We have previously identified a region of linkage to both body mass index (LOD=3.6), age-adjusted diabetes (LOD=1.7) and the combined phenotype of diabesity (LOD=5.2)on chrom 11q23-24. We genotyped 10 markers within this region on 3,000 additional individuals who were selected for BMI, but were not necessarily from families informative for diabetes. There was no linkage to BMI in this second set of Pimas, indicating that the initial linkage was dependent upon an interaction between BMI and diabetes. All known candidate genes in the region from 11q22-24, including the Apo CIII/AIV/A2 gene cluster, two inwardly rectifying potassium channels, and the dopamine receptor DRD2 were analyzed by genotyping several single nucleotide polymorphisms (SNPs)in each gene. Several SNPs in DRD2 showed a significant association with BMI; therefore, this gene was sequenced in its entirety and two SNPs were genotyped in 1300 Pimas. Unfortunately, SNPs detected in DRD2 do not appear to result in the linkage to BMI observed in this region. We have also created a physical map by identifying overlapping YAC clones across the region of linkage on chrom 11q. We are currently contructing a BAC contig across this region. SNPs are being identified on each of the BACs and are then being genotyped on DNAs from 200 informative sibpairs. - positional cloning, single nucleotide polymorphisms, genetic mapping - Human Subjects
