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

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

doi:10.1038/ng.215

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

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

Medicine - Cardiology Division

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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.

Original language	English (US)
Pages (from-to)	1107-1112
Number of pages	6
Journal	Nature Genetics
Volume	40
Issue number	9
DOIs	https://doi.org/10.1038/ng.215
State	Published - Sep 2008

Bibliographical note

Funding Information:
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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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. (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

McCarroll, SA, Huett, A, Kuballa, P, Chilewski, SD, Landry, A, Goyette, P, Zody, MC, Hall, JL, Brant, SR, Cho, JH, Duerr, RH, Silverberg, MS, Taylor, KD, Rioux, JD, Altshuler, D, Daly, MJ & Xavier, RJ 2008, 'Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease', Nature Genetics, vol. 40, no. 9, pp. 1107-1112. https://doi.org/10.1038/ng.215

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title = "Deletion polymorphism upstream of IRGM associated with altered IRGM expression and Crohn's disease",

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.",

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

note = "Funding Information: 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{\textquoteright}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. M{\"u}nz (The Rockefeller University).",

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AU - Landry, Aimee

AU - Goyette, Philippe

AU - Zody, Michael C.

AU - Hall, Jennifer L.

AU - Brant, Steven R.

AU - Cho, Judy H.

AU - Duerr, Richard H.

AU - Silverberg, Mark S.

AU - Taylor, Kent D.

AU - Rioux, John D.

AU - Altshuler, David

AU - Daly, Mark J.

AU - Xavier, Ramnik J.

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

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