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

Nature Genetics volume 44, pages 1341–1348 (2012)Cite this article

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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

Author notes

  1. Lam C Tsoi, Sarah L Spain, Jo Knight, Eva Ellinghaus and Ananth C Viswanathan: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan, USA

    Lam C Tsoi, Jun Ding, Yanming Li, Hyun M Kang, Yun Li & Goncalo R Abecasis

  2. Division of Genetics and Molecular Medicine, King's College London, London, UK

    Sarah L Spain, Francesca Capon, Michael H Allen, Frank O Nestle, Alexandros Onoufriadis, Michael E Weale, Christopher G Mathew, Jonathan N W N Barker & Richard C Trembath

  3. Neuroscience Research, Centre for Addiction and Mental Health, Toronto, Ontario, Canada

    Jo Knight

  4. National Institute for Health Research (NIHR), Biomedical Research Centre, Guy's and St. Thomas' National Health Service (NHS) Foundation Trust, London, UK

    Jo Knight

  5. Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany

    Eva Ellinghaus, Stefan Schreiber, Andreas Ruether & Andre Franke

  6. Department of Dermatology, University of Michigan, Ann Arbor, Michigan, USA

    Philip E Stuart, Trilokraj Tejasvi, Johann E Gudjonsson, John J Voorhees, Ravi Hiremagalore, Rajan P Nair & James T Elder

  7. Department of Clinical Medicine, Trinity College Dublin, St. James's Hospital, Dublin, Ireland

    Ross McManus, Louise Barnes, Ciara Coleman, Judith Conroy, Sean Ennis, Joe McPartlin & Anthony W Ryan

  8. Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland

    Ross McManus, Louise Barnes, Ciara Coleman, Judith Conroy, Sean Ennis, Joe McPartlin & Anthony W Ryan

  9. National Agency for Evaluation of Universities and Research Institutes (ANVUR), Rome, Italy

    Giuseppe Novelli, Emiliano Giardina, Tiziana Lepre & Carlo Perricone

  10. Research Center San Pietro Hospital, Rome, Italy

    Giuseppe Novelli

  11. Department of Medical and Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    Lena Samuelsson & Åsa T Naluai

  12. Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    Joost Schalkwijk, Judith G M Bergboer, Peter C van de Kerkhof & Patrick L J M Zeeuwen

  13. Department of Medicine, Dermatology Unit, Karolinska Institutet, Stockholm, Sweden

    Mona Ståhle, Lotus Mallbris & Katarina Wolk

  14. Department of Dermatology, Western Infirmary, Glasgow, UK

    A David Burden & Joyce Leman

  15. St. John's Institute of Dermatology, King's College London, London, UK

    Catherine H Smith & Jonathan N W N Barker

  16. Department of Infection and Immunity, Academic Unit of Dermatology Research, The University of Sheffield, Sheffield, UK

    Michael J Cork & Rachid Tazi-Ahnini

  17. Genes and Disease Programme, Centre for Genomic Regulation (CRG) and Pompeu Fabra University, Hospital del Mar Research Institute and Public Health and Epidemiology Network Biomedical Research Centre (CIBERESP), Barcelona, Spain

    Xavier Estivill & Eva Riveira-Munoz

  18. Department of Genetics, Division of Human Genetics, Washington University School of Medicine, St. Louis, Missouri, USA

    Anne M Bowcock, Cindy Helms & Jennifer Gardner

  19. Department of Dermatology, University of Utah, Salt Lake City, Utah, USA

    Gerald G Krueger, Kristina Callis Duffin, David Goldgar & Bing Jian Feng

  20. Department of Dermatology, Medical University of Graz, Graz, Austria

    Wolfgang Weger, Angelika Hofer, Wolfgang Salmhofer & Peter Wolf

  21. Arthritis Research UK Epidemiology Unit, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK

    Jane Worthington & Anne Barton

  22. Division of Immunology, Infection and Inflammatory Disease, King's College London, London, UK

    Adrian Hayday

  23. Institute of Human Genetics, University of Bonn, Bonn, Germany

    Per Hoffmann

  24. Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany

    Per Hoffmann

  25. Department of Neurology, Technische Universität München, Munich, Germany

    Juliane Winkelmann

  26. Institute of Human Genetics, Technische Universität München, Munich, Germany

    Juliane Winkelmann

  27. Institute of Human Genetics, Helmholtz Zentrum Munich, German Research Center for Environmental Health, Munich, Germany

