A catalog of potential putative functional variants in psoriasis genome-wide association regions

Psoriasis is a common inflammatory skin disease, with considerable genetic contribution. Genome-wide association studies have successfully identified a number of genomic regions for the risk of psoriasis. However, it is challenging to pinpoint the functional causal variants and then further decipher the genetic mechanisms underlying each region. In order to prioritize potential functional causal variants within psoriasis susceptibility regions, we integrated the genetic association findings and functional genomic data publicly available, i.e. histone modifications in relevant immune cells. We characterized a pervasive enrichment pattern of psoriasis variants in five core histone marks across immune cells/tissues. We discovered that genetic alleles within psoriasis association regions might influence gene expression levels through significantly affecting the binding affinities of 17 transcription factors. We established a catalog of 654 potential functional causal variants for psoriasis and suggested that they significantly overlapped with causal variants for autoimmune diseases. We identified potential causal variant rs79824801 overlay with the peaks of five histone marks in primary CD4+ T cells. Its alternative allele affected the binding affinity of transcription factor IKZF1. This study highlights the complex genetic architecture and complicated mechanisms for psoriasis. The findings will inform the functional experiment design for psoriasis.银屑病是一种常见的炎症性皮肤病，其发病存在显著的遗传贡献。全基因组关联研究（Genome-wide association studies）已成功鉴定出多个与银屑病风险相关的基因组区域。然而，精准定位功能性致病变异并进一步解析各区域背后的遗传机制，仍是一项颇具挑战的工作。为了优先鉴定银屑病易感区域内的潜在功能性致病变异，我们整合了已公开的遗传关联研究结果与功能基因组学数据（functional genomic data），即相关免疫细胞中的组蛋白修饰（histone modifications）数据。我们系统解析了免疫细胞/组织中五类核心组蛋白修饰标记与银屑病变异的普遍富集模式。研究发现，银屑病关联区域内的遗传等位基因可通过显著改变17种转录因子（transcription factors）的结合亲和力，进而影响基因表达水平。我们构建了包含654个银屑病潜在功能性致病变异的数据集，并发现这些变异与自身免疫性疾病的致病变异存在显著重叠。我们鉴定出潜在致病变异rs79824801可与原代CD4+ T细胞中的五类组蛋白修饰峰区域重叠，该变异的等位基因可影响转录因子IKZF1的结合亲和力。本研究揭示了银屑病复杂的遗传架构与发病机制，其研究结果可为银屑病的功能性实验设计提供参考依据。