The African American prostate cancer cases (n
3,621) and controls (n
3,502) in this study are part of a collaborative genome-wide scan of prostate cancer that includes 11 individual studies (Table S1
). Samples were genotyped using the Illumina Infinium 1M-Duo bead array, and following quality control exclusions (see Methods
), the analysis of variants at the known risk loci was performed on 3,425 cases and 3,290 controls. The ages of cases and controls ranged from 23 to 95, with cases and controls having similar ages (mean 65 and 64 years, respectively).
We tested 49 known prostate cancer risk variants located in 28 risk regions (Table S2
, , and ); 43 SNPs were directly genotyped (with call rates >95%), while 6 were imputed with high accuracy (see Methods
. The minor allele frequencies (MAF) of all 49 variants were common (≥0.05) in African Americans, except for rs721048 at 2p15 (MAF, 0.04) and rs12621278 at 2q21 (MAF, 0.02; , ). On average, across all variants tested, the risk allele frequencies (RAFs, i.e. alleles associated with an increased risk of prostate cancer in previous GWAS) were 0.05 greater in African Americans than in Europeans. However, when removing the 12 risk variants at 8q24 () the average difference in RAF over the remaining risk loci was only 0.03.
Associations with common variants at known prostate cancer risk regions in African Americans (3,425 cases, 3,290 controls).
Associations with risk variants at 8q24 in African Americans.
Risk Allele Frequencies in Europeans and African Americans.
We examined the association of local ancestry with prostate cancer risk at each of the 28 risk regions (Table S3
). In addition to 8q24, which we had previously found to be strongly associated with African ancestry 
(OR per European chromosome
), we observed significant associations at 22q13 (OR
0.01), 7p15 (OR
) and 10q26 (OR
). To address the potential for confounding by genetic ancestry, we adjusted for both global and local ancestry in all analyses (see Methods
In previous GWAS, the index signals outside of 8q24 had very modest odds ratios (1.05–1.30 per copy of the risk allele) and our sample size provided ≥80% power to detect the reported effects for 24 of the 37 variants (at p<0.05; Table S2
). We observed positive associations with 28 of the 37 variants (odds ratios (OR) >1) in African Americans and 18 reached nominal statistical significance (p≤0.05; ). Results were similar without adjustment for local ancestry in each region (Table S4
). Of the 19 variants that were not replicated at p<0.05, power was <80% for 9 of the variants.
While power was limited to detect associations at some loci, the lack of replication at loci where power was acceptable (>80%) suggests that the particular risk variant revealed in GWAS in European and Asian populations may not be adequately correlated with the biologically relevant allele in African Americans. In an attempt to identify a better genetic marker of the biologically relevant allele in African Americans we conducted fine-mapping across all risk regions using genotyped SNPs on the 1 M array and imputed SNPs to Phase 2 HapMap (Table S5
, see Methods
). If a marker associated with risk in African Americans represents the same signal as that reported in the initial GWAS, then it should be correlated to some degree with the index signal in the initial GWAS population. Using HapMap data (CEU or JPT+CHB depending upon the initial GWAS population) we catalogued and tested all SNPs that were correlated (r2
≥0.2) with the index signal (within 250 kb), applying a significance criteria αa
, of 0.004 given the large number of correlated tests. This level of significance was based on the number tag SNPs in the HapMap YRI population that capture (r2
≥0.8) all SNPs that were correlated with the index signal in the HapMap CEU (r2
≥0.2; see Methods
). We also looked for novel independent associations, focusing on the genotyped and imputed SNPs that were uncorrelated with the index signal in the initial GWAS populations. Here, we applied a Bonferroni correction for defining novel associations as significant in each region, with αb
estimated as 0.05/the total number of tags needed to capture (r2
≥0.8) all common risk alleles across all risk region in the YRI population (αb
). This is similar to the genome-wide-type correction of 5×10−8
, which accounts for the number of tags needed to capture all common alleles in the genome. For each region, stepwise regression was used with SNPs kept in the final model based on αa
(results for each model are provided in Table S6
Among the SNPs correlated with the index signal in the GWAS population, a more significantly associated marker was identified at 12 regions. For 5 of these regions, the new marker showed only a slightly more significant association than the index signal (<1 order of magnitude change in the p-value; ). However, for 7 regions (2p24, 2p15, 3q21, 6q22, 8q21, 11q13, and 19q13), the new marker appeared to capture risk more strongly than the index signal in African Americans. The risk region at 3q21 is provided in as an example. Here the index signal was not significantly associated with risk in African Americans (rs10934853, OR
1.03, 95% CI, 0.95–1.03, p
0.43), with the most significantly associated marker in African Americans located ~200 kb centromeric from the index signal (rs7641133, OR
1.16, 95% CI 1.08–1.25, p
). These two markers are strongly correlated in Europeans (HapMap CEU, r2
0.91) but not in Africans (HapMap YRI, r2
0.11; ), which suggests that in African Americans rs7641133 is a better proxy of the biologically important allele and may better localize the true association. For some of these regions, the size of the LD blocks differ in populations of African ancestry compared with the GWAS population and thus, may assist in localizing the functional allele (Figure S1
). Using a strict αb
for discovery of novel risk variants we observed no evidence of a second independent signal at any risk region. For variants identified as significantly associated with risk (), odds ratios for homozygous carriers were generally greater than for heterozygous carriers, which provides support for their associations (Table S7
−Log P Plot for Common Alleles at the Chromosome 3q21 Prostate Cancer Risk Locus.