    Juliane Winkelmann

  28. Department of Genetics, University Medical Center and University of Groningen, Groningen, The Netherlands

    Cisca Wijmenga, Isis Ricano-Ponce & Gosia Trynka

  29. Wellcome Trust Sanger Institute, Cambridge, Hinxton, UK

    Cordelia Langford, Sarah Edkins, Robert Andrews, Hannah Blackburn, Panos Deloukas, Leena Peltonen, Sarah E Hunt, Rhian Gwilliam, Suzannah J Bumpstead, Serge Dronov, Matthew Gillman, Emma Gray, Naomi Hammond, Alagurevathi Jayakumar, Owen T McCann, Jennifer Liddle, Marc L Perez, Simon C Potter, Radhi Ravindrarajah, Michelle Ricketts, Matthew Waller, Paul Weston, Sara Widaa & Pamela Whittaker

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

    Amy Strange, Gavin Band, Richard D Pearson, Damjan Vukcevic, Chris C A Spencer, Peter Donnelly, Anna Rautanen, Céline Bellenguez, Colin Freeman, Garrett Hellenthal, Eleni Giannoulatou, Matti Pirinen & Zhan Su

  31. Department of Dermatology, University Hospital, Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany

    Ulrich Mrowietz, Stephan Weidinger, Michael Weichenthal, Enno Christophers & Tilo Henseler

  32. PopGen Biobank, University Hospital Schleswig-Holstein, Kiel, Germany

    Stefan Schreiber

  33. Department of Physiology, Centre of Translational Medicine and Centre for Translational Genomics, University of Tartu, Tartu, Estonia

    Sulev Koks

  34. Department of Dermatology and Venerology, University of Tartu, Tartu, Estonia

    Külli Kingo

  35. Estonian Genome Center, University of Tartu, Tartu, Estonia

    Tonu Esko & Andres Metspalu

  36. Department of Dermatology, Henry Ford Hospital, Detroit, Michigan, USA

    Henry W Lim

  37. Institute of Epidemiology I, Helmholtz Zentrum Munich, German Research Center for Environmental Health, Neuherberg, Germany

    H Erich Wichmann

  38. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-University, Munich, Germany

    H Erich Wichmann

  39. Klinikum Grosshadern, Munich, Germany

    H Erich Wichmann

  40. Department of Medicine, Division of Rheumatology, University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada

    Vinod Chandran, Dafna D Gladman & Fawnda J Pellett

  41. Department of Medicine, Division of Dermatology, University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada

    Cheryl F Rosen

  42. Department of Medicine, Memorial University, St. John's, Newfoundland, Canada

    Proton Rahman

  43. Dermatological Sciences, Salford Royal NHS Foundation Trust, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK

    Christopher E M Griffiths, Richard B Warren & Helen S Young

  44. Institute of Human Genetics, University of Erlangen-Nuremberg, Erlangen, Germany

    Andre Reis, Petra Badorf & Ulrike Hüffmeier

  45. Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden

    Juha Kere

  46. Folkhälsan Institute of Genetics, Helsinki, Finland

    Juha Kere

  47. Department of Medical Genetics, University of Helsinki, Helsinki, Finland

    Juha Kere

  48. Ann Arbor Veterans Affairs Hospital, Ann Arbor, Michigan, USA

    James T Elder

  49. Queen Mary University of London, Barts and the London School of Medicine and Dentistry, London, UK

    Richard C Trembath

  50. National Center for Biotechnology Information, National Library of Medicine, US National Institutes of Health, Bethesda, Maryland, USA

    Justin Paschall

  51. Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California, USA

    Mary J Malloy, Clive R Pullinger & John P Kane

  52. Center for Human Genetics, University of California, San Francisco, San Francisco, California, USA

    Mary J Malloy, Clive R Pullinger & John P Kane

  53. Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA

    Amy Perlmutter & Andrew Miner

  54. Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA

    Robert W Ike

  55. Celera, Alameda, California, USA

    Steven J Schrodi & Ann B Begovich

  56. Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA

    Sampath Prahalad & Stephen L Guthery

  57. Department of Rheumatology, University of Utah, Salt Lake City, Utah, USA

    Sampath Prahalad & Stephen L Guthery

  58. Department of Gastroenterology, University of Utah, Salt Lake City, Utah, USA

    Sampath Prahalad & Stephen L Guthery

  59. Centre National de Génotypage, Institut Génomique, Commissariat à l'Energie Atomique, Evry, France

    Judith Fischer & G Mark Lathrop

  60. Department of Dermatology, University of California, San Francisco, San Francisco, California, USA

    Wilson Liao & Pui Kwok

  61. Department of Dermatology, Baylor University Medical Center, Dallas, Texas, USA

    Alan Menter

  62. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, Texas, USA

    C Wise

  63. Department of Dermatology and Venerology, University of Helsinki, Helsinki, Finland

    Kati Kainu, Ulpu Saarialho-Kere & Sari Suomela

  64. Asklepios Nordseeklinik, Westerland/Sylt, Germany

    Werner Kurrat

  65. TOMESA Clinics, Bad Salzschlirf, Germany

    Wolfgang Küster

  66. Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Jesús Lascorz

  67. Department of Dermatology, University of Göttingen, Göttingen, Germany

    Rotraut Mössner

  68. Department of Dermatology, University of Münster, Münster, Germany

    Funda Schürmeier-Horst & Heiko Traupe

  69. Psoriasis Rehabilitation Hospital, Bad Bentheim, Germany

    Markward Ständer

  70. Department of Endocrinology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    Martin den Heijer

  71. Department of Epidemiology and Biostatistics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    Martin den Heijer

