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.

doi:10.1038/ng.215

Cited by 609 publications

(551 citation statements)

References 27 publications

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“…For example, deletions near IRGM and NEGR1 genes, which were in perfect linkage disequilibrium (LD) with the GWAS-SNPs, were identified for Crohn's disease and body mass index, respectively. 19,20 Our study also showed strong correlations between CNPs and GWAS-SNPs near IRGM and NEGR1 in all 10 populations, but the deletion frequencies varied substantially among the populations. GWAS-SNPs are potentially indirect markers of disease variants, which include CNPs.…”

Section: Populationsupporting

confidence: 60%

Copy number polymorphisms in new HapMap III and Singapore populations

Teo

Naidoo

et al. 2011

J Hum Genet

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Copy number variations can be identified using newer genotyping arrays with higher single nucleotide polymorphisms (SNPs) density and copy number probes accompanied by newer algorithms. applied these to the HapMap II samples and identified 1316 copy number polymorphisms (CNPs). In our study, we applied the same approach to 859 samples from three Singapore populations and seven HapMap III populations. Approximately 50% of the 1291 autosomal CNPs were found to be polymorphic only in populations of non-African ancestry. Pairwise comparisons among the 10 populations showed substantial differences in the CNPs frequencies. Additionally, 698 CNPs showed significant differences with false discovery rate (FDR)o0.01 among the 10 populations and these loci overlap with known disease-associated or pharmacogenetic-related genes such as CFHR3 and CFHR1 (age related macular degeneration), GSTTI (metabolism of various carcinogenic compounds and cancers) and UGT2B17 (prostate cancer and graft-versus-host disease). The correlations between CNPs and genome-wide association studies-SNPs were investigated and several loci, which were previously unreported, that may potentially be implicated in complex diseases and traits were found; for example, childhood acute lymphoblastic leukaemia, age-related macular degeneration, breast cancer, response to antipsychotic treatment, rheumatoid arthritis and type-1 diabetes. Additionally, we also found 5014 novel copy number loci that have not been reported previously by in the 10 populations.

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Section: Populationsupporting

confidence: 60%

Copy number polymorphisms in new HapMap III and Singapore populations

Teo

Naidoo

et al. 2011

J Hum Genet

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“…Further, they sequenced the whole gene and found no non-synonymous variants associated with CD, 17 suggesting that the causal variants may lie in the regulatory or exonic sequences of IRGM in linkage disequilibrium with the associated variants. Interestingly, in a very recent study McCarroll et al 56 have shown that the causal variant responsible for IRGM Figure 1 Pooled data for the ATG16L1 rs2241880 susceptibility allele frequency (SAF). (a) Pooled data of Australian, 39 Belgian, 16 British, 14,21,23,25 Canadian, 31 Dutch, 28 German, 14,29,30 Italian, 27,33 Hungarian, 34 Japanese, 22 New Zealander, 26 North American 15,24 and Spanish cohorts for Crohn's disease (CD).…”

Section: Discussionmentioning

confidence: 99%

Association of ATG16L1 and IRGM genes polymorphisms with inflammatory bowel disease: a meta-analysis approach

et al. 2009

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The aim of this study was to determine the role of the ATG16L1 (rs2241880) and IRGM (rs13361189 and rs4958847) genes polymorphism in Crohn's disease (CD) and ulcerative colitis (UC). Our study included 557 CD and 425 UC patients and 672 ethnically matched Spanish controls and a meta-analysis with the data published to date. The polymorphisms were genotyped using predesigned TaqMan single nucleotide polymorphism genotyping assays. There was a statistically significant difference in the distribution of the ATG16L1 rs2241880 G allele between CD patients and controls in the Spanish population: P ¼ 6.5 Â 10 À9 , odds ratio (OR) ¼ 1.62. Although no differences were observed between UC patients and controls in the Spanish cohort, a meta-analysis demonstrated that the ATG16L1 G allele increase significantly risk for UC (P ¼ 0.0003, pooled OR ¼ 1.08). In addition, our meta-analysis data showed that IRGM rs13361189 and rs4958847 polymorphisms were associated with CD (rs13361189 C allele P ¼ 1.07 Â 10 À19 , pooled OR ¼ 1.34; rs4958847 A allele P ¼ 2.78 Â 10 À17 , pooled OR ¼ 1.31) and UC (rs13361189 P ¼ 0.0069, pooled OR ¼ 1.16; rs4958847 P ¼ 0.014, pooled OR ¼ 1.13). In conclusion, our results confirm the ATG16L1 rs2241880 and IRGM rs13361189 and rs4958847 polymorphisms as important markers for CD susceptibility and indicate that these variants are also associated with UC.

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“…It has been hypothesized that as immunity-related GTPase family M expression can affect the autophagy of internalized bacteria, the deletion might alter the expression level of immunityrelated GTPase family M, thus, contributing to phenotype associated with CD. 44 Pancreatitis Pancreatitis is a multigene-associated disorder, including the cationic trypsinogen gene PRSS1. In the earlier studies, the R122H missense mutation was found to increase the activity of trypsin in vitro, which led to the suggestion that PRSS1 might be a dosage-sensitive gene.…”

Section: Cnv and Susceptibility To Other Common Disorders Hiv/aids Sumentioning

confidence: 99%