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Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease

Nature Genetics volume 40, pages 1107–1112 (2008)Cite this article

Abstract

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 IRGM1,2, but coding-sequence variation has been excluded as a source of this association2. 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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Figure 1: A common, 20-kb deletion polymorphism upstream of IRGM.
Figure 2: Differential expression of IRGM from the deletion (CD risk) and reference (CD protective) haplotypes.
Figure 3: IRGM expression levels affect the autophagy of Salmonella typhimurium in human epithelial cells.

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Acknowledgements

The current work was funded by a US National Institute of Allergy and Infection Diseases grant, AI062773, HL088297, DK43351, and CCIB developmental funds to R.J.X. and by a Lilly Life Sciences Research Fellowship to S.A.M. The National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) IBD Genetics Consortium is funded by the following grants: DK62431 (S.R.B.), DK62422 (J.H.C.), DK62420 (R.H.D.), DK62432 and DK064869 (J.D.R.), DK62423 (M.S.S.), DK62413 (K.D.T.), and DK62429 (J.H.C.). Additional support was provided by the Burroughs Wellcome Foundation (J.H.C.), the Crohn's and Colitis Foundation of America (S.R.B., J.H.C., J.D.R.), and the NIDDK, DK064869 (J.D.R.). M. Garber and C. Bekpen provided helpful discussion; C. Patil and J. Korn provided thoughtful comments on the manuscript. LC3-GFP lentiviral vector was a gift from C. Münz (The Rockefeller University).

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Author notes

  1. Mark J Daly and Ramnik J Xavier: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, 02114, Massachusetts, USA

    Steven A McCarroll, David Altshuler & Mark J Daly

  2. Molecular Biology Department, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, 02114, Massachusetts, USA

    Steven A McCarroll & David Altshuler

  3. The Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, 02142, Massachusetts, USA

    Steven A McCarroll, Shannon D Chilewski, Michael C Zody, John D Rioux, David Altshuler & Mark J Daly

  4. Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, 02114, Massachusetts, USA

    Alan Huett, Petric Kuballa, Aimee Landry & Ramnik J Xavier

  5. Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, 02114, Massachusetts, USA

    Alan Huett & Ramnik J Xavier

  6. Université de Montréal and the Montreal Heart Institute, Research Center, 5000 rue Belanger, Montreal, H1T 1C8, Quebec, Canada

    Philippe Goyette & John D Rioux

  7. Department of Medical Biochemistry and Microbiology, Uppsala University, Box 597, Uppsala, SE-751 24, Sweden

    Michael C Zody

  8. Division of Cardiology, Department of Medicine, University of Minnesota Medical School, Minneapolis, 55455, Minnesota, USA

    Jennifer L Hall

  9. Department of Medicine, Johns Hopkins University, Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, 1503 East Jefferson Street, Baltimore, 21231, Maryland, USA

    Steven R Brant

  10. Department of Medicine, Division of Gastroenterology, Yale University, Inflammatory Bowel Disease (IBD) Center, 300 Cedar Street, New Haven, 06519, Connecticut, USA

    Judy H Cho

  11. Department of Medicine, Division of Gastroenterology, University of Pittsburgh, School of Medicine, Hepatology and Nutrition, University of Pittsburgh Medical Center (UPMC) Presbyterian, 200 Lothrop Street, Pittsburgh, 15213, Pennsylvania, USA

    Richard H Duerr

  12. Department of Human Genetics, University of Pittsburgh, Graduate School of Public Health, 130 Desoto Street, Pittsburgh, 15261, Pennsylvania, USA

    Richard H Duerr

  13. Mount Sinai Hospital IBD Centre, University of Toronto, 441-600 University Avenue, Toronto, M5G 1X5, Ontario, Canada

    Mark S Silverberg

  14. Medical Genetics Institute and Inflammatory Bowel Disease (IBD) Center, Cedars-Sinai Medical Center, 8700 W. Beverly Blvd., Los Angeles, 90048, California, USA

    Kent D Taylor

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  1. Steven A McCarroll
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Corresponding authors

Correspondence to Mark J Daly or Ramnik J Xavier.

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Supplementary Figures 1–3, Supplementary Table 1, Supplementary Note, Supplementary Methods (PDF 398 kb)

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McCarroll, S., Huett, A., Kuballa, P. et al. Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease. Nat Genet 40, 1107–1112 (2008). https://doi.org/10.1038/ng.215

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