Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease
Open accessAbstract
Following recent success in genome-wide association studies, a critical focus of human genetics is to understand how genetic variation at implicated loci influences cellular and disease processes. Crohn's disease (CD) is associated with SNPs around IRGM, but coding-sequence variation has been excluded as a source of this association. We identified a common, 20-kb deletion polymorphism, immediately upstream of IRGM and in perfect linkage disequilibrium (r2 = 1.0) with the most strongly CD-associated SNP, that causes IRGM to segregate in the population with two distinct upstream sequences. The deletion (CD risk) and reference (CD protective) haplotypes of IRGM showed distinct expression patterns. Manipulation of IRGM expression levels modulated cellular autophagy of internalized bacteria, a process implicated in CD. These results suggest that the CD association at IRGM arises from an alteration in IRGM regulation that affects the efficacy of autophagy and identify a common deletion polymorphism as a likely causal variant.
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Structural variants have been associated with autism, schizophrenia, and Crohn's disease.
“SVs have already been associated with diverse diseases, including autism2,3, schizophrenia4,5 and Crohn’s disease6,7.”
From Mapping copy number variation by population-scale genome sequencing (2011) · cites this paper as [7]
Association signals have identified small regions for study but have not yet identified causal genes and mutations; GWASs typically yield regions of 10 to 100 kb, and the causal mutation need not be a SNP (e.g., IRGM deletion upstream of promoter).
“4) Association signals have identified small regions for study but have not yet identified causal genes and mutations.”
From Genetic Mapping in Human Disease (2008) · cites this paper as [91]
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- Authors
- McCarroll, S. A., Huett, A., Kuballa, P., Chilewski, S. D., Landry, A., Goyette, P., Zody, M. C., Hall, J. L., Brant, S. R., Cho, J. H., Duerr, R. H., Silverberg, M. S., Taylor, K. D., Rioux, J. D., Altshuler, D., Daly, M. J., & Xavier, R. J.
- Affiliations
- Broad Institute (US)
- Harvard University (US)
- Montreal Heart Institute (CA)
- University of Minnesota (US)
- Johns Hopkins University (US)
- Yale University (US)
- University of Pittsburgh (US)
- Mount Sinai Hospital (CA)
- Cedars-Sinai Medical Center (US)
- Corresponding author
- Daly, Mark J
- Xavier, Ramnik J
- ORCID
- Venue
- Nature Genetics
- Published
- 2008-08-24
- Volume
- 40
- Issue
- 9
- Pages
- 1107-1112
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC2731799
- OpenAlex
- W2084708009
- Cited by
- 655
- References
- 33
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 16 · 2023: 15 · 2022: 14 · 2021: 21 · 2020: 25 · 2019: 25 · 2018: 27 · 2017: 32 · 2016: 33 · 2015: 44 · 2014: 41 · 2013: 58 · 2012: 64
- FWCI
- 43.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Repository@Nottingham (University of Nottingham) (submittedVersion, cc-by)
- Funders
- National Heart, Lung, and Blood Institute (R01HL088297, HL-088297)
- National Institute of Allergy and Infectious Diseases (AI 062773, R01AI062773)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK083756, DK62432, DK62431, DK064869, DK62423, DK62413, DK62422, R01DK064869, DK62420, DK62429, U01DK062420, DK 43351, U01DK062429, U24DK062429, U01DK062413, U01DK062422, P30DK063491, U01DK062432, P30DK043351, U01DK062431, P30DK040561, U01DK062423)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- IRGM, Crohn's disease, deletion polymorphism, gene expression regulation, autophagy, bacterial clearance, haplotypes, linkage disequilibrium, causal variants
- MeSH terms
- Autophagy, Cell Line, Crohn Disease, Gene Expression Regulation, Humans, Sequence Deletion, GTP-Binding Proteins, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study
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