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

McCarroll, Steven A.; Huett, Alan; Kuballa, Petric; Chilewski, Shannon D.; Landry, Aimee; Goyette, Philippe; Zody, Michael C.; Hall, Jennifer L.; Brant, Steven R.; Cho, Judy H.; Duerr, Richard H.; Silverberg, Mark S.; Taylor, Kent D.; Rioux, John D.; Altshuler, David; Daly, Mark J.; Xavier, Ramnik J.

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 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. © 2008 Nature Publishing Group.

Citation

McCarroll, S. A., Huett, A., Kuballa, P., Chilewski, S. D., Landry, A., Goyette, P., …Xavier, R. J. (2008). Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease. Nature Genetics, 40(9), 1107-1112. https://doi.org/10.1038/ng.215

• Journal Article Type: Article
• Acceptance Date: Jun 18, 2008
• Online Publication Date: Aug 24, 2008
• Publication Date: Aug 24, 2008
• Deposit Date: Aug 15, 2022
• Journal: Nature Genetics
• Print ISSN: 1061-4036
• Electronic ISSN: 1546-1718
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 40
• Issue: 9
• Pages: 1107-1112
• DOI: https://doi.org/10.1038/ng.215
• Public URL: https://nottingham-repository.worktribe.com/output/3181856
• Publisher URL: https://www.nature.com/articles/ng.215#citeas