The NIDDK Inflammatory Bowel Disease Genetics Consortium's (IBDGC) vision is to develop a thorough understanding of the genetic structure of IBD and use this to elucidate the pathophysiology of IBD for improved patient outcomes. The IBDGC was created to advance genetic research on Crohn’s Disease and Ulcerative Colitis. Over the past 15 years, in collaboration with the International IBD Genetics Consortium (IIBDGC), we have identified about 200 susceptibility loci for Inflammatory Bowel Disease (collectively, Crohn’s Disease and Ulcerative Colitis). These newly identified loci have significantly contributed to our understanding of the roles of the innate and acquired immune systems in the pathophysiology of IBD.
The mission of the IBDGC, for the current funding cycle, is to utilize more fully the great wealth of well-characterized patients, biological samples, and data we have amassed over the previous three cycles to elucidate the mechanisms by which associated genetic variants influence pathophysiology. We will work with members within and outside of the IBD community to focus on collaborative, interdisciplinary studies that utilize existing samples and data, and to generate additional resources.
The NIDDK Inflammatory Bowel Disease Genetics Consortium (IBDGC) was created to advance genetic research on Crohn’s Disease and Ulcerative Colitis. The overall objective for the past 15 years has been to identify genes or genomic regions that are associated with increased risk of IBD and with specific phenotypic manifestations. Building on our previous successes, the Consortium has maintained the initial structure of 6 Genetic Research Centers (GRCs) and a Data Coordinating Center (DCC), to apply the genetic knowledge to further exploring the pathophysiology of IBD.
Phase 1: Grant Cycle 2002–2007
The IBD Genetics Consortium was started in 2002 by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). During the first 5 year funding cycle collections included blood for DNA isolation and lymphoblastoid cell lines, and clinical phenotype data for affected independent cases, affected families, and probands with unaffected family controls. We also established a standard phenotyping manual and forms for IBD. Our Genome Wide Association Studies (GWAS) were instrumental in identifying top CD associated loci, specifically NOD2, IL23R and ATG16L1.
- Duerr et al., Science 2006
- Rioux et al., Nature Genetics 2007
Phase 2: Grant Cycle 2007–2012
During Phase 2 collections evolved with the recent genetic findings to focus primarily on independent cases, and population controls. We continued to collect blood for DNA isolation and lymphoblastoid cell lines, and added serum collections. During this time we joined the International IBDGC for several ground-breaking studies. Our GWAS studies were instrumental in identifying the top CD and UC associated loci, and have contributed greatly to several meta-analyses and, specific to CD and UC. These findings allowed us to collaborate with the auto-immune diseases community to design the ImmunoChip (iChip). With a combined total of over 75,000 subjects (IBD cases and controls) the total IBD associated loci to meet genome-wide significance was brought to 163. In addition we learned that many of these loci overlap with other auto-immune diseases, and mycobacterial infection.
- McGovern et al., Nature Genetics 2010
- Rivas et al., Nature Genetics 2011
- Jostins et al., Nature 2012
Phase 3: Grant Cycle 2012–2017
During Phase 3, we began adding value to the genetic associations with functional studies. For this phase we focused on collaborative, multi-disciplinary studies, designed to elucidate the mechanisms whereby risk-conferring genetic variants influence IBD pathophysiology. In addition to previous collections, we began collecting blood for RNA and PBMCs, surgical intestinal tissue and biopsies, and stool and diet. We continued to build on previous GWAS studies, with sequencing of additional populations, and more in-depth interrogation of specific loci with functional studies.
- Palm et al., Cell 2014
- VanDussen et al., Gastroenterology 2014
- Goyette et al., Nature Genetics 2015
- Liu et al., Nature Genetics 2015
- Huang et al., Gastroenterology 2015
- Cleynen et al., Lancet 2015
- Rivas et al., Nature Communications 2016
- Chuang et al., Gastroenterology 2016
- Huang et al., Inflammatory Bowel Disease 2016
- Brant et al., Gastroenterology 2017
- Huang et al., Nature 2017
Phase 4: Grant Cycle 2017–2022
We will continue our focus on functional studies to elucidate the mechanisms whereby risk-conferring genetic variants influence IBD pathophysiology. With a solid understanding of genetic associations for IBD in European ancestry populations, one of our goals for the current phase is to expand IBD genetics to non-European populations. We will augment IBD resources and studies by reaching out to additional collaborators. Additional grant support from NIDDK via the ancillary R01 and R21 mechanism will expedite these collaborations.
- Hui et al., Science Translational Medicine 2018
The governance structure of the Consortium has been very effective in making decisions about specific policies, projects and scientific direction. The Steering Committee (SC), makes all major decisions democratically (e.g., use of Consortium samples and DCC funds, project proposals including those from outside the Consortium and ancillary applications, working group structure). The PIs from each GRC serve as voting members. The chairs of the analytic and clinical translational subcommittees, representatives from NIDDK, the DCC Project Administrator and Technical Director of DCC Operations provide additional expertise and also serve as SC members.
- Chair: John Rioux PhD
- Voting Members: Steve Brant MD, Judy Cho MD, Rick Duerr MD, Dermot McGovern MD, John Rioux PhD, Mark Silverberg MD
- Subcommittee Chairs: Mark Daly PhD, Talin Haritunians PhD, Mark Lazarev MD
- NIDDK Representatives: Robert Karp PhD (Director, Genetics and Genomics Programs of the Division of Digestive Diseases and Nutrition (DDDN)), Peter Perrin PhD (Program Director, DDDN)
- DCC Representatives: Phil Schumm MS, Yashoda Sharma PhD
The DCC facilitates scientific interaction among individual Genetic Research Centers (GRCs) through the collection, organization and analysis of study data, especially with the use of common data structures, existing and novel analytic approaches, and testing of interrelated hypotheses.
- Principal Investigator: Judy H. Cho MD
- Scientific Director of Operations: Ronald A. Thisted PhD
- Technical Director of Operations: Phil Schumm MA
- Project Administrator: Yashoda Sharma PhD
The IBDGC DCC also serves as the Data Coordinator Center for the International IBD Genetics Consortium.
The IBDGC relies on its member GRCs to recruit large numbers of subjects from diverse populations and to leverage the analytic and clinical expertise from their eminent IBD programs. The six GRCs and principal investigators are:
- Cedars Sinai Medical Center: Dermot B. P. McGovern, MD, PhD, MRCP
- Icahn School of Medicine at Mount Sinai: Judy H. Cho, MD
- Rutgers University: Steven R. Brant, MD
- University of Montreal: John D. Rioux, PhD
- University of Pittsburgh: Richard H. Duerr, MD
- University of Toronto: Mark Silverberg, MD, PhD, FRCPC