Genome-wide association study of prostate-specific antigen levels in 392,522 men identifies new loci and improves prediction across ancestry groups
Thomas J. Hoffmann, Rebecca E. Graff, Ravi Madduri, Alex A Rodriguez, Clinton L. Cario, Kun-Jiang Feng, Yu Jiang, Anqi Wang, Robert J. Klein, Brandon L. Pierce, Scott Eggener, Tong Lin, William J. Blot, Jirong Long, Louisa B. Goss, Burcu F. Darst, Timothy R. Rebbeck, Joseph Lachance, Caroline Andrews, Akindele O. Adebiyi, Ben Adusei, Oseremen I. Aisuodionoe-Shadrach, P. Fernandez, Mohamed Jalloh, Rohini Janivara, Wenlong Carl 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 M. Thompson, Hans Lilja, Dilrini K. Ranatunga, Joseph C. 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
Abstract
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. This study shows how including different ancestry groups in a genome-wide association study for prostate-specific antigen levels can improve prostate cancer risk prediction, with implications for population screening.