The goal of this study is to map, clone, sequence, and determine the function of genes, which cause type 2 diabetes. Multiple studies now suggest that one or more genes in the region of chromosome 20q12-13.1 contribute to type 2 diabetes susceptibility in Caucasians. In order to determine the number of genes and contribution which they make to type 2 diabetes susceptibility, the mutant forms of these genes will be identified. The putative type 2 susceptibility genes within 20q12-q13.1 will be precisely defined through disequilibrium analysis using high density SNP maps in a variety of study groups including case-control and sibling pairs discordant for type 2 diabetes. An accurate correlation, expressed sequence physical map of chromosome 20q12-q13.1 will provide the framework for focused analysis of specific regions for linkage disequilibrium. Identification of candidate type 2 diabetes loci in the genetically defined region will be carried out by a detailed sequence survey of genes and non-gene sequences with the initial focus on sequences which are under disequilibrium peaks. SSCP and DNA sequence analysis of aberrantly migrating peaks will be used for this purpose. This effort will be complemented by analysis of increasing volume of sequence from the HGP. Polymorphic sequences which are candidate diabetogenic loci will be surveyed for differences in distribution between normal and type 2 diabetes-affected individuals to identify the diabetogenic gene. Based on SNP disequilibrium studies, coding and non-coding polymorphisms strongly associated with diabetes will be functionally evaluated.