Compelling data support a genetic basis for type 2 diabetes (T2DM), and completed genome scans suggestat least 7 likely susceptibility regions. A major resource to map genes for T2DM was assembled in amulticenter, multiethnic study funded by the American Diabetes Association (GENNID) from 1993-2003which comprises over 6000 individuals including 770 African-American, 1180 Caucasian, and 1190 Hispanicsib pairs. Under 1/3 of this resource has been genotyped. We propose a complete genome scan on allsamples using a 0.6 cM single nucleotide polymorphism (SNP) map, to make the genotype, pedigree, andphenotypic data publicly available in both raw and cleaned forms, and to use this resource to test thehypothesis that T2DM will be characterized by multiple interacting loci, some that are ethnic-specific andothers that will cross ethnic groups. The 5 Specific Aims will include 1) sample and data preparation for thegenome scan; 2) analysis of the genome scan data using multipoint affected sib pair methods applied to boththe full data set and ethnic-specific data, along with secondary parametric, ordered subset, and interactionanalyses; 3) fine mapping of linkage peaks with dense (100 kb) SNP maps across up to 12 new regions andreanalysis of the fine map data; 4) distribution of initial and fine mapping data to all interested diabetesinvestigators upon initialCIDR release and at each stage of cleaning or new data analysis; and 5) a positionalcandidate gene search for likely susceptiblity genes under each linkage peak by choosing tagSNPs frompublic databases and gene screening where needed. We will test for family based association using thedense SNP map, and for an association in 400-500 unrelated cases drawn from GENNID families and 400-500 controls. These studies will provide the basis for future proposals to identify the causative mutations inknown candidate genes or to use linkage disequilibrium to identify additional T2DM susceptibility loci. Theproposed studies will identify the specific genes that increase an individual's risk of getting type 2 diabetes,and will determine whether striking differences in diabetes prevalence across major United States ethnicgroups can be explained in part by different frequencies of risk genes. These studies will determine whetherdifferent pathways cause type 2 diabetes in different ethnic groups, which in turn may lead to new therapiesfor type 2 diabetes that may target specific genetic defects or ethnic-specific pathways.
