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Fine mapping in the MHC region accounts for 18% additional genetic risk for celiac disease


Although dietary gluten is the trigger for celiac disease, risk is strongly influenced by genetic variation in the major histocompatibility complex (MHC) region. We fine mapped the MHC association signal to identify additional risk factors independent of the HLA-DQA1 and HLA-DQB1 alleles and observed five new associations that account for 18% of the genetic risk. Taking these new loci together with the 57 known non-MHC loci, genetic variation can now explain up to 48% of celiac disease heritability.

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Figure 1: Schematic of the stepwise analysis applied in fine mapping the HLA region.

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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.

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Authors and Affiliations



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.

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Correspondence to Cisca Wijmenga.

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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.

Supplementary Figure 4 Stepwise conditional analysis of the MHC-HLA region under a relaxed model, with no adjustment for the effects of HLA-DQ alleles.

Each dot represents –log10 (P) of the variant, including SNPs, classical HLA alleles and amino acid polymorphisms encoded by the HLA genes.

Supplementary Figure 5 Histograms with r2 post-imputation for each of the populations analyzed in this study.

The y axis (frequency) shows the number of variants analyzed, and the x axis shows imputation r2.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5 and Supplementary Tables 1–6. (PDF 1434 kb)

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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).

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