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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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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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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DOI: https://doi.org/10.1038/ng.483
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