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

BSTOP study group

doi:10.1038/s41467-025-56719-8

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

BSTOP study group

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	2051
Journal	Nature Communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-56719-8
Publication status	Published - 28 Feb 2025

Data Availability Statement

This research has been conducted using the UK Biobank Resource (approved project 15147). It uses data provided by patients and collected by the NHS as part of their care and support. Copyright © 2023, NHS England. Re-used with the permission of NHS England and UK Biobank. All rights reserved.

Acknowledgements

We gratefully acknowledge the contributions of patients and family members, other research participants and clinical staff involved in recruitment.

Funding

N.D. is funded by Health Data Research UK (MR/S003126/1). Support for the study was received from the Department of Health through the National Institute for Health and Care Research (NIHR) Bio-Resource Clinical Research Facility and comprehensive Biomedical Research Centre awards to Guy’s and St Thomas’ National Health Service Foundation Trust in partnership with King’s College London and King’s College Hospital National Health Service Foundation Trust (BRC_1215_20006). We acknowledge support from the Psoriasis Association in relation to Biomarkers of Systemic Treatment Outcomes in Psoriasis (RG2/10, RG2/10) and an award to P.D.M. (ST1/19) and FC (ST3/20). This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement number 821511 (Biomarkers in Atopic Dermatitis and Psoriasis). The JU receives support from the European Union’s Horizon 2020 research and innovation programme and the European Federation of Pharmaceutical Industries and Associations (EFPIA). This publication reflects only the authors’ views and the JU is not responsible for any use that may be made of the information it contains. S.K.M. is funded by a NIHR Advanced Fellowship (NIHR302258). This study presents independent research supported by NIHR BioResource Centre Maudsley, NIHR Maudsley Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King’s College London. The BioResource gratefully acknowledge capital equipment funding from the Maudsley Charity (Grant Ref. 980) and Guy’s and St Thomas’s Charity (STR130505). P.D.M. reports a Translational Research Grant (814364) from the National Psoriasis Foundation. L.C.T. received funding from the National Institutes of Health (NIH) (K01 AR072129, P30 AR075043, UC2 AR081033). J.T.E. was supported by awards from NIH (R01AR042742, R01AR050511, R01AR054966, R01AR063611, R01AR065183), the National Psoriasis Foundation (NPF) including an NPF Bridge Grant, the Babcock Memorial Trust, and the Ann Arbor Veterans Affairs Hospital. M.T.P. is supported by a Research Career Development Award from the Dermatology Foundation. X.W. is supported by NIH (R01ES033634, R35GM138121). M.K.S. reports a Translational Research Grant from the NPF. A.C.B. was supported by the University of Michigan A. Alfred Taubman Medical Research Institute via Taubman Emerging Scholar funds and the NIH (K08 AR078251, P30 AR075043). J.E.G. is supported by NIH (P30AR075043) and the Taubman Medical Research Institute. Part of this study was funded by a grant to A.R. and U.H. from the Bundesministerium für Bildung und Forschung (BMBF Metarthros 01EC1407A), by a grant to U.H. from the German Research Foundation (CRC1181-2, project A05) and by a grant to H.B. and F.B. from the Bundesministerium für Bildung und Forschung (BMBF ArthroMark 01EC1401C). The HNR study (Erlangen cohort) is supported by the Heinz Nixdorf Foundation (Germany). Additionally, the study is funded by the German Ministry of Education and Science and the German Research Council (DFG; Project SI 236/8-1, SI236/9-1, ER 155/6-1). The genotyping of the Illumina HumanOmni-1 Quad BeadChips of the HNR subjects was financed by the German Centre for Neurodegenerative Disorders (DZNE), Bonn. T. Traks and K.K. report support from the Estonian Research Council (PUT1465, PRG1189). S.K. is supported by MSWA, The Michael J. Fox Foundation, Shake It Up Australia, and Perron Institute for Neurological and Translational Science. M.T.-L. was supported by the European Union through the European Regional Development Fund (Project No. 2014-2020.4.01.15-0012). R.M. was supported by Estonian Research Council grant PRG1911. T.E. was supported by Estonian Research Council grant PRG1291. The Trøndelag Health Study (The HUNT Study) is a collaboration between HUNT Research Center (Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology), Trøndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. The genotyping in HUNT was financed by the National Institutes of Health; University of Michigan; the Research Council of Norway; the Liaison Committee for Education, Research, and Innovation in Central Norway; and the Joint Research Committee between St Olavs hospital and the Faculty of Medicine and Health Sciences, NTNU. L.T., K.H. and M.L. work in a research unit funded by Stiftelsen Kristian Gerhard Jebsen; Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology; The Liaison Committee for Education, Research and Innovation in Central Norway; the Joint Research Committee between St. Olavs Hospital (Trondheim, Norway) and the Faculty of Medicine and Health Sciences, NTNU - Norwegian University of Science and Technology. M.L. is supported by grants from the Liaison Committee for Education, Research and Innovation in Central Norway and the Joint Research Committee between St Olav’s hospital and the Faculty of Medicine and Health Sciences, NTNU. The study received support from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) Cluster of Excellence 2167 Precision Medicine in Chronic Inflammation (PMI) (EXC 2167-390884018). This work was supported by a grant from Versus Arthritis (21754). This research was co-funded by the NIHR Manchester Biomedical Research Centre (NIHR203308). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. D.J. acknowledges that his research was supported by Cambridge Arthritis Research Endeavour (CARE) and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). W.L. acknowledges funding from NIH (R01AR065174, U01AI119125). The UCSF-MS DNA biorepository is supported by RG-1611-26299 from the National Multiple Sclerosis Society to J.R.O. V.C. is supported by a Pfizer Chair Research Award, Rheumatology, University of Toronto. The Schroeder Arthritis Institute Psoriatic Disease Program is supported by the Krembil Foundation. M.A.S. acknowledges support from the Leo Foundation (LF-OC-22-001033).

