Identification of Key Genes and the Pathophysiology Associated With Major Depressive Disorder Patients Based on Integrated Bioinformatics Analysis


  • 影响因子:3.13
  • DOI:10.3389/fpsyt.2020.00192
  • 作者列表:"Guangyin Zhang","Guangyin Zhang","Shixin Xu","Zhenqing Zhang","Yu Zhang","Yankun Wu","Jing An","Jinyu Lin","Zhuo Yuan","Li Shen","Tianmei Si
  • 发表时间:2020-04-03

Background: At present, laboratory blood tests to support major depressive disorder (MDD) diagnosis are not available. This study aimed to screen potential mRNAs for peripheral blood biomarkers and novel pathophysiology of MDD.Methods: The present study utilized public data from two mRNA microarray datasets to analyze the hub genes changes related to MDD. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of differentially expressed genes (DEGs) were performed. Finally, some potential mRNA quality biomarkers for hub gene expression in blood were identified.Results: A total of 25 significantly co-upregulated DEGs and 98 co-downregulated DEGs were obtained from two datasets. The pathway enrichment analyses showed that co-upregulated genes were significantly enriched in the regulation of cell-matrix adhesion and mitochondrial membrane permeability which were involved in the apoptotic process. Co-downregulated genes were mainly involved in the neutrophil activation which in turn was involved in the immune response, degranulation and cell-mediated immunity, positive regulation of immune response, the Toll-like receptor signaling pathway, and the NOD-like receptor signaling pathway. From the PPI network, 14 hub genes were obtained. Among them, the subnetworks of PLCG1, BCL2A1, TLR8, FADD, and TLR4 screened out from our study have been shown to play a role in immune and inflammation responses.Discussion: The potential molecular mechanisms that have been identified simultaneously include innate immunity, neuroinflammation, and neurotrophic factors for synapse function and development.


背景: 目前还没有支持重性抑郁障碍 (MDD) 诊断的实验室血液检查。本研究旨在筛选潜在的 mRNAs 用于外周血生物标志物和新的 MDD 病理生理学。方法: 本研究利用来自两个 mRNA 微阵列数据集的公共数据来分析与 MDD 相关的 hub 基因变化。对差异表达基因 (DEGs) 进行基因本体论 (GO) 分析和京都基因和基因组百科全书 (KEGG) 通路分析。最后,确定了血液中 hub 基因表达的一些潜在 mRNA 质量生物标志物。结果: 从两个数据集中共获得 25 个显著共上调的 DEGs 和 98 个共下调的 DEGs。通路富集分析表明,共上调的基因在参与凋亡过程的细胞-基质粘附和线粒体膜通透性的调控中显著富集。共下调基因主要参与中性粒细胞活化,进而参与免疫应答、脱颗粒和细胞介导免疫、免疫应答的正调节、 toll 样受体信号通路和 NOD 样受体信号通路。从 PPI 网络中获得 14 个 hub 基因。其中,从我们的研究中筛选出的 PLCG1 、 BCL2A1 、 TLR8 、 FADD 和 TLR4 的子网络已被证明在免疫和炎症反应中发挥作用。讨论: 已经同时确定的潜在分子机制包括先天免疫、神经炎症和神经营养因子对突触功能和发育的影响。



来源期刊:Molecular psychiatry
作者列表:["Li C","Meng F","Garza JC","Liu J","Lei Y","Kirov SA","Guo M","Lu XY"]

METHODS::The adipocyte-derived hormone adiponectin has a broad spectrum of functions beyond metabolic control. We previously reported that adiponectin acts in the brain to regulate depression-related behaviors. However, its underlying neural substrates have not been identified. Here we show that adiponectin receptor 1 (AdipoR1) is expressed in the dorsal raphe nucleus (DRN) and colocalized with tryptophan hydroxylase 2 (TPH2), a marker of serotonin (5-HT) neurons. Selective deletion of AdipoR1 in 5-HT neurons induced anhedonia in male mice, as indicated by reduced female urine sniffing time and saccharin preference, and behavioral despair in female mice and enhanced stress-induced decrease in sucrose preference in both sexes. The expression levels of TPH2 were downregulated with a concurrent reduction of 5-HT-immunoreactivity in the DRN and its two major projection regions, the hippocampus and medial prefrontal cortex (mPFC), in male but not female mice lacking AdipoR1 in 5-HT neurons. In addition, serotonin transporter (SERT) expression was upregulated in both DRN projection fields of male mice but only in the mPFC of female mice. These changes presumably lead to decreased 5-HT synthesis and/or increased 5-HT reuptake, thereby reducing 5-HT transmission. The augmented behavioral responses to the selective serotonin reuptake inhibitor fluoxetine but not desipramine, a selective norepinephrine reuptake inhibitor, observed in conditional knockout male mice supports deficient 5-HT transmission underlying depression-related phenotypes. Our results indicate that adiponectin acts on 5-HT neurons through AdipoR1 receptors to regulate depression-related behaviors in a sex-dependent manner.

