BACKGROUND Psoriasis is a chronic inflammatory skin disease, for which genome-wide association studies (GWAS) have identified many genetic variants as risk markers. However, the details of underlying molecular mechanisms, especially which variants are functional, are poorly understood. METHODS We utilized a computational approach to survey psoriasis-associated functional variants that might affect protein functions or gene expression levels. We developed a pipeline by integrating publicly available datasets provided by GWAS Catalog, FANTOM5, GTEx, SNP2TFBS, and DeepBlue. To identify functional variants on exons or splice sites, we used a web-based annotation tool in the Ensembl database. To search for noncoding functional variants within promoters or enhancers, we used eQTL data calculated by GTEx. The data of variants lying on transcription factor binding sites provided by SNP2TFBS were used to predict detailed functions of the variants. RESULTS We discovered 22 functional variant candidates, of which 8 were in noncoding regions. We focused on the enhancer variant rs72635708 (T > C) in the 1p36.23 region; this variant is within the enhancer region of the ERRFI1 gene, which regulates lipid metabolism in the liver and skin morphogenesis via EGF signaling. Further analysis showed that the ERRFI1 promoter spatially contacts with the enhancer, despite the 170 kb distance between them. We found that this variant lies on the AP-1 complex binding motif and may modulate binding levels. CONCLUSIONS The minor allele rs72635708 (rs72635708-C) might affect the ERRFI1 promoter activity, which results in unstable expression of ERRFI1, enhancing the risk of psoriasis via disruption of lipid metabolism and skin cell proliferation. Our study represents a successful example of predicting molecular pathogenesis by integration and reanalysis of public data.

中文翻译：

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对公共基因组数据的综合分析揭示了通过长程 ERRFI1 增强子导致银屑病风险的可能功能机制。

背景银屑病是一种慢性炎症性皮肤病，全基因组关联研究（GWAS）已确定许多遗传变异作为其风险标记。然而，人们对潜在分子机制的细节，尤其是哪些变体具有功能性，知之甚少。方法我们利用计算方法来调查可能影响蛋白质功能或基因表达水平的银屑病相关功能变异。我们通过集成 GWAS Catalog、FANTOM5、GTEx、SNP2TFBS 和 DeepBlue 提供的公开数据集开发了一个管道。为了识别外显子或剪接位点的功能变异，我们在 Ensembl 数据库中使用了基于网络的注释工具。为了搜索启动子或增强子内的非编码功能变异，我们使用 GTEx 计算的 eQTL 数据。SNP2TFBS 提供的转录因子结合位点上的变体数据用于预测变体的详细功能。结果我们发现了 22 个候选功能变异，其中 8 个位于非编码区域。我们重点关注 1p36.23 区域的增强子变体 rs72635708 (T > C)；该变体位于 ERRFI1 基因的增强子区域内，该区域通过 EGF 信号传导调节肝脏中的脂质代谢和皮肤形态发生。进一步分析表明，ERRFI1 启动子与增强子在空间上接触，尽管它们之间的距离为 170 kb。我们发现该变体位于 AP-1 复合体结合基序上，可能调节结合水平。结论 次要等位基因 rs72635708 (rs72635708-C) 可能影响 ERRFI1 启动子活性，导致 ERRFI1 表达不稳定，通过破坏脂质代谢和皮肤细胞增殖来增加患银屑病的风险。我们的研究代表了通过整合和重新分析公共数据来预测分子发病机制的成功范例。