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 Saklatvala, Maris Teder‐Laving, Laurent F. Thomas, Tanel Traks, Steffen Uebe, G. Aßmann, David Baudry, Frank Behrens, Allison C. Billi, Matthew A. Brown, Harald Burkhardt, Francesca Capon, Raymond T. Chung, Charles Curtis, Michael Duckworth, Eva Ellinghaus, Oliver FitzGerald, Sascha Gerdes, C.E.M. Griffiths, Susanne Gulliver, Philip Helliwell, Pauline Ho, Per Hoffmann, Oddgeir L. Holmen, Zhiming Huang, Kristian Hveem, Deepak R. Jadon, Michaela Köhm, Cornelia Kraus, Céline Lamacchia, Sang Hyuck Lee, Feiyang Ma, Satveer K. Mahil, Neil McHugh, Ross McManus, Ellen Heilmann Modalsli, Michael J. Nissen, Markus M. Nöthen, Vinzenz Oji, Jorge R. Oksenberg, Matthew T. Patrick, Bethany E. Perez White, Andreas Ramming, Jürgen Rech, Cheryl F. Rosen, Mrinal K. Sarkar, Georg Schett, Börge Schmidt, Trilokraj Tejasvi, Heiko Traupe, John J. Voorhees, Eike Matthias Wacker, Richard B. Warren, Rachael Bogle, Stephan Weidinger, Xiaoquan Wen, Zhaolin Zhang, BSTOP study group, A. David Burden, Catherine Smith, Sara Brown, Nick Dand, Satveer K. Mahil, Helen McAteer, Julia Schofield, Stefan Siebert, Andres Metspalu, Lili Milani, Mari Nelis, Anne Barton, Vinod Chandran, Tõnu Esko, John Foerster, André Franke, Dafna D. Gladman, Jóhann E. Guðjónsson, Wayne Gulliver, Ulrike Hüffmeier, Külli Kingo, Sulev Kõks, Wilson Liao, Mari Løset, Reedik Mägi, Rajan P. Nair, Proton Rahman, André Reis, Catherine Smith, Paola Di Meglio, Jonathan N. Barker, Lam C. Tsoi, Michael A. Simpson, James T. Elder
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.