We conducted a multiancestry genome-wide association study of prostate-specific antigen (PSA) levels in 296,754 men (211,342 European ancestry, 58,236 African ancestry, 23,546 Hispanic/Latino and 3,630 Asian ancestry; 96. 5% of participants were from the Million Veteran Program). We identified 318 independent genome-wide significant (P ≤ 5 × 10-8) variants, 184 of which were novel. Most demonstrated evidence of replication in an independent cohort (n = 95,768). Meta-analyzing discovery and replication (n = 392,522) identified 447 variants, of which a further 111 were novel. Out-of-sample variance in PSA explained by our genome-wide polygenic risk scores ranged from 11.6% to 16.6% for European ancestry, 5.5% to 9.5% for African ancestry, 13.5% to 18.2% for Hispanic/Latino and 8.6% to 15.3% for Asian ancestry and decreased with increasing age. Midlife genetically adjusted PSA levels were more strongly associated with overall and aggressive prostate cancer than unadjusted PSA levels. Our study highlights how including proportionally more participants from underrepresented populations improves genetic prediction of PSA levels, offering potential to personalize prostate cancer screening.
Nature genetics. 2025 Feb 10 [Epub ahead of print]
Thomas J Hoffmann, Rebecca E Graff, Ravi K Madduri, Alex A Rodriguez, Clinton L Cario, Karen Feng, Yu Jiang, Anqi Wang, Robert J Klein, Brandon L Pierce, Scott Eggener, Lin Tong, William Blot, Jirong Long, Louisa B Goss, Burcu F Darst, Timothy Rebbeck, Joseph Lachance, Caroline Andrews, Akindele O Adebiyi, Ben Adusei, Oseremen I Aisuodionoe-Shadrach, Pedro W Fernandez, Mohamed Jalloh, Rohini Janivara, Wenlong C Chen, James E Mensah, Ilir Agalliu, Sonja I Berndt, John P Shelley, Kerry Schaffer, Mitchell J Machiela, Neal D Freedman, Wen-Yi Huang, Shengchao A Li, Phyllis J Goodman, Cathee Till, Ian Thompson, Hans Lilja, Dilrini K Ranatunga, Joseph Presti, Stephen K Van Den Eeden, Stephen J Chanock, Jonathan D Mosley, David V Conti, Christopher A Haiman, Amy C Justice, Linda Kachuri, John S Witte
Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA., Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA., Data Science and Learning Division, Argonne National Laboratory, Argonne, IL, USA., Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, USA., Department of Biomedical Data Science, Stanford University, Stanford, CA, USA., Center for Genetic Epidemiology, Department of Population and Preventive Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Department of Public Health Sciences, University of Chicago, Chicago, IL, USA., Comprehensive Cancer Center, University of Chicago, Chicago, IL, USA., Division of Epidemiology, Vanderbilt University Medical Center, Nashville, TN, USA., Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA., Dana Farber Cancer Institute, Harvard T.H. Chan School of Public Health, Boston, MA, USA., School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, USA., Department of Community Medicine, College of Medicine, University of Ibadan, Ibadan, Nigeria., 37 Military Hospital, Accra, Ghana., College of Health Sciences, University of Abuja, Abuja, Nigeria., Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa., Hospital General Idrissa Pouye, Dakar, Senegal., Strengthening Oncology Services Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa., Korle-Bu Teaching Hospital and University of Ghana Medical School, Accra, Ghana., Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, NY, USA., Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA., Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA., Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN, USA., SWOG Statistics and Data Management Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., CHRISTUS Santa Rosa Medical Center Hospital, San Antonio, TX, USA., Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Kaiser Permanente Research Bank, Oakland, CA, USA., Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA., Veterans Administration Connecticut Healthcare System, West Haven, CT, USA., Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, USA. ., Department of Epidemiology and Population Health, Stanford University School of Medicine, Stanford, CA, USA. .