Genetic Variation in the NIDDM1 Region

        Nancy J. Cox, Yukio Horikawa, Naohisa Oda, Craig L. Hanis and Graeme I. Bell
    University of Chicago

A genome-wide screen for loci influencing susceptibility to type 2 diabetes in Mexican Americans from Starr County, TX revealed strong evidence for linkage on 2q near D2S125-D2S140, with the susceptibility locus designated NIDDM1. Positional cloning studies in the NIDDM1 region began with the construction of a bac/pac contig over a 1.7 Mbp region. SNP identification was conducted in 10 MA from the original genome scan. A total of 182 variant sites were identified and studied, most from a region of about 60 kb that was resequenced in the 10 MA because multiple individual SNPs from the region had shown evidence for association with type 2 diabetes. A variety of approaches were developed for analyses of the SNP data from this region, but the common thread is that the approaches assess the evidence of association between SNP allele and/or genotype and the evidence for linkage. For most of these analyses, the formal hypothesis being tested is that there is no linkage disequilibrium between the SNP and the causal variant, but the approaches utilizing the evidence for linkage from the original genome scan appear to be more sensitive and specific for identifying SNPs in strong linkage disequilibrium with the variation affecting susceptibility to disease than commonly used tests of association with disease. Using these approaches, we identified a combination of SNPs within a single gene that showed: 1) significant association with disease,and 2) significant association with the original evidence for linkage. Subsequent analyses with a completely different approach using different aspects of the data, the decay of haplotype sharing approach described by McPeek and Strahs (ASHG, 1999) included only this same locus within the 95% confidence interval. The locus, a ubiquitously expressed calpain protease, calpain 10 (CAPN10), would not have been considered a candidate for affecting susceptibility to type 2 diabetes, but subsequent studies have shown that the same variants associated with type 2 diabetes in Mexican Americans are associated with similar risks in two different European populations (Germany and Finland), as well as an independent sample from Mexico. Three polymorphisms are minimally required to define the high-risk haplotypes, one of which is common in Native American and Asian populations but rare in Europeans, while the other is a common haplotype in all populations examined. The risks associated with different genotype/haplotype combinations are potentially consistent with allelic epistasis: homozygotes for either of the high-risk haplotypes are not at significantly increased risk of diabetes, and one of the haplotypes found in the highest risk haplotype combination is associated with significantly reduced risk of type 2 diabetes in conjunction with another of the common haplotypes. Results of functional studies on one of the key polymorphisms in the at-risk haplotypes suggest that the calpain-10 variation of interest is likely to affect expression of calpain 10.