Multiple common variants for celiac disease influencing immune gene expression

A Corrigendum to this article was published on 01 May 2010

This article has been updated


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.

Accession codes


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.


  1. 1

    van Heel, D.A. et al. A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nat. Genet. 39, 827–829 (2007).

    CAS  Article  Google Scholar 

  2. 2

    van Heel, D.A. & West, J. Recent advances in coeliac disease. Gut 55, 1037–1046 (2006).

    CAS  Article  Google Scholar 

  3. 3

    Sollid, L.M. et al. Evidence for a primary association of celiac disease to a particular HLA-DQ α/β heterodimer. J. Exp. Med. 169, 345–350 (1989).

    CAS  Article  Google Scholar 

  4. 4

    Kim, C.Y., Quarsten, H., Bergseng, E., Khosla, C. & Sollid, L.M. Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease. Proc. Natl. Acad. Sci. USA 101, 4175–4179 (2004).

    CAS  Article  Google Scholar 

  5. 5

    Henderson, K.N. et al. A structural and immunological basis for the role of human leukocyte antigen DQ8 in celiac disease. Immunity 27, 23–34 (2007).

    CAS  Article  Google Scholar 

  6. 6

    Zhernakova, A., van Diemen, C.C. & Wijmenga, C. Detecting shared pathogenesis from the shared genetics of immune-related diseases. Nat. Rev. Genet. 10, 43–55 (2009).

    CAS  Article  Google Scholar 

  7. 7

    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).

    CAS  Article  Google Scholar 

  8. 8

    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).

    CAS  Article  Google Scholar 

  9. 9

    Anderson, C.A. et al. Evaluating the effects of imputation on the power, coverage, and cost efficiency of genome-wide SNP platforms. Am. J. Hum. Genet. 83, 112–119 (2008).

    CAS  Article  Google Scholar 

  10. 10

    Jacobs, K.B. et al. A new statistic and its power to infer membership in a genome-wide association study using genotype frequencies. Nat. Genet. 41, 1253–1257 (2009).

    CAS  Article  Google Scholar 

  11. 11

    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. 12

    Pe'er, I., Yelensky, R., Altshuler, D. & Daly, M.J. Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genet. Epidemiol. 32, 381–385 (2008).

    Article  Google Scholar 

  13. 13

    Dudbridge, F. & Gusnanto, A. Estimation of significance thresholds for genomewide association scans. Genet. Epidemiol. 32, 227–234 (2008).

    Article  Google Scholar 

  14. 14

    Karell, K. et al. HLA types in celiac disease patients not carrying the DQA1*05–DQB1*02 (DQ2) heterodimer: results from the European Genetics Cluster on Celiac Disease. Hum. Immunol. 64, 469–477 (2003).

    CAS  Article  Google Scholar 

  15. 15

    Raychaudhuri, S. et al. Genetic variants at CD28, PRDM1 and CD2/CD58 are associated with rheumatoid arthritis risk. Nat. Genet. 41, 1313–1318 (2009).

    CAS  Article  Google Scholar 

  16. 16

    Raychaudhuri, S. et al. Identifying relationships among genomic disease regions: predicting genes at pathogenic SNP associations and rare deletions. PLoS Genet. 5, e1000534 (2009).

    Article  Google Scholar 

  17. 17

    Smyth, D.J. et al. Shared and distinct genetic variants in type 1 diabetes and celiac disease. N. Engl. J. Med. 359, 2767–2777 (2008).

    CAS  Article  Google Scholar 

  18. 18

    Coenen, M.J. et al. Common and different genetic background for rheumatoid arthritis and coeliac disease. Hum. Mol. Genet. 18, 4195–4203 (2009).

    CAS  Article  Google Scholar 

  19. 19

    Hindorff, L.A. et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl. Acad. Sci. USA 106, 9362–9367 (2009).

    CAS  Article  Google Scholar 

  20. 20

    Yu, W., Clyne, M., Khoury, M.J. & Gwinn, M. Phenopedia and Genopedia: Disease-centered and gene-centered views of the evolving knowledge of human genetic associations. Bioinformatics 26, 145–146 (2010).

    CAS  Article  Google Scholar 

  21. 21

    Han, J.W. et al. Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat. Genet. 41, 1234–1237 (2009).

    CAS  Article  Google Scholar 

  22. 22

    Hunt, K.A. et al. Newly identified genetic risk variants for celiac disease related to the immune response. Nat. Genet. 40, 395–402 (2008).

    CAS  Article  Google Scholar 

  23. 23

    Allen, P.M. Themis imposes new law and order on positive selection. Nat. Immunol. 10, 805–806 (2009).

