Background

Hundreds of variants associated with atopic dermatitis (AD) and psoriasis, 2 common inflammatory skin disorders, have previously been discovered through genome-wide association studies (GWASs). The majority of these variants are in noncoding regions, and their target genes remain largely unclear.

Objective

We sought to understand the effects of these noncoding variants on the development of AD and psoriasis by linking them to the genes that they regulate.

Methods

We constructed genomic 3-dimensional maps of human keratinocytes during differentiation by using targeted chromosome conformation capture (Capture Hi-C) targeting more than 20,000 promoters and 214 GWAS variants and combined these data with transcriptome and epigenomic data sets. We validated our results with reporter assays, clustered regularly interspaced short palindromic repeats activation, and examination of patient gene expression from previous studies.

Results

We identified 118 target genes of 82 AD and psoriasis GWAS variants. Differential expression of 58 of the 118 target genes (49%) occurred in either AD or psoriatic lesions, many of which were not previously linked to any skin disease. We highlighted the genes AFG1L, CLINT1, ADO, LINC00302, and RP1-140J1.1 and provided further evidence for their potential roles in AD and psoriasis.

Conclusions

Our work focused on skin barrier pathology through investigation of the interaction profile of GWAS variants during keratinocyte differentiation. We have provided a catalogue of candidate genes that could modulate the risk of AD and psoriasis. Given that only 35% of the target genes are the gene nearest to the known GWAS variants, we expect that our work will contribute to the discovery of novel pathways involved in AD and psoriasis.

中文翻译：

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分化角质形成细胞中染色质的相互作用揭示了新的特应性皮炎和牛皮癣相关基因

背景

此前通过全基因组关联研究 (GWAS) 发现了数百种与特应性皮炎 (AD) 和牛皮癣这两种常见炎症性皮肤病相关的变异。这些变异大多数位于非编码区域，其靶基因在很大程度上仍不清楚。

客观的

我们试图通过将这些非编码变异与其调节的基因联系起来，了解它们对 AD 和牛皮癣发展的影响。

方法

我们使用针对超过 20,000 个启动子和 214 个 GWAS 变体的靶向染色体构象捕获 (Capture Hi-C) 构建了分化过程中人类角质形成细胞的基因组 3 维图谱，并将这些数据与转录组和表观基因组数据集相结合。我们通过报告分析、聚集的规则间隔短回文重复序列激活以及对先前研究中患者基因表达的检查来验证我们的结果。

结果

我们鉴定了 82 个 AD 和银屑病 GWAS 变异的 118 个靶基因。118 个靶基因中有 58 个（49%）的差异表达发生在 AD 或银屑病病变中，其中许多以前与任何皮肤病无关。我们重点介绍了AFG1L、CLINT1、ADO、LINC00302和RP1-140J1.1基因，并为它们在 AD 和牛皮癣中的潜在作用提供了进一步的证据。

结论

我们的工作重点是通过研究角质形成细胞分化过程中 GWAS 变异的相互作用谱来研究皮肤屏障病理学。我们提供了一系列可以调节 AD 和牛皮癣风险的候选基因。鉴于只有 35% 的目标基因是最接近已知 GWAS 变异的基因，我们预计我们的工作将有助于发现 AD 和牛皮癣相关的新途径。