Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47 (original) (raw)

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In the version of this article initially published, an affiliation was missing for two authors, Maria Gazouli and Nicholas P. Anagnou. They are also affiliated with the Foundation for Biomedical Research of the Academy of Athens in Athens, Greece. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

In memoriam to Marc Lémann, who dedicated his life to his patients but died too soon.

We thank all the 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, the Popgen biobank and infrastructure support through the Deutsche Forschungsgemeinschaft (DFG) cluster of excellence 'Inflammation at Interfaces'. Italian case collections were 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, University of Queensland (Ferguson Fellowship), National Health and Medical Research Council, Australia and by the European Community (5th PCRDT). 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. Activities in Sweden were supported by the Swedish Society of Medicine, the Bengt Ihre Foundation, the Karolinska Institutet, the Swedish National Program for IBD Genetics, the Swedish Organization for IBD, the Swedish Medical Research Council, the Soderbergh Foundation and the Swedish Cancer Foundation. Support for genotyping and genetic data analysis was provided by the Agency for Science Technology and Research (A*STAR), Singapore. We are grateful to the funders and investigators of the Epidemiological Investigation of Rheumatoid Arthritis for providing genotype data from healthy Swedish individuals.

The Wellcome Trust Case Control Consortium 2 project was supported by Wellcome Trust grant 083948/Z/07/Z. We also acknowledge the National Institute for Health Research (NIHR) Biomedical Research Centre awards to Guy's & St. Thomas' National Health Service (NHS) Trust, King's College London and to Addenbrooke's Hospital, University of Cambridge School of Clinical Medicine and to the University of Manchester and Central Manchester Foundation Trust. The NIDDK IBD Genetics Consortium is funded by the following grants: DK062431 (S.R.B.), DK062422 (J.H.C.), DK062420 (R.H.D.), DK062432 (J.D.R.), DK062423 (M.S.S.), DK062413 (D.P.M.), DK076984 (M.J.D.), DK084554 (M.J.D. and D.P.M.) and DK062429 (J.H.C.). J.H.C. is also funded by the Crohn's and Colitis Foundation of America; S.L.G. by DK069513 and Primary Children's Medical Center Foundation; and J.D.R. by US National Institutes of Health (NIH)/NIDDK grant DK064869. Cedars-Sinai is supported by National Center for Research Resources (NCRR) grant M01-RR00425, NIH/NIDDK grant P01-DK046763, DK 063491 and Cedars-Sinai Medical Center Inflammatory Bowel Disease Research Funds. E.L., D.F. and S.V. are senior clinical investigators for the Funds for Scientific Research (FWO/FNRS) Belgium. S. Brand was supported by Deutsche Forschungsgemeinschaft (DFG BR 1912/5-1) and Else Kröner-Fresenius-Stiftung (P50/05/EKMS05/62). M.C. was supported by the Programme Hospitalier de Recherche Clinique. C.A.A. is supported by Wellcome Trust grant WT091745/Z/10/Z. J.C.B. is supported by Wellcome Trust grant WT089120/Z/09/Z. R.K.W. is supported by a clinical fellowship grant (90.700.281) from the Netherlands Organization for Scientific Research (NWO). C.W. is supported by grants from the Celiac Disease Consortium (BSIK03009) and The Netherlands Organization for Scientific Research (NWO, VICI grant 918.66.620). L.H.v.d.B. acknowledges funding from the Prinses Beatrix Fonds, the Adessium Foundation and the Amyotrophic Lateral Sclerosis Association. L.F. received a Horizon Breakthrough grant from the Netherlands Genomics Initiative (93519031) and a VENI grant from NWO (ZonMW grant 916.10.135). R.J.X. and A.N. are funded by DK83756, AI062773, DK043351 and the Helmsley Foundation.

Replication genotyping was supported by unrestricted grants from Abbott Laboratories Ltd, Giuliani SpA, Shire PLC and Ferring Pharmaceuticals. We thank the 1958 British Birth Cohort and Banco Nacional deADN, Salamanca, Spain, who supplied control DNA samples. The IBSEN study group and the Norwegian Bone Marrow Donor Registry are acknowledged for contributing the Norwegian patient and control populations. The Cardiovascular Health Study (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. A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/pi.htm. We thank the members of the Quebec IBD Genetic Consortium, in particular A. Bitton, G. Aumais, E.J. Bernard, A. Cohen, C. Deslandres, R. Lahaie, D. Langelier and P. Paré. Other important contributors are K. Hanigan, N. Huang, P. Webb, D. Whiteman, A. Rutherford, R. Gwilliam, J. Ghori, D. Strachan, W. McCardle, W. Ouwehand, M. Newsky, S. Ehlers, I. Pauselius, K. Holm, C. Sina, M. Regueiro, A. Andriulli and M.C. Renda.

