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Multiple common variants for celiac disease influencing immune gene expression

Nature Genetics 42, 295–302 (2010) | Download Citation

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  • A Corrigendum to this article was published on 01 May 2010

This article has been updated

Abstract

We performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects. We genotyped 113 selected SNPs with PGWAS < 10−4 and 18 SNPs from 14 known loci in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome-wide significance (Pcombined < 5 × 10−8); most contain genes with immune functions (BACH2, CCR4, CD80, CIITA-SOCS1-CLEC16A, ICOSLG and ZMIZ1), with ETS1, RUNX3, THEMIS and TNFRSF14 having key roles in thymic T-cell selection. There was evidence to suggest associations for a further 13 regions. In an expression quantitative trait meta-analysis of 1,469 whole blood samples, 20 of 38 (52.6%) tested loci had celiac risk variants correlated (P < 0.0028, FDR 5%) with cis gene expression.

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Change history

  • 12 March 2010

    In the version of this article initially published online, the P value ranges in the second paragraph of the Results section under (iii) and (iv) were noted incorrectly. These errors have been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank Coeliac UK for assistance with direct recruitment of individuals with celiac disease, and UK clinicians (L.C. Dinesen, G.K.T. Holmes, P.D. Howdle, J.R.F. Walters, D.S. Sanders, J. Swift, R. Crimmins, P. Kumar, D.P. Jewell, S.P.L. Travis and K. Moriarty) who recruited the celiac disease blood samples described in our previous studies1,22. We thank the genotyping facility of the UMCG (J. Smolonska and P. van der Vlies) for generating part of the GWAS and replication data and the gene expression data; R. Booij and M. Weenstra for preparation of Italian samples; H. Ahola, A. Heimonen, L. Koskinen, E. Einarsdottir and K. Löytynoja for their work on Finnish sample collection, preparation and data handling; and E. Szathmári, J.B.Kovács, M. Lörincz and A. Nagy for their work with the Hungarian families. The Health2000 organization, Finrisk consortium, K. Mustalahti, M. Perola, K. Kristiansson and J. Koskinen are thanked for providing the Finnish control genotypes. We thank D.G. Clayton and N. Walker for providing T1DGC data in the required format. We thank the Irish Transfusion Service and Trinity College Dublin Biobank for control samples and V. Trimble, E. Close, G. Lawlor, A. Ryan, M. Abuzakouk, C. O'Morain and G. Horgan for celiac disease sample collection and preparation We acknowledge DNA provided by Mayo Clinic Rochester and thank M. Bonamico and M. Barbato (Department of Paediatrics, Sapienza University of Rome, Italy) for recruiting individuals. We thank Polish clinicians for recruitment of individuals with celiac disease (Z. Domagala, A. Szaflarska-Poplawska, B. Oralewska, W. Cichy, B. Korczowski, K. Fryderek, E. Hapyn, K. Karczewska, A. Zalewska, I. Sakowska-Maliszewska, R. Mozrzymas, A. Zabka, M. Kolasa and B. Iwanczak). We thank M. Szperl for isolating DNA from blood samples provided by the Children's Memorial Health Institute (Warsaw, Poland). Dutch and UK genotyping for the second celiac disease GWAS was funded by the Wellcome Trust (084743 to D.A.v.H.). Italian genotyping for the second celiac disease GWAS was funded by the Coeliac Disease Consortium, an Innovative Cluster approved by the Netherlands Genomics Initiative and partially funded by the Dutch Government (BSIK03009 to C.W.) and by the Netherlands Organisation for Scientific Research (NWO, VICI grant 918.66.620 to C.W.). E.G. is funded by the Italian Ministry of Healthy (grant RC2009). 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). P.C.A.D. is an MRC Clinical Training Fellow (G0700545). G.T. received a Ter Meulen Fund grant from the Royal Netherlands Academy of Arts and Sciences (KNAW). The gene expression study was funded in part by COPACETIC (EU grant 201379). This study makes use of data generated by the Wellcome Trust Case-Control Consortium 2 (WTCCC2). A full list of the WTCCC2 investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk. Funding for the WTCCC2 project was provided by the Wellcome Trust under award 085475. This research utilizes resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Human Genome Research Institute (NHGRI), National Institute of Child Health and Human Development (NICHD) and Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418. We acknowledge the use of BRC Core Facilities provided by the financial support from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust. We acknowledge funding from the NIH: DK050678 and DK081645 (to S.L.N.), NS058980 (to R.A.O.); and DK57892 and DK071003 (to J.A.M.). The collection of Finnish and Hungarian subjects with celiac disease was funded by the EU Commission (MEXT-CT-2005-025270), the Academy of Finland, Hungarian Scientific Research Fund (contract OTKA 61868), the University of Helsinki Funds, the Competitive Research Funding of the Tampere University Hospital, the Foundation of Pediatric Research, the Sigrid Juselius Foundation and the Hungarian Academy of Sciences (2006TKI247 to R.A.). Funding for the collection and genotyping of the Polish samples was provided by UMC Cooperation Project (6/06/2006/NDON). R.M. is funded by Science Foundation Ireland. C. Núñez has a FIS contract (CP08/0213). The Dublin Centre for Clinical Research contributed to collection of samples from affected individuals and is funded by the Irish Health Research Board and the Wellcome Trust. Finally, we thank all individuals with celiac disease and control individuals for participating in this study.

