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

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 Baudry; Frank Behrens; Allison C. Billi; Matthew A. Brown; Harald Burkhardt; Francesca Capon; Raymond Chung; Charles J. Curtis; Michael Duckworth; Eva Ellinghaus; Oliver FitzGerald; Sascha Gerdes; Christopher E. M. Griffiths; Susanne Gulliver; Philip S. Helliwell; Pauline Ho; Per Hoffmann; Oddgeir L. Holmen; Zhi-ming Huang; Kristian Hveem; Deepak Jadon; Michaela Köhm; Cornelia Kraus; Céline Lamacchia; Sang Hyuck Lee; Feiyang Ma; Satveer K. Mahil; Neil McHugh; Ross McManus; Ellen H. Modalsli; Michael J. Nissen; Markus Nöthen; Vinzenz Oji; Jorge R. Oksenberg; Matthew T. Patrick; Bethany E. Perez White; Andreas Ramming; Jürgen Rech; Cheryl Rosen; Mrinal K. Sarkar; Georg Schett; Börge Schmidt; Trilokraj Tejasvi; Heiko Traupe; John J. Voorhees; Eike Matthias Wacker; Richard B. Warren; Rachael Wasikowski; Stephan Weidinger; Xiaoquan Wen; Zhaolin Zhang; Anne Barton; Vinod Chandran; Tõnu Esko; John Foerster; Andre Franke; Dafna D. Gladman; Johann E. Gudjonsson; Wayne Gulliver; Ulrike Hüffmeier; Külli Kingo; Sulev Kõks; Wilson Liao; Mari Løset; Reedik Mägi; Rajan P. Nair; Proton Rahman; André Reis; Catherine H. Smith; Paola Di Meglio; Jonathan N. Barker; Lam C. Tsoi; Michael A. Simpson; James T. Elder

doi:10.1038/s41467-025-56719-8

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

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

Nick Dand, Philip E. Stuart, John Bowes, David Ellinghaus, Joanne Nititham, Jake R. Saklatvala, Maris Teder-Laving, Laurent F. Thomas, Tanel Traks, Steffen Uebe, …

Nature communications, Vol.16(1), 2051

2025

DOI: https://doi.org/10.1038/s41467-025-56719-8

PMCID: PMC11871359

PMID: 40021644

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Abstract

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Article

Humanities and Social Sciences

multidisciplinary

Science

Science (multidisciplinary)

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.

