Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disorder which results from cellular infiltration and destruction of the pancreatic islet cells. The events that initiate this pathogenic process are poorly understood. The tendency of IDDM to cluster in families and the 35-40 percent concordance rate in identical twins suggest that both genetic and environmental factors contribute to IDDM susceptibility. It has been recognized for more than 20 years that a gene or genes in the HLA region plays a significant role in the development of IDDM. However, the segregation of IDDM within families fits no simple pattern and the contribution of other genes to IDDM susceptibility has long been suspected. In an attempt to understand the underlying causes of IDDM, we and others have searched for regions of the human genome that demonstrate genetic linkage to IDDM. Besides HLA, we have identified 1 additional region where there is strongly suggestive evidence of linkage and 6 other regions with at least modest evidence warranting further study. In this current application, we propose to extend these promising results by 4 approaches. (1) There remain gaps in our genome-scan of sufficient size that they could harbor additional, undetected IDDM loci. We will genotype all of our original families using a standard set of markers that will fill these gaps and provide a framework for merging our data with other investigators. (2) We have 231 remaining multiplex IDDM families we have not screened for linkage. We will transfer all of these DNAs to an NIH-sponsored genotyping facility where they can be rapidly and efficiently genotyped. We will then merge this data with that from our previously completed genome-scan, and additional datasets provided by investigators in the UK and conduct a joint linkage analysis. (3) Regions with nominal evidence of linkage in this joining analysis will be saturation mapped to confirm the linkage, define the region, and test for allelic association. (4) Finally, for any region yielding compelling evidence of linkage and/or association, we will pursue positional cloning. Identification of such genes should provide important insights into immune pathways that are disrupted in IDDM and may suggest novel preventative or therapeutic approaches. Joint analyses of the single large database this project will generate (greater than 650 affected sibling pairs genotyped at 10 cM resolution) should provide the best picture yet of what inherited factors contribute to the development of IDDM.