We examined 12 risk variants at 8q24 that had been reported previously to be associated with prostate cancer risk 
with 7 being statistically significant and positively associated with risk (p<0.05). The risk SNP BD11934905 
is not on the Illumina 1 M array and was not genotyped in this study. In contrast with what has been reported in Europeans, the risk allele for rs12543663 was observed to be significantly inversely associated with risk in African Americans (OR
0.028; ). The RAFs for 8 of the 12 alleles are more common in African Americans than Europeans, with the average RAF being 0.46 in African Americans and 0.32 in Europeans. The largest difference in RAFs between populations are noted with variants rs13252298, rs13254738, rs6983561, rs6983267 and rs7000448, which have RAFs that are >0.20 greater in African Americans than in Europeans. When all 12 variants were included in a multivariate model, only 5 remained nominally associated with risk (). In African Americans, many of these index signals were weakly correlated (Figure S2
) and demonstrated stronger multi-allelic correlations (), which suggests that some variants may define similar haplotypes marking the same biologically relevant variants in this population. No significant association was observed with rs7008482 (OR
0.52, computed using data included in the initial report 
) or markers of risk at 8q24 for cancers of the breast, bladder, ovary, or leukemia (rs13281615: OR
0.48; rs9642880: OR
0.13; rs10088218: OR
0.06; rs2456449: OR
To identify markers at 8q24 that best capture risk in African Americans we performed a stepwise analysis of 1,549 genotyped and imputed SNPs spanning the established risk locus (127.8–129.0 Mb). This region contained 132 SNPs with nominal p-values<0.001 (), and 9 common alleles with per allele ORs of 1.16–1.42 () defined the most parsimonious model. Similarly to the previously reported risk variants at 8q24 four of these markers are substantially more common in African Americans than Europeans (average RAF difference
0.07). Eight of these markers show some degree of correlation with the known risk variants and thus are likely to be tagging the same functional allele, albeit for 4 SNPs the correlations are quite weak in the CEU and YRI populations (r2
<0.2; Table S8
) suggesting that they may be marking independent risk variants. For example, SNP rs6987409 (RAF
0.15), which is monomorphic in Europeans, remains significantly associated with risk conditional on the 12 known risk alleles at 8q24 (OR
1.31, 95% CI, 1.16–1.47, p
), which suggests that this SNP may be marking a novel variant that is relevant in African Americans; rs6987409 was the most significant marker in the region ().
−Log P Plot for Common Alleles at 8q24 in African Americans.
We next estimated the cumulative effect of all prostate cancer risk alleles, and compared a summary risk score comprised of unweighted counts of all GWAS reported risk alleles to a risk score that included variants we identified as being associated with risk in African Americans (). Using index signals from GWAS (see Methods
), the risk per allele was 1.08 (95% CI, 1.06–1.09; p
) and individuals in the top quartile of the risk allele distribution were at 2-fold greater risk of prostate cancer compared to those in the lowest quartile (). As expected, the risk score was improved when utilizing the markers that we identified at the known risk loci as being more relevant to African Americans (OR
1.17 95% CI, 1.15–1.19; p
), with risk for those in the top quartile being 3.5-times those in the lowest quartile. When stratifying by first-degree family history of prostate cancer, risk was 4.7-fold greater for those with a family history and in the top quartile of the risk score distribution (3.5% of the population) compared to those without a family history and in the first quartile (). The risk score was associated equally with risk for advanced (n
1,087) and non-advanced (n
1,968) prostate cancer (case-only test: OR
1.02, 95% CI, 1.00–1.05 phet
The association of the total risk score with prostate cancer risk in African Americans.
Using this risk score, we estimate (see Methods
) that in the aggregate, all risk alleles tested explain approximately 11% of risk in first-degree relatives of cases.