精神分裂症脑结构和功能特征的双生子磁共振成像研究

Schizophrenia has a clear genetic predisposition and complex disease clinical phenotype. It is caused by the interaction between multiple genes of minor pathogenic effect and environmental risk factors. Determining effective endophenotypes of schizophrenia will help to reduce the heterogeneity of disease and to improve the statistical power of genetic studies. Given the neurodevelopmental abnormalities of schizophrenia and its potential relationship with genetic and environmental risk factors, it is important to find the genetic and environmental determinants of the schizophrenia associated brain structural and functional features, and determine some effective brain imaging endophenotypes of schizophrenia. Twins are excellent materials to distinguish the difference effects of genetic and environmental factors on human individual traits. The plan of the current project is to 1) build a schizophrenia twins and relatives magnetic resonance imaging (MRI) database, recruiting concordant/disconcordant schizophrenia twins and its co-twins and controls twins (including monozygotic and dizygotic twins); 2) investigate the schizophrenia associated brain structural and functional abnormalities, by using the multi-model MRI data and the latest analysis tools and methods; explore the genetic and environmental determinants of the association between brain abnormalities and schizophrenia, by using the Mx Statistical Modeling for maximum likelihood genetic model fitting to directly estimate model parameters from the concordant/disconcordant monozygotic and dizygotic twins data; 3) examine the correlation of the genetic polymorphism and promoter methylation of the candidate genes with the schizophrenia associated abnormalities due to the genetic or environmental factors. The expected results of this project will help to understand the relationship between genetic and environmental factors and schizophrenia associated brain features, and facilitates the genetic study of schizophrenia by providing effective endophenotypes. And the findings of the pilot study on molecular mechanism of schizophrenia associated abnormalities due to different genetic or environmental factors will provide new clues to the etiology research of schizophrenia.

精神分裂症(SCH)是一种常见的复杂疾病，由多个微效基因协同并与环境因素共同作用所致。既往研究提示，SCH患者的脑结构和功能特征有较高遗传度，同时也受到环境因素的影响，其发生机制可能分别与遗传多态性和表观遗传修饰有关。本项目计划在扩大现有样本数据的基础上，建立SCH双生子影像资源库，深入分析多模态磁共振成像数据，探索SCH脑结构和功能特征；利用共同患病/单一患病、同卵/异卵双生子数据，建立SCH脑结构和功能特征指标的相关遗传模型和结构方程，量化评估上述影像特征的遗传和环境效应，即加性遗传效应、同胞共享环境效应及个体特殊环境效应；继而通过候选基因多态性和DNA甲基化检测，在分子水平上分别验证SCH脑影像特征的遗传和环境效应。项目预期结果有助于了解遗传和环境效应与SCH脑影像特征之间的关系，为确定SCH内表型、减少疾病异质性，以及SCH从表型到分子机制的研究提供线索依据。

本研究在既往研究基础上，完成了14个精神分裂症(SCH)双生子家家系、14对健康同卵双生子对的临床、神经心理、脑影像、遗传及表观遗传数据采集和分析工作；同时，在课题组其他项目的共同努力下建立了含SCH、一级亲属和健康对照(含完备的环境因素评估)的近千人次的SCH多模态影像、遗传和表观遗传数据库。. 基于上述数据库，深入分析SCH临床、认知和MRI数据，发现SCH患者旁边缘系统的脑区灰质体积显著降低，上述灰质体积缺陷与患者的信息处理速度和记忆功能缺陷、较早的发病年龄、更长的病程、更多的住院次数以及更严重的阳性症状关联。双生子影像数据分析，发现SCH遗传风险可能只与工作记忆计算过程中背外侧前额叶(DLPFC)功能缺陷关联。此外，基于SCH核心家系数据，从其最为核心的认知损害(工作记忆)入手探讨相关脑功能异常的遗传效应，发现背外侧前额叶的效率下降和腹外侧前额叶的弥补机制可能是SCH工作记忆损害的特征性脑功能异常模式；从白质结构网络的效率和组织结构入手探讨了脑结构异常的遗传效应，发现SCH患者及其未患病父母全脑白质网络的局部效率下降和rich-club结构的feeder连边强度下降与SCH的家族聚集性有关。此外，基于不同环境风险因素暴露的健康志愿者数据，我们发现儿童期城乡成长经历显著影响内侧前额叶的结构和功能，并影响人际应激的神经处理过程。. 基于全基因组基因分型和甲基化数据，从遗传和表观遗传角度，对SCH遗传和环境风险的脑结构和功能效应的分子遗传学机制进行了一系列研究。发现乙醛脱氢酶2(ALDH2)基因Glu504Lys多态性可能通过破坏患者大脑海马-前额叶的功能连接，参与调节SCH发病机制；采用三因素平行独立成分分析(p-ICA)综合分析脑结构和功能MRI数据和全基因组甲基化表观遗传数据，发现一个功能-结构-甲基化联合共变成份与信息处理速度、推理和问题解决能力以及言语学习表现相关，结果表明城市化相关的环境风险因素可能通过对基因的表观修饰，影响脑结构和功能特征，最终导致行为表型的改变。