精神分裂症关联分析与母亲孕期饥荒致子代易感精神分裂症机制研究

发布时间：2018-08-20 12:49

【摘要】：第一部分精神分裂症关联分析 精神分裂症易感基因和易感位点的研究已经取得了很多成果,位于mRNA3'-UTR的单核苷酸多态性(SNP)可能会影响miRNA与mRNA的结合并最终导致疾病的发生。大量研究表明,miRNA在精神分裂症发病过程中发挥重要作用,但是mRNA3'-UTR的SNPs是否通过改变miRNA和3'-UTR的结合,进而影响基因的表达,从而在精神分裂症发病过程中起作用依然不清楚。因此,十分有必要探究这些SNPs与精神分裂症的关联。 我们采用生物信息学的办法筛选了位于425个精神分裂症候选基因的3'-UTR区域的803个SNPs。基于miRBase数据库,通过用miRanda, microinspector, PicTar和RNAhybrid等计算这些miRNA与SNPs结合的自由能,选择9个最有可能影响miRNA与3'-UTR区域结合的SNPs在汉族人群中验证,结果发现,rs3219151(C＞T, GABRA6)可以显著降低精神分裂症发病风险(OR=0.8121, P=0.008, P adjust=0.03)。 本研究说明,采用新的候选SNPs的选择方法有利于加深对精神分裂症的认识,同时可以提高候选SNPs的筛选效率,为进一步研究miRNA在精神分裂症发病过程中的作用提供研究基础。 第二部分母亲孕期饥荒致子代精神分裂症高度易感机制研究 流行病学研究已经证明出生前饥荒暴露可导致精神分裂症风险上升,出生在饥荒年代的人精神分裂症的相对易感性是正常人的近两倍,国内外学者对出生前饥荒暴露导致精神分裂症发病风险上升的机制研究一直没有中断过。已有研究表明,母亲孕期营养不良可以导致成年子代大脑的结构和功能精神分裂症样异常,但是饥荒导致成年子代精神分裂症易感性增加的机制至今不明。 为了研究饥荒导致子代精神分裂症发病风险上升的机制,我们建立了大鼠饥荒动物模型RLP50,对子代大鼠海马和前额叶皮质全基因组基因表达情况进行分析,发现RP50组后代前额叶皮质中神经递质相关受体表达紊乱,并且嗅觉相关基因表达也有差异。通过对海马的研究发现大规模基因表达重编程,其中表达差异明显的基因主要集中在突触功能相关和转录调控功能相关的功能区域；紧接着我们对海马全基因组甲基化情况进行全基因组甲基化分析,结果表明饥荒组RLP50后代出现一个系统的甲基化重编程,主要表现是基因的高甲基化(86.9%)。对发生甲基化差异的基因进行GO分析发现：差异甲基化基因和差异表达基因共同集中在相同的功能区域,分别是：质膜,RNA聚合酶Ⅱ活性调控,细胞环路,金属阳离子运输,钙离子通道活性和神经元投射环路等。其中最显著的是质膜(表达谱中P=2.37×10-9,DNA甲基化组中P=5.36×10-9)。于此同时我们发现,Mecp2和slc2a1两个基因在海马中表达下调,并且在海马中DNA甲基化显著增高。 综上,本研究表明母亲孕期饥荒导致成年子代海马和前额叶皮质中基因表达重编程,致使大量基因转录活性下降,这种机制可能会导致精神分裂症的发生。
[Abstract]:The first part of the study of schizophrenia association analysis of schizophrenia susceptibility genes and susceptibility sites has achieved a lot of results. Single nucleotide polymorphisms (SNP) located in mRNA3'-UTR may affect the binding of miRNA to mRNA and eventually lead to disease. A large number of studies have shown that miRNAs play an important role in the pathogenesis of schizophrenia, but it is still unclear whether the SNPs of mRNA3'-UTR affects gene expression by altering the binding of miRNA and 3'-UTR, and thus plays an important role in the pathogenesis of schizophrenia. Therefore, it is necessary to explore the association between these SNPs and schizophrenia. We used bioinformatics to screen 803 SNPs in the 3'-UTR region of 425 schizophrenic candidate genes. Based on miRBase database, by using miRanda, microinspector, PicTar and RNAhybrid to calculate the free energy of the combination of miRNA and SNPs, we selected 9 SNPs which are most likely to affect the combination of miRNA and 3'-UTR in Han population. The results showed that rs3219151 (C > T, GABRA6) could significantly reduce the risk of schizophrenia (ORO 0.8121, P < 0.008, P adjust=0.03). This study shows that the new method of selecting candidate SNPs can help to deepen the understanding of schizophrenia, improve the screening efficiency of candidate SNPs, and provide a basis for further study on the role of miRNA in the pathogenesis of schizophrenia. The second part of the study on the mechanism of high susceptibility to maternal famine-induced schizophrenia during pregnancy Epidemiology studies have shown that exposure to pre-natal famine can lead to an increase in the risk of schizophrenia. The relative susceptibility of people born in famine years to schizophrenia is nearly twice as high as that of normal people. Scholars at home and abroad have not interrupted the research on the mechanism of the rise of risk of schizophrenia caused by pre-birth famine exposure. Studies have shown that maternal malnutrition during pregnancy can lead to structural and functional schizophrenia like abnormalities in the brain of adult offspring, but the mechanism of increased susceptibility to schizophrenia caused by famine is still unknown. In order to study the mechanism of increasing the risk of schizophrenia in offspring induced by famine, we established an animal model of famine, RLP50, to analyze the gene expression of the whole genome in hippocampus and prefrontal cortex of rats. It was found that the expression of neurotransmitter-related receptors and olfactory related genes in prefrontal cortex of RP50 group were different. Through the study of hippocampus, it was found that large-scale gene expression reprogramming, in which the difference in gene expression mainly concentrated in synaptic function related and transcriptional regulatory function related functional areas; Then we analyzed the whole genome methylation of hippocampus. The results showed that there was a systematic methylation reprogramming in the progeny of RLP50 in famine group, which was mainly characterized by gene hypermethylation (86.9%). Go analysis showed that the differential methylation genes and differentially expressed genes were concentrated in the same functional region. They were: plasma membrane RNA polymerase 鈪，

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