银屑病的全基因组关联研究荟萃分析确定了影响疾病机制和治疗靶点的新易感等位基因。
GWAS meta-analysis of psoriasis identifies new susceptibility alleles impacting disease mechanisms and therapeutic targets.
作者信息
Dand Nick, Stuart Philip E, Bowes John, Ellinghaus David, Nititham Joanne, Saklatvala Jake R, Teder-Laving Maris, Thomas Laurent F, Traks Tanel, Uebe Steffen, Assmann Gunter, Baudry David, Behrens Frank, Billi Allison C, Brown Matthew A, Burkhardt Harald, Capon Francesca, Chung Raymond, Curtis Charles J, Duckworth Michael, Ellinghaus Eva, FitzGerald Oliver, Gerdes Sascha, Griffiths Christopher E M, Gulliver Susanne, Helliwell Philip, Ho Pauline, Hoffmann Per, Holmen Oddgeir L, Huang Zhi-Ming, Hveem Kristian, Jadon Deepak, Köhm Michaela, Kraus Cornelia, Lamacchia Céline, Lee Sang Hyuck, Ma Feiyang, Mahil Satveer K, McHugh Neil, McManus Ross, Modalsli Ellen H, Nissen Michael J, Nöthen Markus, Oji Vinzenz, Oksenberg Jorge R, Patrick Matthew T, Perez-White Bethany E, Ramming Andreas, Rech Jürgen, Rosen Cheryl, Sarkar Mrinal K, Schett Georg, Schmidt Börge, Tejasvi Trilokraj, Traupe Heiko, Voorhees John J, Wacker Eike Matthias, Warren Richard B, Wasikowski Rachael, Weidinger Stephan, Wen Xiaoquan, Zhang Zhaolin, Barton Anne, Chandran Vinod, Esko Tõnu, Foerster John, Franke Andre, Gladman Dafna D, Gudjonsson Johann E, Gulliver Wayne, Hüffmeier Ulrike, Kingo Külli, Kõks Sulev, Liao Wilson, Løset Mari, Mägi Reedik, Nair Rajan P, Rahman Proton, Reis André, Smith Catherine H, Di Meglio Paola, Barker Jonathan N, Tsoi Lam C, Simpson Michael A, Elder James T
机构信息
Department of Medical & Molecular Genetics, School of Basic & Medical Biosciences, Faculty of Life Sciences & Medicine, King's College London, London, UK.
Health Data Research UK, London, UK.
出版信息
medRxiv. 2023 Oct 5:2023.10.04.23296543. doi: 10.1101/2023.10.04.23296543.
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 , and ). 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.
银屑病是一种常见的、使人衰弱的免疫介导性皮肤病。基因研究已经确定了银屑病风险的生物学机制，包括那些有效疗法所针对的机制。然而，已明确的风险基因座处的变异并不能完全解释银屑病的遗传易感性。为了绘制出银屑病易感性的饱和图谱，我们对18项全基因组关联研究（GWAS）进行了荟萃分析，这些研究包括36466例病例和458078例对照，并确定了109个不同的银屑病易感基因座，其中45个是此前未报道过的。这些基因座包括编码治疗靶点IL17RA和AHR的基因座处的易感变异，以及支持潜在新药物靶点的有害编码变异（包括在 、 和 中的变异）。我们进行了一项全转录组关联研究，以确定银屑病易感变异的调控作用，并将这些作用与银屑病受累皮肤中的单细胞表达谱进行交叉参考，突出了造血细胞发育的转录调控和干扰素信号传导的表观遗传调控在银屑病病理生物学中的作用。
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