关键词: 暂无
翻译标题与摘要 下载文献
作者列表:["Torretta S","Rampino A","Basso M","Pergola G","Di Carlo P","Shin JH","Kleinman JE","Hyde TM","Weinberger DR","Masellis R","Blasi G","Pennuto M","Bertolino A"]

METHODS::Multiple schizophrenia (SCZ) risk loci may be involved in gene co-regulation mechanisms, and analysis of coexpressed gene networks may help to clarify SCZ molecular basis. We have previously identified a dopamine D2 receptor (DRD2) coexpression module enriched for SCZ risk genes and associated with cognitive and neuroimaging phenotypes of SCZ, as well as with response to treatment with antipsychotics. Here we aimed to identify regulatory factors modulating this coexpression module and their relevance to SCZ. We performed motif enrichment analysis to identify transcription factor (TF) binding sites in human promoters of genes coexpressed with DRD2. Then, we measured transcript levels of a group of these genes in primary mouse cortical neurons in basal conditions and upon overexpression and knockdown of predicted TFs. Finally, we analyzed expression levels of these TFs in dorsolateral prefrontal cortex (DLPFC) of SCZ patients. Our in silico analysis revealed enrichment for NURR1 and ERR1 binding sites. In neuronal cultures, the expression of genes either relevant to SCZ risk (Drd2, Gatad2a, Slc28a1, Cnr1) or indexing coexpression in our module (Btg4, Chit1, Osr1, Gpld1) was significantly modified by gain and loss of Nurr1 and Err1. Postmortem DLPFC expression data analysis showed decreased expression levels of NURR1 and ERR1 in patients with SCZ. For NURR1 such decreased expression is associated with treatment with antipsychotics. Our results show that NURR1 and ERR1 modulate the transcription of DRD2 coexpression partners and support the hypothesis that NURR1 is involved in the response to SCZ treatment.SIGNIFICANCE STATEMENT In the present study, we provide in silico and experimental evidence for a role of the TFs NURR1 and ERR1 in modulating the expression pattern of genes coexpressed with DRD2 in human DLPFC. Notably, genetic variations in these genes is associated with SCZ risk and behavioral and neuroimaging phenotypes of the disease, as well as with response to treatment. Furthermore, this study presents novel findings on a possible interplay between D2 receptor-mediated dopamine signaling involved in treatment with antipsychotics and the transcriptional regulation mechanisms exerted by NURR1. Our results suggest that coexpression and co-regulation mechanisms may help to explain some of the complex biology of genetic associations with SCZ.

翻译标题与摘要 下载文献
作者列表:["Chadha R","Meador-Woodruff JH"]

METHODS::Abnormal neurotransmission is central to schizophrenia (SZ). Alterations across multiple neurotransmitter systems in SZ suggest that this illness may be associated with dysregulation of core intracellular processes such as signaling pathways that underlie the regulation and integration of these systems. The AKT-mTOR signaling cascade has been implicated in SZ by gene association, postmortem brain and animal studies. AKT and mTOR are serine/threonine kinases which play important roles in cell growth, proliferation, survival, and differentiation. Both AKT and mTOR require phosphorylation at specific sites for their complete activation. mTOR forms two functionally distinct multiprotein complexes, mTOR Complex 1 (mTORC1) and Complex 2 (mTORC2). mTORC1 mediates ribosome biogenesis, protein translation, and autophagy, whereas mTORC2 contributes to actin dynamics. Altered protein synthesis and actin dynamics can lead to an abnormal neuronal morphology resulting in deficits in learning and memory. Currently, there is a lack of direct evidence to support the hypothesis of disrupted mTOR signaling in SZ, and we have addressed this by characterizing this signaling pathway in SZ brain. We found a reduction in AKT and mTOR protein expression and/or phosphorylation state in dorsolateral prefrontal cortex (DLPFC) from 22 pairs of SZ and matched comparison subjects. We also found reduced protein expression of GβL, a subunit protein common to both mTOR complexes. We further investigated mTOR complex-specific subunit composition and phosphorylation state, and found abnormal mTOR expression in both complexes in SZ DLPFC. These findings provide evidence that proteins associated with the AKT-mTOR signaling cascade are downregulated in SZ DLPFC.

关键词: 暂无
翻译标题与摘要 下载文献