Inflammatory bowel disease (IBD) consists of Crohn's disease (CD) and ulcerative colitis (UC)-- two chronic idiopathic inflammatory diseases of the gastrointestinal tract. Studies of the genetic epidemiology and of animal models demonstrate that these diseases are determined in large measure by genetic factors. These data also indicate that UC and CD share some common genetic factors, but have additional distinct genetic determinants. However, the specific nature of the genetic factors predisposing to both or either of these diseases remains poorly defined. In order to identify susceptibility genes for these diseases, we have already initiated a systematic scan in CD families with markers at 10 cM interval and identified 19 regions where genes predisposing to IBD may be located (including loci on chr. 12 and chr. 16 and the MHC region). The goal of this project is to further confirm and refine the initial linkage findings and ultimately to identify the genes predisposing an individual to IBD or subforms of IBD. We will first perform, with an increased number of CD families, fine linkage mapping to a density of 2-3 cM in those regions where initial evidence for linkage to CD was observed (aim 1). Any regions showing evidence of linkage to CD will then be tested in UC and mixed (both UC and CD) families (aim 2). For those regions where there is strong evidence of linkage, linkage disequilibrium mapping will be carried out, utilizing both family and case-control panels in a multi-phase design to narrow the region containing the susceptibility genes (aim 4). Then, candidate genes at these regions will be evaluated by screening for mutations and changes in the level of expression (aim 5). All linkage and linkage disequilibrium mapping analysis will be conducted in the sample as a whole, as well as in subgroups defined by ethnicity, subclinical markers, or known linked loci (aim 3). Both two point and multipoint linkage analysis methods will be employed for all linkage analyses. The transmission/disequilibrium test will be used for linkage disequilibrium mapping. This study will eventually lead to identifying genes predisposing to these most debilitating of gastrointestinal diseases, with implications for the assessment of individual risk for IBD, for diagnosis and clinical management of patients, and for basic understanding of the mechanisms of disease pathogenesis fundamental for the development of novel and individualized therapies.