Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry
Year: 2023
Type: article
Study design: Observational Study
Abstract: Genome-wide polygenic risk scores (GW-PRS) have been reported to have better predictive ability than PRS based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer risk variants from multi-ancestry GWAS and fine-mapping studies (PRS 269 ). GW-PRS models were trained using a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls used to develop the multi-ancestry PRS 269 . Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California/Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI=0.635-0.677) in African and 0.844 (95% CI=0.840-0.848) in European ancestry men and corresponding prostate cancer OR of 1.83 (95% CI=1.67-2.00) and 2.19 (95% CI=2.14-2.25), respectively, for each SD unit increase in the GW-PRS. However, compared to the GW-PRS, in African and European ancestry men, the PRS 269 had larger or similar AUCs (AUC=0.679, 95% CI=0.659-0.700 and AUC=0.845, 95% CI=0.841-0.849, respectively) and comparable prostate cancer OR (OR=2.05, 95% CI=1.87-2.26 and OR=2.21, 95% CI=2.16-2.26, respectively). Findings were similar in the validation data. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the multi-ancestry PRS 269 constructed with fine-mapping.
Authors: Burcu F. Darst, Jiayi Shen, Ravi K. Madduri, Alexis A. Rodriguez, Yukai Xiao, Xin Sheng, Edward J. Saunders, Tokhir Dadaev, Mark N. Brook, Thomas J. Hoffmann, Kenneth Muir, Peggy Wan, Loic Le Marchand, Lynne Wilkens, Ying Wang, Johanna Schleutker, Robert J. MacInnis, Cezary Cybulski, David E. Neal, Børge G. Nordestgaard, Sune F. Nielsen, Jyotsna Batra, Judith A. Clements, Australian Prostate Cancer BioResource, Henrik Grönberg, Nora Pashayan, Ruth C. Travis, Jong Y. Park, Demetrius Albanes, Stephanie Weinstein, Lorelei A. Mucci, David J. Hunter, Kathryn L. Penney, Catherine M. Tangen, Robert J. Hamilton, Marie-Élise Parent, Janet L. Stanford, Stella Koutros, Alicja Wolk, Karina D. Sørensen, William J. Blot, Edward D. Yeboah, James E. Mensah, Yong-Jie Lu, Daniel J. Schaid, Stephen N. Thibodeau, Catharine M. West, Christiane Maier, Adam S. Kibel, Géraldine Cancel-Tassin, Florence Menegaux, Esther M. John, Eli Marie Grindedal, Kay-Tee Khaw, Sue A. Ingles, Ana Vega, Barry S. Rosenstein, Manuel R. Teixeira, NC-LA PCaP Investigators, Manolis Kogevinas, Lisa Cannon-Albright, Chad Huff, Luc Multigner, Radka Kaneva, Robin J. Leach, Hermann Brenner, Ann W. Hsing, Rick A. Kittles, Adam B. Murphy, Christopher J. Logothetis, Susan L. Neuhausen, William B. Isaacs, Barbara Nemesure, Anselm J. Hennis, John Carpten, Hardev Pandha, Kim De Ruyck, Jianfeng Xu, Azad Razack, Soo-Hwang Teo, Canary PASS Investigators, Lisa F. Newcomb, Jay H. Fowke, Christine Neslund-Dudas, Benjamin A. Rybicki, Marija Gamulin, Nawaid Usmani, Frank Claessens, Manuela Gago-Dominguez, Jose Esteban Castelao, Paul A. Townsend, Dana C. Crawford, Gyorgy Petrovics, Graham Casey, Monique J. Roobol, Jennifer F. Hu, Sonja I. Berndt, Stephen K. Van Den Eeden, Douglas F. Easton, Stephen J. Chanock, Michael B. Cook, Fredrik Wiklund, John S. Witte, Rosalind A. Eeles, Zsofia Kote-Jarai, Stephen Watya, John M. Gaziano, Amy C. Justice, David V. Conti, Christopher A. Haiman
Institutions: University of Southern California, Fred Hutch Cancer Center, Argonne National Laboratory, Institute of Cancer Research, University of California, San Francisco, University of Manchester, University of Hawaii Cancer Center, American Cancer Society, University of Turku, The University of Melbourne, Cancer Council Victoria, International Hereditary Cancer Center, Pomeranian Medical University, University of Cambridge, Cancer Research UK, John Radcliffe Hospital, University of Oxford, Cancer Research UK Cambridge Center, Addenbrooke's Hospital, University of Copenhagen, Herlev Hospital, Copenhagen University Hospital, Gentofte Hospital, Translational Research Institute, Queensland