复杂疾病易感基因区段的表观遗传调控及生物学功能研究

Schizophrenia is a common mental disorder and genetic factor play a major role in the development of schizophrenia. In recent years, genome-wide association analysis has identified a number of susceptible genetic loci for schizophrenia. Many of these associated loci are located in non-coding regions including introns and intergenic regions, which is hard to interpret the underlying biological functions and pathogenic mechanisms. Previous studies suggested that the genetic loci located within the linkage disequilibrium region of positive SNPs were involved into the development of schizophrenia. Based on the chromatin conformation capture technology, the susceptibility loci can regulate downstream genes through long-range chromatin interaction. Recently, we conducted the GWAS study of schizophrenia and transancestry meta-analyses with the GWAS data from Psychiatry Genomics Consortium. In the transancestry analysis, a total of 113 genetic loci reached genome-wide significance,30 loci of which were novel. Using the recent technologies including ChIP-seq, chromosome conformation capture and CRISPR/cas9, etc., we will examine the gene expression regulatory mechanisms within the susceptible gene regions identified from the above mentioned GWAS study, detect the unknown chromosomal regions interacting with the susceptible gene regions and also explore the impact of the deletion of susceptible gene fragment on the target genes and related signaling pathways. The study will provide important clues for follow-up GWAS study of complex diseases.

精神分裂症是一种常见的精神障碍疾病，遗传是其重要的发病因素。近年来全基因组关联分析研究鉴定出多个精神分裂症的易感基因位点，这些位点大多位于内含子、基因间隔区等非编码区域内，难以解释潜在的生物学功能和致病机制。研究发现，与阳性标签SNP连锁不平衡区段的基因均有可能介导疾病的发生，且基于染色质构象捕获技术发现易感基因位点可通过长距离远程调控靶基因实现其基因表达调控的功能。最近，申请人参与的一项精神分裂症多种族样本的GWAS研究，发现了113个全基因组阳性关联位点，其中30个是新发现的基因位点。本项目将基于这些前期的GWAS研究结果，结合最近的ChIP-seq、染色质构象捕获技术及CRISPR/cas9 技术等研究易感基因区段内的基因调控机制，明确与易感基因区段相互作用的染色体区域，探讨易感基因区段的缺失表达对相互作用的靶基因及相关信号通路的影响，从而为复杂疾病的GWAS后续研究提供重要线索。

本课题主要围绕着神经元干细胞的诱导分化过程中的组蛋白修饰和染色质高级结构的表观遗传修饰的变化而展开，同时我们也关注精神分裂症易感基因区段及相关的表观遗传调控，我们完成了预定的年度计划，其主要的发现有：以锌指蛋白家族的转录因子以及ribsomal protein家族基因在神经元的诱导过程中发挥着重要的作用，诱导分化过程中受多种组蛋白修饰及染色质高级结构等复杂的表观遗传调控机制。同时，围绕着复杂疾病的转录组和表观组学等科学问题，在精神分裂症、抑郁症、以及新型冠状病毒等疾病的候选易感基因和药物靶点鉴定方面开展了相关的研究，取得了一系列的研究成果。在本课题的资助下共在线发表12篇SCI论文， 培养了5名硕士研究生（1名研究生获得国家奖学金），上述研究成果为复杂疾病的临床转化医学提供了重要的理论依据。