Author information

    • Patrick C A Dubois
    •  & Gosia Trynka

    These authors contributed equally to this work.

Affiliations

  1. Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

    • Patrick C A Dubois
    • , Lude Franke
    • , Karen A Hunt
    • , Graham A R Heap
    • , Nicholas A Bockett
    • , Vanisha Mistry
    •  & David A van Heel

  2. Genetics Department, University Medical Center and Groningen University, Groningen, The Netherlands.

    • Gosia Trynka
    • , Lude Franke
    • , Jihane Romanos
    • , Rudolf S N Fehrmann
    • , Elvira Oosterom
    • , Mathieu Platteel
    •  & Cisca Wijmenga

  3. The Genome Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

    • Alessandra Curtotti
    •  & Charles A Mein

  4. Division of Biomedical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.

    • Alexandra Zhernakova

  5. Department of Preventive Medicine, University of Debrecen, Debrecen, Hungary.

    • Róza Ádány
    •  & Szilvia Fiatal

  6. National Institute for Health and Welfare, Helsinki, Finland.

    • Arpo Aromaa
    •  & Veikko Salomaa

  7. Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy.

    • Maria Teresa Bardella

  8. Department of Medical Sciences, University of Milan, Milan, Italy.

    • Maria Teresa Bardella

  9. Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht, The Netherlands.

    • Leonard H van den Berg
    •  & Jan H Veldink

  10. Clinical Immunology Department, Hospital Clínico San Carlos, Madrid, Spain.

    • Emilio G de la Concha
    • , Bárbara Dema
    • , Miguel Fernández-Arquero
    • , Concepción Núñez
    •  & Elena Urcelay

  11. Public Health Research Group of Hungarian Academy of Sciences, Medical & Health Science Center, University of Debrecen, Debrecen, Hungary.

    • Szilvia Fiatal

  12. Unitá di Aterosclerosi e Trombosi, I.R.C.C.S Casa Sollievo della Sofferenza, S. Giovanni Rotondo, Foggia, Italy.

    • Elvira Grandone

  13. NIHR GSTFT/KCL Comprehensive Biomedical Research Centre, King's College London School of Medicine, Guy's Hospital, London, UK.