Author information

Author notes

  1. Gabrielle Boucher, Charlie W Lees, Andre Franke and Mauro D'Amato: These authors contributed equally to this work.
  2. Hakon Hakonarson, Graham Radford-Smith, Richard H Duerr, Séverine Vermeire and Rinse K Weersma: These authors jointly supervised this work.

Authors and Affiliations

  1. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK
    Carl A Anderson, Suzannah Bumpstead, James A B Floyd, Katherine I Morley & Jeffrey C Barrett
  2. Université de Montréal, Medicine, Montréal, Québec, Canada
    Gabrielle Boucher, Philippe Goyette, Caroline Lagacé, Gilles Jobin & John D Rioux
  3. Montreal Heart Institute, Research Center, Montréal, Québec, Canada
    Gabrielle Boucher, Philippe Goyette, Caroline Lagacé & John D Rioux
  4. University of Edinburgh, Western General Hospital, Gastrointestinal Unit, Molecular Medicine Centre, Edinburgh, UK
    Charlie W Lees & Jack Satsangi
  5. Christian-Albrechts-University Kiel, Institute of Clinical Molecular Biology, Kiel, Germany
    Andre Franke, David Ellinghaus & Stefan Schreiber
  6. Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden
    Mauro D'Amato
  7. Cedars-Sinai Medical Center, Inflammatory Bowel and Immunobiology Research Institute, Los Angeles, California, USA
    Kent D Taylor, Dermot P McGovern & Stephan R Targan
  8. Addenbrooke's Hospital, University of Cambridge, Gastroenterology Research Unit, Cambridge, UK
    James C Lee & Miles Parkes
  9. The Children's Hospital of Philadelphia, Center for Applied Genomics, Philadelphia, Pennsylvania, USA
    Marcin Imielinski
  10. Unit of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico-Casa Sollievo della Sofferenza (IRCCS-CSS) Hospital, San Giovanni Rotondo, Italy
    Anna Latiano, Orazio Palmieri & Vito Annese
  11. Division of Gastroenterology, Department of Medicine, University of Pittsburgh School of Medicine, Hepatology and Nutrition, Pittsburgh, Pennsylvania, USA
    Regan Scott, Leonard Baidoo & Richard H Duerr
  12. Department of Gastroenterology, Erasmus Hospital, Free University of Brussels, Brussels, Belgium
    Leila Amininejad
  13. Department of Pediatrics, The Children's Hospital of Philadelphia, Center for Pediatric Inflammatory Bowel Disease, Philadelphia, Pennsylvania, USA
    Robert N Baldassano & Hakon Hakonarson
  14. Department of Medicine, University of Otago, Christchurch, New Zealand
    Murray Barclay, Rebecca Roberts & Richard Gearry
  15. Department of Medicine, Johns Hopkins University School of Medicine, Meyerhoff Inflammatory Bowel Disease Center, Baltimore, Maryland, USA
    Theodore M Bayless & Steven R Brant
  16. Department of Medicine II, University Hospital Munich, Munich, Germany
    Stephan Brand & Jürgen Glas
  17. Department of Gastroenterology, Universitätsmedizin Berlin, Charité, Campus Mitte, Berlin, Germany
    Carsten Büning
  18. Université de Lille Department of Hepato-Gastroenterology, Lille, France
    Jean-Frédéric Colombel
  19. Cincinnati Children's Hospital Medical Center, Pediatric Gastroenterology, Cincinnati, Ohio, USA
    Lee A Denson
  20. Department of Hepatology and Gastroenterology, Ghent University Hospital, Ghent, Belgium
    Martine De Vos & Debby Laukens
  21. Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California, USA
    Marla Dubinsky
  22. Department of Gastroenterology, Torbay Hospital, Torbay, Devon, UK
    Cathryn Edwards
  23. Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands
    Rudolf S N Fehrmann, Lude Franke, Cisca Wijmenga & Harm-Jan Westra
  24. Department of Gastroenterology, Mater Health Services, Brisbane, Australia
    Timothy Florin
  25. Department of Gastroenterology, Erasmus Hospital, Free University of Brussels, Brussels, Belgium
    Denis Franchimont
  26. Department of Genetics, University of Liège, Faculty of Veterinary Medicine, Liège, Belgium
    Michel Georges
  27. Department of Internal Medicine, University of Washington, Cardiovascular Health Research Unit, Seattle, Washington, USA
    Nicole L Glazer
  28. Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah, USA
    Stephen L Guthery
  29. Cedars-Sinai Medical Center, Medical Genetics Institute, Los Angeles, California, USA
    Talin Haritunians, Dermot P McGovern & Jerome I Rotter
  30. Queensland Institute of Medical Research, Oncogenomics Laboratory, Brisbane, Australia
    Nicholas K Hayward
  31. Université Paris Diderot, Paris, France
    Jean-Pierre Hugot
  32. Department of Gastroenterology, Hôpital Maisonneuve-Rosemont, Montréal, Québec, Canada
    Gilles Jobin
  33. The University of Western Australia, School of Medicine and Pharmacology, Fremantle, Australia
    Ian Lawrance
  34. Université Paris Diderot, GETAID group, Paris, France
    Marc Lémann
  35. Tel Aviv University, Pediatric Gastroenterology Unit, Wolfson Medical Center and Sackler School of Medicine, Tel Aviv, Israel
    Arie Levine
  36. Division of Gastroenterology, Centre Hospitalier Universitaire Université de Liège, Liège, Belgium
