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Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction

Conti DV 1 , Darst BF 1 , Moss LC 1 , Saunders EJ 2 , Sheng X 1 , Chou A 1 Show all authors , Schumacher FR 3 , Olama AAA 4 , Benlloch S 4 , Dadaev T 2 , Brook MN 2 , Sahimi A 1 , Hoffmann TJ 5 , Takahashi A 6 , Matsuda K 7 , Momozawa Y 8 , Fujita M 9 , Muir K 10 , Lophatananon A 10 , Wan P 1 , Le Marchand L 11 , Wilkens LR 11 , Stevens VL 12 , Gapstur SM 12 , Carter BD 12 , Schleutker J 13 , Tammela TLJ 14 , Sipeky C 13 , Auvinen A 15 , Giles GG 16 , Southey MC 17 , MacInnis RJ 16 , Cybulski C 18 , Wokołorczyk D 18 , Lubiński J 18 , Neal DE 19 , Donovan JL 20 , Hamdy FC 21 , Martin RM 20 , Nordestgaard BG 22 , Nielsen SF 22 , Weischer M 23 , Bojesen SE 22 , Røder MA 24 , Iversen P 24 , Batra J 25 , Chambers S 26 , Moya L 25 , Horvath L 27 , Clements JA 25 , Tilley W 28 , Risbridger GP 29 , Gronberg H 30 , Aly M 30 , Szulkin R 30 , Eklund M 30 , Nordström T 30 , Pashayan N 31 , Dunning AM 32 , Ghoussaini M 33 , Travis RC 34 , Key TJ 34 , Riboli E 35 , Park JY 36 , Sellers TA 36 , Lin HY 37 , Albanes D 38 , Weinstein SJ 38 , Mucci LA 39 , Giovannucci E 39 , Lindstrom S 40 , Kraft P 41 , Hunter DJ 42 , Penney KL 43 , Turman C 41 , Tangen CM 44 , Goodman PJ 44 , Thompson IM 45 , Hamilton RJ 46 , Fleshner NE 46 , Finelli A 47 , Parent MÉ 48 , Stanford JL 49 , Ostrander EA 50 , Geybels MS 49 , Koutros S 38 , Freeman LEB 38 , Stampfer M 43 , Wolk A 51 , Håkansson N 51 , Andriole GL 52 , Hoover RN 38 , Machiela MJ 38 , Sørensen KD 53 , Borre M 54 , Blot WJ 55 , Zheng W 55 , Yeboah ED 56 , Mensah JE 56 , Lu YJ 57 , Zhang HW 58 , Feng N 59 , Mao X 57 , Wu Y 60 , Zhao SC 61 , Sun Z 62 , Thibodeau SN 63 , McDonnell SK 64 , Schaid DJ 64 , West CML 65 , Burnet N 66 , Barnett G 67 , Maier C 68 , Schnoeller T 69 , Luedeke M 70 , Kibel AS 71 , Drake BF 52 , Cussenot O 72 , Cancel-Tassin G 72 , Menegaux F 73 , Truong T 73 , Koudou YA 74 , John EM 75 , Grindedal EM 76 , Maehle L 76 , Khaw KT 77 , Ingles SA 78 , Stern MC 78 , Vega A 79 , Gómez-Caamaño A 80 , Fachal L 4 , Rosenstein BS 81 , Kerns SL 82 , Ostrer H 83 , Teixeira MR 84 , Paulo P 84 , Brandão A 84 , Watya S 85 , Lubwama A 85 , Bensen JT 86 , Fontham ETH 38 , Mohler J 87 , Taylor JA 88 , Kogevinas M 89 , Llorca J 90 , Castaño-Vinyals G 89 , Cannon-Albright L 91 , Teerlink CC 91 , Huff CD 92 , Strom SS 92 , Multigner L 93 , Blanchet P 94 , Brureau L 94 , Kaneva R 95 , Slavov C 96 , Mitev V 95 , Leach RJ 97 , Weaver B 97 , Brenner H 98 , Cuk K 98 , Holleczek B 99 , Saum KU 98 , Klein EA 100 , Hsing AW 101 , Kittles RA 102 , Murphy AB 103 , Logothetis CJ 104 , Kim J 104 , Neuhausen SL 105 , Steele L 105 , Ding YC 105 , Isaacs WB 106 , Nemesure B 107 , Hennis AJM 107 , Carpten J 108 , Pandha H 109 , Michael A 109 , De Ruyck K 110 , De Meerleer G 111 , Ost P 111 , Xu J 112 , Razack A 113 , Lim J 113 , Teo SH 114 , Newcomb LF 115 , Lin DW 115 , Fowke JH 116 , Neslund-Dudas C 117 , Rybicki BA 117 , Gamulin M 118 , Lessel D 119 , Kulis T 120 , Usmani N 121 , Singhal S 121 , Parliament M 121 , Claessens F 122 , Joniau S 123 , Van den Broeck T 122 , Gago-Dominguez M 124 , Castelao JE 125 , Martinez ME 126 , Larkin S 127 , Townsend PA 109 , Aukim-Hastie C 109 , Bush WS 128 , Aldrich MC 129 , Crawford DC 128 , Srivastava S 130 , Cullen JC 130 , Petrovics G 130 , Casey G 131 , Roobol MJ 132 , Jenster G 132 , van Schaik RHN 133 , Hu JJ 134 , Sanderson M 135 , Varma R 136 , McKean-Cowdin R 1 , Torres M 136 , Mancuso N 1 , Berndt SI 38 , Van Den Eeden SK 137 , Easton DF 4 , Chanock SJ 38 , Cook MB 38 , Wiklund F 30 , Nakagawa H 9 , Witte JS 5 , Eeles RA 2 , Kote-Jarai Z 2 , Haiman CA 138