  72. University of Dundee, Dundee, UK

    Linda E Campbell & W H Irwin McLean

  73. Department of Dermatology, University College Hospital Galway, Galway, Ireland

    Caitriona Cusack & Trevor Markham

  74. Department of Dermatology, St. Vincent's University Hospital, Dublin, Ireland

    Oliver Fitzgerald, Phil Gallagher, Brian Kirby, Sarah F Rogers & Agnieszka Zawirska

  75. Department of Clinical Medicine, Trinity College Dublin, Our Lady's Children's Hospital Crumlin, Dublin, Ireland

    Alan D Irvine

  76. Dermatology Service, Hospital del Mar–Instituto Municipal de Asistencia Sanitaria (IMAS), Barcelona, Spain

    Gemma Martín-Ezquerra & Ramon M Pujol

  77. Department of Dermatology and Venereology, Sahlgrenska University Hospital, Gothenburg, Sweden

    Annica Inerot

  78. National Psoriasis Foundation, Portland, Oregon, USA

    Andrew Henschel, Marin Aurand & Bruce Bebo

  79. Institute of Genetic Epidemiology, Helmholtz Zentrum Munich, German Research Center for Environmental Health, Neuherberg, Germany

    Christian Gieger

  80. Research Unit Molecular Epidemiology, Helmholtz Zentrum Munich, German Research Center for Environmental Health, Neuherberg, Germany

    Thomas Illig

  81. Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University of Duisburg-Essen, Essen, Germany

    Susanne Moebus & Karl-Heinz Jöckel

  82. Clinic of Cardiology, West German Heart Centre, University Hospital of Essen, University Duisburg-Essen, Essen, Germany

    Raimund Erbel

  83. Department of Statistics, University of Oxford, Oxford, UK

    Peter Donnelly

  84. Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, Suciaco, Western Australia, Australia

    Jenefer M Blackwell

  85. Genetics and Infection Laboratory, Cambridge Institute of Medical Research, Addenbrooke's Hospital, Cambridge, UK

    Jenefer M Blackwell

  86. Division of Psychological Medicine and Psychiatry, Biomedical Research Centre for Mental Health at the Institute of Psychiatry, King's College London, London, UK

    Elvira Bramon

  87. The South London and Maudsley NHS Foundation Trust, Denmark Hill, London, UK.,

    Elvira Bramon

  88. Diamantina Institute of Cancer, Immunology and Metabolic Medicine, Princess Alexandra Hospital, University of Queensland, Brisbane, Queensland, Australia

    Matthew A Brown

  89. Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK

    Juan P Casas

  90. Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland

    Aiden Corvin

  91. Department of Psychological Medicine, Cardiff University School of Medicine, Heath Park, Cardiff, UK.,

    Nicholas Craddock

  92. Molecular and Physiological Sciences, The Wellcome Trust, London, UK

    Audrey Duncanson

  93. Centre for Gastroenterology, Barts and the London School of Medicine and Dentistry, London, UK

    Janusz Jankowski

  94. Clinical Neurosciences, St. George's University of London, London, UK

    Hugh S Markus

  95. Oxford Centre for Diabetes, Endocrinology and Metabolism (ICDEM), Churchill Hospital, Oxford, UK

    Mark I McCarthy

  96. Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee, UK

    Colin N A Palmer

  97. Social, Genetic and Developmental Psychiatry Centre, King's College London Institute of Psychiatry, Denmark Hill, London, UK.,

    Robert Plomin

  98. University of Cambridge Department of Clinical Neurosciences, Addenbrooke's Hospital, Cambridge, UK

    Stephen J Sawcer

  99. Department of Cardiovascular Science, University of Leicester, Glenfield Hospital, Leicester, UK

    Nilesh Samani

  100. Glaucoma Research Unit, Moorfields Eye Hospital NHS Foundation Trust, London, UK

    Ananth C Viswanathan

  101. Department of Genetics, University College London Institute of Ophthalmology, London, UK

    Ananth C Viswanathan

  102. Department of Molecular Neuroscience, Institute of Neurology, London, UK

    Nicholas W Wood

Authors
  1. Lam C Tsoi
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  2. Sarah L Spain
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  3. Jo Knight
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Consortia

