Multiple common variants for celiac disease influencing immune gene expression

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

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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Figure 1: Coexpression analysis of genes mapping to 40 genome-wide significant and suggestive celiac disease regions in 33,109 heterogenous human samples from the Gene Expression Omnibus.

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Gene Expression Omnibus

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

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.

Correspondence to Lude Franke or David A van Heel.

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Supplementary Note, Supplementary Tables 1–3 and Supplementary Figures 1–3 (PDF 2306 kb)

Supplementary Data 1

Results for the top 1000 markers (XLS 1385 kb)

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