Details

Title: GWAS meta-analysis of psoriasis identifies new susceptibility alleles impacting disease mechanisms and therapeutic targets
Authors/Creators: Nick Dand - King's College London
Philip E. Stuart - University of Michigan
John Bowes - Arthritis UK
David Ellinghaus - Christian-Albrechts-Universität zu Kiel
Joanne Nititham - University of California, San Francisco
Jake R. Saklatvala - King's College London
Maris Teder-Laving - University of Tartu
Laurent F. Thomas - Norwegian University of Science and Technology
Tanel Traks - University of Tartu
Steffen Uebe - Universitätsklinikum Erlangen
Gunter Assmann - RUB University Hospital JWK Minden, Department of Rheumatology, Jose-Carreras Centrum for Immuno- and Gene Therapy, University of Saarland Medical School
David Baudry - King's College London
Frank Behrens - Goethe University Frankfurt
Allison C. Billi - University of Michigan
Matthew A. Brown - King's College London
Harald Burkhardt - Fraunhofer Institute for Translational Medicine and Pharmacology
Francesca Capon - King's College London
Raymond Chung - National Institute for Health Research
Charles J. Curtis - King's College London
Michael Duckworth - King's College London
Eva Ellinghaus - Christian-Albrechts-Universität zu Kiel
Oliver FitzGerald - University College Dublin
Sascha Gerdes - University of Lübeck
Christopher E. M. Griffiths - King's College London
Susanne Gulliver - Nexus Clinical Research (Canada)
Philip S. Helliwell - University of Leeds
Pauline Ho - University of Manchester
Per Hoffmann - University Hospital Bonn
Oddgeir L. Holmen - Norwegian University of Science and Technology
Zhi-ming Huang - University of California, San Francisco
Kristian Hveem - Norwegian University of Science and Technology
Deepak Jadon - University of Cambridge
Michaela Köhm - Goethe University Frankfurt
Cornelia Kraus - Universitätsklinikum Erlangen
Céline Lamacchia - University Hospital of Geneva
Sang Hyuck Lee - King's College London
Feiyang Ma - University of Michigan
Satveer K. Mahil - National Health Service
Neil McHugh - University of Bath
Ross McManus - Trinity College Dublin
Ellen H. Modalsli - Norwegian University of Science and Technology
Michael J. Nissen - University Hospital of Geneva
Markus Nöthen - University Hospital Bonn
Vinzenz Oji - University of Münster
Jorge R. Oksenberg - University of California, San Francisco
Matthew T. Patrick - University of Michigan
Bethany E. Perez White - Department of Dermatology, Northwestern University
Andreas Ramming - Friedrich-Alexander-Universität Erlangen-Nürnberg
Jürgen Rech - Universitätsklinikum Erlangen
Cheryl Rosen - University of Toronto
Mrinal K. Sarkar - University of Michigan
Georg Schett - Friedrich-Alexander-Universität Erlangen-Nürnberg
Börge Schmidt - University of Duisburg-Essen
Trilokraj Tejasvi - University of Michigan Medical School
Heiko Traupe - University of Münster
John J. Voorhees - University of Michigan
Eike Matthias Wacker - Christian-Albrechts-Universität zu Kiel
Richard B. Warren - Manchester Academic Health Science Centre
Rachael Wasikowski - University of Michigan Medical School
Stephan Weidinger - University of Lübeck
Xiaoquan Wen - University of Michigan
Zhaolin Zhang - University of Michigan
Anne Barton - Arthritis UK
Vinod Chandran - Toronto Western Hospital
Tõnu Esko - University of Tartu
John Foerster - University of Dundee
Andre Franke - Christian-Albrechts-Universität zu Kiel
Dafna D. Gladman - University Health Network
Johann E. Gudjonsson - University of Michigan Medical School
Wayne Gulliver - Memorial University of Newfoundland
Ulrike Hüffmeier - Universitätsklinikum Erlangen
Külli Kingo - Tartu University Hospital
Sulev Kõks - Murdoch University
Wilson Liao - University of California, San Francisco
Mari Løset - St Olav's University Hospital
Reedik Mägi - University of Tartu
Rajan P. Nair - University of Michigan
Proton Rahman - Memorial University of Newfoundland
André Reis - Universitätsklinikum Erlangen
Catherine H. Smith - National Health Service
Paola Di Meglio - King's College London
Jonathan N. Barker - King's College London
Lam C. Tsoi - University of Michigan
Michael A. Simpson - King's College London
James T. Elder - University of Michigan
Publication Details: Nature communications, Vol.16(1), 2051
Publisher: Springer Nature; BERLIN
Number of pages: 14
Grant note: 821511 / Innovative Medicines Initiative (IMI) (https://doi.org/10.13039/501100010767) STR130505 / Guy's and St Thomas' Charity (https://doi.org/10.13039/501100000380) 814364 / National Psoriasis Foundation (NPF) (https://doi.org/10.13039/100003185) SI 236/8-1, SI236/9-1, ER 155/6-1; EXC 2167-390884018, CRC1181-2/project A05 / Deutsche Forschungsgemeinschaft (German Research Foundation) (https://doi.org/10.13039/501100001659) BRC_1215_20006, NIHR302258, NIHR203308, BRC-1215-20014 / DH | National Institute for Health Research (NIHR) (https://doi.org/10.13039/501100000272) RG2/10, ST1/19, ST3/20 / Psoriasis Association (https://doi.org/10.13039/100013126) PUT1465, PRG1189, PRG1911, PRG1291 / Eesti Teadusagentuur (Estonian Research Council) (https://doi.org/10.13039/501100002301) 980 / Maudsley Charity (https://doi.org/10.13039/100012176) Versus Arthritis - grant reference number 21754 Additional funding support from the following bodies are also acknowledged, as detailed in the funding section of the manuscript: Ann Arbor Veterans Hospital; Babcock Memorial Trust; Cambridge Arthritis Research Endeavour (CARE); Dermatology Foundation; Faculty of Medicine and Health Sciences, NTNU; German Centre for Neurodegenerative Disorders (DZNE), Bonn; German Ministry of Education and Science; Heinz Nixdorf Foundation (Germany); Joint Research Committee between St Olav’s Hospital and the Faculty of Medicine and Health Sciences, NTNU; Krembil Foundation; Liaison Committee for Education, Research, and Innovation in Central Norway; The Michael J. Fox Foundation; MSWA; National Institutes of Health; Perron Institute for Neurological and Translational Science; Pfizer Chair Research Award in Rheumatology; Research Council of Norway; Shake It Up Australia; Stiftelsen Kristian Gerhard Jebsen; Taubman Medical Research Institute; University of Michigan 2014-2020.4.01.15-0012 / EC | European Regional Development Fund (Europski Fond za Regionalni Razvoj) (https://doi.org/10.13039/501100008530)
Identifiers: 991005748542707891
Murdoch Affiliation: Centre for Molecular Medicine and Innovative Therapeutics
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.106 Rheumatology; 1.106.737 Psoriasis
Web Of Science research areas: Genetics & Heredity
ESI research areas: Clinical Medicine