Letter | Published:

A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1

Nature Genetics volume 42, pages 985990 (2010) | Download Citation


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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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.

Author information

Author notes

    • Amy Strange
    •  & Francesca Capon

    These authors contributed equally to this work.

    • Peter Donnelly
    •  & Richard C Trembath

    These authors jointly supervised this work.


  1. Wellcome Trust Centre for Human Genetics, Oxford, UK.

    • Amy Strange
    • , Chris C A Spencer
    • , Gavin Band
    • , Céline Bellenguez
    • , Colin Freeman
    • , Matti Pirinen
    • , Anna Rautanen
    • , Zhan Su
    •  & Peter Donnelly
  2. Division of Genetics and Molecular Medicine, King's College London, London, UK.

    • Francesca Capon
    • , Jo Knight
    • , Michael E Weale
    • , Michael H Allen
    • , Christopher G Mathew
    • , Frank O Nestle
    • , Alexandros Onoufriadis
    • , Catherine H Smith
    • , Jonathan N Barker
    •  & Richard C Trembath
  3. National Institute for Health Research (NIHR), Biomedical Research Centre, Guy's and St. Thomas' National Health Service (NHS) Foundation Trust and King's College London, London, UK.

    • Jo Knight
    • , Frank O Nestle
    •  & Richard C Trembath
  4. Arthritis Research, UK Epidemiology Unit, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.

    • Anne Barton
    •  & Jane Worthington
  5. Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Judith G M Bergboer
    • , Joost Schalkwijk
    •  & Patrick L J M Zeeuwen
  6. Genetics and Infection Laboratory, Cambridge Institute of Medical Research, Addenbrooke's Hospital, Cambridge, UK.

    • Jenefer M Blackwell
  7. Division of Psychological Medicine and Psychiatry, Biomedical Research Centre for Mental Health at the Institute of Psychiatry, King's College London and The South London and Maudsley NHS Foundation Trust, Denmark Hill, London, UK.

    • Elvira Bramon
  8. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

    • Suzannah J Bumpstead
    • , Panos Deloukas
    • , Sarah Edkins
    • , Emma Gray
    • , Sarah E Hunt
    • , Cordelia Langford
    • , Simon C Potter
    •  & Leena Peltonen
  9. Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.

    • Juan P Casas
  10. Academic Unit of Dermatology Research, Department of Infection and Immunity, The University of Sheffield, Sheffield, UK.

    • Michael J Cork
    •  & Rachid Tazi-Ahnini
  11. Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland.

    • Aiden Corvin
  12. Department of Statistics, University of Oxford, Oxford, UK.

    • Alexander Dilthey
    • , Stephen Leslie
    • , Loukas Moutsianas
    • , Gilean McVean
    •  & Peter Donnelly
  13. Molecular and Physiological Sciences, The Wellcome Trust, London, UK.

    • Audrey Duncanson
  14. Genes and Disease Programme, Centre for Genomic Regulation (CRG) and Public Health and Epidemiology Network Biomedical Research Center (CIBERESP), Barcelona, Spain.

    • Xavier Estivill
    •  & Eva Riveira-Munoz
  15. St. Vincent's University Hospital, Dublin, Ireland.

    • Oliver Fitzgerald
    •  & Brian Kirby
  16. Department of Biopathology, Centre of Excellence for Genomic risk Assessment in Multifactorial and Complex Diseases, School of Medicine, University of Rome Tor Vergata, Rome, Italy.

    • Emiliano Giardina
    •  & Giuseppe Novelli
  17. Department of Dermatology, Medical University of Graz, Graz, Austria.

    • Angelika Hofer
    • , Wolfgang Salmhofer
    •  & Wolfgang Weger
  18. Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany.

    • Ulrike Hüffmeier
    •  & André Reis
  19. Department of Clinical Medicine, Trinity College Dublin, Our Lady's Children's Hospital Crumlin, Dublin, Ireland.

    • Alan D Irvine
  20. Centre for Gastroenterology, Bart's and the London School of Medicine and Dentistry, London, UK.

    • Janusz Jankowski
  21. Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Jesús Lascorz
  22. Department of Dermatology, Western Infirmary, Glasgow, UK.

    • Joyce Leman
    •  & A David Burden
  23. Dermatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.

    • Lotus Mallbris
    • , Mona Ståhle
    •  & Katarina Wolk
  24. Clinical Neurosciences, St. George's University of London, London, UK.

    • Hugh S Markus
  25. Epithelial Genetics Group, Division of Molecular Medicine, Colleges of Life Sciences and Medicine, Dentistry and Nursing, University of Dundee, Dundee, UK.

    • W H Irwin McLean
  26. Department of Clinical Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Ireland.

    • Ross McManus
    •  & Anthony W Ryan
  27. Institute of Molecular Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Ireland.

    • Ross McManus
    •  & Anthony W Ryan
  28. Department of Dermatology, University of Göttingen, Göttingen, Germany.

    • Rotraut Mössner
  29. Department of Medical and Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

    • Åsa T Naluai
    •  & Lena Samuelsson
  30. Biomedical Research Institute, Ninewells Hospital and Medical School, Dundee, UK.

    • Colin N A Palmer
  31. La Sapienza University of Rome, Unit of Rheumatology, Department of Clinic and Medical Therapy, Rome, Italy.

    • Carlo Perricone
  32. Social, Genetic and Developmental Psychiatry Centre, King's College London Institute of Psychiatry, Denmark Hill, London, UK.

    • Robert Plomin
  33. Dermatology Service, Hospital del Mar-Institut Municipal d'Assisténcia Sanitári (IMAS), Barcelona, Spain.

    • Ramon M Pujol
  34. University of Cambridge Department of Clinical Neurosciences, Addenbrooke's Hospital, Cambridge, UK.

    • Stephen J Sawcer
    •  & Adrian Hayday
  35. St. John's Institute of Dermatology, King's College London, London, UK.

    • Catherine H Smith
    •  & Jonathan N Barker
  36. Department of Dermatology, University of Münster, Münster, Germany.

    • Heiko Traupe
  37. Glaucoma Research Unit, Moorfields Eye Hospital NHS Foundation Trust, London, UK.

    • Ananth C Viswanathan
  38. Department of Genetics, University College London Institute of Ophthalmology, London, UK.

    • Ananth C Viswanathan
  39. Dermatological Sciences, Salford Royal NHS Foundation Trust, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.

    • Richard B Warren
    • , Helen S Young
    •  & Christopher E M Griffiths
  40. Department of Molecular Neuroscience, Institute of Neurology, Queen Square, London, UK.

    • Nicholas Wood
  41. Division of Immunology, Infection and Inflammatory Disease, King's College London, London, UK.

    • Adrian Hayday
  42. Immuno Surveillance Laboratory, London Research Institute, London, UK.

    • Adrian Hayday
  43. Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.

    • Juha Kere
  44. Science for Life Laboratory, Stockholm, Sweden.

    • Juha Kere
  45. Folkhälsan Institute of Genetics, Helsinki, Finland.

    • Juha Kere
  46. Department of Medical Genetics, University of Helsinki, Finland.

    • Juha Kere
  47. Medical Research Council Centre for Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, Bristol, UK.

    • David M Evans
  48. Diamantina Institute of Cancer, Immunology and Metabolic Medicine, Princess Alexandra Hospital, University of Queensland, Brisbane, Queensland, Australia.

    • David M Evans
    •  & Matthew A Brown


  1. Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control Consortium 2



    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.

    Competing interests

    The author declare no competing financial interests.

    Corresponding authors

    Correspondence to Peter Donnelly or Richard C Trembath.

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      Supplementary Tables 1–9, Supplementary Figures 1–4 and Supplementary Note.

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      Supplementary Table 9

      Other SNPs with GWAS p-value less than 10-4

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