The ability to detect recent natural selection in the human population would have profound implications for the study of human history and for medicine. Here, we introduce a framework for detecting the genetic imprint of recent positive selection by analysing long-range haplotypes in human populations. We first identify haplotypes at a locus of interest (core haplotypes). We then assess the age of each core haplotype by the decay of its association to alleles at various distances from the locus, as measured by extended haplotype homozygosity (EHH). Core haplotypes that have unusually high EHH and a high population frequency indicate the presence of a mutation that rose to prominence in the human gene pool faster than expected under neutral evolution. We applied this approach to investigate selection at two genes carrying common variants implicated in resistance to malaria: G6PD and CD40 ligand. At both loci, the core haplotypes carrying the proposed protective mutation stand out and show significant evidence of selection. More generally, the method could be used to scan the entire genome for evidence of recent positive selection.

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...

Population stratification refers to differences in allele frequencies between cases and controls due to systematic differences in ancestry rather than association of genes with disease. It has been proposed that false positive associations due to stratification can be controlled by genotyping a few dozen unlinked genetic markers. To assess stratification empirically, we analyzed data from 11 case-control and casecohort association studies. We did not detect statistically significant evidence for stratification but did observe that assessments based on a few dozen markers lack power to rule out moderate levels of stratification that could cause false positive associations in studies designed to detect modest genetic risk factors. After increasing the number of markers and samples in a case-cohort study (the design most immune to stratification), we found that stratification was in fact present. Our results suggest that modest amounts of stratification can exist even in well designed studies.