After the recent discovery that common genetic variation in 8q24 influences inherited risk of prostate cancer, we genotyped 2,973 SNPs in up to 7,518 men with and without prostate cancer from five populations. We identified seven risk variants, five of them previously undescribed, spanning 430 kb and each independently predicting risk for prostate cancer (P = 7.9 × 10 −19 for the strongest Correspondence should be addressed to D.R. (reich@genetics.med.harvard.edu). COMPETING INTERESTS STATEMENTThe authors declare no competing financial interests. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript association, and P < 1.5 × 10 −4 for five of the variants, after controlling for each of the others). The variants define common genotypes that span a more than fivefold range of susceptibility to cancer in some populations. None of the prostate cancer risk variants aligns to a known gene or alters the coding sequence of an encoded protein.We recently carried out an admixture scan in African Americans with prostate cancer 1 , highlighting a 3.8-Mb region of chromosome 8 (125.68-129.48 Mb in build 35 of the reference sequence) as containing risk alleles that are highly differentiated in frequency between West Africans and European Americans ( Fig. 1a and Supplementary Table 1 online). Independently, another group 2 localized the same region via linkage analysis and identified specific variants in a region spanning from 128.54-128.62 Mb (denoted 'region 1') that were associated with increased risk of prostate cancer. We replicated the associations after genotyping the same variants in independent samples 1 . However, our data and analyses indicated that the variants in region 1 are insufficient to explain the magnitude of the admixture signal in African Americans with prostate cancer.To search for additional variants that might also contribute to risk at 8q24, we selected SNPs to capture common genetic variation across the admixture peak based on data from the International HapMap Project (see Methods). We genotyped a total of 1,521 variants (including the alleles of microsatellite DG8S737) in 1,175 African American affected individuals with age at diagnosis <72 years and 837 African American controls (Table 1). We genotyped the same variants in 465 European American cases and 446 European American controls.Analysis of these data identified a cluster of genetic variants that we denote 'region 2' in a span of linkage disequilibrium from 128.14-128.28 Mb. These variants are hundreds of kilobases away from the region 1 described in ref. 2 , and the strongest single-SNP association is significant at P = 6.5 × 10 −7 (Fig. 1b and Supplementary Table 2 online). We followed up by genotyping the most associated SNPs in additional cases and controls from five populations: African Americans, Japanese Americans, Native Hawaiians, Latinos and European Americans (for a total sample size of 4,266 individuals with prostate cancer and 3,252 controls) (see Methods and Supplementary Table 3 online). Analysis...

A whole-genome admixture scan in 1,597 African Americans identified a 3.8 Mb interval on chromosome 8q24 as significantly associated with susceptibility to prostate cancer [logarithm of odds (LOD) ‫؍‬ 7.1]. The increased risk because of inheriting African ancestry is greater in men diagnosed before 72 years of age (P < 0.00032) and may contribute to the epidemiological observation that the higher risk for prostate cancer in African Americans is greatest in younger men (and attenuates with older age). The same region was recently identified through linkage analysis of prostate cancer, followed by fine-mapping. We strongly replicated this association (P < 4.2 ؋ 10 ؊9 ) but find that the previously described alleles do not explain more than a fraction of the admixture signal. Thus, admixture mapping indicates a major, still-unidentified risk gene for prostate cancer at 8q24, motivating intense work to find it. association ͉ human genetics