Advances in present understanding of pathophysiologic mechanisms in inflammatory bowel disease (IBD) have been enhanced enormously through genetic approaches. IBD genetics advances have been catalyzed through large collaborative efforts, notably the NIDDK IBD Genetics Consortium (NIDDK IBDGC), comprised of a central data coordinating center (DCC) and six genetics research centers (GRCs). We present preliminary data from the Immunochip project, a large international collaborative effort, which has identified 163 loci associated to IBD. Data management for Immunochip project has been managed by the NIDDK IBDGC DCC. Importantly, the identification of such a large number of new loci increases the power to integrate complementary datasets to develop predictive models that will deepen our understanding of altered biologic pathways underlying IBD susceptibility. This proposal outlines progress gene identification and network analyses. This knowledge will be critical in more accurately prioritizin which pathways to target for the development of new therapies.
In Specific Aim 1, we propose to generate high quality IBD association datasets that are the foundation of a deeper understanding of disease pathogenesis. Integration of extremely large genome-wide association studies (GWAS), Immunochip data, and upcoming custom IBD exome chip data will be undertaken. Comparative studies in non-European ancestry IBD cohorts, including African-American and Puerto Rican IBD using both genome-wide and targeted approaches are proposed. Fine-mapping and annotation will refine the molecular basis for association signals.
In Specific Aim 2, we provide a framework for integration genetic association data with complementary datasets in order to develop increasingly improved predictive models. Priorities for biospecimens collections and major new """"""""-omics"""""""" based studies are proposed.
In Specific Aim 3, we propose to enhance and expand DCC capabilities to accommodate the accelerating pace of discovery. The DCC has played an essential in successfully managing a marked increase of responsibilities and pace of discovery. This project is highly innovative due to the scope of the project and data generated, the novel integration of complementary data and cross-disciplinary, cross-institutional and cross-consortial collaborative and training efforts.

Public Health Relevance

The goal of the NIDDK Inflammatory Bowel Disease Genetics Consortium is to advance genetic and clinical understanding of Crohn's disease and Ulcerative Colitis. The Data Coordinating Center (DCC) will facilitate scientific interaction between the genetic centers that make up the Consortium and with the scientific community, through the collection, organization and analysis of research data. The DCC plays a key role in the planning, development and implementation of the studies and objectives of the Consortium.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1-GRB-7 (O4))
Program Officer
Karp, Robert W
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Internal Medicine/Medicine
Schools of Medicine
New Haven
United States
Zip Code
Li, Dalin; Achkar, Jean-Paul; Haritunians, Talin et al. (2016) A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition. Gastroenterology 151:724-32
Taleban, Sasha; Li, Dalin; Targan, Stephan R et al. (2016) Ocular Manifestations in Inflammatory Bowel Disease Are Associated with Other Extra-intestinal Manifestations, Gender, and Genes Implicated in Other Immune-related Traits. J Crohns Colitis 10:43-9
Rivas, Manuel A; Graham, Daniel; Sulem, Patrick et al. (2016) A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis. Nat Commun 7:12342
Cleynen, Isabelle; Boucher, Gabrielle; Jostins, Luke et al. (2016) Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study. Lancet 387:156-67
Chuang, Ling-Shiang; Villaverde, Nicole; Hui, Ken Y et al. (2016) A Frameshift in CSF2RB Predominant Among Ashkenazi Jews Increases Risk for Crohn's Disease and Reduces Monocyte Signaling via GM-CSF. Gastroenterology 151:710-723.e2
Sasaki, Mark M; Skol, Andrew D; Hungate, Eric A et al. (2016) Whole-exome Sequence Analysis Implicates Rare Il17REL Variants in Familial and Sporadic Inflammatory Bowel Disease. Inflamm Bowel Dis 22:20-7
Kopylov, Uri; Boucher, Gabrielle; Waterman, Matti et al. (2016) Genetic Predictors of Benign Course of Ulcerative Colitis-A North American Inflammatory Bowel Disease Genetics Consortium Study. Inflamm Bowel Dis 22:2311-6
Baskovich, Brett; Hiraki, Susan; Upadhyay, Kinnari et al. (2016) Expanded genetic screening panel for the Ashkenazi Jewish population. Genet Med 18:522-8
Cho, Judy H; Feldman, Marc (2015) Heterogeneity of autoimmune diseases: pathophysiologic insights from genetics and implications for new therapies. Nat Med 21:730-8
Huang, Chengrui; Haritunians, Talin; Okou, David T et al. (2015) Characterization of genetic loci that affect susceptibility to inflammatory bowel diseases in African Americans. Gastroenterology 149:1575-86

Showing the most recent 10 out of 58 publications