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

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 new polygenic risk score reached 16.9% (95% CI=16.1%-17.8%) in European ancestry, 9.5% (95% CI=7.0%-12.2%) in African ancestry, 18.6% (95% CI=15.8%-21.4%) in Hispanic/Latino, and 15.3% (95% CI=12.7%-18.1%) in Asian ancestry, and lower for higher age. Our study highlights how including proportionally more participants from underrepresented populations improves genetic prediction of PSA levels, with potential to personalize prostate cancer screening. ### Competing Interest Statement JSW and CLC are non-employee co-founders of Avail Bio. HL is named on a patent for intact PSA assays and a patent for a statistical method to detect prostate cancer that is licensed to and commercialized by OPKO Health. HL receives royalties from sales of the test and has stock in OPKO Health. ### Funding Statement The Precision PSA study is supported by funding from the National Institutes of Health (NIH) National Cancer Institute (NCI) under award number R01CA241410 (PI: JSW) and U01CA261339 (MPI: JSW). LK is supported by funding from the National Cancer Institute (R00CA246076). REG is supported by a Young Investigator Award from the Prostate Cancer Foundation. HL is supported in part by NIH/NCI by a Cancer Center Support Grant to Memorial Sloan Kettering Cancer Center (P30 CA008748, PI: Vickers, S), U01-CA266535 (PI: Carlsson, S), R01-CA244948 (PI: RJK), and Swedish Cancer Society (Cancerfonden 20 1354 PJF; PI: HL). This work was supported by research grants from the NIH National Institute of General Medical Sciences (NIGMS) under award number R01GM130791 (PI: JDM); the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai; the Office of Research Infrastructure of the National Institutes of Health under award number S10OD026880 and NIH/NCI funding (R01CA175491, R01CA244948; PI: RJK); the National Cancer Institute of the National Institutes of Health (UM1CA182883, PI: CM Tangen/IM Thompson; U10CA37429, PI: CD Blanke). MADCaP was supported by U01CA184374 (PI: TR). COMPASS was supported by P30CA014599. Support for GERA participant enrollment, survey completion, and biospecimen collection for RPGEH was provided by the Robert Wood Johnson Foundation, the Wayne and Gladys Valley Foundation, the Ellison Medical Foundation, and Kaiser Permanente national and regional benefit programs. GERA genotyping was funded by National Institute on Aging and NIH Common Fund (grant RC2 AG-036607 to Cathy Schaeffer and Neil Risch). The All of Us Research Program is supported by the National Institutes of Health, Office of the Director: Regional Medical Centers: 1 OT2 OD026549; 1 OT2 OD026554; 1 OT2 OD026557; 1 OT2 OD026556; 1 OT2 OD026550; 1 OT2 OD 026552; 1 OT2 OD026553; 1 OT2 OD026548; 1 OT2 OD026551; 1 OT2 OD026555; IAA #: AOD 16037; Federally Qualified Health Centers: HHSN 263201600085U; Data and Research Center: 5 U2C OD023196; Biobank: 1 U24 OD023121; The Participant Center: U24 OD023176; Participant Technology Systems Center: 1 U24 OD023163; Communications and Engagement: 3 OT2 OD023205; 3 OT2 OD023206; and Community Partners: 1 OT2 OD025277; 3 OT2 OD025315; 1 OT2 OD025337; 1 OT2 OD025276. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funders had no role in study design, data collection and analysis, the decision to publish, or preparation of the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: VA Central IRB of the VA gave ethical approval for this work. Vanderbilt University IRB of Vanderbilt University gave ethical approval for this work. The Meharry Medical College IRB of the Meharry Medical College gave ethical approval for this work. The Kaiser Permanente Northern California Institutional Review Board of Kaiser Permanente gave ethical approval for this work. The University of California Institutional Review Board of the University of California gave ethical approval for this work. The North West Multi-centre Research Ethics Committee of the UK Biobank gave ethical approval for this work. The Institutional Review Boards at each participating center of the National Cancer Institute gave ethical approval for this work. The Vanderbilt University Medical Center of the Vanderbilt University gave ethical approval for this work. The local ethics committe of the Malmo Diet and Cancer Study gave ethical approval for this work. The University of Chicago Biological Sciences Division Institutional Review Board Committee A of the University of Chicago gave ethical approval for this work. Local and national institutional review boards of MadCAP gave ethical approval for this work. The ethics review board of the Program for the Protection of Human Subjects of Mount Sinai School of Medicine of umount Sinia School of Medicine gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes