A prior genomic scan in Pima Indians living in the United States indicated an obesity susceptibility locus on chromosome 11q23-24 (LOD=3.6). There was also evidence that the same genomic region contained a susceptibility locus for type 2 diabetes mellitus (T2DM)(LOD=1.7). Bivariate linkage analysis for the combined phenotype diabesity gave the strongest evidence for a susceptibility locus (LOD= 5.2). Linkage to body mass index (BMI) at this precise genomic region (D11S4464) has been replicated in Caucasians from the Framingham Heart Study and in morbidly obese males in pedigrees from Utah (Myriad Genetics). The region of linkage in Pima Indians spans approximately 24 Mb. Our current goal is to positionally clone the gene(s) responsible for the linkage. Positional candidate genes across the region of linkage are being sequenced to identify genetic variants. In addition, linkage disequilibrium (LD) mapping is being used to narrow the susceptibility region. For LD mapping, single nucleotide polymorphisms (SNPs) are being systematically identified and genotyped at 25 kB intervals across the region of linkage. To date, approximately 700 SNPs that span our region of linkage have been individually genotyped in 1229 DNA samples, and tested for association with either BMI or T2DM. Two separate regions have been preliminarily identified that contain multiple SNPs significantly associated with BMI and diabetes. A preliminary interpretation of our current L.D. mapping data is that more than one gene is responsible for the linkage to diabetes and BMI on chromosome 11q23-24.