    CAS  Article  Google Scholar 

  24. 24

    Sato, T. et al. Dual functions of Runx proteins for reactivating CD8 and silencing CD4 at the commitment process into CD8 thymocytes. Immunity 22, 317–328 (2005).

    CAS  Article  Google Scholar 

  25. 25

    Woolf, E. et al. Runx3 and Runx1 are required for CD8 T cell development during thymopoiesis. Proc. Natl. Acad. Sci. USA 100, 7731–7736 (2003).

    CAS  Article  Google Scholar 

  26. 26

    Wang, J. & Fu, Y.X. LIGHT (a cellular ligand for herpes virus entry mediator and lymphotoxin receptor)-mediated thymocyte deletion is dependent on the interaction between TCR and MHC/self-peptide. J. Immunol. 170, 3986–3993 (2003).

    CAS  Article  Google Scholar 

  27. 27

    Zamisch, M. et al. The transcription factor Ets1 is important for CD4 repression and Runx3 up-regulation during CD8 T cell differentiation in the thymus. J. Exp. Med. 206, 2685–2699 (2009).

    CAS  Article  Google Scholar 

  28. 28

    Vafiadis, P. et al. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat. Genet. 15, 289–292 (1997).

    CAS  Article  Google Scholar 

  29. 29

    Bonasio, R. et al. Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus. Nat. Immunol. 7, 1092–1100 (2006).

    CAS  Article  Google Scholar 

  30. 30

    Klein, L., Hinterberger, M., Wirnsberger, G. & Kyewski, B. Antigen presentation in the thymus for positive selection and central tolerance induction. Nat. Rev. Immunol. 9, 833–844 (2009).

    CAS  Article  Google Scholar 

  31. 31

    Nejentsev, S., Walker, N., Riches, D., Egholm, M. & Todd, J.A. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324, 387–389 (2009).

    CAS  Article  Google Scholar 

  32. 32

    Trynka, G. et al. Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-κB signalling. Gut 58, 1078–1083 (2009).

    CAS  Article  Google Scholar 

  33. 33

    Garner, C.P. et al. Replication of celiac disease UK genome-wide association study results in a US population. Hum. Mol. Genet. 18, 4219–4225 (2009).

    CAS  Article  Google Scholar 

  34. 34

    Plenge, R.M. et al. Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat. Genet. 39, 1477–1482 (2007).

    CAS  Article  Google Scholar 

  35. 35

    Franke, L. et al. Detection, imputation, and association analysis of small deletions and null alleles on oligonucleotide arrays. Am. J. Hum. Genet. 82, 1316–1333 (2008).

    CAS  Article  Google Scholar 

  36. 36

    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).

    CAS  Article  Google Scholar 

  37. 37

    Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    CAS  Article  Google Scholar 

  38. 38

    Yu, K. et al. Population substructure and control selection in genome-wide association studies. PLoS One 3, e2551 (2008).

    Article  Google Scholar 

  39. 39

    Risch, N.J. Searching for genetic determinants in the new millennium. Nature 405, 847–856 (2000).

    CAS  Article  Google Scholar 

  40. 40

    Edgar, R., Domrachev, M. & Lash, A.E. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 30, 207–210 (2002).

    CAS  Article  Google Scholar 

  41. 41

    Bolstad, B.M., Irizarry, R.A., Astrand, M. & Speed, T.P. A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 19, 185–193 (2003).

    CAS  Article  Google Scholar 

  42. 42

    Sherlock, G. Analysis of large-scale gene expression data. Brief. Bioinform. 2, 350–362 (2001).

    CAS  Article  Google Scholar 

  43. 43

    Alter, O., Brown, P.O. & Botstein, D. Singular value decomposition for genome-wide expression data processing and modeling. Proc. Natl. Acad. Sci. USA 97, 10101–10106 (2000).

    CAS  Article  Google Scholar 

  44. 44

    Heap, G.A. et al. Genome-wide analysis of allelic expression imbalance in human primary cells by high throughput transcriptome resequencing. Hum. Mol. Genet. 19, 122–134 (2010).

    CAS  Article  Google Scholar 

  45. 45

    Heap, G.A. et al. Complex nature of SNP genotype effects on gene expression in primary human leucocytes. BMC Med. Genomics 2, 1 (2009).

    Article  Google Scholar 

  46. 46

    Franke, L. & Jansen, R.C. eQTL analysis in humans. Methods Mol. Biol. 573, 311–328 (2009).

    CAS  Article  Google Scholar 

Download references


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 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.

Corresponding authors

Correspondence to Lude Franke or David A van Heel.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

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)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Dubois, P., Trynka, G., Franke, L. et al. Multiple common variants for celiac disease influencing immune gene expression. Nat Genet 42, 295–302 (2010).

Download citation

Further reading


Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing