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GWAS meta-analysis of psoriasis identifies new susceptibility alleles impacting disease mechanisms and therapeutic targets

Author

Listed:
  • Nick Dand

    (King’s College London
    Health Data Research UK)

  • Philip E. Stuart

    (University of Michigan Medical School)

  • John Bowes

    (The University of Manchester
    The University of Manchester)

  • David Ellinghaus

    (Christian-Albrechts-University of Kiel)

  • Joanne Nititham

    (University of California San Francisco)

  • Jake R. Saklatvala

    (King’s College London)

  • Maris Teder-Laving

    (University of Tartu)

  • Laurent F. Thomas

    (NTNU - Norwegian University of Science and Technology
    NTNU - Norwegian University of Science and Technology
    NTNU - Norwegian University of Science and Technology
    Trondheim University Hospital)

  • Tanel Traks

    (University of Tartu)

  • Steffen Uebe

    (FAU Erlangen-Nürnberg)

  • Gunter Assmann

    (Department of Rheumatology
    University of Saarland Medical School)

  • David Baudry

    (King’s College London)

  • Frank Behrens

    (Goethe University
    Fraunhofer Institute for Translational Medicine and Pharmacology ITMP
    Fraunhofer Cluster of Excellence Immune-mediated Diseases CIMD
    Goethe University)

  • Allison C. Billi

    (University of Michigan Medical School)

  • Matthew A. Brown

    (King’s College London
    Canary Wharf)

  • Harald Burkhardt

    (Fraunhofer Institute for Translational Medicine and Pharmacology ITMP
    Fraunhofer Cluster of Excellence Immune-mediated Diseases CIMD
    Goethe University)

  • Francesca Capon

    (King’s College London)

  • Raymond Chung

    (Camberwell
    South London and Maudsley Hospital)

  • Charles J. Curtis

    (Camberwell
    South London and Maudsley Hospital)

  • Michael Duckworth

    (King’s College London)

  • Eva Ellinghaus

    (Christian-Albrechts-University of Kiel)

  • Oliver FitzGerald

    (University College Dublin)

  • Sascha Gerdes

    (Campus Kiel)

  • Christopher E. M. Griffiths

    (King’s College London
    NIHR Manchester Biomedical Research Centre
    King’s College Hospital NHS Foundation Trust)

  • Susanne Gulliver

    (Newlab Clinical Research Inc)

  • Philip S. Helliwell

    (University of Leeds)

  • Pauline Ho

    (The University of Manchester
    The University of Manchester
    Manchester University NHS Foundation Trust)

  • Per Hoffmann

    (School of Medicine & University Hospital Bonn)

  • Oddgeir L. Holmen

    (NTNU - Norwegian University of Science and Technology
    Nord-Trøndelag Hospital Trust)

  • Zhi-ming Huang

    (University of California San Francisco)

  • Kristian Hveem

    (NTNU - Norwegian University of Science and Technology
    NTNU - Norwegian University of Science and Technology
    Nord-Trøndelag Hospital Trust)

  • Deepak Jadon

    (University of Cambridge)

  • Michaela Köhm

    (Goethe University
    Fraunhofer Institute for Translational Medicine and Pharmacology ITMP
    Fraunhofer Cluster of Excellence Immune-mediated Diseases CIMD
    Goethe University)

  • Cornelia Kraus

    (FAU Erlangen-Nürnberg)

  • Céline Lamacchia

    (Geneva University Hospital)

  • Sang Hyuck Lee

    (Camberwell
    South London and Maudsley Hospital)

  • Feiyang Ma

    (University of Michigan Medical School
    University of Michigan)

  • Satveer K. Mahil

    (King’s College London
    Guy’s and St Thomas’ National Health Service (NHS) Foundation Trust)

  • Neil McHugh

    (University of Bath)

  • Ross McManus

    (Trinity College Dublin)

  • Ellen H. Modalsli

    (NTNU - Norwegian University of Science and Technology
    Trondheim University Hospital)

  • Michael J. Nissen

    (Geneva University Hospital)

  • Markus Nöthen

    (School of Medicine & University Hospital Bonn)

  • Vinzenz Oji

    (University of Münster)

  • Jorge R. Oksenberg

    (University of California)

  • Matthew T. Patrick

    (University of Michigan Medical School)

  • Bethany E. Perez White

    (Northwestern University)

  • Andreas Ramming

    (Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen
    Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen)

  • Jürgen Rech

    (Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen
    Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen)

  • Cheryl Rosen

    (University of Toronto)

  • Mrinal K. Sarkar

    (University of Michigan Medical School)

  • Georg Schett

    (Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen
    Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen)

  • Börge Schmidt

    (University of Duisburg-Essen)

  • Trilokraj Tejasvi

    (University of Michigan Medical School
    Ann Arbor Veterans Affairs Hospital)

  • Heiko Traupe

    (University of Münster)

  • John J. Voorhees

    (University of Michigan Medical School)

  • Eike Matthias Wacker

    (Christian-Albrechts-University of Kiel)

  • Richard B. Warren

    (The University of Manchester
    Salford Royal Hospital, Northern Care Alliance NHS Foundation Trust, Manchester Academic Health Science Centre)

  • Rachael Wasikowski

    (University of Michigan Medical School)

  • Stephan Weidinger

    (Campus Kiel)

  • Xiaoquan Wen

    (University of Michigan)

  • Zhaolin Zhang

    (University of Michigan Medical School)

  • Anne Barton

    (The University of Manchester
    The University of Manchester
    Manchester University NHS Foundation Trust)

  • Vinod Chandran

    (University Health Network and University of Toronto)

  • Tõnu Esko

    (University of Tartu)

  • John Foerster

    (University of Dundee)

  • Andre Franke

    (Christian-Albrechts-University of Kiel)

  • Dafna D. Gladman

    (University Health Network and University of Toronto)

  • Johann E. Gudjonsson

    (University of Michigan Medical School)

  • Wayne Gulliver

    (Newlab Clinical Research Inc
    Memorial University of Newfoundland)

  • Ulrike Hüffmeier

    (FAU Erlangen-Nürnberg)

  • Külli Kingo

    (University of Tartu
    Tartu University Hospital)

  • Sulev Kõks

    (Perron Institute for Neurological and Translational Science
    Murdoch University)

  • Wilson Liao

    (University of California San Francisco)

  • Mari Løset

    (NTNU - Norwegian University of Science and Technology
    Trondheim University Hospital)

  • Reedik Mägi

    (University of Tartu)

  • Rajan P. Nair

    (University of Michigan Medical School)

  • Proton Rahman

    (Memorial University of Newfoundland)

  • André Reis

    (FAU Erlangen-Nürnberg)

  • Catherine H. Smith

    (King’s College London
    Guy’s and St Thomas’ National Health Service (NHS) Foundation Trust)

  • Paola Di Meglio

    (King’s College London)

  • Jonathan N. Barker

    (King’s College London
    Guy’s and St Thomas’ National Health Service (NHS) Foundation Trust)

  • Lam C. Tsoi

    (University of Michigan Medical School
    University of Michigan
    University of Michigan)

  • Michael A. Simpson

    (King’s College London)

  • James T. Elder

    (University of Michigan Medical School
    Ann Arbor Veterans Affairs Hospital)

Abstract

Psoriasis is a common, debilitating immune-mediated skin disease. Genetic studies have identified biological mechanisms of psoriasis risk, including those targeted by effective therapies. However, the genetic liability to psoriasis is not fully explained by variation at robustly identified risk loci. To refine the genetic map of psoriasis susceptibility we meta-analysed 18 GWAS comprising 36,466 cases and 458,078 controls and identified 109 distinct psoriasis susceptibility loci, including 46 that have not been previously reported. These include susceptibility variants at loci in which the therapeutic targets IL17RA and AHR are encoded, and deleterious coding variants supporting potential new drug targets (including in STAP2, CPVL and POU2F3). We conducted a transcriptome-wide association study to identify regulatory effects of psoriasis susceptibility variants and cross-referenced these against single cell expression profiles in psoriasis-affected skin, highlighting roles for the transcriptional regulation of haematopoietic cell development and epigenetic modulation of interferon signalling in psoriasis pathobiology.

