慢性缺陷型精神分裂症外周免疫系统分子遗传与表观遗传特征研究

Deficit schizophrenia (DS), characterized by the presence of primary and enduring negative symptoms, has been demonstrated as severe social function decline and poor treatment response, which suggested DS representing a homogeneous disease entity. The research on DS might help to decrease discrepancy in genetic, biology and neuroimage findings of schizophrenia and contribute to the understanding of disease etiology and prediction biomarker for the long-term prognosis. Based on immune hypothesis of schizophrenia, the present study will conduct the genetic and epigenetic research to investigate peripheral immunological feature and its relationship with final functional outcomes in chronic DS patients. The chronic DS, non-deficit schizophrenia (NDS) patients and healthy control subjects will be recruited and matched on age and gender. The psychotic symptom, social function and neurocognition will be evaluated at time of recruitment. Peripheral blood mononuclear cells will be extracted to identify differentially expressed genes across three groups by the whole genomic cDNA microarray and prove by independent sampler. We will further investigate gene polymorphism and DNA methylation of the differentially expressed genes. The influcence of SNP polymorphism and DNA promoter methylation on the expression of candidated genes will analyzed. We will explore the correlation between the SNP and DNA methylation with the negative symptoms, cognitve impairement and social functional outcome of the DS and NDS patients in order to search the predictive biomarkers of the prognosis of schizophrenic patients. We expect that these studies will contribute to our understanding of the etiopathological heterogeneity among schizophrenic patients and improve the future study for clinical medication of schizophrenia.

缺陷型精神分裂症（DS）以原发性、持久性阴性症状为基本临床特征，其药物治疗疗效差且持续衰退，可能是一种独立疾病亚型，对其研究可提高同质性、有助于阐明DS临床不良结局的生物学特征。本课题基于精神分裂症（SCH）免疫异常学说，利用分子遗传和表观遗传策略，募集中国汉族慢性缺陷型和非缺陷型SCH患者，匹配正常对照组，进行多维度神经认知和社会功能评估；通过全基因组表达谱芯片筛查组间外周血单个核细胞差异性表达基因，利用生物信息统计分析选取候选基因后以独立样本验证，对经验证的差异性表达基因进一步检测其分子遗传与DNA甲基化特征，以探讨DS外周免疫特征性生物标志，并分析分子遗传和表观遗传对基因表达的可能影响，及其与患者阴性症状、认知和社会功能的关联性，探讨它们作为精神分裂症临床预后生物学指标的可能性，为阐明SCH不同临床远期结局的生物学异质性机制提供理论依据，期望能最终有利于推进SCH的有效临床治疗。

缺陷型精神分裂症（DS）以原发性、持久性阴性症状为基本临床特征，其药物治疗疗效差且持续衰退，可能是一种独立疾病亚型，对其研究可提高同质性、有助于阐明DS临床不良结局的生物学特征。本课题探讨了DS患者神经认知和社会认知特征，并且基于精神分裂症免疫异常学说，通过DS患者外周血免疫基因差异性表达筛选、分析相关基因启动子区DNA甲基化状态，同时开展了神经影像学拓展研究。本研究国内外首次发现注意功能和认知灵活性分别是DS和非缺陷型（NDS）患者核心认知损害领域，介导临床特征对其他认知领域的影响；DS和NDS患者均存在显著的面部表情认知缺陷和述情障碍，DS患者恐惧认知和情感识别与述情障碍“外向型思维”因子分显著负相关，DS患者具有显著的社会认知缺陷。本研究基于全基因组表达谱芯片研究初步结果进行独立样本验证发现9个免疫系统基因（CXCL1、MMP9、CHI3L1、IL-6、IL-12B、ADM、 RIPK2、ADSS和CDC42）在DS和NDS患者外周单核细胞中存在表达差异，其中ADSS、CXCL1和MMP9基因启动区DNA甲基化特征具有特征性改变；本研究未发现上述基因在两患者间存在DNA多态性差异。本课题组拓展研究发现DS和NDS患者具有不同的皮层厚度和全脑静息态拓扑学网络特征。本项目系列研究阐述了DS患者神经和社会认知、免疫基因表达和表观遗传以及神经影像的特异性改变，提示DS可能为精神分裂症独立疾病亚型，为慢性缺陷型精神分裂症临床不良结局相关的神经认知和生物遗传机制提供了初步研究证据。