Abstract 1054: A combined genome-wide-association and admixture analysis of prostate cancer risk in men of African ancestry in the <i>All of Us</i> Research Program

Men of African ancestry are known to suffer increased rates of prostate cancer incidence and mortality. While many studies have identified common variants that are specific to, or at elevated frequency in African populations, the genetic basis of this healthcare disparity remains to be fully worked out. Admixture analysis is a computational tool for identifying local genetic ancestry across individual genomes, and is potentially useful for detecting shared, disease-associated haplotypes in populations, such as African Americans, who derive from multiple ancestry groups. Our hypothesis was that genome-wide admixture mapping could be used as a proxy for a genome-wide linkage scan in unrelated individuals, so that a direct comparison of the loci implicated by genome-wide association studies (GWAS) and linkage analysis could be made. To this end, we conducted a case-control GWAS, and a cases-only admixture mapping in 8,957 men at least fifty years-old of African ancestry (578 cases, 8,379 controls) in the All of Us Research Program. In total, we tested 5,856,945 common polymorphisms and indels (MAF ≥ 0.05), and found a genome-wide significant variant rs73705708 (P = 8.8 × 10−13) at the previously implicated 8q24 locus. We then conducted admixture analysis using RFMix v. 2.0, with phased input being supplied by Beagle v. 5.4, and detected a statistically significant increase in local European ancestry (Z &amp;lt; −6) in the 14q23 region near the GPHN gene, as well as a statistically significant increase in local African ancestry (Z &amp;gt; 4) near the HLA region at 6p22; neither region was implicated by the GWAS. And although we observed a nominally significant peak (Z &amp;gt; 3) as expected in the 8q24 region, we overall found little correlation (R2 = 0.0003) between GWAS P-value and admixture Z-score in our cohort. These results support the hypothesis that regions of the genome inherited from a common ancestral population represent a distinct set of risk loci to those identified by GWAS, and suggest that the genetic basis of prostate cancer risk and disparities may have additional unidentified contributions. The authors of this study gratefully acknowledge All of Us participants for their contributions, without whom this research would not have been possible, and the National Institutes of Health’s All of Us Research Program, for making available the participant data examined in this study. All data used in this study came from All of Us Research Program’s Controlled Tier Dataset v. 7, available to authorized users on the Researcher Workbench. Citation Format: William Letsou, David Mushiyev, Daniel Galvin Gusmano. A combined genome-wide-association and admixture analysis of prostate cancer risk in men of African ancestry in the All of Us Research Program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1054.