Novel Crohn Disease Locus Identified by Genome-Wide Association Maps to a Gene Desert on 5p13.1 and Modulates Expression of PTGER4

Abstract

To identify novel susceptibility loci for Crohn disease (CD), we undertook a genome-wide association study with more than 300,000 SNPs characterized in 547 patients and 928 controls. We found three chromosome regions that provided evidence of disease association with p-values between 10−6 and 10−9. Two of these (IL23R on Chromosome 1 and CARD15 on Chromosome 16) correspond to genes previously reported to be associated with CD. In addition, a 250-kb region of Chromosome 5p13.1 was found to contain multiple markers with strongly suggestive evidence of disease association (including four markers with p < 10−7). We replicated the results for 5p13.1 by studying 1,266 additional CD patients, 559 additional controls, and 428 trios. Significant evidence of association (p < 4 × 10−4) was found in case/control comparisons with the replication data, while associated alleles were over-transmitted to affected offspring (p < 0.05), thus confirming that the 5p13.1 locus contributes to CD susceptibility. The CD-associated 250-kb region was saturated with 111 SNP markers. Haplotype analysis supports a complex locus architecture with multiple variants contributing to disease susceptibility. The novel 5p13.1 CD locus is contained within a 1.25-Mb gene desert. We present evidence that disease-associated alleles correlate with quantitative expression levels of the prostaglandin receptor EP4, PTGER4, the gene that resides closest to the associated region. Our results identify a major new susceptibility locus for CD, and suggest that genetic variants associated with disease risk at this locus could modulate cis-acting regulatory elements of PTGER4.

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

“…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). (b) Pooled data of Australian, 39 British, 21,23,37 Canadian, 31 Dutch, 28 German, 14,29,30 Italian, 33 Hungarian, 34 New Zealander, 26,39 North American 15 and Spanish cohorts for ulcerative colitis (UC).…”

“…[14][15][16][21][22][23][24][25][26][27][28][29][30][31][32][33][34]38,39 Funnel plots and Egger tests were performed to analyse the publication bias of the meta-analysis. No statistically significant values were observed in CD studies (P ¼ 0.6) or UC studies (P ¼ 0.4), with symmetric funnel plots for both studies (Supplementary Figure 1).…”

“…[18][19][20] Association of CD with the ATG16L1 T300A (rs2241880) polymorphism was reported simultaneously by different GWASs. [14][15][16] A large number of subsequent association studies have replicated the strong association of this gene with CD. [21][22][23][24][25][26][27][28][29][30][31][32][33][34] IRGM (immunity-related guanosine triphosphatase, the human homologue of mouse Irgm/Lrg47) encodes a GTP-binding protein that induces autophagy and plays an important role in innate immunity against intracellular pathogens.…”

“…Interestingly, recent genomewide association studies (GWASs) of CD have reported a strong association with two crucial genes in the autophagy process, ATG16L1 and IRGM. [14][15][16][17] ATG16L1 encodes a protein that interacts with the Atg12p-Atg5p conjugate during formation of the preautophagosomal structure, which is essential for autophagy. [18][19][20] Association of CD with the ATG16L1 T300A (rs2241880) polymorphism was reported simultaneously by different GWASs.…”

No association between TNFSF15 and IL23R with ulcerative colitis in Koreans

“…[1][2][3][4] The incidence of IBD is relatively higher in Caucasian than in Asian populations; however, the incidence in Asia is increasing. 5,6 Of the two types of IBD, the genetic contribution to disease risk has been documented more extensively and clearly for CD [7][8][9][10][11][12][13][14][15][16][17] than for UC. [18][19][20][21] So far, linkage and genome-wide association studies have identified more than 30 CD-susceptibility loci in Caucasian populations.…”