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Nat Genet. Author manuscript; available in PMC Jul 31, 2009.
Published in final edited form as:
Published online Apr 27, 2008. doi:  10.1038/ng.145
PMCID: PMC2719289

Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn’s disease


We report results of a nonsynonymous SNP scan for ulcerative colitis and identify a previously unknown susceptibility locus at ECM1. We also show that several risk loci are common to ulcerative colitis and Crohn’s disease (IL23R, IL12B, HLA, NKX2-3 and MST1), whereas autophagy genes ATG16L1 and IRGM, along with NOD2 (also known as CARD15), are specific for Crohn’s disease. These data provide the first detailed illustration of the genetic relationship between these common inflammatory bowel diseases.

Ulcerative colitis and Crohn’s disease are debilitating inflammatory bowel diseases (IBDs) affecting 1 in 250 individuals of Northern European ancestry. Genetic epidemiological data suggest that they share some but not all susceptibility loci. NOD2, identified in 2001, is specific to Crohn’s disease. Recently, we and others used genome-wide association scans (GWAS) to identify at least ten more loci confirmed to be associated with risk of Crohn’s disease (reviewed in ref. 1).

We now present the first nonsynonymous SNP (nsSNP) scan in ulcerative colitis. We used a staged experimental design. Our discovery cohort of 905 ulcerative colitis cases and 1,465 controls (panel 1) were genotyped using an array custom-made for the Welcome Trust Case Control Consortium (WTCCC; Supplementary Methods online)2. After removing poorly performing samples and markers, we analyzed 10,886 nsSNPs and MHC tag SNPs (Supplementary Methods and Supplementary Figs. 1​-3 online). We found 33 markers from 21 distinct loci associated at P < 0.001. These were then genotyped in another 936 ulcerative colitis cases and 1,470 control subjects (panel 2; statistics on all cases and controls summarized in Supplementary Table 1 online). Five SNPs from three loci replicated (Table 1 and Supplementary Table 2 online). Finally, we tested 16 SNPs tagging 13 known Crohn’s disease-associated loci for association with ulcerative colitis (Table 2 and Supplementary Table 3 online)1.

Table 1
Summary of results at SNPs showing replicated association with ulcerative colitis by Cochran-Armitage trend tests
Table 2
Association study results for SNPs previously associated with Crohn’s disease in the WTCCC study in 1,841 ulcerative colitis cases and 1,470 controls

Of loci not previously associated with IBD, the strongest association in panel 1 was at two nsSNPs in ECM1 on chromosome 1q21.2 (P = 1.3 × 10−4 at rs3737240; P = 2.6 × 10−4 at rs13294). As this was the strongest new signal, we genotyped these markers in panel 2 and in another independent cohort of 1,146 cases and 1,559 controls (panel 3), and we observed support for the association in both (Table 1). After combining all three panels (2,987 cases and 4,494 controls), association at rs3737240 was significant at P = 2.3 × 10−6 and rs13294 at P = 7.9 × 10−6. The result at rs3737240 withstands Bonferroni correction for 10,886 markers (threshold for significance P < 4 × 10−6) and meets suggested significance levels of P < 10−4 to P < 10−6 for gene-centric studies2,3. Association at ECM1 may be specific to ulcerative colitis, as this region was not associated with Crohn’s disease in the WTCCC scan4.

The ECM1 locus, delimited by recombination hotspots, spans 290 kb and includes MRPS21, PRPF3 and TARS2. nsSNPs in flanking blocks showed no association. In additional mapping experiments, we genotyped seven SNPs that fully tag ECM1 in 1,841 cases (from panels 1 and 2) and 1,470 controls (panel 2), with rs11205387 and rs11810419 showing association with ulcerative colitis (Supplementary Table 4 online). Conditional regression analysis showed that neither nsSNP in ECM1 fully explained the association. Fine mapping will identify whether the causal variant maps within ECM1 or elsewhere in this haplotype block. However, ECM1 is a plausible candidate gene for ulcerative colitis: it encodes extracellular matrix protein 1, a glycoprotein expressed in small and large intestine, and it interacts with the basement membrane and inhibits matrix metalloproteinase 9 (ref. 5). Notably, ECM1 strongly activates NF-κB signaling6, a key immune regulator. Expression is upregulated in colorectal cancer and metastases, implicating ECM1 in epithelial-stromal interaction5. rs3737240 and rs13294 encode substitutions T130M and G290S: Thr130, residing within a collagen IV binding domain, is conserved in primates and pigs but not rodents, whereas Gly290 is not conserved. Of note, the WTCCC observed modest association between these ECM1 SNPs and ankylosing spondylitis, a related inflammatory disorder (P = 0.0041 and 0.0044, respectively)4.

