Abstract
Atopic dermatitis is a common inflammatory skin disease with a strong heritable component. Pathogenetic models consider keratinocyte differentiation defects and immune alterations as scaffolds1, and recent data indicate a role for autoreactivity in at least a subgroup of patients2. FLG (encoding filaggrin) has been identified as a major locus causing skin barrier deficiency3. To better define risk variants and identify additional susceptibility loci, we densely genotyped 2,425 German individuals with atopic dermatitis (cases) and 5,449 controls using the Immunochip array followed by replication in 7,196 cases and 15,480 controls from Germany, Ireland, Japan and China. We identified four new susceptibility loci for atopic dermatitis and replicated previous associations. This brings the number of atopic dermatitis risk loci reported in individuals of European ancestry to 11. We estimate that these susceptibility loci together account for 14.4% of the heritability for atopic dermatitis.
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Acknowledgements
We thank all individuals with atopic dermatitis, their families, control individuals and clinicians for their participation. We thank T. Wesse, T. Henke, S.S. Sabet, S. Greve, I. Urbach, G. Patone, C. Flachmeier, S. Kolberg and G. Born for expert technical help. This study was supported by the Deutsche Forschungsgemeinschaft (DFG) grant FR 2821/2-1, the German Ministry of Education and Research (BMBF) through the National Genome Research Network (NGFN; 01GS 0818 and 01GS 0812 to Y.-A.L.) and the PopGen biobank. S.W. is supported by a Heisenberg fellowship of the DFG (WE 2678/7-1). The project received infrastructure support through the DFG Clusters of Excellence 'Inflammation at Interfaces'. A.D.I. is supported by the National Children's Research Centre, Dublin. A.D.I. and I.M. are supported by the Wellcome Trust (reference 090066/B/09/Z and 092530/Z/10/Z).
S. Brand is supported by DFG grant BR1912/6-1 and the Else-Kröner-Fresenius-Stiftung (stipend 2010_EKES.32). We acknowledge US National Institutes of Health grant 1R01CA141743-01 (R.H.D., principal investigator) and the University of Pittsburgh Genomics and Proteomics Core Laboratories for the Immunochip genotyping services. This work was supported by Wellcome Trust Programme and Bioresources grants (090066/B/09/Z and 092530/Z/10/Z) to W.H.I.M. and A.D.I. and a Wellcome Trust Strategic Award (098439/Z/12/Z) to W.H.I.M. Parts of this study were funded by the General Program of National Natural Science Foundation of China (31171224), the Program for New Century Excellent Talents in University (NCET-11-0889), the Science and Technological Foundation of Anhui Province for Outstanding Youth (1108085J10) and a pre-project of State Key Basic Research Program 973 of China (2012CB722404).
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S.W., A.F., Y.-A.L. and D.E. designed the experiments. E.R., J.E.-G., A.M., I.M., N.H., H.S., U.M.-H., M.H., M. Kubo, W.H.I.M. and N.N. performed wet lab experiments. D.E., H.B. and S.M. analyzed the data. S.W., Y.-A.L., N.N., L.M., R.F.-H. and T.W. provided German case samples. H.S. helped providing case samples. M.T., A.T., Y.N., T.H. and M. Kubo provided Japanese replication data. A.D.I., S. Brown, M.A.M. and C.M.F. provided Irish replication data. L.S., X. Zuo, S.Y. and X. Zhang provided Chinese replication data. B.O.B. provided German control samples from the Echinococcus Multilocularis and Internal Diseases in Leutkirch (EMIL) study. P.H. and M.M.N. provided German control samples. S. Brand, J.G. and C.B. provided German control samples, which were genotyped at the University of Pittsburgh Genomics and Proteomics Core Laboratories (R.H.D., principal investigator). J.W. and T.I. provided German control samples. M. Kabesch provided Immunochip data from the cases with asthma from the Multicenter Asthma Genetics in Childhood (MAGIC) and International Study of Asthma and Allergies in Childhood (ISAAC) studies. H.P., K.H., T.I., C.H., L.C.T., P.S. and J.T.E. contributed and analyzed expression data. S.W., A.F., S.S., N.H. and Y.-A.L. supervised the experiments. D.E., H.B., S.W. and A.F. wrote the paper. All authors reviewed, edited and approved the final manuscript.
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Supplementary Text and Figures
Supplementary Tables 1–3, 5, 6 and 9–11 and Supplementary Figures 1–8 (PDF 2156 kb)
Supplementary Table 4
Results of association analysis from Immunochip (panel A of Supplementary Table 1) and replication (panel B-D of Supplementary Table 1) data. (XLSX 20 kb)
Supplementary Table 7
Results of top SNPs for the endophenotypes 'AD and asthma' and 'AD no asthma' and comparison with results from an independent asthma immunochip experiment as well as or other related phenotypes. (XLSX 14 kb)
Supplementary Table 8
Details on 1000 Genomes coding SNPs (cSNPs) that are highly correlated with the SNPs listed in Table 1. (XLSX 13 kb)
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Ellinghaus, D., Baurecht, H., Esparza-Gordillo, J. et al. High-density genotyping study identifies four new susceptibility loci for atopic dermatitis. Nat Genet 45, 808–812 (2013). https://doi.org/10.1038/ng.2642
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DOI: https://doi.org/10.1038/ng.2642
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