Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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 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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  2. Parkes, M. et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat. Genet. 39, 830–832 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Singh, S.B., Davis, A.S., Taylor, G.A. & Deretic, V. Human IRGM induces autophagy to eliminate intracellular mycobacteria. Science 313, 1438–1441 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Hampe, J. et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat. Genet. 39, 207–211 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Rioux, J.D. et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat. Genet. 39, 596–604 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. McCarroll, S.A. et al. Common deletion polymorphisms in the human genome. Nat. Genet. 38, 86–92 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Bekpen, C. et al. The interferon-inducible p47 (IRG) GTPases in vertebrates: loss of the cell autonomous resistance mechanism in the human lineage. Genome Biol. 6, R92 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Duerr, R.H. et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cowles, C.R., Hirschhorn, J.N., Altshuler, D. & Lander, E.S. Detection of regulatory variation in mouse genes. Nat. Genet. 32, 432–437 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Campbell, C.D., Kirby, A., Nemesh, J., Daly, M.J. & Hirschhorn, J.N. A survey of allelic imbalance in F1 mice. Genome Res. 18, 555–563 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hosokawa, N., Hara, Y. & Mizushima, N. Generation of cell lines with tetracycline-regulated autophagy and a role for autophagy in controlling cell size. FEBS Lett. 581, 2623–2629 (2007).

    PubMed  Google Scholar 

  12. Takahashi, Y. et al. Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat. Cell Biol. 9, 1142–1151 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bejerano, G. et al. A distal enhancer and an ultraconserved exon are derived from a novel retroposon. Nature 441, 87–90 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Kamal, M., Xie, X. & Lander, E.S. A large family of ancient repeat elements in the human genome is under strong selection. Proc. Natl. Acad. Sci. USA 103, 2740–2745 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nishihara, H., Smit, A.F. & Okada, N. Functional noncoding sequences derived from SINEs in the mammalian genome. Genome Res. 16, 864–874 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lowe, C.B., Bejerano, G. & Haussler, D. Thousands of human mobile element fragments undergo strong purifying selection near developmental genes. Proc. Natl. Acad. Sci. USA 104, 8005–8010 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Santangelo, A.M. et al. Ancient exaptation of a CORE-SINE retroposon into a highly conserved mammalian neuronal enhancer of the proopiomelanocortin gene. PLoS Genet. 3, 1813–1826 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Ruda, V.M. et al. Tissue specificity of enhancer and promoter activities of a HERV-K(HML-2) LTR. Virus Res. 104, 11–16 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Hinds, D.A., Kloek, A.P., Jen, M., Chen, X. & Frazer, K.A. Common deletions and SNPs are in linkage disequilibrium in the human genome. Nat. Genet. 38, 82–85 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Conrad, D.F., Andrews, T.D., Carter, N.P., Hurles, M.E. & Pritchard, J.K. A high-resolution survey of deletion polymorphism in the human genome. Nat. Genet. 38, 75–81 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Redon, R. et al. Global variation in copy number in the human genome. Nature 444, 444–454 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Conrad, D.F. & Hurles, M.E. The population genetics of structural variation. Nat. Genet. 39, S30–S36 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. McCarroll, S.A. & Altshuler, D.M. Copy-number variation and association studies of human disease. Nat. Genet. 39, S37–S42 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Stranger, B.E. et al. Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 315, 848–853 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Schmid, D., Pypaert, M. & Münz, C. Antigen-loading compartments for major histocompatibility complex class II molecules continuously receive input from autophagosomes. Immunity 26, 79–92 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Niess, J.H. et al. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 307, 254–258 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Beuzón, C.R. et al. Salmonella maintains the integrity of its intracellular vacuole through the action of SifA. EMBO J. 19, 3235–3249 (2000).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Macville, M. et al. Comprehensive and definitive molecular cytogenetic characterization of HeLa cells by spectral karyotyping. Cancer Res. 59, 141–150 (1999).

    CAS  PubMed  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Mark J Daly or Ramnik J Xavier.

Supplementary information

Supplementary Text and Figures

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

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.215

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing