Abstract
To identify new susceptibility loci for psoriasis, we undertook a genome-wide association study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified associations at eight previously unreported genomic loci. Seven loci harbored genes with recognized immune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2). These associations were replicated in 9,079 European samples (six loci with a combined P < 5 × 10−8 and two loci with a combined P < 5 × 10−7). We also report compelling evidence for an interaction between the HLA-C and ERAP1 loci (combined P = 6.95 × 10−6). ERAP1 plays an important role in MHC class I peptide processing. ERAP1 variants only influenced psoriasis susceptibility in individuals carrying the HLA-C risk allele. Our findings implicate pathways that integrate epidermal barrier dysfunction with innate and adaptive immune dysregulation in psoriasis pathogenesis.
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Acknowledgements
The principal funding for this study was provided by the Wellcome Trust, as part of the Wellcome Trust Case Control Consortium 2 project (083948/Z/07/Z). We also thank S. Bertrand, J. Bryant, S.L. Clark, J.S. Conquer, T. Dibling, J.C. Eldred, S. Gamble, C. Hind, A. Wilk, C.R. Stribling and S. Taylor of the Wellcome Trust Sanger Institute's Sample and Genotyping Facilities for technical assistance. We thank D. Davison for making available his program 'Shellfish' for calculating principal components in large genetic datasets. Case collections were supported by the Netherlands Organization for Health Research and Development (P.L.J.M.Z.); the Swedish Medical Research Council, Karolinska Institutet, Karolinska University Hospital, Psoriasis Foundation, AFA Insurance and Welander Finsen Foundation (M.S.); the Association for the Defence of Psoriasis Patients (G.N.); Psoriasis Association and the Cecil King Memorial Foundation (M.J.C.); the Swedish Psoriasis Association (L.S.); the German Research Foundation (Tr 228/5-4 and Re 679/10-4) and The Interdisciplinary Centre for Clinical Research (IZKF B32/A8) of the University of Erlangen-Nuremberg (A. Reis); the Spanish Ministry of Science and Innovation (grant SAF 2008-00357) and the 'Generalitat de Catalunya' Departments of Health and Universities and Innovation (X.E.); the Genetic Repository in Ireland for Psoriasis and Psoriatic Arthritis (GRIPPsA), the Dublin Centre for Clinical Research (DCCR, funded by the Irish Health Research Board), The Wellcome Trust and Science Foundation Ireland (R. McManus); National Institute for Health Research, Manchester Biomedical Research Centre (J.W., C.E.M.G., R.B.W., H.S.Y.); and Arthritis Research UK (J.W., grant 17552). P. Donnelly was supported in part by a Wolfson-Royal Society Merit Award, and A.O. was supported by a PhD studentship from The Generation Trust. We also acknowledge support from the UK Medical Research Council (to R.C.T., F.O.N., A.H. and J.N.B., grant G0601387), the Wellcome Trust (F.O.N., grant 078173/Z/05/Z) and the Department of Health through the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre awards to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London (J. Knight., M.E.W., C.G.M., F.O.N., A. Hayday and J.N.B.) and the NIHR award to Moorfields Eye Hospital NHS Foundation Trust and University College London Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology (A.C.V.). We acknowledge use of the British 1958 Birth Cohort DNA collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02, and of the UK National Blood Service controls funded by the Wellcome Trust. We thank W. Bodmer and B. Winney for use of the People of the British Isles DNA collection, which was funded by the Wellcome Trust.
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F.C., A.D.B., C.E.M.G., J. Kere, A. Reis, J.N.B. and R.C.T. oversaw cohort collection for both the discovery and the replication datasets. The WTCCC2 DNA, genotyping, data quality control and informatics group (S.J.B., P. Deloukas, S.E., E. Gray, S.E.H., C.L. and S.C.P.) executed GWAS sample handling, genotyping and quality control. Members of the WTCCC2 analysis group (C.C.A.S., A.S., G.B., C.B., C.F., M.P., Z.S. and P. Donnelly), J. Knight and M.E.W. performed statistical analyses. A. Dilthey, S.L., L. Moutsianas and G.M. performed HLA imputation and analyses. D.M.E. and M.A.B. provided advice on similarities of association to another autoimmune disease. A.S., F.C., C.C.A.S., J. Knight, M.E.W., A. Hayday, J.N.B., P. Donnelly and R.C.T. contributed to writing the manuscript. The WTCCC2 Management Committee (P. Donnelly (chair), J.M.B., E.B., J.P.C., A. Duncanson, J.J., H.S.M., C.G.M., C.N.A.P., R.P., S.J.S., A. Rautanen, A.C.V., N.W., M.A.B., L.P. and R.C.T.) monitored the execution of the GWAS. The GAP Consortium (R.C.T. (chair), M.H.A., A.B., J.G.M.B., M.J.C., A.C., X.E., O.F., E. Giardina, A. Hofer, U.H., A.D.I., B.K., J. Lascorz, J. Leman, L. Mallbris, W.H.I.M., R. McManus, R. Mössner, Å.T.N., F.O.N., G.N., A.O., C.P., R.M.P., E.R.M., A.W.R., W.S., L.S., J.S., C.H.S., M.S., R.T.A., H.T., R.B.W., W.W., K.W., J.W., H.S.Y. and P.L.J.M.Z.) contributed to sample collection. All authors reviewed the final manuscript.
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Supplementary Text and Figures
Supplementary Tables 1–9, Supplementary Figures 1–4 and Supplementary Note. (PDF 6704 kb)
Supplementary Table 9
Other SNPs with GWAS p-value less than 10-4 (XLS 37 kb)
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Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control Consortium 2. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat Genet 42, 985–990 (2010). https://doi.org/10.1038/ng.694
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DOI: https://doi.org/10.1038/ng.694
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