联合GWAS、eQTL系统性鉴定调控癫痫风险的SNP变异

癫痫是最常见的神经系统疾病之一，多在儿童期起病，儿童癫痫的患病率约为5-10/1000人，大约70%的癫痫病因与遗传因素有关。单核苷酸多态性（SNP）作为基因组中最广泛存在的遗传标记，已被发现与疾病易感性有关。本课题的前期工作中，我们利用全基因组关联研究（GWAS）筛选的癫痫风险相关的SNP位点中，仅0.2%的位点分布在外显子，其余52.3%分布在基因间区，41.2%分布在内含子，但这些非编码序列的SNP位点如何影响癫痫发病，迄今尚未完全明确。我们通过GWAS进行区域注释，发现有些SNP位于增强子区域，还有些SNP与转录抑制因子有关。本课题拟在前期数据的基础上，通过STARR-seq、双荧光素酶实验鉴定非编码序列中有调控功能的SNP，并通过eQTL分析、CRISPR/Cas9 Knock Out验证调控型SNP对靶基因的调控作用，对探索儿童癫痫的发病机制并指导临床诊疗具有重要意义。

Epilepsy is one of the most common neurological disorders during childhood, the prevalence of which is about 5 to 10 per children. The reason of epilepsy is multiple, about 70% is related with genetic factors. As the most widely existing genetic marker, single nucleotide polymorphism (SNP) has been found to be associated with disease susceptibility. In our previous genome-wide association study (GWAS), we found that only 0.2% SNP associated with epilepsy risk located in exons, 52.3% in intergenic region, and 41.2% in introns. However, the influence of most of the SNPs located in non-coding sequence on the development of epilepsy remains unclear. By region annotation in our GWAS, we found that some of these SNPs located in enhancer regions, while some other SNPs were related with transcription inhibitors. On the basis of our previous GWAS data, we plan to further identify the SNPs with regulatory function by STARR-seq and luciferase reporter assay in non-coding sequence. Then we will further investigate the regulation of SNPs on the expression of target genes by eQTL analysis and CRISPR/Cas9 knock out.