    • Peter M Green
    •  & Muddassar M Mirza

  14. Department of Pulmonology, University Medical Center and Groningen University, Groningen, The Netherlands.

    • Harry J M Groen

  15. Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

    • Rhian Gwilliam
    • , Sarah E Hunt
    • , Owen T McCann
    • , Katherine I Morley
    • , Leena Peltonen
    • , Panos Deloukas
    •  & Jeffrey C Barrett

  16. Department of Paediatric Gastroenterology, University Medical Centre Utrecht, Utrecht, The Netherlands.

    • Roderick H J Houwen
    •  & Victorien M Wolters

  17. Paediatric Research Centre, University of Tampere Medical School and Tampere University Hospital, Tampere, Finland.

    • Katri Kaukinen
    • , Kalle Kurppa
    •  & Markku Mäki

  18. Department of Clinical Medicine, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland.

    • Dermot Kelleher
    • , Graham Turner
    •  & Ross McManus

  19. Heim Pal Childrens Hospital, Budapest, Hungary.

    • Ilma Korponay-Szabo

  20. Department of Pediatrics, Medical and Health Science Center, University of Debrecen, Hungary.

    • Ilma Korponay-Szabo

  21. Gastrointestinal Unit, Mater Misericordiae University Hospital, Dublin, Ireland.

    • Padraic MacMathuna

  22. Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.

    • Maria Cristina Mazzilli
    •  & Barbara Mora

  23. Department of Paediatrics, Leiden University Medical Centre, Leiden, The Netherlands.

    • M Luisa Mearin
    •  & Joachim J Schweizer

  24. Department of Gastroenterology, VU Medical Center, Amsterdam, The Netherlands.

    • Chris J Mulder
    • , Greetje J Tack
    •  & Wieke H M Verbeek

  25. Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.

    • Joseph A Murray

  26. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.

    • Roel A Ophoff

  27. Rudolf Magnus Institute, University Medical Center Utrecht, Utrecht, The Netherlands.

    • Roel A Ophoff

  28. Center for Neurobehavioral Genetics, University of California, Los Angeles, California, USA.

    • Roel A Ophoff

  29. Pediatric Gastroenterology Department, Hospital La Paz, Madrid, Spain.

    • Isabel Polanco

  30. Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland.

    • Leena Peltonen

  31. Department of Gastroenterology, Hepatology and Immunology, Children's Memorial Health Institute, Warsaw, Poland.

    • Anna Rybak

  32. European Laboratory for Food Induced Disease, University of Naples Federico II, Naples, Italy.

    • Maria Pia Sperandeo
    •  & Luigi Greco

  33. Department of Gastroenterology and Hepatology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands.

    • Rinse K Weersma

  34. Department of Pathology, Children's Memorial Health Institute, Warsaw, Poland.

    • Bozena Cukrowska

  35. Department of Population Sciences, Beckman Research Institute of the City of Hope, Duarte, California, USA.

    • Susan L Neuhausen

  36. Department of Experimental Medicine, Faculty of Medicine University of Milano-Bicocca, Monza, Italy.

    • Donatella Barisani

  37. Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.

    • Paivi Saavalainen

  38. Research Program for Molecular Medicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.

    • Paivi Saavalainen

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Contributions

D.A.v.H. and C.W. designed, co-ordinated and led the study. Experiments were performed in the labs of C.W., D.A.v.H., C.A.M., P.D. and P.M.G. Major contributions were: (i) DNA sample preparation: P.C.A.D., G.T., K.A.H., J.R., A.Z. and P.S.; (ii) genotyping: P.C.A.D., G.T., K.A.H., A.C., J.R. and R.G.; (iii) expression data generation: H.J.M.G., L.H.v.d.B., R.A.O., R.K.W. and L.F.; (iv) case-control association analyses: P.C.A.D., G.T., L.F., J.C.B. and D.A.v.H.; (v) expression analyses: L.F., G.A.R.H. and R.S.N.F.; (vi) manuscript preparation: P.C.A.D., G.T., L.F., R.S.N.F., G.A.R.H., J.C.B., C.W. and D.A.v.H. Other authors contributed variously to sample collection and all other aspects of the study. All authors reviewed the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Lude Franke or David A van Heel.

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    Results for the top 1000 markers

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https://doi.org/10.1038/ng.543

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