    Cecile Libioulle & Edouard Louis
  37. Azienda Ospedaliero Universitaria (AOU) Careggi, Unit of Gastroenterology SOD2, Florence, Italy
    Monica Milla & Vito Annese
  38. Queensland Institute of Medical Research, Molecular Epidemiology, Brisbane, Australia
    Grant W Montgomery & Zhen Z Zhao
  39. Department of Medicine, Ninewells Hospital and Medical School, Dundee, UK
    Craig Mowat & Anne Phillips
  40. Massachusetts General Hospital, Harvard Medical School, Gastroenterology Unit, Boston, Massachusetts, USA
    Aylwin Ng & Ramnik J Xavier
  41. Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, Massachusetts, USA
    Aylwin Ng & Ramnik J Xavier
  42. University of Manchester Department of Medical Genetics, Manchester, UK
    William Newman
  43. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
    Roel A Ophoff
  44. University of Florence, Institute of Human Genetics, Florence, Italy
    Laura Papi
  45. Department of Hepato-Gastroenterology, University Hospital of Nancy, Vandoeuvre-lès-Nancy, France
    Laurent Peyrin-Biroulet
  46. Department of Gastroenterology, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
    Julián Panés
  47. Department of Medical and Molecular Genetics, King's College London School of Medicine, Guy's Hospital, London, UK
    Natalie J Prescott & Christopher G Mathew
  48. Department of Medicine, Yale University, Section of Digestive Diseases, New Haven, Connecticut, USA
    Deborah D Proctor, Yashoda Sharma & Judy H Cho
  49. Royal Hospital for Sick Children, Paediatric Gastroenterology and Nutrition, Glasgow, UK
    Richard Russell & David C Wilson
  50. Division of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium
    Paul Rutgeerts & Séverine Vermeire
  51. Department of Gastroenterology, Guy's & St. Thomas' NHS Foundation Trust, St. Thomas' Hospital, London, UK
    Jeremy Sanderson
  52. Department of Gastroenterology, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
    Miquel Sans
  53. Department of Health Studies, University of Chicago, Chicago, Illinois, USA
    Philip Schumm
  54. Division of Gastroenterology, University of Bern, Inselspital, Bern, Switzerland
    Frank Seibold
  55. Queensland Institute of Medical Research, Inflammatory Bowel Diseases, Brisbane, Australia
    Lisa A Simms & Graham Radford-Smith
  56. Genome Institute of Singapore, Human Genetics, Singapore
    Mark Seielstad
  57. Institute for Human Genetics, University of California San Francisco, San Francisco, California, USA
    Mark Seielstad
  58. University of Toronto, Mount Sinai Hospital Inflammatory Bowel Disease Centre, Toronto, Ontario, Canada
    A Hillary Steinhart & Mark S Silverberg
  59. Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands
    Leonard H van den Berg
  60. Medical Department, Rikshospitalet University Hospital, Oslo, Norway
    Morten Vatn & Tom H Karlsen
  61. Leiden University Medical Center, Experimental Gastroenterology, Leiden, The Netherlands
    Hein Verspaget
  62. The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
    Thomas Walters & Anne M Griffiths
  63. Child Life and Health, University of Edinburgh, Edinburgh, Scotland, UK
    David C Wilson
  64. Department of Gastroenterology, Academic Medical Center, Amsterdam, The Netherlands
    Cyriel Y Ponsioen
  65. Medical Department, Viborg Regional Hospital, Viborg, Denmark
    Vibeke Andersen
  66. Department of Clinical Science Intervention and Technology, Karolinska Institutet, Stockholm, Sweden
    Leif Torkvist
  67. Department of Biology, University of Athens, School of Medicine, Athens, Greece
    Maria Gazouli & Nicholas P Anagnou
  68. Foundation for Biomedical Research of the Academy of Athens,, Athens, Greece
    Maria Gazouli & Nicholas P Anagnou
  69. Department of Gastroenterology, Kaunas University of Medicine, Kaunas, Lithuania
    Limas Kupcinskas & Jurgita Sventoraityte
  70. Newcastle University, Institute of Human Genetics, Newcastle upon Tyne, UK
    John C Mansfield
  71. Department of Genetics and Department of Pediatrics, Emory School of Medicine, Atlanta, Georgia, USA
    Subra Kugathasan
  72. Department of Medicine, Örebro University Hospital, Örebro, Sweden
    Jonas Halfvarson
  73. Peninsula College of Medicine and Dentistry, Barrack Road, Exeter, UK
    Tariq Ahmad
  74. INSERM, U1019, Lille, France
    Mathias Chamaillard
  75. Department of Genetics, Yale University, Yale School of Medicine, New Haven, Connecticut, USA
    Judy H Cho
  76. Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany
    Stefan Schreiber
  77. Massachusetts General Hospital, Harvard Medical School, Center for Human Genetic Research, Boston, Massachusetts, USA
    Mark J Daly
  78. Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
    Hakon Hakonarson
  79. Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA
    Richard H Duerr
  80. Department of Gastroenterology, University Medical Center Groningen, Groningen, The Netherlands
    Rinse K Weersma

