抑郁症CAv1.2介导的信号转导通路基因与环境作用机制研究

Depression is a common mental illness, but its pathogenesis is not clear, the abnormal signal pathways is the newest hypothesis of genetic susceptibility of depression. The latest research shows that the flow-mediated calcium CAV1.2 can activate CaMKIV, CaMKIV further activation of CREB, and ultimately affect the expression of genes associated with depression. Up to now, the relationship between the related gene of CaMKIV- CaMKIV-CREB signal-transduction pathways and depression have not yet studied. Under the principle of informed consent, the case-control study method were use to select 1000 cases of depression and 1000 health persons from The First Special Hospital of Harbin.The whole genomic sequencing method were employed to screen the SNP site or haplotype of CACNA1C,CaMKIV and CREB1, and then SNaPshot method was used to test gene polymorphism of CACNA1C gene, CAMKIV and CREB.The multiple factor dimension reduction method and the logistic regression analysis method were selected to test the relationship between gene-gene interaction, gene-environment interaction and depression, and explore genetic susceptibility factors and environmental factors on the influence of the depression, clarify the mechanism of CACNA1C gene (CAV1.2), CAMKIV and CREB genes on depression, and to provide theoretical basis for prevention and effective treatment of depression.

抑郁症是一种常见的精神疾病，但其发病机制尚不清楚，信号通路异常是抑郁症遗传易感性的最新假说。最新研究显示，CAv1.2介导的钙内流可以激活CaMKIV，CaMKIV进一步激活CREB，最终影响抑郁症相关基因的表达。但是CAv1.2-CAMKIV-CREB信号通路相关基因与抑郁症的关系尚未见到。本研究在知情同意原则下，采用病例对照的研究方法，在哈尔滨市第一专科医院收集抑郁症患者和对照者各1000例，使用全基因组测序方法，筛查CACNA1C、CaMKIV和CREB1中基因SNP位点或单倍型，并应用SNaP shot技术对其进行基因多态性检测。通过多因子降维法、logistic回归等方法分析基因-基因、基因-环境之间交互作用与抑郁症的关系，探索遗传易感因素和环境因素对抑郁症的影响，阐明CAv1.2-CAMKIV-CREB信号通路基因对抑郁症的作用机理，为抑郁症的预防和有效治疗提供理论依据。

抑郁症是常见的精神障碍，严重影响了人类的身心健康和社会功能，但其发病机理尚不完全清楚，抑郁症的发病并不是简单地通过神经递质的异常改变产生的，而是通过细胞内复杂的信号转导发挥作用的。既往有研究证实CREB与抑郁症发病机制及抗抑郁药起效过程存在显著相关性，那么如果存在能够直接、快速激活CREB的信号通路，将会成为抑郁症发病中的关键通路，而电压门控钙通道1.2亚型（CaV1.2）-钙/钙调蛋白依赖激酶4（CAMKIV）-CREB信号通路在激活CREB中是最直接有效的。目前，国内外关于CaV1.2-CAMKIV-CREB信号转导通路基因-基因、基因-环境交互作用与抑郁症的关联研究较少且结论不一。因此本研究基于抑郁症相关信号通路CaV1.2-CaMKIV-CREB，探讨基因和环境因素共同作用与抑郁症的关系。本研究分别提取中国北方地区820名汉族单相抑郁症患者和820名汉族健康对照者基因组DNA，采用全基因测序的方法，检测两组Cav1.2信号转导通路上CACNA1C基因、CAMK4基因、CREB1基因多态性位点的基因型和等位基因频率。采用χ2检验、广义多因子降维法（GMDR）和Logistic回归分析进行数据的处理。研究结果发现CACNA1C基因rs1006737、rs7297582，CAMKIV基因rs899036位点基因型分布与抑郁症有关联；基因-基因交互模型CACNA1C基因rs1006737-CACNA1C基因rs7297582-CACNA1基因rs4565905-CACNA1C基因rs2239073-CACNA1C基因rs4765937-CACNA1C基因rs2239015-CAMKIV基因rs899036-CAMKIV基因rs2300777-CREB1基因rs2551941联合作用是抑郁症易感基因-基因最佳交互模型；CACNA1C基因rs1006737、rs4565905、rs72975827，CAMKIV基因rs10509643与负性生活事件之间存在交互作用。