PROJECT SUMMARY The Project Summary must contain a summary of the proposed activity suitable for dissemination to the public. It should be a self-contained description of the project and should contain a statement of objectives and methods to be employed. It should be informative to other persons working in the same or related fields and insofar as possible understandable to a scientifically or technically literate lay reader. This section must be no longer than 30 lines of text Brief summary. The Montreal-Boston Collaborative group co-founded the NIDDK IBD Genetics Consortium in 2002. Since then, our group has played a pivotal role in the identification of >150 genetic risk factors for IBD and made significant advances in the understanding their role in health and disease. The current proposal is meant to build on our successes and to support (1) our recruitment of IBD patients and healthy controls for the publicly-available NIDDK Repository, (2) our efforts to identify key genetic risk factors for IBD, and (3) our innovative work in understanding the biological basis of IBD. Background. There is no doubt that the success of the genome-wide association studies (GWAS) in identifying genetic risk factors for IBD (>150 independent risk factors) presents us with new challenges to be faced in the years ahead. The primary challenge is how we can translate these genetic discoveries into a more comprehensive biological understanding of IBD pathogenesis. What is equally clear, although there are some notable exceptions (e.g. IL23R, ATG16L1) GWA studies have not directly led to the causal genes or specific functional variants, and this has greatly limited the ability to extract causal biology from these discoveries. Recently, however, we have demonstrated conclusively how sequencing of IBD genes has led to (1) the identification of the causal gene within regions harboring multiple candidates, and (2) the identification of rarer, higher penetrance alleles with more obvious functional consequence than the low penetrance, non- coding variants that have led to the discovery of these regions. These are critical steps for the genetic study of IBD as they will enable us to interpret the biological insight from the GWAS findings much more directly and precisely, providing a bridge from GWAS associations to functional biology. Objectives. We have two main objectives: (1) To develop patient and control resources that will enhance the Consortium's capacity to identify genes, genetic variation and biological mechanisms contributing to the pathogenesis of IBD, and (2) To obtain a biologic understanding how specific rare genetic variants in associated genes predispose or protect an individual from developing IBD. Methods. In order to meet our first objective, we will take advantage of our network of >10 university-based hospitals with dedicated IBD clinics that has a proven track record of 10+ years in the recruitment of individuals for IBD genetic studies for the NIDDK IBD Genetics Consortium and the publicly-available NIDDK Repository. For our second objective, we will combine unique state-of-the-art gene sequencing data and genome-wide genetic data in order to identify rare causal genetic variation and innovative integrative biology approaches to demonstrate the role that this genetic variation has in determining why some individuals develop IBD and why others are protected from these diseases.