Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction

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.

Admixed Populations Improve Power for Variant Discovery and Portability in Genome-Wide Association Studies

“…In addition, complex traits in admixed groups potentially harbor differing genetic architectures and varying environmental exposures compared to most widely studied groups such as Europeans. Some biomedical traits have higher risk prevalence in admixed groups, such as prostate cancer in African Americans ( Bhardwaj et al, 2017 ; Conti et al, 2021 ), asthma in Puerto Ricans ( Lara et al, 2006 ; Pino-Yanes et al, 2015 ), obesity and type II diabetes in Native Hawaiians ( Maskarinec et al, 2009 ), and active tuberculosis in a South African admixed population ( Chimusa et al, 2014 ), which are likely attributed to elevated ancestry-specific risk allele frequency. Among anthropometric traits, skin pigmentation in groups with admixed ancestry harbor greater phenotypic variance than those with single ancestries ( Martin et al, 2017b ).…”

Immune Inflammation Pathways as Therapeutic Targets to Reduce Lethal Prostate Cancer in African American Men

“…This observation led to the hypothesis that ancestral factors may predispose men of sub-Saharan African ancestry to prostate cancer and a more aggressive disease [3,19]. Recent observations revealing the association of genetic ancestral factors with prostate cancer risk support this hypothesis [20][21][22][23][24]. Moreover, men of African ancestry are at an increased risk of developing fatal prostate cancer in the United States and England [2] and present with more aggressive disease in the Caribbean and sub-Saharan Africa [3,25].…”

Germline Genetics of Prostate Cancer: Prevalence of Risk Variants and Clinical Implications for Disease Management

“…or in the PCa-specific risk genes, HOXB13 [ 7 , 8 ]. Apart from these moderate-to-high risk genes, GWAS using panels of genome-spanning SNVs have identified ~269 low-risk variants associated with prostate cancer incidence, including multiple loci in the 8q24 region, 17q region, and other chromosomes [ 8 , 9 , 10 , 11 ]. Polygenic risk scores based on inherited SNVs have been developed for risk stratification and screening [ 12 , 13 , 14 , 15 ]; however, their clinical utility for risk assessment, or guiding screening or treatment recommendations remains to be investigated in ongoing studies.…”