Fine mapping in the MHC region accounts for 18% additional genetic risk for celiac disease (original) (raw)

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Acknowledgements

We thank J. Senior for carefully reading the manuscript and C. Gonzalez-Arevalo for the graphics. This study was funded by a grant from the Celiac Disease Consortium, an Innovative Cluster approved by the Netherlands Genomics Initiative (to C.W.), a European Research Council advanced grant (FP/2007–2013/ERC grant 2012-322698) (to C.W.), a grant from the Dutch Reumafonds (11-1-101) (to A.Z.) and a Rosalind Franklin Fellowship from the University of Groningen (to A.Z.). S.R. and P.I.W.d.B. received support from the US National Institutes of Health (1R01AR062886). P.I.W.d.B. holds a VIDI award from the Netherlands Organization for Scientific Research (NWO project 016.126.354). S.R. is also supported by a Doris Duke Clinical Scientist Development Award.

Author information

Author notes

  1. Javier Gutierrez-Achury and Alexandra Zhernakova: These authors contributed equally to this work.
  2. Cisca Wijmenga and Paul I W de Bakker: These authors jointly supervised this work.

Authors and Affiliations

  1. Department of Genetics, University Medical Center, University of Groningen, Groningen, the Netherlands
    Javier Gutierrez-Achury, Alexandra Zhernakova, Jihane Romanos & Cisca Wijmenga
  2. Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
    Sara L Pulit & Paul I W de Bakker
  3. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK
    Gosia Trynka
  4. Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
    Karen A Hunt & David A van Heel
  5. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
    Soumya Raychaudhuri
  6. Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
    Soumya Raychaudhuri
  7. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA
    Soumya Raychaudhuri
  8. Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, University of Manchester, Manchester, UK
    Soumya Raychaudhuri
  9. Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
    Paul I W de Bakker

Authors

  1. Javier Gutierrez-Achury
  2. Alexandra Zhernakova
  3. Sara L Pulit
  4. Gosia Trynka
  5. Karen A Hunt
  6. Jihane Romanos
  7. Soumya Raychaudhuri
  8. David A van Heel
  9. Cisca Wijmenga
  10. Paul I W de Bakker

Contributions

J.G.-A., A.Z., C.W. and P.I.W.d.B. designed the study and analyzed and interpreted the data. S.L.P. imputed the data. J.G.-A., G.T., K.A.H. and J.R. prepared the data for analysis. D.A.v.H. and C.W. collected and genotyped samples. J.G.-A., A.Z., C.W. and P.I.W.d.B. wrote the manuscript. J.G.-A., A.Z., S.L.P., D.A.v.H., S.R., C.W. and P.I.W.d.B. critically discussed the manuscript and received feedback from the other authors.

Corresponding author

Correspondence toCisca Wijmenga.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Frequencies of DQ2.5, DQ2.2, DQ8 and DQ7.5, the most common haplotypes in celiac disease cases.

The map illustrates the differences among European countries and shows a clear gradient in the frequencies from north to south, especially for DQ2.5 and DQ7.5.

Supplementary Figure 2 Association results for amino acids in HLA-DQα1 and HLA-DQβ1.

(a) Amino acid position 74 in HLA-DQβ1 showed the strongest association with celiac disease (P = 10−1,981). (b) Controlling for position 74 in HLA-DQβ1, position 47 in HLA-DQα1 was significantly associated with celiac disease (P = 10−236). (c) Controlling for positions 74 in HLA-DQβ1 and 47 in HLA-DQα1, position 57 was significantly associated with celiac disease (P = 10−93). (d) After controlling for positions 74 and 57 in HLA-DQβ1 and 47 in HLA-DQα1, position 25 in HLA-DQα1 was significantly associated with celiac disease (P = 1.6 x 10−9). (e) After controlling for positions 74 and 57 in HLA-DQβ1 and positions 47 and 25 in HLA-DQα1, no amino acid position was significant (position 197 in HLA-DQβ1, P > 2.6 × 10−6). Gray arrows indicate the drop in association after conditional analysis.

Supplementary Figure 3 Stepwise conditional analysis of the MHC-HLA region under a conservative model, where HLA-DQA1 and HLA-DQB1 four-digit alleles were included in the model to control for their effects.

With this analysis, we identified five independent associations outside the HLA-DQ and HLA-DR loci. Each dot represents –log10 (P) of the variant, including SNPs, classical HLA alleles and amino acid polymorphisms encoded by the HLA genes.

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Gutierrez-Achury, J., Zhernakova, A., Pulit, S. et al. Fine mapping in the MHC region accounts for 18% additional genetic risk for celiac disease.Nat Genet 47, 577–578 (2015). https://doi.org/10.1038/ng.3268

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