PROJECT ABSTRACT The NIDDK IBD Genetics Consortium’s (IBDGC) mission is to characterize the genetic architecture of IBD phenotypes, particularly in populations currently underrepresented in IBD genomic studies, and to elucidate the biological mechanisms by which genetic variants influence IBD pathophysiology, phenotypes and clinical course. This proposal is to serve as the data coordinating center (DCC) for the IBDGC in a cooperative agreement with genetics research centers (GRCs) to benefit the field broadly. The DCC has played an essential role in the International IBD Genetics Consortium (IIBDGC), resulting in very large, well-powered cohorts that can statistically refine association signals. However, less than 10% of present IIBDGC patients are from African- American and Hispanic/LatinX IBD patients. For both scientific and social justice reasons, the NIDDK IBDGC is strongly prioritizing recruitment of African-American and Hispanic/LatinX IBD patients for genetic and genomic studies. In Aim 1, the DCC will optimize power and enhance pathophysiologic insight across diverse populations affected by IBD by coordinating, standardizing and tracking increased recruitment of African-American and Hispanic/LatinX IBD patients by the GRCs to more than double present cohort sizes. By so doing, substantially increased power to refine allelic effects may be achieved. Integration with multi-omic ATAC + transcriptome single cell data may provide further refinement of association signals between Crohn’s disease and ulcerative colitis and across populations. Complete mapping of sequence data for the NIDDK IBDGC lymphoblastoid lymphocyte repository from over 9000 patients will enable for broad use and dissemination. In Aim 2, the DCC will provide high-quality operational services optimized to the scientific objectives of the Consortium, including data collection, management and distribution; guidance in study design and data analysis; researching and facilitating use of new platforms and technologies; and supporting Consortium governance, communication and administration. We shall also substantially enhance our Data Commons and website to promote and facilitate discovery and usage. In Aim 3, in selected clinical scenarios of unmet medical needs, the DCC will enable longitudinal analyses prioritized by the NIDDK IBDGC Steering Committee, and to scale and standardize multi- omic cellular data. The NIDDK IBDGC has made major investments in serial biosampling in ileal resection Crohn’s disease cohorts, which powerfully tracks the earliest steps in disease recurrence. Mechanistic insight may well be accrued via serial sampling (systemic and tissue-based) in other key scenarios, such as acute, hospitalized flares in ulcerative colitis and perianal fistulae in Crohn’s disease. The power of GWAS locus identification lies in the definitive mapping from trait to outcome (disease development). Given the polygenicity of IBD, more complete explication of multi-omics in dive...