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 Arthur Brown; Harald Burkhardt; Francesca Capon; Raymond T. Chung; Charles J. C. Curtis; Michael Duckworth; Eva Ellinghaus; Oliver FitzGerald; Sascha Gerdes; Christopher E.M. Griffiths; Susanne R. Gulliver; Philip Helliwell; Pauline Ho; Per Hoffmann; Oddgeir L. Holmen; Zhiming Huang

doi:10.1038/s41467-025-56719-8

Genetic & Genomic MedicineNature CommunicationsFeb 28, 2025

Peer-reviewed journal article

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

Nick Dand iD, Philip E. Stuart iD, John Bowes iD, David Ellinghaus iD, Joanne Nititham iD, Jake R. Saklatvala iD, Maris Teder‐Laving iD, Laurent F. Thomas iD, Tanel Traks iD, Steffen Uebe iD, Gunter Assmann iD, David Baudry iD, Frank Behrens iD, Allison C. Billi iD, Matthew Arthur Brown iD, Harald Burkhardt iD, Francesca Capon iD, Raymond T. Chung iD, Charles J. C. Curtis iD, Michael Duckworth iD, Eva Ellinghaus iD, Oliver FitzGerald iD, Sascha Gerdes iD, Christopher E.M. Griffiths iD, Susanne R. Gulliver iD, , James T. Elder iD

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 move towards a saturation 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 45 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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