University of Technology, Chris O’Brien Lifehouse, The Kinghorn Cancer Centre, Monash University, The University of Adelaide, Karolinska Institutet, University College London, Moffitt Cancer Center, Division of Cancer Epidemiology and Genetics, Harvard University, Brigham and Women's Hospital, University of Toronto, Princess Margaret Cancer Centre, Institut National de la Recherche Scientifique, Université de Montréal, University of Washington, Uppsala University, Aarhus University, Aarhus University Hospital, Vanderbilt University, International Epidemiology Institute, Vanderbilt University Medical Center, University of Ghana, Korle Bu Teaching Hospital, Queen Mary University of London, Barts Cancer Institute, Mayo Clinic, Manchester Academic Health Science Centre, The Christie Hospital, The Christie NHS Foundation Trust, Sorbonne Université, Hôpital Tenon, Onco-Urologie Prédictive, Inserm, Université Paris-Saclay, Centre de recherche en Epidémiologie et Santé des Populations, Stanford Medicine, Stanford Cancer Institute, Stanford University, Oslo University Hospital, Centre for Biomedical Network Research on Rare Diseases, Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago, Icahn School of Medicine at Mount Sinai, Universidade do Porto, IPO Porto, Instituto de Ciências Biomédicas Albel Salazar, Universitat Pompeu Fabra, Municipal Institute for Medical Research, Barcelona Institute for Global Health, Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública, Hospital del Mar Research Institute, University of Utah, George E. Wahlen Department of VA Medical Center, The University of Texas MD Anderson Cancer Center, École des Hautes Études en Santé Publique, Institut de Recherche en Santé, Environnement et Travail, Université de Rennes, Medical University of Sofia, The University of Texas at San Antonio Health Science Center, German Cancer Research Center, National Center for Tumor Diseases, Deutsches Konsortium für Translationale Krebsforschung, City Of Hope National Medical Center, City of Hope, Northwestern University, Beckman Research Institute, Johns Hopkins University, Johns Hopkins Hospital, Stony Brook University, University of the West Indies, University of Surrey, Ghent University, Endeavor Health, University of Malaya, Cancer Research Malaysia, Subang Jaya Medical Centre, University of Tennessee Health Science Center, Henry Ford Health, Henry Ford Hospital, University Hospital Centre Zagreb, University of Zagreb, University of Alberta, Cross Cancer Institute, KU Leuven, Complejo Hospitalario Universitario de Santiago, Servicio Gallego de Salud, Moores Cancer Center, University Hospital Complex Of Vigo, Health Innovation Manchester, NIHR Manchester Biomedical Research Centre, Cancer Research UK Manchester Centre, Case Western Reserve University, Uniformed Services University of the Health Sciences, University of Virginia, Erasmus MC, Erasmus MC Cancer Institute, University of Miami, Sylvester Comprehensive Cancer Center, Kaiser Permanente, Kaiser Permanente Northern California, Royal Marsden NHS Foundation Trust, Makerere University, VA Boston Healthcare System, Yale University, VA Connecticut Healthcare System
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
Funders: Prostate Cancer Foundation, Fred Hutchinson Cancer Research Center, Office of Research and Development, Health Services Research and Development, University of Washington, Andy Hill CARE Fund, Cancer Research UK, National Institutes of Health, Medical Research Council, National Cancer Institute, National Center for Advancing Translational Sciences
Awards: G1044130170, G1121368709, G1740625458, G2197093662, G3341328273, Elucidating Loci Involved in Prostate Cancer Suceptibility, G3772185282, G4123960777, G4332769686, G4546625446, G4610789202, G5229491074, G5271742736, G6566571199, G6594529311, G798245942, G8364336973, G8937490936, G9000062987, G9000165364, G9000291011, G9000343765
OpenAlex ID: W4380322075