Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity

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Abstract

To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense.

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Acknowledgements

Major support for this study was provided by the US National Institutes of Health, the Wellcome Trust and the German Research Foundation. We thank J.C. Barrett for contribution to the design of the Immunochip and helpful analytical discussion, as well as E. Gray, S. Bumpstead, D. Simpkin and the staff of the Wellcome Trust Sanger Institute Sample Management and Genotyping teams for their genotyping and analytical contributions. We acknowledge use of the British 1958 Birth Cohort DNA collection, funded by the UK Medical Research Council (G0000934) and the Wellcome Trust (068545/Z/02), and the UK National Blood Service controls, funded by the Wellcome Trust. We acknowledge CASP for the contribution of GWAS data, as well as the provision of control DNA samples by the Cooperative Research in the Region of Augsburg (KORA) and Heinz-Nixdorf Recall (Risk Factors, Evaluation of Coronary Calcification and Lifestyle) study (HNR) and genotyping data generated by the Dietary, Lifestyle and Genetic determinants of Obesity and Metabolic syndrome (DILGOM) Consortium. We thank the Barbara and Neal Henschel Charitable Foundation for their support of the National Psoriasis Victor Henschel BioBank. We acknowledge the Genetic repository in Ireland for Psoriasis and Psoriatic Arthritis (GRIPPsA), the Irish blood transfusion service/Trinity College Dublin Biobank and the Dublin Centre for Clinical Research (funded by the Health Research Board and the Wellcome Trust). A detailed list of contributing consortia and relevant funding support is provided in the Supplementary Note.

Author information

J.T.E., R.C.T. and G.R.A. designed and directed the study. R.P.N., M.W., J.D., J.J.V., J.T.E., F.C., J.N.W.N.B., M.H.A., C.H.S., A.D.B., C.E.M.G., A.R., J. Kere, X.E., W.W., J. Worthington, R.T.-A., M.S., G.N., L.S., R.M., M.J.C., J.S., A.F., S.W., S.K., K.K., T.E., A.M., A.M.B., G.G.K., D.D.G., P.R., U.M., F.O.N., A.H., J. Winkelmann, S.S., C.W., C.L., S.E., R.A., V.C., C.F.R., H.B., H.W.L. and H.E.W. contributed to sample collection and phenotyping. J. Knight coordinated the samples and data sets for the Genetic Analysis of Psoriasis (GAP) consortium. J.T.E. coordinated the PAGE samples and data sets. P.D., A.S., G.B., R.D.P., D.V. and C.C.A.S. contributed to the design of the Immunochip. J. Knight, P.E.S., G.R.A. and H.M.K. advised on the statistical analysis. C.L., S.E., R.A., H.B., E.E., P.H. and R.P.N. performed genotyping. E.E., S.L.S., L.C.T. and H.M.K. performed the genotype calling. S.L.S., L.C.T., Y.L. and J.D. performed genotype imputation and statistical analysis. F.C., J.N.W.N.B., J.E.G., T.T., J.T.E. and A.F. prepared Box 1. L.C.T., S.L.S., F.C. and J.T.E. drafted the manuscript and prepared the figures and tables. E.E., J.E.G., J. Knight, P.E.S., R.P.N., R.C.T., T.T., G.R.A., J.N.W.N.B. and A.F. edited and revised the manuscript. All authors approved the final draft.

Correspondence to Goncalo R Abecasis or James T Elder or Richard C Trembath.

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