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

Nature Genetics volume 41, pages 1335–1340 (2009)Cite this article

Abstract

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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GenBank/EMBL/DDBJ

Gene Expression Omnibus

References

  1. 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 

  2. Van Limbergen, J., Wilson, D.C. & Satsangi, J. The genetics of Crohn's disease. Annu. Rev. Genomics Hum. Genet. 10, 89–116 (2009).

    Article  CAS  Google Scholar 

  3. Cho, J.H. The genetics and immunopathogenesis of inflammatory bowel disease. Nat. Rev. Immunol. 8, 458–466 (2008).

    Article  CAS  Google Scholar 

  4. 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 

  5. 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 

  6. 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 

  7. 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 

  8. Vernier-Massouille, G. et al. Natural history of pediatric Crohn's disease: a population-based cohort study. Gastroenterology 135, 1106–1113 (2008).

    Article  Google Scholar 

  9. Van Limbergen, J. et al. Definition of phenotypic characteristics of childhood-onset inflammatory bowel disease. Gastroenterology 135, 1114–1122 (2008).

    Article  Google Scholar 

  10. Rioux, J.D. et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat. Genet. 39, 596–604 (2007).

    Article  CAS  Google Scholar 

  11. The 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).

  12. Libioulle, C. et al. Novel Crohn 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 

  13. Barrett, J.C. et al. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat. Genet. 41, 703–707 (2009).

    Article  CAS  Google Scholar 

  14. Dixon, A.L. et al. A genome-wide association study of global gene expression. Nat. Genet. 39, 1202–1207 (2007).

    Article  CAS  Google Scholar 

  15. Li, X., Thyssen, G., Beliakoff, J. & Sun, Z. The novel PIAS-like protein hZimp10 enhances Smad transcriptional activity. J. Biol. Chem. 281, 23748–23756 (2006).

    Article  CAS  Google Scholar 

  16. Steinman, L. A brief history of TH17, the first major revision in the TH1/TH2 hypothesis of T cell-mediated tissue damage. Nat. Med. 13, 139–145 (2007).

    Article  CAS  Google Scholar 

  17. Bettelli, E., Oukka, M. & Kuchroo, V.K.T. TH-17 cells in the circle of immunity and autoimmunity. Nat. Immunol. 8, 345–350 (2007).

    Article  CAS  Google Scholar 

  18. Hakonarson, H. et al. A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene. Nature 448, 591–594 (2007).

    Article  CAS  Google Scholar 

  19. Pritchard, J.K., Stephens, M. & Donnelly, P. Inference of population structure using multilocus genotype data. Genetics 155, 945–959 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Luca, D. et al. On the use of general control samples for genome-wide association studies: genetic matching highlights causal variants. Am. J. Hum. Genet. 82, 453–463 (2008).

    Article  CAS  Google Scholar 

  21. Patterson, N., Price, A.L. & Reich, D. Population structure and eigenanalysis. PLoS Genet. 2, e190 (2006).

    Article  Google Scholar 

  22. 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 

  23. 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 

  24. 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 

Download references

Acknowledgements

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.

Author information

Author notes

  1. Marcin Imielinski, Robert N Baldassano, Anne Griffiths, Richard K Russell, Vito Annese, Marla Dubinsky and Subra Kugathasan: These authors contributed equally to the manuscript.

  2. Mark S Silverberg, Jack Satsangi and Hakon Hakonarson: These authors jointly directed the work.

Authors and Affiliations

  1. Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Marcin Imielinski, Jonathan P Bradfield, Patrick Sleiman, Cecilia E Kim, Kai Wang, Joseph T Glessner, Haitao Zhang, Edward C Frackelton, Cuiping Hou, James H Flory, George Otieno, Rosetta M Chiavacci, Struan F A Grant & Hakon Hakonarson

  2. Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    Robert N Baldassano, Robert Grundmeier, David Piccoli, Struan F A Grant & Hakon Hakonarson

