We previously carried out T2D linkage analysis in the families of many of our stage 1 cases (10). None of the 10 loci in Table 1 had large T2D logarithm of the odds (LOD) scores, although those for FTO and TCF7L2 were 0.63 and 0.60 and so were nominally significant. LOD scores for six of the 10 loci were greater than 0.2, as compared to 2.2 that would be expected for random genome locations. This suggests enrichment for T2D-associated loci in regions with modest evidence of T2D linkage (P = 0.01) but that the power of the linkage approach was insufficient to distinguish these signals from background noise.The ability to construct a list of ten robust and replicated T2D-associated loci (Table 1) represents a landmark in efforts to identify genetic variants that predispose to complex human diseases, although the specific predisposing variants and even the relevant genes remain to be defined. We examined the combined risk of T2D based on these 10 loci in our stage 1 + 2 sample by constructing a logistic regression model and predicting T2D risk for each person (8). We found a fourfold variation in T2D risk from the lowest to highest predicted risk groups, which is of potential interest for a personalized preventive-medicine program (Fig. 2). However, these predictions from our data may be biased as compared to predictions based on the general population, likely owing to the overestimation of ORs due to the "winner's curse," enrichment for familial T2D cases, and exclusion of individuals with impaired glucose tolerance or impaired fasting glucose.Thirty years ago, James V. Neel labeled T2D as "the geneticist's nightmare" (32), predicting that the discovery of genetic factors in T2D would be thoroughly challenging. Until recently, his prediction has proven true. Although large samples and collaboration among three groups were required, we can confidently state that new diabetes risk factors have been identified. Each gene discovery points to a pathway that contributes to pathogenesis, and all of these proteins and their relevant pathways represent potential drug targets for the prevention or treatment of diabetes. Based on the number of other interesting results observed in these studies, it is likely that there are additional T2D-predisposing loci to be found. Even though much remains to be done, we are at last awakening from Jim Neel's nightmare.