Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci

• Type of Material: Article
• Authors: A. Franke, University of Kiel; D. P. B. McGovern, Cedars Sinai Medical Center; J. C. Barrett, Wellcome Trust Sanger Institute; K. Wang, Childrens Hospital of Philadelphia; G. L. Radford-Smith, Queensland Institute of Medical Research; T. Ahmad, Peninsula College; C. W. Lees, University of Edinburgh; T. Balschun, University of Kiel; J. Lee, University of Cambridge; R. Roberts, University of Otago; C. A. Anderson, Wellcome Trust Sanger Institute; J. C. Bis, University of Washington; S. Bumpstead, Wellcome Trust Sanger Institute; D. Ellinghaus, University of Kiel; E. M. Festen, University of Groningen; M. Georges, University of Liege; T. Green, Harvard University; T. Haritunians, Cedars Sinai Medical Center; L. Jostins, Wellcome Trust Sanger Institute; A. Latiano, IRCCS CSS Hospital; C. G. Mathew, King's College London; G. W. Montgomery, Queensland Institute of Medical Research; N. J. Prescott, King's College London; S. Raychaudhuri, Harvard University; J. I. Rotter, Cedars Sinai Medical Center; P. Schumm, University of Chicago; Y. Sharma, Yale University; L. A. Simms, Queensland Institute of Medical Research; K. D. Taylor, Cedars Sinai Medical Center; D. Whiteman, Queensland Institute of Medical Research; C. Wijmenga, University of Groningen; R. N. Baldassano, Childrens Hospital of Philadelphia; M. Barclay, University of Otago; T. M. Bayless, Johns Hopkins University; S. Brand, University of Munich; C. Buning, Universitätsmedizin Berlin; A. Cohen, Montreal Jewish General Hospital; J-F. Colombel, Université de Lille; M. Cottone, Cervello Hospital, Italy; L. Stronati, ENEA, Department of Biology of Radiations and Human Health, Rome, Italy; T. Denson, Cincinnati Childrens Hospital Medical Center; M. De Vos, Ghent University; R. D'Inca, University Hospital Padua, Italy; M. Dubinsky, Cedars Sinai Medical Center; C. Edwards, Torbay Hospital, UK; T. Florin, Mater Health Services, Australia; D. Franchimont, Free University of Brussels; R. Gearry, University of Otago; J. Glas, University of Munich; A. Van Gossum, Free University of Brussels; S. L. Guthery, University of Utah; J. Halfvarson, Orebro University Hospital; H. W. Verspaget, Leiden University; J-P. Hugot, Université Paris Diderot; A. Karban, Technion Israel Institute of Technology; D. Laukens, Ghent University; I. Lawrance, University of Western Australia; M. Lemann, Université Paris Diderot; A. Levine, Tel Aviv University; C. Libioulle, University of Liege; E. Louis, University of Liege; C. Mowat, University of Dundee; W. Newman, University of Manchester; J. Panes, Hospital Clinic Barcelona; A. Phillips, University of Dundee; D. D. Proctor, Yale University; M. Regueiro, University of Pittsburgh; R. Russell, Yorkhill Hosp; P. Rutgeerts, Univ Hosp Gasthuisberg; J. Sanderson, St Thomas Hosp; M. Sans, Hospital Clinic Barcelona; F. Seibold, University of Bern; A. H. Steinhart, University of Toronto; P. C. F. Stokkers, University of Amsterdam; L. Torkvist, Karolinska Institutet; G. Kullak-Ublick, University of Zurich; D. Wilson, University of Edinburgh; T. Walters, University of Toronto; S. R. Targan, Cedars Sinai Medical Center; S. R. Brant, Johns Hopkins University; J. D. Rioux, University of Montreal; M. D'Amato, Karolinska Institutet; R. Weersma, University of Groningen; Subramaniam Kugathasan, Emory University; A. M. Griffiths, University of Toronto; J. C. Mansfield, University of Newcastle; S. Vermeire, University of Leuven; R. H. Duerr, University of Pittsburgh; M. S. Silverberg, University of Toronto; J. Satsangi, University of Edinburgh; S. Schreiber, University of Kiel; J. H. Cho, Yale University; V. Annese, IRCCS CSS Hospital; H. Hakonarson, Childrens Hospital of Philadelphia; M. J. Daly, Harvard University; M. Parkes, University of Cambridge
• Language: English
• Date: 2010-12-01
• Publisher: Nature Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2010 Nature America, Inc. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1038/ng.717
• Title of Journal or Parent Work: Nature Genetics
• Volume: 42
• Issue: 12
• Start Page: 1118
• End Page: 1126
• Grant/Funding Information: RW is supported by a clinical fellow grant (90700281) from the Netherlands Organization for Scientific Research; EL, DF and SV are senior clinical investigators for the Funds for Scientific Research (FWO/FNRS) Belgium.; edars Sinai supported by NCRR grant M01-RR00425; NIH/NIDDK grant P01-DK046763; DK 063491; and Cedars-Sinai Medical Center Inflammatory Bowel Disease Research Funds.; JCB is supported by Wellcome Trust grant WT089120/Z/09/Z. Replication genotyping was supported by unrestricted grants from Abbott Laboratories Ltd and Giuliani SpA.; SB was supported by the “Deutsche Forschungsgemeinschaft” (DFG; BR 1912/5-1).; Also 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 also acknowledge the NIHR Biomedical Research Centre awards to Guy’s & St Thomas’ NHS Trust / King’s College London and to Addenbrooke’s Hospital / University of Cambridge School of Clinical Medicine.; his study was supported by the German Ministry of Education and Research through the National Genome Research Network and infrastructure support through the DFG cluster of excellence “Inflammation at Interfaces”.; We acknowledge funding provided by Royal Brisbane and Women’s Hospital Foundation; University of Queensland (Ferguson Fellowship); National Health and Medical Research Council, Australia and by the European Community (5th PCRDT) and by the European Crohn’s and Colitis Organization.; The NIDDK IBD Genetics Consortium is funded by the following grants: DK062431 (S.R.B.), DK062422 (J.H.C.), DK062420 (R.H.D.), DK062432 & DK064869 (J.D.R.), DK062423 (M.S.S.), DK062413 (D.P.B.M.), DK76984 (MD), and DK084554 (MD and DPBM), and DK062429 (J.H.C.).; UK case collections were supported by the National Association for Colitis and Crohn’s disease, Wellcome Trust, Medical Research Council UK and Peninsular College of Medicine and Dentistry, Exeter.; he CHS 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.; J.H.C. is also funded by the Crohn’s and Colitis Foundation of America; and SLG by DK069513 and Primary Children’s Medical Center Foundation.
• Keywords: Autophagy; Activation; Identification; Contribute; Common variants; Genetics & Heredity; Sequence variants; NEDD4 family; Science & Technology; Gene; Life Sciences & Biomedicine; Association; Inflammatory bowel disease
• Research Categories: Biology, Molecular; Biology, Genetics; Health Sciences, Immunology; Health Sciences, Epidemiology

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.