Authors

  1. Carl A Anderson
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  2. Gabrielle Boucher
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  3. Charlie W Lees
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  4. Andre Franke
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  5. Mauro D'Amato
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  6. Kent D Taylor
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  7. James C Lee
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  8. Philippe Goyette
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  9. Marcin Imielinski
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  10. Anna Latiano
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  11. Caroline Lagacé
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  12. Regan Scott
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  13. Leila Amininejad
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  14. Suzannah Bumpstead
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  15. Leonard Baidoo
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  16. Robert N Baldassano
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  17. Murray Barclay
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  18. Theodore M Bayless
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  19. Stephan Brand
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  20. Carsten Büning
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  21. Jean-Frédéric Colombel
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  22. Lee A Denson
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  23. Martine De Vos
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  24. Marla Dubinsky
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  25. Cathryn Edwards
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  26. David Ellinghaus
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  27. Rudolf S N Fehrmann
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  28. James A B Floyd
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  29. Timothy Florin
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Contributions

C.W.L., A.F., K.D.T., J.C.L., M.I., A. Latiano, L.A., L.B., R.N.B., M.B., T.M.B., S. Brand, C.B., J.-F.C., L.A.D., M.D.V., M.D., C.E., R.S.N.F., T.F., D.F., M. Georges, J.G., N.L.G., S.L.G., T.H., N.K.H., J.-P.H., G.J., D.L., I.L., M.L., A. Levine, C. Libioulle, E.L., D.P.M., M.M., C.M., A.N., W.N., R.A.O., L.P., O.P., L.P.-B., J.P., A.P., N.J.P., D.D.P., R. Roberts, R. Russell, P.R., J. Sanderson, M. Sans, P.S., F.S., Y.S., M. Seielstad, A.H.S., S.R.T., L.H.v.d.B., M.V., H.V., T.W., C.W., D.C.W., H.-J.W., C.Y.P., V. Andersen, L.T., M. Gazouli, N.P.A., T.H.K., L.K., J. Sventoraityte, J.C.M., S.K., M.S.S., J.H., J.I.R., C.G.M., A.M.G., R.G., T.A., S.R.B., M.C., J. Satsangi, J.H.C., S.S., M.P., V. Annese, H.H., G.R.-S., R.H.D., S.V., R.K.W. and J.D.R. established DNA collections, recruited patients or assembled phenotypic data. A.F., M.D., P.G., C. Lagacé, R.S., S. Bumpstead, C. Libioulle, D.P.M., G.W.M., L.A.S., Z.Z.Z., M.C., R.H.D. and J.D.R. conducted or supervised laboratory work. C.A.A., G.B., D.E., J.A.B.F., L.F., K.I.M., A.N., R.A.O., R.J.X., M.J.D., J.C.B., R.K.W. and J.D.R. performed or supervised statistical analyses. C.A.A., G.B., C.W.L., G.R.-S., R.H.D., S.V., R.K.W. and J.D.R. drafted the manuscript. All authors read and approved the final manuscript before submission.

Corresponding authors

Correspondence toCarl A Anderson or John D Rioux.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1, 2, 4–6 and 8 and Supplementary Figures 1–3. (PDF 3143 kb)

Supplementary Table 3a

Cohort specific results for all SNPs listed in Table 1 and Table 2 (XLSX 63 kb)

Supplementary Table 3b

Cohort specific results for all SNPs included in follow-up phase, but failed our thresholds for follow-up (XLSX 38 kb)

Supplementary Table 7

Summary of candidate genes mapping from in silico analysis on the 47 UC loci (XLSX 13 kb)

Supplementary Table 9

Results from the International IBD Genetics Consortium CD and UC meta-analyses for the 99 loci reported for association in CD and/or UC (XLSX 37 kb)

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Anderson, C., Boucher, G., Lees, C. et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47.Nat Genet 43, 246–252 (2011). https://doi.org/10.1038/ng.764

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