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Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis

Abstract

Atopic dermatitis (AD) is a commonly occurring chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing atopic dermatitis are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 affected individuals and 20,565 controls from 16 population-based cohorts and then examined the ten most strongly associated new susceptibility loci in an additional 5,419 affected individuals and 19,833 controls from 14 studies. Three SNPs reached genome-wide significance in the discovery and replication cohorts combined, including rs479844 upstream of OVOL1 (odds ratio (OR) = 0.88, P = 1.1 × 10−13) and rs2164983 near ACTL9 (OR = 1.16, P = 7.1 × 10−9), both of which are near genes that have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster at 5q31.1 (OR = 1.11, P = 3.8 × 10−8). We also replicated association with the FLG locus and with two recently identified association signals at 11q13.5 (rs7927894; P = 0.008) and 20q13.33 (rs6010620; P = 0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in atopic dermatitis pathogenesis.

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Figure 1: Manhattan plot for the discovery genome-wide association meta-analysis of atopic dermatitis after excluding all SNPs with minor allele frequency (MAF) <1% and r2 <0.3 or proper info <0.4. λGC = 1.017.
Figure 2: Forest plots for the association of SNP markers with atopic dermatitis.

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Acknowledgements

The full list of acknowledgments for each study is provided in the Supplementary Note.

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Study-level data analysis: L.P., M.S., A.R., K.B., L.D., M.A.F., A.C.A., J.P.T., E.A., H. Baurecht, B.F., P.H., N.M.W., I.C., R.M., J.A.C., M.M.G.-B., M. Kerkhof, A. Sääf, A.F., D.E., S.B.M., B.S.P., J.P.K., N.J.T., M.M.-N., F.G., M. March, M. Mangino, T.D.S., V.B., C.M.T.T., E.T., M.I., A. Simpson, J.-J.H., H.A.S., B.C., E.K.-M., E.M., A.C., B.J., N.M.P.-H., D.G., D.L.J., H.P., K.H. and D.P.S. Study design: L.P., M.S., C.-M.C., L.D., J.P.T., B.F., P.M.A.S., M. Kerkhof, E.D., A.-L.H., A.P., J.P., M. Kaakinen, G.D.S., J. Henderson, H.-E.W., N.N., A.L., T.M., E.A.N., A.H., A.G.U., C.M.v.D., F.R., J.C.d.J., R.J.P.v.d.V., H.A.B., J.C.M., T.D.S., P.S., W.N., A. Simpson, D.P., G.H.K., H.A.S., H. Bisgaard, D.I.B., A.C., N.M.P.-H., H.H., M. Melbye, D.L.J., V.W.V.J., C.G., M.-R.J., J. Heinrich, D.M.E. and S.W. Manuscript writing: L.P., M.S., A.R., K.B., J. Heinrich, D.M.E. and S.W. Data collection: K.B., L.D., J.P.T., B.F., R.M., M. Kerkhof, R.F.-H., E.D., S.B.M., A.-L.H., A.P., J.P., M. Kaakinen, D.L.D., P.A.M., A.C.H., G.W.M., P.J.T., M.C.M., P.L.S., J. Henderson, S.M.R., W.M., A.L., T.M., E.A.N., J.C.d.J., R.J.P.v.d.V., M.W., R.J., F.G., H.A.B., J.C.M., F.M., T.D.S., V.B., C.E.P., P.G.H., P.S., M.I., W.N., A. Simpson, D.P., G.H.K., H.A.S., B.C., E.K.-M., H. Bisgaard, E.M., D.I.B., A.C., B.J., N.M.P.-H., L.J.P., M. Melbye, D.L.J., V.W.V.J., N.G.M., M.-R.J., J. Heinrich and S.W. Genotyping: R.M., A.F., A.I.F.B., J.L.B., P.D., S.M.R., N.K., E.R., W.M., A.L., A.G.U., F.R., M.W., C.K., C.E.P., T.I., C.S., B.J., L.J.P. and M.-R.J. Revising and reviewing paper: L.P., M.S., C.-M.C., A.R., K.B., L.D., M.A.F., A.C.A., J.P.T., E.A., H. Baurecht, B.F., P.M.A.S., P.H., N.M.W., I.C., R.M., J.A.C., M.M.G.-B., M. Kerkhof, A. Sääf, A.F., D.E., R.F. -H., E.D., S.B.M., A.-L.H., A.P., J.P., A.I.F.B., J.L.B., M. Kaakinen, D.L.D., P.A.M., A.C.H., G.W.M., P.J.T., M.C.M., P.L.S., B.S.P., G.D.S., J. Henderson, J.P.K., N.J.T., P.D., S.M.R., H.-E.W., M.M.-N., N.N., N.K., E.R., W.M., A.L., T.M., E.A.N., A.H., A.G.U., C.M.v.D., F.R., J.C.d.J., R.J.P.v.d.V., M.W., R.J., F.G., H.A.B., J.C.M., C.K., F.M., M. March, M. Mangino, T.D.S., V.B., C.E.P., P.G.H., P.S., C.M.T.T., E.T., T.I., M.I., W.N., A. Simpson, J.-J.H., D.P., G.H.K., H.A.S., C.S., B.C., E.K.-M., H. Bisgaard, E.M., D.I.B., A.C., B.J., N.M.P.-H., L.J.P., D.G., H.H., M. Melbye, D.L.J., V.W.V.J., C.G., D.P.S., N.G.M., M.-R.J., J. Heinrich, D.M.E., H.P., K.H. and S.W.

AAGC provided results for the replication analysis, and GOYA provided results for the discovery analysis.

Corresponding author

Correspondence to Lavinia Paternoster.

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Competing interests

D.P. received funding for research from AstraZeneca, GlaxoSmithKline (GSK) and Nycomed. Travel to the European Respiratory Society (ERS) or American Thoracic Society (ATS) conferences was partially funded by AstraZeneca, GSK, Chiesi and Nycomed. She has been a consultant for AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Nycomed and Teva Pharmaceutical Industries.

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Paternoster, L., Standl, M., Chen, CM. et al. Meta-analysis of genome-wide association studies identifies three new risk loci for atopic dermatitis. Nat Genet 44, 187–192 (2012). https://doi.org/10.1038/ng.1017

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