Suggested Citation

  • Nick Dand & Philip E. Stuart & John Bowes & David Ellinghaus & Joanne Nititham & Jake R. Saklatvala & Maris Teder-Laving & Laurent F. Thomas & Tanel Traks & Steffen Uebe & Gunter Assmann & David Baudr, 2025. "GWAS meta-analysis of psoriasis identifies new susceptibility alleles impacting disease mechanisms and therapeutic targets," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56719-8
    DOI: 10.1038/s41467-025-56719-8
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    References listed on IDEAS

    as
    1. Lam C. Tsoi & Philip E. Stuart & Chao Tian & Johann E. Gudjonsson & Sayantan Das & Matthew Zawistowski & Eva Ellinghaus & Jonathan N. Barker & Vinod Chandran & Nick Dand & Kristina Callis Duffin & Cha, 2017. "Large scale meta-analysis characterizes genetic architecture for common psoriasis associated variants," Nature Communications, Nature, vol. 8(1), pages 1-8, August.
    2. Matthew T. Patrick & Philip E. Stuart & Kalpana Raja & Johann E. Gudjonsson & Trilokraj Tejasvi & Jingjing Yang & Vinod Chandran & Sayantan Das & Kristina Callis-Duffin & Eva Ellinghaus & Charlotta En, 2018. "Genetic signature to provide robust risk assessment of psoriatic arthritis development in psoriasis patients," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    3. Cun-Jin Zhang & Chenhui Wang & Meiling Jiang & Chunfang Gu & Jianxin Xiao & Xing Chen & Bradley N. Martin & Fangqiang Tang & Erin Yamamoto & Yibo Xian & Han Wang & Fengling Li & R. Balfour Sartor & Ho, 2018. "Act1 is a negative regulator in T and B cells via direct inhibition of STAT3," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    4. Matthew T. Patrick & Qinmengge Li & Rachael Wasikowski & Nehal Mehta & Johann E. Gudjonsson & James T. Elder & Xiang Zhou & Lam C. Tsoi, 2022. "Shared genetic risk factors and causal association between psoriasis and coronary artery disease," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    5. Ashley Budu-Aggrey & Ben Brumpton & Jess Tyrrell & Sarah Watkins & Ellen H Modalsli & Carlos Celis-Morales & Lyn D Ferguson & Gunnhild Åberge Vie & Tom Palmer & Lars G Fritsche & Mari Løset & Jonas Bi, 2019. "Evidence of a causal relationship between body mass index and psoriasis: A mendelian randomization study," PLOS Medicine, Public Library of Science, vol. 16(1), pages 1-18, January.
    6. Tune H. Pers & Juha M. Karjalainen & Yingleong Chan & Harm-Jan Westra & Andrew R. Wood & Jian Yang & Julian C. Lui & Sailaja Vedantam & Stefan Gustafsson & Tonu Esko & Tim Frayling & Elizabeth K. Spel, 2015. "Biological interpretation of genome-wide association studies using predicted gene functions," Nature Communications, Nature, vol. 6(1), pages 1-9, May.
    7. Lam C. Tsoi & Sarah L. Spain & Eva Ellinghaus & Philip E. Stuart & Francesca Capon & Jo Knight & Trilokraj Tejasvi & Hyun M. Kang & Michael H. Allen & Sylviane Lambert & Stefan W. Stoll & Stephan Weid, 2015. "Enhanced meta-analysis and replication studies identify five new psoriasis susceptibility loci," Nature Communications, Nature, vol. 6(1), pages 1-8, November.
    Full references (including those not matched with items on IDEAS)

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