Affiliations 

  • 1 Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA
  • 2 The Institute of Cancer Research, London, UK
  • 3 Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA
  • 4 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
  • 5 Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA
  • 6 Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
  • 7 Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
  • 8 Laboratory for Genotyping Development, RIKEN Center of Integrative Medical Sciences, Yokohama, Japan
  • 9 Laboratory for Cancer Genomics, RIKEN Center of Integrative Medical Sciences, Yokohama, Japan
  • 10 Division of Population Health, Health Services Research and Primary Care, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
  • 11 Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
  • 12 Behavioral and Epidemiology Research Group, Research Program, American Cancer Society, Atlanta, GA, USA
  • 13 Institute of Biomedicine, University of Turku, Turku, Finland
  • 14 Department of Urology, Tampere University Hospital and Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
  • 15 Unit of Health Sciences, Faculty of Social Sciences, Tampere University, Tampere, Finland
  • 16 Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
  • 17 Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
  • 18 International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  • 19 Nuffield Department of Surgical Sciences, University of Oxford, John Radcliffe Hospital, Oxford, UK
  • 20 Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
  • 21 Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
  • 22 Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  • 23 Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark
  • 24 Copenhagen Prostate Cancer Center, Department of Urology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  • 25 Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia
  • 26 University of Technology, Sydney, New South Wales, Australia
  • 27 Chris O'Brien Lifehouse (COBLH), Camperdown, Sydney, New South Wales, Australia
  • 28 Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia
  • 29 Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia
  • 30 Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
  • 31 Department of Applied Health Research, University College London, London, UK
  • 32 Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Strangeways Laboratory, Cambridge, UK
  • 33 Open Targets, Wellcome Sanger Institute, Hinxton, UK
  • 34 Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
  • 35 Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
  • 36 Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA
  • 37 School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, USA
  • 38 Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA
  • 39 Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA
  • 40 Department of Epidemiology, University of Washington, Seattle, WA, USA
  • 41 Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA
  • 42 Nuffield Department of Population Health, University of Oxford, Oxford, UK
  • 43 Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, MA, USA
  • 44 SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
  • 45 CHRISTUS Santa Rosa Hospital - Medical Center, San Antonio, TX, USA
  • 46 Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
  • 47 Division of Urology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
  • 48 Epidemiology and Biostatistics Unit, Centre Armand-Frappier Santé Biotechnologie, Institut National de la Recherche Scientifique, Laval, Quebec, Canada
  • 49 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
  • 50 National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
  • 51 Division of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
  • 52 Washington University School of Medicine, St Louis, MI, USA
  • 53 Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
  • 54 Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
  • 55 Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
  • 56 University of Ghana Medical School, Accra, Ghana
  • 57 Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, London, UK
  • 58 Second Military Medical University, Shanghai, China
  • 59 Wuxi Second Hospital, Nanjing Medical University, Wuxi, China
  • 60 Department of Urology, First Affiliated Hospital, The Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
  • 61 Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, China
  • 62 The People's Hospital of Liaoning Province, The People's Hospital of China Medical University, Shenyang, China
  • 63 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
  • 64 Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
  • 65 Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Radiotherapy Related Research, The Christie Hospital NHS Foundation Trust, Manchester, UK
  • 66 Division of Cancer Sciences, University of Manchester, Manchester Cancer Research Centre, Manchester Academic Health Science Centre, and The Christie NHS Foundation Trust, Manchester, UK
  • 67 University of Cambridge Department of Oncology, Oncology Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
  • 68 Humangenetik Tuebingen, Tuebingen, Germany
  • 69 Department of Urology, University Hospital, Ulm, Germany
  • 70 genetikum, Neu-Ulm, Germany
  • 71 Division of Urologic Surgery, Brigham and Womens Hospital, Boston, MA, USA
  • 72 Sorbonne Universite, Tenon Hospital, Paris, France
  • 73 Exposome and Heredity, CESP (UMR 1018), Paris-Saclay Medical School, Paris-Saclay University, Inserm, Gustave Roussy, Villejuif, France
  • 74 CESP (UMR 1018), Paris-Saclay Medical School, Paris-Saclay University, Inserm, Villejuif, France