Keywords

Psoriasis/genetics
Humans
Genetic Predisposition to Disease
Genome-Wide Association Study
Alleles
Polymorphism, Single Nucleotide
Receptors, Interleukin-17/genetics
Transcriptome
Skin/metabolism
Receptors, Aryl Hydrocarbon/genetics

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10.1038/s41467-025-56719-8Licence: CC BY

Cite this

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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.",

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author = "{BSTOP study group} and Nick Dand and Stuart, {Philip E} and John Bowes and David Ellinghaus and Joanne Nititham and Saklatvala, {Jake R} and Maris Teder-Laving and Thomas, {Laurent F} and Tanel Traks and Steffen Uebe and Gunter Assmann and David Baudry and Frank Behrens and Billi, {Allison C} and Brown, {Matthew A} and Harald Burkhardt and Francesca Capon and Raymond Chung and Curtis, {Charles J} and Michael Duckworth and Eva Ellinghaus and Oliver FitzGerald and Sascha Gerdes and Griffiths, {Christopher E M} and Susanne Gulliver and Helliwell, {Philip S} and Pauline Ho and Per Hoffmann and Holmen, {Oddgeir L} and Zhi-Ming Huang and Kristian Hveem and Deepak Jadon and Michaela K{\"o}hm and Cornelia Kraus and C{\'e}line Lamacchia and Lee, {Sang Hyuck} and Feiyang Ma and Mahil, {Satveer K} and Neil McHugh and Ross McManus and Modalsli, {Ellen H} and Nissen, {Michael J} and Markus N{\"o}then and Vinzenz Oji and Oksenberg, {Jorge R} and Patrick, {Matthew T} and {Perez White}, {Bethany E} and Andreas Ramming and J{\"u}rgen Rech and Cheryl Rosen",

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AB - 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.

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KW - Receptors, Interleukin-17/genetics

KW - Transcriptome

KW - Skin/metabolism

KW - Receptors, Aryl Hydrocarbon/genetics

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DO - 10.1038/s41467-025-56719-8

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JO - Nature Communications

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

Abstract

Data Availability Statement

Acknowledgements

Funding

Keywords

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