Replicating earlier findings7, multiple MHC markers showed strong association with ulcerative colitis in panel 1 (Supplementary Fig. 4 online). Association peaked around rs6927022 (P = 4.7 × 10−8) in a 400-kb haplotype block containing BTNL2 and the HLA loci HLA-DQA1, HLA-DRA, HLA-DRB5 and HLA-DRB1, and was independently replicated (Table 1; rs6927022 could not be genotyped in panel 2 for technical reasons). Previous reports confirmed association between HLA-DRB1 and ulcerative colitis7,8 but did not resolve whether the causal variant lay within this or a neighboring haplotype block. Our high marker density and large panel size successfully resolved this issue: distal to the recombination hotspots, association diminished substantially, indicating that the causal variant does indeed map to this block.

Resolving the causal variant within this block is hindered by tight linkage disequilibrium (LD). Association between BTNL2 variants and ulcerative colitis in Japanese populations was explained by LD with HLA-DRB1*1502 (ref. 9). We stratified BTNL2 genotypes by DRB1*1502 status: clear residual association with BTNL2 (P = 0.0036 at rs9268480) suggests contribution of this gene or another in LD with it. DRB1*0103 was previously associated with ulcerative colitis, especially severe disease7,8. Whether this rare allele accounts for the signal we observed awaits formal HLA genotyping.

To clarify genetic correlations between ulcerative colitis and Crohn’s disease, we partitioned WTCCC Crohn’s disease cases into colonic-only (n = 501) and ileal-only (n = 534) subphenotypes, and implemented a ‘within-cases’ test of association on the GWAS data (Supplementary Methods). We found that multiple HLA markers within the 400-kb block identified in our ulcerative colitis scan were significantly associated with colonic Crohn’s disease, peaking at rs3129872 (P = 6.8 × 10−9, HLA-DRA). This corroborates previous association between HLA-DRB1*0103 and colonic Crohn’s disease10 and refines the signal to this haplotype block. Compared to healthy controls (MAF = 0.292), the allele frequency at rs3129872 was significantly elevated in colonic Crohn’s disease cases (P = 4.8 × 10−4, MAF = 0.347) and reduced in ileal cases (P = 5.18 × 10−5, MAF = 0.231). We nominally replicated this association (P = 9.7 × 10−3) in our smaller Crohn’s disease replication cohort (Supplementary Table 5 online). Thus, determinants within this haplotype block both increase risk of ulcerative colitis and colon-only Crohn’s disease and decrease risk of small bowel Crohn’s disease. This suggests shared pathogenic mechanisms for colonic forms of IBD distinct from small bowel inflammation.

The third replicable locus detected in the nsSNP scan was MST1 on chromosome 3p21, a region also associated with Crohn’s disease4,11. nsSNP rs3197999 (Ppanel 1+2 = 6.0 × 10−6​; Table 1) results in amino acid change R689C. We subsequently genotyped 20 SNPs tagging the MST1 locus and seven nsSNPs from surrounding genes with MAF > 0.02, capturing (r2 > 0.8) 70/73 Hapmap SNPs from the 193-kb haplotype block encompassing this locus and 86/93 and 122/136 HapMap SNPs from the 301-kb and 279-kb flanking blocks, respectively. Association peaked at MST1 (Supplementary Table 4). Conditional regression analysis showed a marginally significant haplotype effect with rs34823813 and rs9853352. The latter two SNPs in RNF123 and IHPK1 are within the same haplotype block as MST1 and are in strong LD (r2 = 0.95). Although their contribution to ulcerative colitis risk cannot be excluded, the evidence more strongly implicates nsSNP rs3197999 as causal or in strong LD with the causal variant at this locus. Arg689 is strongly conserved in mammals, and MST1 is known to suppress cell-mediated immunity by down-regulating IL-12 (ref. 12).

Finally, we genotyped 16 SNPs tagging 13 Crohn’s disease-associated loci identified by GWAS1 in 1,841 ulcerative colitis cases (panels 1 and 2) and 1,470 controls (panel 2). Previous smaller studies, including our own using a panel partially overlapping with the current dataset (Supplementary Methods), had identified modest association between ulcerative colitis and IL23R variants13,14. Here this association was confirmed (P = 1.3 × 10−5 at rs11805303) (Table 2 and Supplementary Table 3) and refined by genotyping five additional IL23R SNPs. In contrast to earlier reports13,14, in ulcerative colitis, but consistent with findings in Crohn’s disease14, conditional regression analysis in our large ulcerative colitis panel demonstrated that rs11209026 (R381G) provided the strongest signal (P = 8.9 × 10−8, OR = 0.53), with evidence that additional independent variants also contribute to ulcerative colitis risk (Supplementary Table 4). Association was also observed at rs6556416 in IL12B (P = 6.8 × 10−4), which encodes a subunit shared by IL-12 and IL-23 (Table 2). Thus, the Th17 pathway seems as relevant to ulcerative colitis as to Crohn’s disease13,14, ankylosing spondylitis2 and psoriasis15.

