基于基因组遗传信息网络的甲基苯丙胺诱导精神障碍关键易感基因的筛选及其作用机制研究

Psychosis caused by drug addiction can damage the health, and often lead to many crimes, which is greatly harmful to the society. Previous studies have indicated that genetic factors play an important role in the drug addiction and psychosis, but the exact variations in genetic susceptibility to the disease and their underlying mechanisms remain unclear. Thus, in the study proposal, we will first perform genome-wide association analysis (GWAS) in the samples of methamphetamine-induced psychosis (MIP) patients and methamphetamine dependence patients without psychosis, and integrate the data from ENCODE and GWAS to get detailed functional elements annotations for the results of GWAS to extract characteristics of DNA functional elements for MIP. Then we will predict MIP susceptibility variations using these characteristics in a genome-wide scale. Secondly, we will also innovatively integrate the gene interaction information from GWAS data with biological molecular interaction information from public databases to establish biological interaction networks of MIP susceptibility genes, and then screen predicted MIP susceptibility variations in the networks. Subsequently, we will identify the most significant MIP-associated gene by Q-PCR and eQTL analysis in the GWAS samples. Finally, we will detect the expression of the key MIP-associated gene in the prefrontal cortex and hippocampus in the animal model, and determine the neurotransmitter system and its signal transduction pathway which mostly affect the expression of the key MIP-associated gene in the cell model. Based on the molecular biological experiment, we will clarify the upstream and downstream mechanisms of the key MIP-associated gene in the pathogenesis of MIP. The results of this research will systematically elucidate the role and molecular mechanism of the key MIP-associated gene in regulatory networks of MIP, which would also lay a solid foundation to further understand the molecular mechanisms of MIP.

药物成瘾引起的精神障碍不仅损害健康，且常引发犯罪，社会危害极大。以往研究表明遗传因素在药物成瘾和精神障碍中均参与了作用，但确切的易感基因及其作用机制尚不清楚。因此，本项目拟以滥用甲基苯丙胺后出现精神障碍（MIP）患者为研究对象，利用全基因组关联分析（GWAS）及DNA功能元件数据（ENCODE）注释，发现并提取特征性功能元件，继而在全基因组范围内预测MIP易感遗传标记；通过构建的MIP易感基因生物学交互网络，对预测的MIP易感遗传标记进一步筛选后，利用Q-PCR和eQTL分析，发现并最终确定导致MIP的关键易感基因；最后在动物模型中检测该基因在前额叶皮质和海马中的表达，同时在细胞模型中筛选对该基因表达影响最大的神经递质系统及信号通路，并通过功能实验明确该基因在MIP中的下游作用和上游调控机制，最终阐明该基因在MIP网络调控中的作用与机制，为进一步理解甲基苯丙胺诱导精神障碍的分子机制奠定基础

甲基苯丙胺是一种具有强烈成瘾性的中枢神经兴奋剂，甲基苯丙胺的滥用不仅损害身体健康，还会产生精神障碍，如幻觉、妄想、好斗，引发一系列的社会问题。在法医学司法鉴定实践中，鉴定甲基苯丙胺对活体精神状态的影响，以及甲基苯丙胺诱导的精神障碍（MIP）在相关案件发生中参与的作用是法医学司法鉴定必须解决的重要问题。以往研究表明遗传因素在药物成瘾和精神障碍中均参与了作用，但确切的易感基因及其作用机制尚不清楚。本项目以人群为研究对象，使用DNA芯片对西北汉族的MIP患者和METH依赖无精神障碍患者进行了全基因组常见遗传变异位点的检测，初步完成了西北汉族MIP的全基因组常见遗传变异谱的绘制，确定了16个达到全基因组显著关联的位点，为了进一步确定MIP的分险基因，利用Q-PCR和eQTL分析，发现了FADS1和SNX16在汉族人群和欧洲人群中的 MIP 风险中发挥作用。同时我们开发了一站式GWAS多维分析平台GWASdmp，利用该平台预测出了Notch信号通路与MIP的高度关联，并初步阐明了内侧前额叶皮层Notch信号通路通过Hes1依赖性抑制GABAB1受体表达介导MIP的分子机制。在此基础上进一步开发了基于全新机器学习算法的多组学数据整合分析方法，该方法可以提高对多组学数据分析的能力，它可以有效地预测潜在的疾病相关ncRNA调控网络，利用该方法预测到了let7b-IL6调控轴在SCZ中的作用，实验结果表明过表达let-7b或者抑制IL-6的表达可以显著改善MK-801诱导精神分裂症样行为，包括焦虑、抑郁和认知障碍。我们的研究在遗传方面对MIP提供了诸多证据，对多组学数据的分析提供了借鉴与方向，为进一步理解MIP的分子机制奠定基础。