Expressive

rs1000113 (IRGM): Crohn's Disease Risk Variant

Key takeaways

  • rs1000113 at the IRGM locus is associated with susceptibility to Crohn's disease and IBD across multiple populations
  • A landmark British GWAS found 9 independent Crohn's disease signals, each with generally modest individual effect sizes
  • A cross-ancestry analysis of over 45,000 IBD cases identified 320 associated loci, including 81 newly discovered ones
  • Crohn's disease genetics appear more dependent on ancestry background than ulcerative colitis genetics
  • This variant increases expression of a nearby gene across at least eight tissue types, including lung and adipose tissue

Key takeaways

  • rs1000113 at the IRGM locus is associated with susceptibility to Crohn's disease (CD) and inflammatory bowel disease (IBD) across multiple populations
  • A landmark British GWAS found 9 independent CD susceptibility signals, each with generally modest individual effect sizes
  • A cross-ancestry analysis of over 45,000 IBD cases identified 320 associated loci, including 81 newly discovered ones
  • CD genetic architecture appears more dependent on ancestry background than ulcerative colitis (UC) genetics
  • This variant increases expression of a nearby gene (ENSG00000291115) across at least eight tissue types, including lung and adipose tissue

What the research says A genome-wide association study (GWAS - a method that simultaneously tests hundreds of thousands of positions across the genome for links to disease) of approximately 2,000 CD cases and 3,000 controls from the British population identified 9 independent CD susceptibility signals at a stringent significance threshold (P<5×10^-7), with effect sizes at identified loci described as generally modest, consistent with the polygenic nature of common complex diseases. A subsequent large cross-ancestry meta-analysis combining 14,393 East Asian IBD cases (7,372 CD) with approximately 30,000 European cases - totalling 45,106 cases and 353,562 controls - identified 320 IBD-associated loci (81 novel) and found that the genetic architecture of CD was more ancestry-dependent than that of UC, illustrated by the TNFSF15 locus showing an odds ratio of 1.75 (95% CI: 1.57-1.91) for CD in East Asian populations versus 1.15 (95% CI: 1.11-1.17) in European populations.

Reported associations

  • Crohn's disease (CD): Among 9 independent CD susceptibility signals identified at P<5×10^-7 in a British GWAS of approximately 2,000 CD cases and 3,000 shared controls; effect sizes across the identified loci were generally modest
  • Inflammatory bowel disease (IBD) - cross-ancestry: The locus is among 320 IBD-associated loci from a meta-analysis of 45,106 total cases and 353,562 controls spanning East Asian and European ancestries, of which 81 loci were newly identified
  • IBD subtype distinction: CD shows greater genetic dependence on ancestry background than UC; the TNFSF15 locus, cited as a representative example, has an odds ratio of 1.75 (95% CI: 1.57-1.91) in East Asian versus 1.15 (95% CI: 1.11-1.17) in European populations for CD, illustrating the magnitude of ancestry-driven effect-size differences at some IBD loci

Evidence quality The British GWAS (approximately 2,000 CD cases, 3,000 controls) confirmed 9 CD loci meeting P<5×10^-7 and validated the genome-wide association approach for common disease, while noting that modest effect sizes at most loci underscore the necessity of large samples. The cross-ancestry meta-analysis substantially increased statistical power (45,106 total cases, 353,562 controls across East Asian and European cohorts) and minimized population stratification artefact, as confirmed by genomic inflation factors (λ₁₀₀₀ = 0.99-1.05) and LD score regression (a statistical method for detecting systematic biases in association results) intercepts of 1.02-1.06. No direct conflict between the two studies was identified; the cross-ancestry work extended and refined the earlier European-centric findings. Notably, the provided study excerpts do not report variant-level statistics for rs1000113 individually, so specific odds ratios or p-values for this SNP alone are not derivable from these sources.

Tissue-specific expression effects

  • ENSG00000291115: The alternate allele at rs1000113 is associated with increased expression of this gene across eight tissue types - lung (p=9.4×10^-7³), esophageal muscle layer (p=2.9×10^-74), sun-unexposed skin (p=1.8×10^-80), tibial nerve (p=3.1×10^-78), visceral adipose tissue (p=3.6×10^-8²), thyroid (p=2.6×10^-7³), subcutaneous adipose tissue (p=5.7×10^-79), and sun-exposed lower-leg skin (p=2.6×10^-77) - all results are highly statistically significant (GTEx v11, 953 donors, FDR<0.05) GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.

Frequently asked questions

What is the IRGM gene and why is it linked to gut disease?

IRGM is a gene at a locus associated with inflammatory bowel disease, particularly Crohn's disease. Large-scale genetic studies have confirmed it as one of hundreds of IBD susceptibility regions identified across both European and East Asian populations.

Is rs1000113 linked to Crohn's disease?

Yes. A genome-wide association study in approximately 2,000 Crohn's disease cases identified this region as one of nine independent susceptibility signals at P<5×10^-7. A larger cross-ancestry study of over 45,000 IBD cases further confirmed IBD associations at this locus across multiple populations.

Does rs1000113 affect gene expression in the body?

Yes. GTEx data indicate the alternate allele at rs1000113 is associated with increased expression of a nearby gene (ENSG00000291115) across at least eight tissue types, including lung, adipose tissue, and thyroid, all at very high statistical significance.

Does ancestry change how IBD risk genes like IRGM work?

Research shows that Crohn's disease genetic architecture is more ancestry-dependent than ulcerative colitis. Specific loci can differ substantially in allele frequency or effect size between East Asian and European populations - for example, TNFSF15 shows an odds ratio of 1.75 in East Asian versus 1.15 in European populations for Crohn's disease risk.

How widespread is inflammatory bowel disease globally?

As of 2017, approximately 6.8 million people globally had been diagnosed with IBD, with rising incidence especially in recently industrialized countries. Genetic research has now identified over 300 associated loci, advancing the understanding of disease biology.