Type 2 diabetes is a major public health problem arising from polygenic susceptibility and environmental exposures, including the metabolic environment induced by obesity. Several diabetes susceptibility genes have been identified by convergence of detailed phenotyping and high-density genotyping for genome-wide association (GWA) studies. The Framingham Heart Study (FHS) has a long history of comprehensive phenotyping related to cardiovascular disease risk factors including diabetes, has acquired 100K and will soon acquire 550K SNP GWA study data (as part of the NHLBI FHS SHARe study), and is positioned to contribute GWA study data to diabetes gene discovery. In the FHS 100K GWA study we implemented screening methods to derive a set of SNPs probably enriched for true positive associations with diabetes and related quantitative traits. Here our Aims are to 1) linkage disequilibrium (LD) map and replicate FHS 100K SNP-diabetes associations: we hypothesize that increased 550K SNP density and greater SHARe subject numbers (N~9,000) used for in silico LD mapping and replication of 100K associations will produce a promising subset of 100K SNPs that will replicate in independent samples (from the Nurses'Health and Health Professionals Follow-Up, MGH and NHANES III Studies;N~10,000);2) integrate FHS 550K data with other GWA studies (Diabetes Genetics Initiative, Wellcome Trust CCC, FUSION;N~11,000) to replicate promising SNPs, and vice versa (to assess their top results for replication and further characterization in FHS);thus, first-stage in silico replication of SNPs in independent GWA studies will guide subsequent genotyping, replication and LD mapping in independent samples;and 3) assess interaction: we hypothesize that accounting for gene-environment interaction (specifically, obesity) will identify novel SNPs and will strengthen evidence for association of specific SNPs with diabetes traits. We respond to PAR-06-216, }Ancillary Studies to } NIDDK and NHLBI} Research Studies} with a diabetes-oriented ancillary study to the NHLBI-funded parent Framingham Heart Study. Preliminary studies strongly suggest that the project will lead to replicated identification of novel diabetes susceptibility genes important in the community. Knowledge of the genetic basis of type 2 diabetes is critical to identify new approaches to prevention and control of the worldwide diabetes epidemic. 7. Project Narrative Type 2 diabetes is a major, increasing public health problem caused by genetic susceptibility and obesity. This project will use genome-wide association studies in about 30,000 people to reveal the genetic basis of type 2 diabetes, and will test genetic interactions with obesity that increase risk for diabetes. Expanded knowledge of genes predisposing to type 2 diabetes and their interaction with obesity is critical to identify novel strategies for prevention and control of the worldwide diabetes epidemic.