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Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region

Abstract

Ulcerative colitis is a common form of inflammatory bowel disease with a complex etiology. As part of the Wellcome Trust Case Control Consortium 2, we performed a genome-wide association scan for ulcerative colitis in 2,361 cases and 5,417 controls. Loci showing evidence of association at P < 1 × 10−5 were followed up by genotyping in an independent set of 2,321 cases and 4,818 controls. We find genome-wide significant evidence of association at three new loci, each containing at least one biologically relevant candidate gene, on chromosomes 20q13 (HNF4A; P = 3.2 × 10−17), 16q22 (CDH1 and CDH3; P = 2.8 × 10−8) and 7q31 (LAMB1; P = 3.0 × 10−8). Of note, CDH1 has recently been associated with susceptibility to colorectal cancer, an established complication of longstanding ulcerative colitis. The new associations suggest that changes in the integrity of the intestinal epithelial barrier may contribute to the pathogenesis of ulcerative colitis.

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Figure 1: Plot of genome-wide association results.
Figure 2: Regional association plots for the three newly discovered loci.

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References

  1. Rubin, G.P., Hungin, A.P., Kelly, P.J. & Ling, J. Inflammatory bowel disease: epidemiology and management in an English general practice population. Aliment. Pharmacol. Ther. 14, 1553–1559 (2000).

    Article  CAS  Google Scholar 

  2. Eaden, J.A., Abrams, K.R. & Mayberry, J.F. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut 48, 526–535 (2001).

    Article  CAS  Google Scholar 

  3. Xavier, R.J. & Podolsky, D.K. Unravelling the pathogenesis of inflammatory bowel disease. Nature 448, 427–434 (2007).

    Article  CAS  Google Scholar 

  4. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  5. Anderson, C.A. et al. Investigation of Crohn's disease risk loci in ulcerative colitis further defines their molecular relationship. Gastroenterology 136, 523–529 (2009).

    Article  Google Scholar 

  6. Barrett, J.C. et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat. Genet. 40, 955–962 (2008).

    Article  CAS  Google Scholar 

  7. Duerr, R.H. et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006).

    Article  CAS  Google Scholar 

  8. Fisher, S.A. et al. Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease. Nat. Genet. 40, 710–712 (2008).

    Article  CAS  Google Scholar 

  9. Franke, A. et al. Replication of signals from recent studies of Crohn's disease identifies previously unknown disease loci for ulcerative colitis. Nat. Genet. 40, 713–715 (2008).

    Article  CAS  Google Scholar 

  10. Hampe, J. et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn's disease in ATG16L1. Nat. Genet. 39, 207–211 (2007).

    Article  CAS  Google Scholar 

  11. Libioulle, C. et al. Novel Crohn's disease locus identified by genome-wide association maps to a gene desert on 5p13.1 and modulates expression of PTGER4. PLoS Genet. 3, e58 (2007).

    Article  Google Scholar 

  12. Parkes, M. et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat. Genet. 39, 830–832 (2007).

    Article  CAS  Google Scholar 

  13. Satsangi, J. et al. Contribution of genes of the major histocompatibility complex to susceptibility and disease phenotype in inflammatory bowel disease. Lancet 347, 1212–1217 (1996).

    Article  CAS  Google Scholar 

  14. Franke, A. et al. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat. Genet. 40, 1319–1323 (2008).

    Article  CAS  Google Scholar 

  15. Silverberg, M.S. et al. Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study. Nat. Genet. 41, 216–220 (2009).

    Article  CAS  Google Scholar 

  16. Yamagata, K. et al. Mutations in the hepatocyte nuclear factor-4α gene in maturity-onset diabetes of the young (MODY1). Nature 384, 458–460 (1996).

    Article  CAS  Google Scholar 

  17. Barroso, I. et al. Population-specific risk of type 2 diabetes conferred by HNF4A P2 promoter variants: a lesson for replication studies. Diabetes 57, 3161–3165 (2008).

    Article  CAS  Google Scholar 

  18. Kathiresan, S. et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat. Genet. 41, 56–65 (2009).

    Article  CAS  Google Scholar 

  19. Battle, M.A. et al. Hepatocyte nuclear factor 4α orchestrates expression of cell adhesion proteins during the epithelial transformation of the developing liver. Proc. Natl. Acad. Sci. USA 103, 8419–8424 (2006).

    Article  CAS  Google Scholar 

  20. Garrison, W.D. et al. Hepatocyte nuclear factor 4α is essential for embryonic development of the mouse colon. Gastroenterology 130, 1207–1220 (2006).

    Article  CAS  Google Scholar 

  21. Ahn, S.H. et al. Hepatocyte nuclear factor 4α in the intestinal epithelial cells protects against inflammatory bowel disease. Inflamm. Bowel Dis. 14, 908–920 (2008).

    Article  Google Scholar 

  22. Karayiannakis, A.J. et al. Expression of catenins and E-cadherin during epithelial restitution in inflammatory bowel disease. J. Pathol. 185, 413–418 (1998).

    Article  CAS  Google Scholar 

  23. Houlston, R.S. et al. Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer. Nat. Genet. 40, 1426–1435 (2008).

    Article  CAS  Google Scholar 

  24. Muise, A.M. et al. Polymorphisms in E-cadherin (CDH1) result in a mis-localised cytoplasmic protein that is associated with Crohn's disease. Gut 58, 1121–1127 (2009).

