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Common variants at five new loci associated with early-onset inflammatory bowel disease


The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide association study in early-onset IBD involving 3,426 affected individuals and 11,963 genetically matched controls recruited through international collaborations in Europe and North America, thereby extending the results from a previous study of 1,011 individuals with early-onset IBD1. We have identified five new regions associated with early-onset IBD susceptibility, including 16p11 near the cytokine gene IL27 (rs8049439, P = 2.41 × 10−9), 22q12 (rs2412973, P = 1.55 × 10−9), 10q22 (rs1250550, P = 5.63 × 10−9), 2q37 (rs4676410, P = 3.64 × 10−8) and 19q13.11 (rs10500264, P = 4.26 × 10−10). Our scan also detected associations at 23 of 32 loci previously implicated in adult-onset Crohn's disease and at 8 of 17 loci implicated in adult-onset ulcerative colitis, highlighting the close pathogenetic relationship between early- and adult-onset IBD.

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Figure 1: Overview of genome-wide association results.
Figure 2: Colonic and LCL mRNA expression of genes in significantly associated loci.

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We thank all participating subjects and families. We thank the medical assistants, nursing staff and clinicians at CHOP who assisted with the recruitment of control subjects, which made this work possible; and members of the International HapMap and Wellcome Trust Case Control Consortiums for publicly providing data that were critically important for part of our analyses. The following physicians of the SIGENP (Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition) contributed by providing DNA samples and clinical information from their patients: A. Andriulli, M.R. Valvano, O. Palmieri, F. Bossa, E. Colombo, M. Pastore, M. D'Altilia, O. Borrelli, C. Bascietto, A. Ferraris, B. Papadatou, A. Diamanti, P. Lionetti, E. Pozzi, A. Barabino, A. Calvi, G.L. de' Angelis, G. Guariso, V. Lodde, G. Vieni, C. Sferlazzas, S. Accomando, G. Iacono, E. Berni Canani, A.M. Staiano, V. Rutigliano, D. De Venuto, C. Romano, G. Lombardi, S. Nobile, C. Catassi and A. Campanozzi. The following physicians of SPGHANG (Scottish Pediatric Gastroenterology, Hepatology and Nutrition Group) contributed by providing DNA samples and clinical information from their patients: W.M. Bisset, P.M. Gillett, G. Mahdi and P. McGrogan. This research was supported by the Children's Hospital of Philadelphia, the Primary Children's Medical Center Foundation and grants DK069513, M01-RR00064, M01 RR002172-26 and C06-RR11234 from the National Center for Research Resources. All genome-wide genotyping was funded by an Institute Development Award from the Children's Hospital of Philadelphia. M.S. is funded by NIH/NIDDK grant DK062423 and the Gale and Graham Wright Research Chair in Digestive Diseases. T.W. received fellowship funding support jointly from the Canadian Association of Gastroenterology (CAG), Crohn's Colitis Foundation of Canada (CCFC), Canadian Institutes of Health Research (CIHR) and Astra-Zeneca. A.M. received a CCFC/CAG/CIHR Transition Award and Canadian Child Health Clinician Scientist Program (CCHCSP) Award for training. J.L. received Junior Faculty Development Award from Children's Hospital Boston. J.E. is supported by a Training grant (T32 DK007477) from NIDDK. S.L.G. received support from the Primary Children's Medical Center Foundation, NIDDK (DK069513) and NCRR (M01-RR00064 and C06-RR11234). J.V.L. was funded by a Research Training Fellowship from Action Medical Research, the Gay-Ramsay-Steel-Maitland or Stafford Trust and the Hazel M Wood Charitable Trust. D.C.W. is the holder of a Medical Research Council Patient Cohorts Research Initiative award (G0800675). Financial assistance was also provided by a Wellcome Trust Programme Grant (072789/Z/03/Z), the Chief Scientist Office of the Scottish Government Health Department, a University of Edinburgh Medical Faculty Fellowship and the GI/Nutrition Research Fund, Child Life and Health, University of Edinburgh.

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M.I., R.N.B., A.G., R.K.R., V.A., M. Dubinsky, S.K., S.F.A.G., M.S.S., J. Satsangi and H.H. participated in study conception and design. R.N.B., A.G., R.K.R., V.A., M. Dubinsky, S.K., T.D.W., S.S., R.G., M.C., A. Latiano, B.D., J. Stempack, D.J.A., K.T., B.K., J.L., J.E., R.G., M. Stephens, A. Levine, D.P., J.V.L., S.C., S.L.G., C.E.K., G.D.F., E.C.F., C.H., G.O., R.M.C., A.M., L.D., D.C.W., M.S.S., S.F.A.G., J. Satsangi, H.H., D.S.M., D.M. and M.B.H. recruited patients and directed sample collection. C.E.K., E.C.F., G.O., R.M.C. and J.T.G. performed genotyping and quality-control measures on all data sets and H.H. supervised all sample organization and genotyping. L.D., R.G. and A.M. supervised gene expression experiments. M.I. performed statistical analysis with supervision from H.H. M.I., J.P.B., P.S., K.W., H.Z, R.G., J.H.F. and M. Daly provided bioinformatics, database and statistical support. M.I. and H.H. wrote the manuscript. M.I., R.N.B., A.G., R.K.R., V.A., M. Dubinsky, S.K., S.F.A.G., M.S.S., J. Satsangi and H.H. participated in drafting and critical revision of the manuscript. All authors contributed to the final paper, with M.I., R.N.B., A.G., R.K.R., V.A., M. Dubinsky, S.K., M.S.S., J. Satsangi and H.H. playing key roles.

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Correspondence to Hakon Hakonarson.

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A full list of members appears in a Supplementary Note.

A full list of members appears in a Supplementary Note.

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Supplementary Tables 1–5 and Supplementary Figures 1–3 (PDF 1177 kb)

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Imielinski, M., Baldassano, R., Griffiths, A. et al. Common variants at five new loci associated with early-onset inflammatory bowel disease. Nat Genet 41, 1335–1340 (2009).

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