  • 75 Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA
  • 76 Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
  • 77 Clinical Gerontology Unit, University of Cambridge, Cambridge, UK
  • 78 Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA
  • 79 Fundación Pública Galega Medicina Xenómica, Santiago De Compostela, Spain
  • 80 Department of Radiation Oncology, Complexo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain
  • 81 Department of Radiation Oncology and Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  • 82 Department of Radiation Oncology, University of Rochester Medical Center, Rochester, NY, USA
  • 83 Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA
  • 84 Department of Genetics, Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal
  • 85 Uro Care, Kampala, Uganda
  • 86 Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
  • 87 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
  • 88 Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
  • 89 ISGlobal, Barcelona, Spain
  • 90 CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
  • 91 Division of Epidemiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA
  • 92 Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
  • 93 University of Rennes, Inserm, EHESP, Irset (Research Institute for Environmental and Occupational Health), Rennes, France
  • 94 CHU de Pointe-à-Pitre, University of the French Antilles, University of Rennes, Inserm, EHESP, Irset (Research Institute for Environmental and Occupational Health), Pointe-à-Pitre, France
  • 95 Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University of Sofia, Sofia, Bulgaria
  • 96 Department of Urology and Alexandrovska University Hospital, Medical University of Sofia, Sofia, Bulgaria
  • 97 Department of Urology, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
  • 98 Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 99 Saarland Cancer Registry, Saarbrücken, Germany
  • 100 Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA
  • 101 Department of Medicine and Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA
  • 102 Division of Health Equities, Department of Population Sciences, City of Hope, Duarte, CA, USA
  • 103 Department of Urology, Northwestern University, Chicago, IL, USA
  • 104 Department of Genitourinary Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
  • 105 Department of Population Sciences, Beckman Research Institute of the City of Hope, Duarte, CA, USA
  • 106 James Buchanan Brady Urological Institute, Johns Hopkins Hospital and Medical Institution, Baltimore, MD, USA
  • 107 Department of Family, Population and Preventive Medicine, Stony Brook University, Stony Brook, NY, USA
  • 108 Department of Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
  • 109 Faculty of Health and Medical Sciences, The University of Surrey, Guildford, UK
  • 110 Department of Basic Medical Sciences, Faculty of Medicine and Health Sciences, Ghent University, Gent, Belgium
  • 111 Department of Radiotherapy, Ghent University Hospital, Gent, Belgium
  • 112 Program for Personalized Cancer Care and Department of Surgery, NorthShore University HealthSystem, Evanston, IL, USA
  • 113 Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 114 Cancer Research Malaysia (CRM), Outpatient Centre, Subang Jaya Medical Centre, Subang Jaya, Malaysia
  • 115 Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA
  • 116 Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
  • 117 Department of Public Health Sciences, Henry Ford Hospital, Detroit, MI, USA
  • 118 Department of Oncology, University Hospital Centre Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia
  • 119 Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • 120 Department of Urology, University Hospital Center Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia
  • 121 Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada
  • 122 Molecular Endocrinology Laboratory, Department of Cellular and Molecular Medicine, Leuven, Belgium
  • 123 Department of Urology, University Hospitals Leuven, Leuven, Belgium
  • 124 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
  • 125 Genetic Oncology Unit, CHUVI Hospital, Complexo Hospitalario Universitario de Vigo, Instituto de Investigación Biomédica Galicia Sur (IISGS), Vigo, Spain
  • 126 Moores Cancer Center, Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA
  • 127 The University of Southampton, Southampton General Hospital, Southampton, UK
  • 128 Cleveland Institute for Computational Biology, Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA
  • 129 Department of Thoracic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
  • 130 Center for Prostate Disease Research, Uniformed Services University, Bethesda, MD, USA
  • 131 Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
  • 132 Department of Urology, Erasmus University Medical Center, Rotterdam, the Netherlands
  • 133 Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, the Netherlands
  • 134 The University of Miami School of Medicine, Sylvester Comprehensive Cancer Center, Miami, FL, USA
  • 135 Department of Family and Community Medicine, Meharry Medical College, Nashville, TN, USA
  • 136 Southern California Eye Institute, CHA Hollywood Presbyterian Medical Center, Los Angeles, CA, USA
  • 137 Division of Research, Kaiser Permanente, Northern California, Oakland, CA, USA
  • 138 Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA. haiman@usc.edu
Nat Genet, 2021 Jan;53(1):65-75.
PMID: 33398198 DOI: 10.1038/s41588-020-00748-0

Abstract

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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