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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01DK062429-15
Application #
8734381
Study Section
Special Emphasis Panel (ZDK1-GRB-7 (O4))
Program Officer
Karp, Robert W
Project Start
2002-09-30
Project End
2017-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
15
Fiscal Year
2014
Total Cost
$1,268,759
Indirect Cost
$434,589
Name
Icahn School of Medicine at Mount Sinai
Department
Genetics
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Brant, Steven R; Okou, David T; Simpson, Claire L et al. (2017) Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease. Gastroenterology 152:206-217.e2
Yadav, Pankaj; Ellinghaus, David; Rémy, Gaëlle et al. (2017) Genetic Factors Interact With Tobacco Smoke to Modify Risk for Inflammatory Bowel Disease in Humans and Mice. Gastroenterology 153:550-565
Hinks, A; Bowes, J; Cobb, J et al. (2017) Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases. Ann Rheum Dis 76:765-772
Huang, Hailiang; Fang, Ming; Jostins, Luke et al. (2017) Fine-mapping inflammatory bowel disease loci to single-variant resolution. Nature 547:173-178
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
Levine, Adam P; Pontikos, Nikolas; Schiff, Elena R et al. (2016) Genetic Complexity of Crohn's Disease in Two Large Ashkenazi Jewish Families. Gastroenterology 151:698-709
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
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
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
Baskovich, Brett; Hiraki, Susan; Upadhyay, Kinnari et al. (2016) Expanded genetic screening panel for the Ashkenazi Jewish population. Genet Med 18:522-8

Showing the most recent 10 out of 62 publications