Generalizability of established prostate cancer risk variants in men of African ancestry

Abstract

Genome-wide association studies have identified more than 80 risk variants for prostate cancer, mainly in European or Asian populations. The generalizability of these variants in other racial/ethnic populations needs to be understood before the loci can be used widely in risk modeling. In our study, we examined 82 previously reported risk variants in 4,853 prostate cancer cases and 4,678 controls of African ancestry. We performed association testing for each variant using logistic regression adjusted for age, study and global ancestry. Of the 82 known risk variants, 68 (83%) had effects that were directionally consistent in their association with prostate cancer risk and 30 (37%) were significantly associated with risk at p < 0.05, with the most statistically significant variants being rs116041037 (p = 3.7 × 10(-26) ) and rs6983561 (p = 1.1 × 10(-16) ) at 8q24, as well as rs7210100 (p = 5.4 × 10(-8) ) at 17q21. By exploring each locus in search of better markers, the number of variants that captured risk in men of African ancestry (p < 0.05) increased from 30 (37%) to 44 (54%). An aggregate score comprised of these 44 markers was strongly associated with prostate cancer risk [per-allele odds ratio (OR) = 1.12, p = 7.3 × 10(-98) ]. In summary, the consistent directions of effects for the vast majority of variants in men of African ancestry indicate common functional alleles that are shared across populations. Further exploration of these susceptibility loci is needed to identify the underlying biologically relevant variants to improve prostate cancer risk modeling in populations of African ancestry.

Keywords: African ancestry; generalizability; genetic risk variant; prostate cancer.

Figure 1. Effect Size Comparison of Known Risk Variants in Previous GWAS and in Men of African Ancestry

The odds ratio (OR) and 95% confidence interval (CI) for 82 known risk variants in previous GWAS and in men of African ancestry (AA). For SNPs reported in multi-stage GWAS, the OR and 95% CI from the largest replication stage was used for comparison. The red dots represent ORs in this study; the blue diamonds represent ORs in previous GWAS. The horizontal bars represent the corresponding 95% CIs. For each tested allele, frequency and statistical power (%) in AA are provided in the parentheses. The SNPs are sorted based on the ORs in AA. Detailed information for each SNP is provided in Supplementary Table S2.

Figure 2. A Regional Association Plot of the Prostate Cancer Risk Locus at Chromosome 12q13

The -log₁₀ p-values are from the association with prostate cancer risk in men of African ancestry (AA). Squares are genotyped SNPs and circles are imputed SNPs. The index SNP (rs902774), originally identified in a European GWAS, is designated by a purple square. The r² shown is estimated in Europeans from 1000 Genomes Project (1000G EUR) in relation to rs902774. Grey symbols are SNPs not in 1000G EUR (r² cannot be estimated). The top red circle represents a better marker of risk in AA (rs55958994) at this locus. The plot was generated using LocusZoom (http://csg.sph.umich.edu/locuszoom/).