Genetic hitchhiking and population bottlenecks contribute to prostate cancer disparities in men of African descent

Abstract

Prostate cancer (CaP) incidence and mortality rates in African and African American men are greatly elevated compared to other ethnicities. This disparity is likely explained by a combination of social, environmental, and genetic factors. A large number of susceptibility loci have been reported by genome-wide association studies (GWAS), but the contribution of these loci to CaP disparities is unclear. Here we investigated the population structure of 68 previously reported GWAS loci and calculated Genetic Disparity Contribution (GDC) statistics to identify SNPs that contribute the most to differences in CaP risk across populations. By integrating GWAS results with allele frequency data, we generated Genetic Risk Scores (GRS) for 45 African and 19 non-African populations. Tests of natural selection were used to assess why some SNPs have large allele frequency differences across populations. We report that genetic predictions of CaP risks are highest for West African men and lowest for East Asian men. These differences may be explained by the out-of-Africa bottleneck and natural selection. A small number of loci appear to drive elevated CaP risks in men of African descent including rs9632117, rs6983267, rs10896449, rs10993994, and rs817826. Although most CaP-associated loci are evolving neutrally, there are multiple instances where alleles have hitchhiked to high frequencies with linked adaptive alleles. For example, a protective allele at 2q37 appears to have risen to high frequency in Europe due to selection acting on pigmentation. Our results suggest that evolutionary history contributes to the high rates of CaP in African and African American men.