Genome-wide association study of prostate-specific antigen levels in 392,522 men identifies new loci and improves cross-ancestry prediction

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 E. Eggener; Tong Lin; William J. Blot; Jirong Long; Louisa B. Goss; Burcu F. Darst; Timothy Richard Rebbeck; Joseph Lachance; Caroline V. Andrews; Akindele Olupelumi Adebiyi; Ben Adusei; Oseremen Inokhoife Aisuodionoe-Shadrach; Pedro W. Fernandez; Mohamed Jalloh; Rohini Janivara; Wenlong Carl Chen; James Edward Mensah; Ilir Agalliu; Sonja I. Berndt; John P. Shelley

doi:10.1101/2023.10.27.23297676

Genetic & Genomic MedicinemedRxivOct 27, 2023

Preprint

Genome-wide association study of prostate-specific antigen levels in 392,522 men identifies new loci and improves cross-ancestry prediction

Thomas J. Hoffmann iD, Rebecca E. Graff iD, Ravi Madduri iD, Alex A Rodriguez iD, Clinton L. Cario iD, Kun-Jiang Feng iD, Yu Jiang iD, Anqi Wang iD, Robert J. Klein iD, Brandon L. Pierce iD, Scott E. Eggener iD, Tong Lin iD, William J. Blot iD, Jirong Long iD, Louisa B. Goss iD, Burcu F. Darst iD, Timothy Richard Rebbeck iD, Joseph Lachance iD, Caroline V. Andrews iD, Akindele Olupelumi Adebiyi iD, Ben Adusei, Oseremen Inokhoife Aisuodionoe-Shadrach iD, Pedro W. Fernandez iD, Mohamed Jalloh iD, Rohini Janivara iD, , John S. Witte iD

Abstract

We conducted a multi-ancestry 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; 3,630 Asian ancestry; 96.5% of participants were from the Million Veteran Program). We identified 318 independent genome-wide significant (p[≤]5e-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%-16.6% in European ancestry, 5.5%-9.5% in African ancestry, 13.5%-18.2% in Hispanic/Latino, and 8.6%-15.3% in Asian ancestry, and decreased with increasing age. Mid-life genetically-adjusted PSA levels were more strongly associated with overall and aggressive prostate cancer than unadjusted PSA. Our study highlights how including proportionally more participants from underrepresented populations improves genetic prediction of PSA levels, offering potential to personalize prostate cancer screening.

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