    Article  CAS  Google Scholar 

  25. Peignon, G. et al. E-cadherin-dependent transcriptional control of apolipoprotein A-IV gene expression in intestinal epithelial cells: a role for the hepatic nuclear factor 4. J. Biol. Chem. 281, 3560–3568 (2006).

    Article  CAS  Google Scholar 

  26. Vowinkel, T. et al. Apolipoprotein A-IV inhibits experimental colitis. J. Clin. Invest. 114, 260–269 (2004).

    Article  CAS  Google Scholar 

  27. Schmehl, K., Florian, S., Jacobasch, G., Salomon, A. & Korber, J. Deficiency of epithelial basement membrane laminin in ulcerative colitis affected human colonic mucosa. Int. J. Colorectal Dis. 15, 39–48 (2000).

    Article  CAS  Google Scholar 

  28. Styrkarsdottir, U. et al. Multiple genetic loci for bone mineral density and fractures. N. Engl. J. Med. 358, 2355–2365 (2008).

    Article  CAS  Google Scholar 

  29. Liu, Y. et al. A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. PLoS Genet. 4, e1000041 (2008).

    Article  Google Scholar 

  30. Kugathasan, S. et al. Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease. Nat. Genet. 40, 1211–1215 (2008).

    Article  CAS  Google Scholar 

  31. Zhernakova, A. et al. Genetic analysis of innate immunity in Crohn's disease and ulcerative colitis identifies two susceptibility loci harboring CARD9 and IL18RAP. Am. J. Hum. Genet. 82, 1202–1210 (2008).

    Article  CAS  Google Scholar 

  32. Festen, E.A. et al. Genetic variants in the region harbouring IL2/IL21 associated with ulcerative colitis. Gut 58, 799–804 (2009).

    Article  CAS  Google Scholar 

  33. Korn, J.M. et al. Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs. Nat. Genet. 40, 1253–1260 (2008).

    Article  CAS  Google Scholar 

  34. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article  CAS  Google Scholar 

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Acknowledgements

The principal funding for this study was provided by the Wellcome Trust, as part of the Wellcome Trust Case Control Consortium 2 project (083948/Z/07/Z). We thank all subjects who contributed samples and consultants and nursing staff across the UK who helped with recruitment of study subjects. We also thank S. Bertrand, J. Bryant, S.L. Clark, J.S. Conquer, T. Dibling, J.C. Eldred, S. Gamble, C. Hind, A. Wilk, C.R. Stribling and S. Taylor of the Wellcome Trust Sanger Institute's Sample and Genotyping Facilities for technical assistance. Case collections were supported by the National Association for Colitis and Crohn's Disease (NACC), the Wellcome Trust, the Medical Research Council UK, the Guy's and St. Thomas' Charity, the Clinical Research Facility at the Peninsular College of Medicine and Dentistry, Exeter, the Torbay Hospital Medical Fund and the Evelyn Trust. P. Donnelly was supported in part by a Wolfson–Royal Society Merit Award. We also acknowledge support from the UK Medical Research Council (R.C.T., grant G0601387), the Special Trustees of Moorfields National Health Service (NHS) Foundation Trust, and the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre awards to Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London, the Cambridge University Hospitals NHS Foundation Trust in partnership with the University of Cambridge School of Clinical Medicine, the Central Manchester NHS Foundation Trust in partnership with the University of Manchester, and Moorfields Eye Hospital in partnership with University College London Institute of Ophthalmology. We acknowledge use of the British 1958 Birth Cohort DNA collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02, and thank W. Bodmer and B. Winney for use of the People of the British Isles DNA collection, which was funded by the Wellcome Trust.

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J.C.L., C.W.L., N.J.P., A.P., E.W., K.P., H.Z., H.D., E.R.N., D.M., K.B., T.E. and L.C. were involved in establishing DNA collections and/or assembling phenotypic data. C.W.L., A.P., E.W., D.M., H.D., A.J.L., C.M., J.D.S., D.P.J., C.E., T.A., J.C.M., J. Satsangi and M.P. recruited patients. W.G.N., C.E., T.A., J.C.M., J.D.S., M.P. and C.G.M. supervised clinical and laboratory work. The WTCCC2 DNA, genotyping, data QC and informatics group executed GWAS sample handling, genotyping and quality control. The WTCCC2 data and analysis group, J.C.B. and C.A.A. performed statistical analyses. J.C.B., J.C.L., C.W.L., N.J.P., C.C.A.S., C.A.A., T.A., P. Donnelly, J. Satsangi, M.P. and C.G.M. contributed to writing the manuscript. The WTCCC2 management committee conceived and oversaw the design and execution of the GWAS. WTCCC2 group memberships are specified in the full author list.

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Correspondence to Jeffrey C Barrett or Chris C A Spencer.

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Supplementary Tables 1–4 and Supplementary Figures 1–4 (PDF 532 kb)

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The UK IBD Genetics Consortium., The Wellcome Trust Case Control Consortium 2. Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. Nat Genet 41, 1330–1334 (2009). https://doi.org/10.1038/ng.483

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