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

Michael A. Simpson; James T. Elder

doi:10.1038/s41467-025-56719-8

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

, , Michael A. Simpson (Lead / Corresponding author), James T. Elder (Lead / Corresponding author)

Postgraduate Medicine

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7 Citations (Scopus)

11 Downloads (Pure)

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
Article number	2051
Number of pages	14
Journal	Nature Communications
Volume	16
Issue number	1
Early online date	28 Feb 2025
DOIs	https://doi.org/10.1038/s41467-025-56719-8
Publication status	E-pub ahead of print - 28 Feb 2025

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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

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Cite this

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

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.",

author = "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 Huang, \{Zhi Ming\} 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 Brown, \{Sara J.\} and Smith, \{Catherine H.\} and John Foerster and Simpson, \{Michael A.\} and Elder, \{James T.\}",

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doi = "10.1038/s41467-025-56719-8",

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AU - Stuart, Philip E.

AU - Bowes, John

AU - Ellinghaus, David

AU - Nititham, Joanne

AU - Saklatvala, Jake R.

AU - Teder-Laving, Maris

AU - Thomas, Laurent F.

AU - Traks, Tanel

AU - Uebe, Steffen

AU - Assmann, Gunter

AU - Baudry, David

AU - Behrens, Frank

AU - Billi, Allison C.

AU - Brown, Matthew A.

AU - Burkhardt, Harald

AU - Capon, Francesca

AU - Chung, Raymond

AU - Curtis, Charles J.

AU - Duckworth, Michael

AU - Ellinghaus, Eva

AU - FitzGerald, Oliver

AU - Gerdes, Sascha

AU - Griffiths, Christopher E.M.

AU - Gulliver, Susanne

AU - Helliwell, Philip S.

AU - Ho, Pauline

AU - Hoffmann, Per

AU - Holmen, Oddgeir L.

AU - Huang, Zhi Ming

AU - Hveem, Kristian

AU - Jadon, Deepak

AU - Köhm, Michaela

AU - Kraus, Cornelia

AU - Lamacchia, Céline

AU - Lee, Sang Hyuck

AU - Ma, Feiyang

AU - Mahil, Satveer K.

AU - McHugh, Neil

AU - McManus, Ross

AU - Modalsli, Ellen H.

AU - Nissen, Michael J.

AU - Nöthen, Markus

AU - Oji, Vinzenz

AU - Oksenberg, Jorge R.

AU - Patrick, Matthew T.

AU - Perez White, Bethany E.

AU - Brown, Sara J.

AU - Smith, Catherine H.

AU - Foerster, John

AU - Simpson, Michael A.

AU - Elder, James T.

PY - 2025/2/28

Y1 - 2025/2/28

N2 - 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.

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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DO - 10.1038/s41467-025-56719-8

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VL - 16

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2051

ER -

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

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