精神分裂症工作记忆障碍相关易感基因的功能研究

The impairments of working memory (WM) and other cognitive impairments have been recognized as the core feature in schizophrenia (SCZ). The accumulated evidence has verified that neurodevelopmental abnormalities might be the biological bases of the WM impairments in schizophrenia. Moreover, the genome-wide association study (GWAS) of SCZ we have just published also suggested that several susceptibility genes of SCZ might be correlated with neurodevelopment. In the present program, we intended to implement the stage 3 validation of GWAS in an independent sample (3000 SCZ cases and 3000 healthy controls) from our previous article. Furthermore, 100 pairs of SCZ cases and controls should be enrolled for the MRI scanning, cognitive assessment, and exon-sequencing examination for the susceptibility genes of the stage 3 GWAS. By using the quantitative trait locus (QTL) analyses, we will further explore the correlations among WM impairments, neuroimaging abnormalities, common / rare genetic variations of susceptibility genes correlated with neurodeveloment in SCZ. Based on the above findings, we will then observe the changes of WM in genetic modified animal models. The optogenetic and neuroimaging techniques will be also used to explore the neural circuit or network changes in brain tissues of animal models. The potential functions should be explored by using the in situ hybridization, RNAi, and other methods. The expected findings of this program might be helpful for clarifying the pathogenesis of SCZ.

工作记忆损害是精神分裂症(分裂症)的核心临床特征。研究提示分裂症工作记忆损害与神经发育异常有关且具高度遗传易感性，本项目组前期分裂症全基因组关联研究(GWAS)也发现多个神经发育相关易感基因。本研究拟采用Sequenom方法，在独立大样本(3000对分裂症患者和对照者)中对前期GWAS结果进行验证；进而对另外100对分裂症患者和对照者进行认知功能评估、脑影像检测和易感基因外显子测序，综合分析工作记忆损害、遗传变异和脑影像特征，确定可能与分裂症工作记忆损害关联的神经发育易感基因。在此基础上构建基因修饰动物模型，利用小动物脑成像、光遗传、电生理等技术了解工作记忆损害的脑网络特征及相关神经环路改变与行为异常的关系；继而采用多种基因功能研究方法，探讨易感基因的亚细胞定位、时空表达、基因转录调控、蛋白质相互作用和细胞信号转导通路等。本研究预期结果将有助于阐释分裂症工作记忆损害相关神经环路的分子机制。

本研究针对精神分裂症的工作记忆损害特征开展了一系列影像遗传学及分子机制探索。影像研究发现，精神分裂症患者旁边缘区域灰质体积显著下降，并和认知功能、临床症状相关；患者及其未患病父母背外侧前额叶皮层的激活增加，可能是该脑区功能受损效率下降的表现，可作为精神分裂症工作记忆损害的特征性生物学标记。基于大样本全基因组关联研究发现4个汉族人群精神分裂症新易感基因VRK2、GABBR1、AS3MT和ARL3，并在国际精神疾病遗传研究联盟(PGC)大样本数据中进行验证。发现参与血糖代谢调节的两个易感基因的多态性与抗精神病药所致体重增加在全基因组水平显著关联(PTPRD, GFPT2)，并在独立样本中得以重复验证。发现ALDH2基因Glu504Lys多态性与精神分裂症显著关联，并主要通过影响海马-前额叶这一典型异常功能连接来影响患病风险。发现PREX1基因与神经发育障碍关联，揭示了海马CA1区兴奋性神经元突触后P-Rex1信号通路在调控长时程抑制和神经发育障碍相关社交行为中的作用。并对OPCML、EZH2、STON2等新型易感基因参与精神分裂症工作记忆调节的分子机制进行了深入探索，后续研究将提供更为重要理论依据。