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^{1, 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.

1. Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114, USA
2. Molecular Biology Department, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
3. The Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
4. Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114, USA
5. Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
6. Université de Montréal and the Montreal Heart Institute, Research Center, 5000 rue Belanger, Montreal, Quebec H1T 1C8, Canada.
7. Department of Medical Biochemistry and Microbiology, Uppsala University, Box 597, Uppsala, SE-751 24, Sweden.
8. Division of Cardiology, Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.
9. Johns Hopkins University, Department of Medicine, Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, 1503 East Jefferson Street, Baltimore, Maryland 21231, USA.
10. Yale University, Department of Medicine, Division of Gastroenterology, Inflammatory Bowel Disease (IBD) Center, 300 Cedar Street, New Haven, Connecticut 06519, USA.
11. University of Pittsburgh, School of Medicine, Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center (UPMC) Presbyterian, 200 Lothrop Street, Pittsburgh, Pennsylvania 15213, USA.
12. University of Pittsburgh, Graduate School of Public Health, Department of Human Genetics, 130 Desoto Street, Pittsburgh, Pennsylvania 15261, USA.
13. Mount Sinai Hospital IBD Centre, University of Toronto, 441-600 University Avenue, Toronto, Ontario M5G 1X5, Canada.
14. Medical Genetics Institute and Inflammatory Bowel Disease (IBD) Center, Cedars-Sinai Medical Center, 8700 W. Beverly Blvd., Los Angeles, California 90048, USA.
15. These authors contributed equally to this work.

Correspondence to: Ramnik J Xavier^4,5,15 e-mail: xavier@molbio.mgh.harvard.edu

Correspondence to: Mark J Daly^1,3,15 e-mail: mjdaly@chgr.mgh.harvard.edu

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