These observations indicate that most, if not all, of these alleles show directionally similar association to T2D across many populations. Such a pattern indicates that the causal alleles at these validated risk loci (which have yet to be found) likely predate the migrations that separated these populations now residing in Europe, Africa, East Asia, the Pacific Islands and the Americas. We note that this pattern is unexpected under the recently described “common SNP, rare mutation” model of Goldstein that suggests that GWAS signals with common alleles for T2D and other diseases may be “synthetic associations” created by one or more rare alleles [19]–[21]. Under the Goldstein Hypothesis the consistent associations that we noted at these loci across populations would only be observed if, in each population, one or more distinct rare alleles arose at each locus, and they happened to arise each time on the same haplotype background. Although possible, this scenario seems unlikely, and a more parsimonious explanation would be the “synthetic association” hypothesis of Goldstein does not apply to a majority of these T2D SNPs.
