精神分裂症易感基因的脑机制研究

Schizophrenia is a kind of complex genetic disease. Previous candidate gene studies and recent whole-genome wide association studies have suggested many risk genes for schizophrenia, however the brain mechanism of most of these risk genes was still unknown. The current project started from the working memory and executive function, using combined data at both behavioral level and brain MRI level, to test the brain mechanism of these risk gene polymorphisms. The project included two stages. The first stage, we used our collected behavioral data (1000 patients and 1000 controls) to test the association between schizophrenia related gene polymorphisms and working memory and executive functions. The second stage, we will collect MRI data (N-BACK fMRI, Stroop fMRI, resting state fMRI, DTI and so on) of 100 patients and 100 controls. MRI data analysis will include three aspects, that is the brain acivation analysis, the brain structural and functional connectivity analysis and brain network (for both structural and fucntional) analysis. By this way, we hope to establish the link of schizophrenia risk gene polymorphism →brain（key region, connectivity and network）→behavior（working memory and executive function）→disease.

精神分裂症是一种复杂的多基因遗传病，过去的候选基因研究和最近的全基因组关联研究已发现若干与精神分裂症相关的基因多态性，但这些基因多态性与精神分裂症相关的机制不清。本项目从精神分裂症核心认知缺陷，即工作记忆和执行功能出发，联合使用行为和磁共振研究手段，研究精神分裂症易感基因的脑机制。研究分两个阶段，第一阶段采集精神分裂症和正常对照研究样本各1000例，探索已知精神分裂症风险基因多态性与工作记忆和执行功能的相关性，第二阶段采集精神分裂症患者和正常对照的核磁共振数据各100例，包括任务状态（工作记忆任务和执行控制任务）下和静息态下的fMRI、弥散张量成像等，进行脑激活区检测（寻找基因多态性作用的关键脑区）、脑功能和结构连接分析及脑网络分析三个水平的细致分析。如此建立从易感基因多态性→脑（关键脑区、连接和网络）→行为（工作记忆和执行功能）→疾病（精神分裂症）的联系的联系通路.

阴性症状、阳性症状和认知缺陷是精神分裂症的三大核心症状。广泛使用的各种抗精神病药物可以有效地改善阴性和阳性症状，但却无法改善认知缺陷。因此，筛选精神分裂症认知缺陷的靶基因并在此基础上研发可有效改善精神分裂症认知缺陷的药物非常重要。既往国内外大样本GWAS，尤其是PGC2已经提示了108个精神分裂症风险基因。本项目从PGC2提示的108个基因出发，联合使用行为和磁共振研究手段评估精神分裂症的工作记忆缺陷，较为系统地探讨了这108个基因与工作记忆缺陷的相关性。通过本项目的实施，我们进一步筛选出ZNF804A、MIR137、CACNA1C、CAMKK2和ANK3等与认知障碍相关的基因，这些都有可能成为未来精神分裂症认知缺陷新药研发的候选靶基因。