基于网络分析的精神分裂症与双相障碍共享基因风险位点及其功能研究

Schizophrenia (SCZ) and bipolar disorder (BD) are both major public health problems. SCZ and BD have genetic overlapping, however, the underlying genetic mechanism shared by SCZ and BD has not been clarified. We constructed a molecular network shared by SCZ and BD and then predicted and optimized thirteen new hub genes by network analysis. Pathway analysis showed that these hub genes were involved in various biological processes which are closely related to the pathological mechanism of SCZ/BD，such as signal transduction, cell communication, the nervous system and the immune system. We assume that hub genes polymorphisms is possibly significantly associated with the risk of both SCZ and BD, and they possibly participate in the shared genetic mechanism of the two diseases through many relevant biological processes. We intend to validate our hypothesis by association studies and cell experiments. Firstly, "cross-disorder study" design will be adopt to find out the risk SNPs which are significantly associated with SCZ and BD. Secondly, combining Dual-Luciferase reporter assay system and real-time PCR, the impact of risk loci on gene expression will be detected that can shed new lights on genetic mechanism shared by SCZ and BD. Our expected research results can provide molecular genetics evidence for establishing the diagnosis and classification system of mental diseases based on biological pathogenesis and exploring molecular therapeutic targets, thus promoting the secondary prevention of major mental diseases.

精神分裂症（SCZ）和双相障碍（BD）都是重大公共卫生问题，两病存在遗传交叠，但二者共享遗传基础尚未阐明。我们前期运用网络分析构建了SCZ与BD共享分子网络，预测和优选出13个新的两病共享核心基因，通路分析显示这些基因参与多种与SCZ和BD发生机制密切相关的信号转导、细胞通讯、神经系统及免疫系统生物过程。据此，我们假设：这些核心基因遗传多态性可能对SCZ和BD的发生风险都有显著影响，它们可能通过多种生物过程参与两病共享遗传基础。拟进行如下研究：在大样本人群中进行"跨疾病"遗传关联研究，从人群水平验证SCZ和BD风险基因位点；然后, 结合双荧光素酶报告基因系统、RT-PCR等技术, 通过细胞实验深入研究风险位点对基因表达的影响，从而对两病共享遗传机制提出新阐释。本研究可望为建立基于生物学病因的精神疾病诊断分类系统、以及探寻精神病药物治疗靶点提供分子遗传学依据，从而促进重性精神疾病二级预防。

精神分裂症和双相障碍都是重大公共问题，两病存在遗传交叠，但两病的共享遗传基础尚未完全阐明。本项目通过大样本人群关联研究鉴别出了精神分裂症和/或双相障碍易感风险遗传变异，并通过细胞实验对这些风险基因位点的生物学功能进行了初步研究。首先，在548例精神分裂症、512例双相障碍、598例对照样本人群中，运用MassARRAY技术，完成了40个单核苷酸多态性（SNP）位点的基因分型，发现PRKCA基因rs7342847与精神分裂症、双相障碍的发生风险均显著关联，是两病共享风险遗传变异；PIK3R1基因的rs3730089、rs3756668多态性分别与精神分裂症、双相障碍的易感性显著关联，PIK3R1基因是两病共享易感基因；另外，还鉴别出了5个精神分裂症的易感遗传变异、3个双相障碍的风险基因位点。然后，运用qRT-PCR技术，在48例精神分裂症、48例双相障碍、50例对照样本中，测定了前期通过网络分析优选出的13个基因的外周血mRNA表达水平，发现CTNNB1、FYN、GNAI1、PRKCA、PRKCB、TP53、YWHAB这7个基因表达与精神分裂症、双相障碍的发生均相关。最后，通过双荧光素酶报告基因实验，发现4个（位于基因3’UTR区）精神分裂症和/或双相障碍易感遗传变异可通过影响miRNA介导的结合抑制作用来影响基因表达。本项目的研究成果可为进一步进行精神疾病的病因机制探索、高危人群筛查、诊断分类、治疗靶点探寻提供分子遗传学依据，从而促进精神疾病的二级预防。本项目已资助发表SCI论文7篇；培养硕士研究生6名，其中2人已获得硕士学位，4人在读。本项目预算总费用45万元，累计支出43.99万元，各项支出基本与预算相符。剩余经费1.01万元，剩余经费计划用于本项目研究后续支出。