Geographic and haplotype structure of candidate type 2 diabetes susceptibility variants at the calpain-10 locus

Abstract

Recently, a positional cloning study proposed that haplotypes at the calpain-10 locus (CAPN10) are associated with increased risk of type 2 diabetes, or non-insulin-dependent diabetes mellitus, in Mexican Americans, Finns, and Germans. To inform the interpretation of the original mapping results and to look for evidence for the action of natural selection on CAPN10, we undertook a population-based genotyping survey of the candidate susceptibility variants. First, we genotyped sites 43, 19, and 63 (the haplotype-defining variants previously proposed) and four closely linked SNPs, in 561 individuals from 11 populations from five continents, and we examined the linkage disequilibrium among them. We then examined the ancestral state of these sites by sequencing orthologous portions of CAPN10 in chimpanzee and orangutan (the identity of sites 43 and 19 was further investigated in a limited sample of other great apes and Old World and New World monkeys). Our survey suggests larger-than-expected differences in the distribution of CAPN10 susceptibility variants between African and non-African populations, with common, derived haplotypes in European and Asian samples (including one of two proposed risk haplotypes) being rare or absent in African samples. These results suggest a history of positive natural selection at the locus, resulting in significant geographic differences in polymorphism frequencies. The relationship of these differences to disease risk is discussed.

Figure 1

The human CAPN10 locus on chromosome 2, showing the locations of seven previously identified susceptibility variants surveyed here. The locations of the sites, relative to the numbering in the reference sequence AF158748, are 22751 (site 44), 22762 (site 43), 23325 (site 56), 23928 (site 59), 25830 (site 19), 33021 (site 30), and 34288 (site 63).

Figure 2

F_ST values between African and non-African samples at CAPN10, compared to those observed at 86 RFLPs. The distribution of values, estimated for a collection of previously assayed biallelic RFLPs (Bowcock et al. 1987, 1991a), is shown. Above the histogram, the approximate F_ST values observed for the seven susceptibility variants in this study are indicated. The percentile rank of each site, relative to the observed distribution, is given in parentheses.

Figure 3

State changes at SNP-43 and Indel-19 in primates. The nucleotide observed at sites orthologous to SNP-43 in humans is shown in the left-hand tree, whereas the number of 32-bp repeat units present in the region orthologous to Indel-19 is shown in the right-hand tree. Note that trees are not drawn to scale. Mya = million years ago.