  3. Division of Gastroenterology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Robert N Baldassano, Debra J Abrams & David Piccoli

  4. The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

    Anne Griffiths, Thomas D Walters & Aleixo Muise

  5. Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Glasgow, UK

    Richard K Russell

  6. Department of Medical Sciences, Gastroenterology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) 'Casa Sollievo della Sofferenza' (CSS), San Giovanni Rotondo, Italy

    Vito Annese

  7. Departments of Pediatrics and Common Disease Genetics, Cedars Sinai Medical Center, Los Angeles, California, USA

    Marla Dubinsky, Kent Taylor & Dermot McGovern

  8. Department of Pediatrics, Emory University School of Medicine and Children's Health Care of Atlanta, Atlanta, Georgia, USA

    Subra Kugathasan

  9. Department of Pediatrics, University of Alabama at Birmingham, Alabama, USA

    Shehzad Saeed

  10. Center for Biomedical Informatics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Robert Grundmeier

  11. Gastroenterology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome and SIGENP, Italy

    Massimo Castro & Anna Latiano

  12. Mendel Institute, La Sapienza University of Rome, IRCCS-CSS Hospital, S. Giovanni Rotondo, Italy

    Bruno Dallapiccola

  13. Mount Sinai Hospital Inflammatory Bowel Disease Centre, University of Toronto, Toronto, Ontario, Canada

    Joanne Stempak & Mark S Silverberg

  14. Department of Pediatrics, University of California, San Francisco, California, USA

    Melvin B Heyman

  15. Department of Pediatrics, The Baylor College of Medicine, Houston, Texas, USA

    George D Ferry

  16. University of Chicago Comer Children's Hospital, Chicago, Illinois, USA

    Barbara Kirschner

  17. Division of Gastroenterology, Children's Hospital, Boston, Massachusetts, USA

    Jessica Lee, Jonah Essers & Richard Grand

  18. Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA

    Michael Stephens

  19. Pediatric Gastroenterology Unit, Wolfson Medical Center, Tel Aviv University, Tel Aviv, Israel

    Arie Levine

  20. Division of Medical Sciences, Gastrointestinal Unit, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh, UK

    Johan Van Limbergen & Jack Satsangi

  21. Pediatric Gastroenterology and Liver Unit, La Sapienza University of Rome and SIGENP, Italy

    Salvatore Cucchiara

  22. Department of Pathology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Dimitri S Monos

  23. Department of Pediatrics, University of Utah School of Medicine and Primary Children's Medical Center, Salt Lake City, Utah, USA

    Stephen L Guthery

  24. Division of Gastroenterology, The Center for Inflammatory Bowel Disease, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA

    Lee Denson

  25. Paediatric Gastroenterology and Nutrition, Royal Hospital for Sick Children, Edinburgh and Child Life and Health, University of Edinburgh, UK

    David C Wilson

  26. Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Struan F A Grant & Hakon Hakonarson

  27. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA

    Mark Daly

Authors
  1. Marcin Imielinski
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  2. Robert N Baldassano
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  5. Vito Annese
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  7. Subra Kugathasan
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  8. Jonathan P Bradfield
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  13. Kai Wang
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  16. Haitao Zhang
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  18. Cuiping Hou
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  19. James H Flory
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  20. George Otieno
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  21. Rosetta M Chiavacci
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  28. Kent Taylor
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  30. Melvin B Heyman
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  31. George D Ferry
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  33. Jessica Lee
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  42. Stephen L Guthery
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  44. David C Wilson
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  45. Struan F A Grant
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  46. Mark Daly
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  48. Jack Satsangi
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  49. Hakon Hakonarson
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Consortia

Western Regional Research Alliance for Pediatric IBD

International IBD Genetics Consortium

Contributions

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.

Corresponding author

Correspondence to Hakon Hakonarson.

Additional information

A full list of members appears in a Supplementary Note.

A full list of members appears in a Supplementary Note.

Supplementary information

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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). https://doi.org/10.1038/ng.489

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