Dand Nick, Mucha Sören, Tsoi Lam C, Mahil Satveer K, Stuart Philip E, Arnold Andreas, Baurecht Hansjörg, Burden A David, Callis Duffin Kristina, Chandran Vinod, Curtis Charles J, Das Sayantan, Ellinghaus David, Ellinghaus Eva, Enerback Charlotta, Esko Tõnu, Gladman Dafna D, Griffiths Christopher E M, Gudjonsson Johann E, Hoffman Per, Homuth Georg, Hüffmeier Ulrike, Krueger Gerald G, Laudes Matthias, Lee Sang Hyuck, Lieb Wolfgang, Lim Henry W, Löhr Sabine, Mrowietz Ulrich, Müller-Nurayid Martina, Nöthen Markus, Peters Annette, Rahman Proton, Reis André, Reynolds Nick J, Rodriguez Elke, Schmidt Carsten O, Spain Sarah L, Strauch Konstantin, Tejasvi Trilokraj, Voorhees John J, Warren Richard B, Weichenthal Michael, Weidinger Stephan, Zawistowski Matthew, Nair Rajan P, Capon Francesca, Smith Catherine H, Trembath Richard C, Abecasis Goncalo R, Elder James T, Franke Andre, Simpson Michael A, Barker Jonathan N
Division of Genetics and Molecular Medicine, Faculty of Life Sciences & Medicine, King's College London, London, UK.
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
Hum Mol Genet. 2017 Nov 1;26(21):4301-4313. doi: 10.1093/hmg/ddx328.
Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study, we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11 861 psoriasis cases and 28 610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; P = 1.50 × 10-8, OR = 1.10), and association of common protein-altering variants at 11 loci previously implicated in psoriasis susceptibility. We validate previous reports of protective low-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (encoding a Janus kinase), in each case establishing a further series of protective rare variants (minor allele frequency < 0.01) via gene-wide aggregation testing (IFIH1: pburden = 2.53 × 10-7, OR = 0.707; TYK2: pburden = 6.17 × 10-4, OR = 0.744). Both genes play significant roles in type I interferon (IFN) production and signalling. Several of the protective rare and low-frequency variants in IFIH1 and TYK2 disrupt conserved protein domains, highlighting potential mechanisms through which their effect may be exerted.
银屑病是一种常见的炎症性皮肤病，已确定多个遗传易感性位点，但很少能解析为特定的功能变异。在本研究中，我们试图识别常见和罕见的与银屑病相关的以基因为中心的变异。我们使用外显子阵列对四个独立队列进行基因分型，共有11861例银屑病病例和28610例对照，通过统计荟萃分析汇总数据集。单变异分析在TNFSF15基因座发现了一个先前未报道的风险位点（rs6478108；P = 1.50×10-8，OR = 1.10），以及先前与银屑病易感性相关的11个基因座上常见的蛋白质改变变异的关联。我们验证了先前关于IFIH1（编码一种先天性抗病毒受体）和TYK2（编码一种Janus激酶）内保护性低频蛋白质改变变异的报道，在每种情况下，通过全基因聚集测试确定了一系列进一步的保护性罕见变异（次要等位基因频率<0.01）（IFIH1：p负担 = 2.53×10-7，OR = 0.707；TYK2：p负担 = 6.17×10-4，OR = 0.744）。这两个基因在I型干扰素（IFN）的产生和信号传导中都起着重要作用。IFIH1和TYK2中的几个保护性罕见和低频变异破坏了保守的蛋白质结构域，突出了它们发挥作用的潜在机制。
