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

by Teder-Laving, Maris , Huang, Zhi-ming , Tejasvi, Trilokraj , Tsoi, Lam C. , Baudry, David , Schett, Georg , Schmidt, Börge , Barton, Anne , Di Meglio, Paola , FitzGerald, Oliver , Rosen, Cheryl , Gerdes, Sascha , Ellinghaus, Eva , Ho, Pauline , Brown, Matthew A. , Assmann, Gunter , Lamacchia, Céline , Saklatvala, Jake R. , Chung, Raymond , Griffiths, Christopher E. M. , Gulliver, Susanne , Hveem, Kristian , Chandran, Vinod , Nissen, Michael J. , Patrick, Matthew T. , Gudjonsson, Johann E. , Elder, James T. , Nair, Rajan P. , McManus, Ross , Burkhardt, Harald , Franke, Andre , Gulliver, Wayne , Ellinghaus, David , Bowes, John , Duckworth, Michael , Rahman, Proton , Billi, Allison C. , Lee, Sang Hyuck , Barker, Jonathan N. , Wasikowski, Rachael , Hüffmeier, Ulrike , Esko, Tõnu , Voorhees, John J. , Kõks, Sulev , Reis, André , Hoffmann, Per , Wen, Xiaoquan , Nititham, Joanne , Uebe, Steffen , Jadon, Deepak , Helliwell, Philip S. , Mägi, Reedik , Curtis, Charles J. , Stuart, Philip E. , Kraus, Cornelia , Wacker, Eike Matthias , Modalsli, Ellen H. , Holmen, Oddgeir L. , Mahil, Satveer K. , Dand, Nick , Ma, Feiyang , Rech, Jürgen , Traupe, Heiko , Gladman, Dafna D. , Traks, Tanel

in 45/43 / 45/91 / 631/208/205/2138 / 692/699/4033 / Alleles / Epigenetics / Gene regulation / Genetic Predisposition to Disease - genetics / Genome-Wide Association Study / Genomic analysis / Hematopoietic stem cells / Humanities and Social Sciences / Humans / Meta-analysis / multidisciplinary / Polymorphism, Single Nucleotide / Psoriasis / Psoriasis - drug therapy / Psoriasis - genetics / Science / Science (multidisciplinary) / Skin diseases / Susceptibility / Therapeutic targets / Transcriptome / Transcriptomes

2025

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2025

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2025

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Journal Article

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

Teder-Laving, Maris,

Huang, Zhi-ming,

Tejasvi, Trilokraj,

Tsoi, Lam C.,

Baudry, David,

Schett, Georg,

Schmidt, Börge,

Barton, Anne,

Di Meglio, Paola,

FitzGerald, Oliver,

Rosen, Cheryl,

Gerdes, Sascha,

Ellinghaus, Eva,

Ho, Pauline,

Brown, Matthew A.,

Assmann, Gunter,

Lamacchia, Céline,

Saklatvala, Jake R.,

Chung, Raymond,

Griffiths, Christopher E. M.,

Gulliver, Susanne,

Hveem, Kristian,

Chandran, Vinod,

Nissen, Michael J.,

Patrick, Matthew T.,

Gudjonsson, Johann E.,

Elder, James T.,

Nair, Rajan P.,

McManus, Ross,

Burkhardt, Harald,

Franke, Andre,

Gulliver, Wayne,

Ellinghaus, David,

Bowes, John,

Duckworth, Michael,

Rahman, Proton,

Billi, Allison C.,

Lee, Sang Hyuck,

Barker, Jonathan N.,

Wasikowski, Rachael,

Hüffmeier, Ulrike,

Esko, Tõnu,

Voorhees, John J.,

Kõks, Sulev,

Reis, André,

Hoffmann, Per,

Wen, Xiaoquan,

Nititham, Joanne,

Uebe, Steffen,

Jadon, Deepak,

Helliwell, Philip S.,

Mägi, Reedik,

Curtis, Charles J.,

Stuart, Philip E.,

Kraus, Cornelia,

Wacker, Eike Matthias,

Modalsli, Ellen H.,

Holmen, Oddgeir L.,

Mahil, Satveer K.,

Dand, Nick,

Ma, Feiyang,

Rech, Jürgen,

Traupe, Heiko,

Gladman, Dafna D.,

Traks, Tanel

2025

Overview

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. Psoriasis is a partially heritable skin disorder, the genetic basis of which is not fully understood. Here, the authors use genome-wide association meta-analysis to discover psoriasis susceptibility loci and genes, which encode existing and potential new drug targets.

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Publisher

Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio

Subject

/ 45/91

/ Alleles