Abstract
We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10−8). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.
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Acknowledgements
We thank all subjects who contributed samples and the physicians and nursing staff who helped with recruitment globally. This study was supported by the German Ministry of Education and Research through the National Genome Research Network and infrastructure support through the Deutsche Forschungsgemeinschaft cluster of excellence 'Inflammation at Interfaces' and by the Italian Ministry for Health GR-2008-1144485, with case collections supported by the Italian Group for IBD and the Italian Society for Paediatric Gastroenterology, Hepatology and Nutrition. We acknowledge funding provided by the Royal Brisbane and Women's Hospital Foundation; the University of Queensland (Ferguson Fellowship); the National Health and Medical Research Council, Australia, and by the European Community (Fifth Framework Program for Research and Development Technology) and by the European Crohn's and Colitis Organization. UK case collections were supported by the National Association for Colitis and Crohn's disease, Action Medical Research, Wellcome Trust, Medical Research Council UK, the University of Edinburgh and the Peninsular College of Medicine and Dentistry, Exeter. We also acknowledge the National Institute of Health Research (NIHR) Biomedical Research Centre awards to Guy's & St. Thomas' National Health Service Trust/King's College London and to Addenbrooke's Hospital/University of Cambridge School of Clinical Medicine. The NIDDK IBD Genetics Consortium is funded by the following grants: DK062431 (S.R.B.), DK062422 (J.H.C.), DK062420 (R.H.D.), DK062432 and DK064869 (J.D.R.), DK062423 (M.S.S.), DK062413 (D.P.B.M.), DK76984 (M.J.D.) and DK084554 (M.J.D. and D.P.B.M.) and DK062429 (J.H.C.). J.H.C. is also funded by the Crohn's and Colitis Foundation of America, and S.L.G. is funded by DK069513 and the Primary Children's Medical Center Foundation. Cedars Sinai was supported by National Center for Research Resources (NCRR) grant M01-RR00425; US National Institutes of Health/NIDDK grant P01-DK046763; DK 063491; and Cedars-Sinai Medical Center Inflammatory Bowel Disease Research Funds. R.K.W. is supported by a clinical fellow grant (90700281) from The Netherlands Organization for Scientific Research. E.L., D.F. and S.V. are senior clinical investigators for the Funds for Scientific Research (FWO/FNRS) Belgium. S.B. was supported by the Deutsche Forschungsgemeinschaft (DFG; BR 1912/5-1). J.C. Barrett is supported by Wellcome Trust grant WT089120/Z/09/Z. Replication genotyping was supported by unrestricted grants from Abbott Laboratories Ltd. and Giuliani SpA. We acknowledge the Wellcome Trust Case Control Consortium. We thank the 1958 British Birth Cohort and Banco Nacional de ADN, Salamanca, Spain, who supplied control DNA samples. The Cardiovascular Health Studies research reported in this article was supported by contract numbers N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, grant numbers U01 HL080295 and R01 HL087652 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm. Other significant contributors were K. Hanigan, Z.-Z. Zhao, N. Huang, P. Webb, N. Hayward, A. Rutherford, R. Gwilliam, J. Ghori, D. Strachan, W. McCardle, W. Ouwehand, M. Newsky, S. Ehlers, I. Pauselius, K. Holm, C. Sina, L. Baidoo, A. Andriulli and M.C. Renda.
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A.F., D.P.B.M., G.L.R.-S., T.A., J.L., R. Roberts, J.C. Bis, T.H., A. Latiano, C.G.M., N.J.P., J.I.R., P.S., Y.S., L.A.S., K.D.T., D. Whiteman, C.W., G.K.-U., J.D.R., M.D.'A., R.K.W., S.V., R.H.D., J. Satsangi, S.S., V.A., H.H. and M.P. were involved in establishing DNA collections and/or assembling phenotypic data. A.F., D.E., J.C. Barrett, K.W., T.G., S.R., C.A.A., L.J. and M.J.D. performed statistical analyses. D.P.B.M., G.L.R.-S., C.W.L., E.M.F., R.N.B., M.B., T.M.B., S. Brand, C.B., A.C., J.-F.C., M.C., L.S., T.D., M.D.V., R.D.'I., M.D., C.E., T.F., D.F., A.M.G., R.G., J.G., A.V.G., S.L.G., J.H., H.W.V., J.-P.H., A.K., D.L., I.L., M.L., A. Levine, C.L., E.L., C.M., W.N., J.P., A.P., D.D.P., M.R., P.R., R. Russell, J. Satsangi, M.S.S., M.S., F.S., A.H.S., P.C.F.S., S.R.T., L.T., T.W., S.R.B., R.K.W., S.K., A.M.G., J.C.M., S.V., D. Wilson, R.H.D., M.S., J. Sanderson, S.S., J.H.C., V.A. and M.P. recruited patients. A.F., D.P.B.M., T.B., S. Bumpstead, J.I.R., M.G. and G.W.M. supervised laboratory work. A.F., D.P.B.M., J.C. Barrett, K.W., S. Brand, R.H.D., J. Satsangi, S.S., J.H.C., M.J.D. and M.P. contributed to writing the manuscript. All authors read and approved the final manuscript before submission.
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Supplementary information
Supplementary Text and Figures
Supplementary Tables 1–6, Supplementary Figures 1–4 and Supplementary Note. (PDF 1562 kb)
Supplementary Table 3
Odds ratios (OR) and risk allele frequencies (RAF) for the 71 SNPs listed in Tables 1 and 2 (XLS 75 kb)
Supplementary Table 4
Raw allele counts and empirical variance for the 71 SNPs listed in Tables 1 and 2 (XLS 170 kb)
Supplementary Table 6
Positional candidate genes mapping within regions of confirmed association with Crohn's disease (XLS 65 kb)
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Franke, A., McGovern, D., Barrett, J. et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet 42, 1118–1125 (2010). https://doi.org/10.1038/ng.717
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DOI: https://doi.org/10.1038/ng.717
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