In most human populations, the ability to digest lactose contained in milk usually disappears in childhood, but in European-derived populations, lactase activity frequently persists into adulthood (Scrimshaw and Murray 1988). It has been suggested (Cavalli-Sforza 1973; Hollox et al. 2001; Enattah et al. 2002; Poulter et al. 2003) that a selective advantage based on additional nutrition from dairy explains these genetically determined population differences (Simoons 1970; Kretchmer 1971; Scrimshaw and Murray 1988; Enattah et al. 2002), but formal population-genetics-based evidence of selection has not yet been provided. To assess the population-genetics evidence for selection, we typed 101 single-nucleotide polymorphisms covering 3.2 Mb around the lactase gene. In northern European-derived populations, two alleles that are tightly associated with lactase persistence (Enattah et al. 2002) uniquely mark a common (~77%) haplotype that extends largely undisrupted for >1 Mb. We provide two new lines of genetic evidence that this long, common haplotype arose rapidly due to recent selection: (1) by use of the traditional F(ST) measure and a novel test based on p(excess), we demonstrate large frequency differences among populations for the persistence-associated markers and for flanking markers throughout the haplotype, and (2) we show that the haplotype is unusually long, given its high frequency--a hallmark of recent selection. We estimate that strong selection occurred within the past 5,000-10,000 years, consistent with an advantage to lactase persistence in the setting of dairy farming; the signals of selection we observe are among the strongest yet seen for any gene in the genome.

A general question for linkage disequilibrium-based association studies is how power to detect an association is compromised when tag SNPs are chosen from data in one population sample and then deployed in another sample. Specifically, it is important to know how well tags picked from the HapMap DNA samples capture the variation in other samples. To address this, we collected dense data uniformly across the four HapMap population samples and eleven other population samples. We picked tag SNPs using genotype data we collected in the HapMap samples and then evaluated the effective coverage of these tags in comparison to the entire set of common variants observed in the other samples. We simulated case-control association studies in the non-HapMap samples under a disease model of modest risk, and we observed little loss in power. These results demonstrate that the HapMap DNA samples can be used to select tags for genome-wide association studies in many samples around the world.

The common missense single nucleotide polymorphism (SNP) K121Q in the ectoenzyme nucleotide pyrophosphate phosphodiesterase (ENPP1) gene has recently been associated with type 2 diabetes in Italian, U.S., and South-Asian populations. A three-SNP haplotype, including K121Q, has also been associated with obesity and type 2 diabetes in French and Austrian populations. We set out to confirm these findings in several large samples. E ctoenzyme nucleotide pyrophosphate phosphodiesterase (ENPP1), also known as plasma cell membrane glycoprotein 1 (PC-1), downregulates insulin signaling by inhibiting the insulin receptor's tyrosine kinase activity. This inhibition is proposed to confer insulin resistance in mammals. The ENPP1 gene is located on 6q22-23, a locus linked to obesity and diabetes in several studies (1-4). Recent studies of variation in the ENPP1 gene have found an association of the common missense single nucleotide polymorphism (SNP) K121Q (rs1044498) and of a threemarker haplotype (which includes K121Q) with the risk of diabetes and obesity. Abate et al. (5) reported that the Q-allele was associated with diabetes in South-Asian and Caucasian populations. Meyre et al. (6) described a three-SNP risk haplotype in the ENPP1 gene (formed by the three minor alleles of rs1044498 K-allele, rs1799774 delTallele, and rs7754561 G-allele) that was associated with increased risk of diabetes and obesity in adults and obese children. Bacci et al. (7) also reported an association of the minor allele in K121Q with insulin resistance and atherogenesis in diabetic individuals. Their meta-analysis of 4,425 control subjects and 2,834 patients with type 2 diabetes showed an odds ratio (OR) of 1.29 ([95% CI 1.09 -1.53], P ϭ 0.003) under a dominant model. In contrast, Matsuoka et al. (8) found that the Q-allele was not associated with diabetes and that the K-allele rather than the Q-allele was associated with obesity in both Caucasians and African Americans. Given this cumulative yet conflicting evidence for association with diabetes and obesity, we tested whether the K121Q variant or the risk haplotype (Q-delT-G) are associated with diabetes and/or obesity in several large case-control and family-based cohorts ascertained for both phenotypes. RESEARCH DESIGN AND METHODSObese and lean individuals from the U.S. and Poland (Table 1) were selected from a collection of Ͼ60,000 subjects recruited by Genomics Collaborative for a diverse set of disease studies, including healthy people and groups with osteoarthritis, rheumatoid arthritis, asthma, hypertension, coronary artery disease, myocardial infarction, hyperlipidemia, stroke, type 2 diabetes, or From the