Independent and population-specific association of risk variants at the IRGM locus with Crohn's disease

Natalie J. Prescott*, Katherine M. Dominy, Michiaki Kubo, Cathryn M. Lewis, Sheila A. Fisher, Richard Redon, Ni Huang, Barbara Elaine Stranger, Katarzyna Blaszczyk, Barry Hudspith, Gareth Parkes, Naoya Hosono, Keiko Yamazaki, Clive M. Onnie, Alastair Forbes, Emmanouil T. Dermitzakis, Yusuke Nakamura, John C. Mansfield, Jeremy Sanderson, Matthew E. HurlesRoland G. Roberts, Christopher G. Mathew

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

90 Scopus citations


DNA polymorphisms in a region on chromosome 5q33.1 which contains two genes, immunity related GTPase related family, M (IRGM) and zinc finger protein 300 (ZNF300), are associated with Crohn's disease (CD). The deleted allele of a 20 kb copy number variation (CNV) upstreamof IRGM was recently shown to be in strong linkage disequilibrium(LD)withtheCD-associated single nucleotide polymorphisms and is itself associatedwithCD (P < 0.01). The deletionwas correlatedwith increased or reduced expression of IRGMin transformed cells in a cell line-dependentmanner, and has been proposed as a likely causal variant.We report here that small insertion/deletion polymorphisms in the promoter and 5′ untranslated region of IRGM are, together with the CNV, strongly associated with CD (P = 1.37 × 10-5 to 1.40 × 10-9), and that the CNV and the 5′-untranslated region variant -308(GTTT)5 contribute independently to CD susceptibility (P = 2.6 × 10-7 and P = 2 × 10-5, respectively). We also show that the CD risk haplotype is associated with a significant decrease in IRGM expression (P < 10-12) in untransformed lymphocytes from CD patients. Further analysis of these variants in a Japanese CD case-control sample and of IRGM expression in HapMap populations revealed that neither the IRGM insertion/deletion polymorphisms nor the CNV was associated with CD or with altered IRGM expression in the Asian population. This suggests that the involvement of the IRGM risk haplotype in the pathogenesis of CD requires gene-gene or gene-environment interactions which are absent in Asian populations, or that none of the variants analysed are causal, and that the true causal variants arose after the European-Asian split.

Original languageEnglish (US)
Article numberddq041
Pages (from-to)1828-1839
Number of pages12
JournalHuman molecular genetics
Issue number9
StatePublished - Jan 27 2010

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics
  • Molecular Biology


Dive into the research topics of 'Independent and population-specific association of risk variants at the IRGM locus with Crohn's disease'. Together they form a unique fingerprint.

Cite this