Collaborative Association Study of Psoriasis (CASP)

  • Kristina Callis Duffin
  • , Cindy Helms
  • , David Goldgar
  • , Yun Li
  • , Justin Paschall
  • , Mary J Malloy
  • , Clive R Pullinger
  • , John P Kane
  • , Jennifer Gardner
  • , Amy Perlmutter
  • , Andrew Miner
  • , Bing Jian Feng
  • , Ravi Hiremagalore
  • , Robert W Ike
  • , Enno Christophers
  • , Tilo Henseler
  • , Andreas Ruether
  • , Steven J Schrodi
  • , Sampath Prahalad
  • , Stephen L Guthery
  • , Judith Fischer
  • , Wilson Liao
  • , Pui Kwok
  • , Alan Menter
  • , G Mark Lathrop
  • , C Wise
  •  & Ann B Begovich

Genetic Analysis of Psoriasis Consortium

  • Alexandros Onoufriadis
  • , Michael E Weale
  • , Angelika Hofer
  • , Wolfgang Salmhofer
  • , Peter Wolf
  • , Kati Kainu
  • , Ulpu Saarialho-Kere
  • , Sari Suomela
  • , Petra Badorf
  • , Ulrike Hüffmeier
  • , Werner Kurrat
  • , Wolfgang Küster
  • , Jesús Lascorz
  • , Rotraut Mössner
  • , Funda Schürmeier-Horst
  • , Markward Ständer
  • , Heiko Traupe
  • , Judith G M Bergboer
  • , Martin den Heijer
  • , Peter C van de Kerkhof
  • , Patrick L J M Zeeuwen
  • , Louise Barnes
  • , Linda E Campbell
  • , Caitriona Cusack
  • , Ciara Coleman
  • , Judith Conroy
  • , Sean Ennis
  • , Oliver Fitzgerald
  • , Phil Gallagher
  • , Alan D Irvine
  • , Brian Kirby
  • , Trevor Markham
  • , W H Irwin McLean
  • , Joe McPartlin
  • , Sarah F Rogers
  • , Anthony W Ryan
  • , Agnieszka Zawirska
  • , Emiliano Giardina
  • , Tiziana Lepre
  • , Carlo Perricone
  • , Gemma Martín-Ezquerra
  • , Ramon M Pujol
  • , Eva Riveira-Munoz
  • , Annica Inerot
  • , Åsa T Naluai
  • , Lotus Mallbris
  • , Katarina Wolk
  • , Joyce Leman
  • , Anne Barton
  • , Richard B Warren
  • , Helen S Young
  • , Isis Ricano-Ponce
  •  & Gosia Trynka

Psoriasis Association Genetics Extension

  • Fawnda J Pellett
  • , Andrew Henschel
  • , Marin Aurand
  • , Bruce Bebo
  • , Christian Gieger
  • , Thomas Illig
  • , Susanne Moebus
  • , Karl-Heinz Jöckel
  •  & Raimund Erbel

Wellcome Trust Case Control Consortium 2

  • Peter Donnelly
  • , Leena Peltonen
  • , Jenefer M Blackwell
  • , Elvira Bramon
  • , Matthew A Brown
  • , Juan P Casas
  • , Aiden Corvin
  • , Nicholas Craddock
  • , Audrey Duncanson
  • , Janusz Jankowski
  • , Hugh S Markus
  • , Christopher G Mathew
  • , Mark I McCarthy
  • , Colin N A Palmer
  • , Robert Plomin
  • , Anna Rautanen
  • , Stephen J Sawcer
  • , Nilesh Samani
  • , Ananth C Viswanathan
  • , Nicholas W Wood
  • , Céline Bellenguez
  • , Colin Freeman
  • , Garrett Hellenthal
  • , Eleni Giannoulatou
  • , Matti Pirinen
  • , Zhan Su
  • , Sarah E Hunt
  • , Rhian Gwilliam
  • , Suzannah J Bumpstead
  • , Serge Dronov
  • , Matthew Gillman
  • , Emma Gray
  • , Naomi Hammond
  • , Alagurevathi Jayakumar
  • , Owen T McCann
  • , Jennifer Liddle
  • , Marc L Perez
  • , Simon C Potter
  • , Radhi Ravindrarajah
  • , Michelle Ricketts
  • , Matthew Waller
  • , Paul Weston
  • , Sara Widaa
  •  & Pamela Whittaker

Contributions

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.

Corresponding authors

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

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1–10, Supplementary Figures 1–5 and Supplementary Note (PDF 2509 kb)

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Tsoi, L., Spain, S., Knight, J. et al. Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity. Nat Genet 44, 1341–1348 (2012). https://doi.org/10.1038/ng.2467

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