Abstract: Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 [95% confidence interval (CI) 4.84?5.29] for men of European ancestry to 3.74 [95% CI 3.36?4.17] for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher [95% CI 2.14?2.22], and men of East Asian ancestry 0.73-times lower [95% CI 0.71?0.76], than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction. Prostate cancer incidence varies across ancestry groups and is approximately 75% higher in African Americans and 45% lower in Asians, compared with non-Hispanic Whites.1 Age, family history of prostate cancer and germline variation are the most established risk factors for prostate cancer, with as much as 57% of the variability in prostate cancer risk estimated to be due to genetic factors.2 Accordingly, it is hypothesized that genetic factors are likely to contribute, in part, to population disparities in prostate cancer incidence.3 Genome-wide association and fine-mapping studies of prostate cancer have been conducted mainly in populations of European ancestry and have discovered ~180 germline risk variants for prostate cancer, with some more frequent in specific populations.4?14 Genetic risk scores (GRS) comprised of these variants have been demonstrated to identify men at higher risk of prostate cancer; however, they have been developed and optimized for populations of European ancestry. In this study, we combined data from genome-wide association studies (GWAS) for 107,247 prostate cancer cases and 127,006 controls, including men from European, African, East Asian and Hispanic populations, to identify common genetic variants associated with disease risk across populations. We also developed a GRS for prostate cancer to evaluate risk stratification due to genetic factors across population groups, with GRS validation conducted in two independent studies. Based on the GRS, we estimated relative prostate cancer risks for difference population groups as well as lifetime and age-specific absolute risks of prostate cancer due to genetic factors.

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