Precision IBD via genetics and genomics: integrating International and multi-omic datasets, expanding studies in diverse populations, and defining mechanisms of unmet clinical needs in IBD

Icahn School Of Medicine At Mount Sinai, New York NY

Investigators

Linked publications & trials

Abstract

NOTE: You must submit in Word format, not PDF, for eRA to update all the systems. The NIDDK IBD Genetics Consortium’s (IBDGC) mission is to characterize the genetic architecture of IBD phenotypes, 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. In Aim 1, the DCC will optimize power and enhance pathophysiologic insight in clinical areas of unmet need in IBD by coordinating, standardizing and tracking increased recruitment across the GRCs. 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 and assist Ancillary studies. 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 sharing mechanisms and website to promote and facilitate discovery and usage by the IBD community at large. 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 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 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 complex genetic architecture of IBD, comprehensive explication of multi-omics across the entire IBD patient population will provide a key means of defining cellular and therapeutic mechanisms, enabling Precision Medicine for IBD broadly.Â