Prostate cancer genetic risk and associated aggressive disease in men of African ancestry

African ancestry is a significant risk factor for prostate cancer and advanced disease. Yet, genetic studies have largely been conducted outside the context of Sub-Saharan Africa, identifying 278 common risk variants contributing to a multiethnic polygenic risk score, with rare variants focused on a panel of roughly 20 pathogenic genes. Based on this knowledge, we are unable to determine polygenic risk or differentiate prostate cancer status interrogating whole genome data for 113 Black South African men. To further assess for potentially functional common and rare variant associations, here we interrogate 247,780 exomic variants for 798 Black South African men using a case versus control or aggressive versus non-aggressive study design. Notable genes of interest include HCP5, RFX6 and H3C1 for risk, and MKI67 and KLF5 for aggressive disease. Our study highlights the need for further inclusion across the African diaspora to establish African-relevant risk models aimed at reducing prostate cancer health disparities.Co-founding SAPCS members the late Professor Philip A. Venter and retired urologist Dr. Richard Monare from the University of Limpopo in South Africa, as well as the Medical Research Council (MRC) of South Africa for SAPCS seed-funding; supported by a Cancer Association of South Africa (CANSA), the National Health and Medical Research Council (NHMRC) of Australia, Ideas grants, the U.S.A. Congressionally Directed Medical Research Programs (CDMRP) Prostate Cancer Research Program (PCRP) through an Idea Development Award, HEROIC Consortium Award, and the Petre Foundation via the University of Sydney Foundation, Australia.https://www.nature.com/ncomms/am2024School of Health Systems and Public Health (SHSPH)SDG-03:Good heatlh and well-bein