Among other Crohn’s disease-associated loci, association with ulcerative colitis was also seen for the transcription factor gene NKX2-3 (for rs10883365, P = 3.3 × 10−4 in the ulcerative colitis panel and P = 2.4 × 10−6 using the expanded WTCCC control panel; Table 2). Thus, NKX2-3 represents another generic IBD locus. However, no association with ulcerative colitis was seen at IRGM (P = 0.72), PTPN2 (P = 0.17), ATG16L1 (P = 0.11) or the chromosome 5p13 gene desert (P = 0.19), despite 80% power to detect an allelic OR = 1.15 with MAF = 0.17 at P = 0.05 (PTPN2 effect in Crohn’s disease) and >95% power for OR = 1.36 with MAF = 0.12 at P = 0.0001 (comparable to IRGM and ATG16L1 in Crohn’s disease).

Several Crohn’s disease-associated loci, including the MST1 locus and variants in the IL-23 pathway, evidently also contribute to ulcerative colitis susceptibility. However, some are disease-specific. Notably, genes associated with Crohn’s disease but not ulcerative colitis, including NOD2 and autophagy genes ATG16L1 and IRGM, affect intracellular handling of bacterial antigens, suggesting distinct pathogenic mechanisms relating to microbial processing. Additional susceptibility loci have yet to be identified, and the scene is set for GWA scans for ulcerative colitis. However, in identifying a previously unknown ulcerative colitis–associated locus at ECM1 and defining the extent of its overlap with Crohn’s disease-associated loci, we have made substantial progress both in understanding the key pathogenic pathways for ulcerative colitis and in illuminating the genetic relationship between these two forms of inflammatory bowel disease.

Supplementary Material

Supplementary Information


We thank the DNA Collections and Genotyping facilities at the Wellcome Trust Sanger Institute and King’s College London for sample preparation and quality control of the ulcerative colitis cohort and conducting genotyping, in particular A. Chaney, D. Simpkin, C. Hind, T. Dibling and D. Soars; and the DNA and Genotyping Informatics teams for data handling. We acknowledge the National Association for Colitis and Crohn’s disease (NACC), Procter and Gamble (unrestricted educational grant), the Evelyn Trust, the Wexham Trust and the NIHR Cambridge Biomedical Research Centre who supported the study. We also acknowledge use of DNA from the 1958 British Birth Cohort collection (D. Strachan, S. Ring, W. McArdle and M. Pembrey), funded by the Medical Research Council and Wellcome Trust, and NACC and the Wellcome Trust who supported case collections. S.A.F. is supported by a Research Council UK fellowship. M.T. is supported by a Wellcome Trust Clinical Research Training Fellowship. We thank all subjects who contributed samples and consultants and nursing staff across the UK who helped with recruitment of study subjects.


Note: Supplementary information is available on the Nature Genetics website.

Published online at http://www.nature.com/naturegenetics

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1. Mathew CG. Nat. Rev. Genet. 2008;9:9–14. [PubMed]
2. Wellcome Trust Case Control Consortium Nat. Genet. 2007;39:1329–1337. [PMC free article] [PubMed]
3. Thomas DC, Clayton DG. J. Natl. Cancer Inst. 2004;96:421–423. [PubMed]
4. Wellcome Trust Case Control Consortium Nature. 2007;447:661–678. [PMC free article] [PubMed]
5. Chan I, Liu L, Hamada T, Sethuraman G, McGrath JA. Exp. Dermatol. 2007;16:881–890. [PubMed]
6. Matsuda A, et al. Oncogene. 2003;22:3307–3318. [PubMed]
7. Stokkers PC, Reitsma PH, Tytgat GN, van Deventer SJ. Gut. 1999;45:395–401. [PMC free article] [PubMed]
8. Satsangi J, et al. Lancet. 1996;347:1212–1217. [PubMed]
9. Mochida A, et al. Tissue Antigens. 2007;70:128–135. [PubMed]
10. Silverberg MS, et al. Inflamm. Bowel Dis. 2003;9:1–9. [PubMed]
11. Parkes M, et al. Nat. Genet. 2007;39:830–832. [PMC free article] [PubMed]
12. Morrison AC, Wilson CB, Ray M, Correll PH. J. Immunol. 2004;172:1825–1832. [PubMed]
13. Tremelling M, et al. Gastroenterology. 2007;132:1657–1664. [PMC free article] [PubMed]
14. Duerr RH, et al. Science. 2006;314:1461–1463. [PubMed]
15. Cargill M, et al. Am. J. Hum. Genet. 2007;80:273–290. [PMC free article] [PubMed]
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