department of Surgical Sciences, , Uppsala University, ; SE-751 85 Uppsala, Sweden
                [183 ]ISNI 0000 0001 0738 8966, GRID grid.15895.30, Department of Urology, Faculty of Medicine and Health, , Örebro University, ; SE-701 82 Örebro, Sweden
                Author information
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                http://orcid.org/0000-0002-3486-3168
                http://orcid.org/0000-0002-8969-2378
                http://orcid.org/0000-0002-7178-3431
                http://orcid.org/0000-0002-3073-7463
                http://orcid.org/0000-0001-6429-988X
                http://orcid.org/0000-0003-4646-6247
                http://orcid.org/0000-0003-4915-7546
                http://orcid.org/0000-0001-8494-732X
                http://orcid.org/0000-0003-0843-2468
                http://orcid.org/0000-0002-1863-0305
                http://orcid.org/0000-0002-8853-4722
                http://orcid.org/0000-0001-7387-6845
                http://orcid.org/0000-0002-9583-6382
                http://orcid.org/0000-0002-4902-5490
                http://orcid.org/0000-0002-6503-0011
                http://orcid.org/0000-0002-2209-5376
                http://orcid.org/0000-0002-7256-9752
                http://orcid.org/0000-0002-9605-0461
                http://orcid.org/0000-0002-1954-7220
                http://orcid.org/0000-0002-7501-1834
                http://orcid.org/0000-0002-2943-6786
                http://orcid.org/0000-0002-1343-8752
                http://orcid.org/0000-0003-2444-3247
                http://orcid.org/0000-0002-3698-6241
                Article
                4109
                10.1038/s41467-018-04109-8
                5995836
                29892050
                43926f51-99bc-4dab-bef2-83d1e92b4740
                © The Author(s) 2018

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                : 28 April 2017
                : 5 April 2018
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