In this study we will locate and identify genes contributing to glucose homeostasis and adiposity in the IRAS Family Study. The molecular genetics will be carried out by two collaborating laboratories at the Center for Human Genomics at Wake Forest University and the Cedars-Sinai Molecular Genetics Core Facility incorporating the molecular genetic, bioinformatics, and analytical skills of these laboratories to identify genes contributing to glucose homeostasis and adiposity. Initially targeted linkage studies will be carried out for the most likely locations for linkage consisting of fine mapping previously identified linkage locations. Analysis of this data will provide confirmation and some narrowing of linkage peaks and elimination of other locations due to inability to confirm evidence of linkage. Two high quality linkage peaks will be chosen for high intensity analysis. Haplotype maps will be constructed for the chromosomal region with a target SNP density of 1 SNP/10 kb or greater. This construction effort will be based upon genotyping large numbers of SNPs on DNAs from the Hispanic and African American families in the IRASFS and result in a high density SNP map with the SNPs in defined haplotype LD blocks. The SNP map will be used as the framework for intensive SNP genotyping of the IRASFS DNA collection for comprehensive association analysis of regions under the linkage peaks. This association analysis should lead to the identification of specific SNPs and haplotype blocks associated with the appropriate phenotype. The phenotype associated haplotype blocks will be the subject of intensive molecular analysis to identify the alleles contributing to the phenotype. Initially this will take the form of sequencing the block in multiple individual DNAs to comprehensively identify sequence variants in the region, e.g. create an """"""""ultra high density"""""""" SNP map of the associated chromosomal region. These new SNPs will be genotyped on the IRASFS DNAs to identify the trait defining alleles.
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