BACKGROUND Genome-wide association studies (GWAS) have uncovered many genetic risk loci for psoriasis, yet many remain uncharacterised in terms of the causal gene and their biological mechanism in disease. This is largely a result of the findings that over 90% of GWAS variants map outside of protein-coding DNA and instead are enriched in cell type- and stimulation-specific gene regulatory regions. RESULTS Here, we use a disease-focused Capture Hi-C (CHi-C) experiment to link psoriasis-associated variants with their target genes in psoriasis-relevant cell lines (HaCaT keratinocytes and My-La CD8+ T cells). We confirm previously assigned genes, suggest novel candidates and provide evidence for complexity at psoriasis GWAS loci. For one locus, uniquely, we combine further epigenomic evidence to demonstrate how a psoriasis-associated region forms a functional interaction with the distant (> 500 kb) KLF4 gene. This interaction occurs between the gene and active enhancers in HaCaT cells, but not in My-La cells. We go on to investigate this long-distance interaction further with Cas9 fusion protein-mediated chromatin modification (CRISPR activation) coupled with RNA-seq, demonstrating how activation of the psoriasis-associated enhancer upregulates KLF4 and its downstream targets, relevant to skin cells and apoptosis. CONCLUSIONS This approach utilises multiple functional genomic techniques to follow up GWAS-associated variants implicating relevant cell types and causal genes in each locus; these are vital next steps for the translation of genetic findings into clinical benefit.

中文翻译：

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绘制银屑病易感位点 DNA 相互作用图谱突出显示 KLF4 作为 9q31 中的靶基因。


背景全基因组关联研究（GWAS）已经发现了银屑病的许多遗传风险位点，但许多位点在致病基因及其疾病生物学机制方面仍未得到表征。这主要是因为超过 90% 的 GWAS 变异定位在蛋白质编码 DNA 之外，而是富集于细胞类型和刺激特异性基因调控区域。结果在这里，我们使用以疾病为中心的捕获 Hi-C (CHi-C) 实验，将银屑病相关变异与其在银屑病相关细胞系（HaCaT 角质形成细胞和 My-La CD8+ T 细胞）中的靶基因联系起来。我们确认了先前分配的基因，提出了新的候选基因，并为银屑病 GWAS 位点的复杂性提供了证据。对于一个基因座，我们结合了进一步的表观基因组证据来证明银屑病相关区域如何与远处（> 500 kb）KLF4 基因形成功能性相互作用。这种相互作用发生在 HaCaT 细胞中的基因和活性增强子之间，但在 My-La 细胞中则不然。我们继续通过 Cas9 融合蛋白介导的染色质修饰（CRISPR 激活）与 RNA-seq 相结合进一步研究这种长距离相互作用，证明银屑病相关增强子的激活如何上调 KLF4 及其下游靶点，这些靶点与皮肤细胞和皮肤细胞相关。细胞凋亡。结论 该方法利用多种功能基因组技术来追踪 GWAS 相关变异，这些变异涉及每个基因座的相关细胞类型和因果基因；这些是将遗传发现转化为临床效益的重要后续步骤。