Characterizing genetic risk at known prostate cancer susceptibility loci in African Americans

Abstract

GWAS of prostate cancer have been remarkably successful in revealing common genetic variants and novel biological pathways that are linked with its etiology. A more complete understanding of inherited susceptibility to prostate cancer in the general population will come from continuing such discovery efforts and from testing known risk alleles in diverse racial and ethnic groups. In this large study of prostate cancer in African American men (3,425 prostate cancer cases and 3,290 controls), we tested 49 risk variants located in 28 genomic regions identified through GWAS in men of European and Asian descent, and we replicated associations (at p≤0.05) with roughly half of these markers. Through fine-mapping, we identified nearby markers in many regions that better define associations in African Americans. At 8q24, we found 9 variants (p≤6×10(-4)) that best capture risk of prostate cancer in African Americans, many of which are more common in men of African than European descent. The markers found to be associated with risk at each locus improved risk modeling in African Americans (per allele OR = 1.17) over the alleles reported in the original GWAS (OR = 1.08). In summary, in this detailed analysis of the prostate cancer risk loci reported from GWAS, we have validated and improved upon markers of risk in some regions that better define the association with prostate cancer in African Americans. Our findings with variants at 8q24 also reinforce the importance of this region as a major risk locus for prostate cancer in men of African ancestry.

Figure 1. Risk Allele Frequencies in Europeans and African Americans.

The distribution of risk allele frequencies (RAF) for the 49 index SNPs (from Table 1 and Table 2) in Europeans (EA) and African Americans (AA). The variants are sorted based on the RAF in EAs.

Figure 2. −Log P Plot for Common Alleles at the Chromosome 3q21 Prostate Cancer Risk Locus.

The index signal (rs10934853) is designated by a purple diamond. The r² shown is that in Europeans from HapMap (CEU) in relation to rs10934853. −Log P-values are those observed in African Americans from logistic regression models adjusted for age, study, global ancestry (the 1^st 10 eigenvectors) and local ancestry. Circles are genotyped SNPs and squares are imputed SNPs. Grey circles are SNPs not in HapMap (r² can not be estimated). The plot was generate using LocusZoom .

Figure 3. −Log P Plot for Common Alleles at 8q24 in African Americans.

−Log P-values for alleles in the region 127.8–129.0 Mb in African Americans from logistic regression models adjusted for age, study, global ancestry (the 1^st 10 eigenvectors) and local ancestry. Pairwise correlations in the HapMap YRI population are shown in relation to rs6987404, which was the most significant marker in the region (p = 1.8×10⁻¹¹). Circles are genotyped SNPs and squares are imputed SNPs. Grey circles are SNPs not in HapMap (r² can not be estimated). The lines below demarcate the five risk regions (R) as defined in , , , , . The plot was generate using LocusZoom . The nine SNPs highlighted are from the stepwise analysis presented in Table 2.