| Objective: Major depressive disorder(MDD)is a complex disorder of mental system caused by many factors,such as environment,psychology and so on.With the increasing number of depression patients in the world,severe depression has become the second largest disease after human heart disease.It not only seriously affects the health and life of the patients,but also brings a heavy burden to the family and the whole society.To explore the molecular mechanism of depression is the basis for the development of drugs and treatments for the prevention and treatment of this disease.In recent years,many genes that may have genetic association with MDD have been identified by genetic association studies of candidate genes or genome-wide association studies.However,in many cases,the role of these genes and their interactions in the pathogenesis of MDD remains unclear.This study will attempt to carry out a systematic and comprehensive analysis of genes associated with MDD.We collected significant MDD-related susceptibility genes by screening human genetic association studies,and then revealed biological processes associated with these genes based on functional analysis and crosstalk analysis.Explore the path modules involved in disease and the relationship between them.In addition,the MDD specific sub-network was constructed in the context of human protein interaction group,which provided more information on the relationship between MDD-related genes and introduced new genes that might be associated with the disease.In a word,we explore the molecular mechanism of MDD at the level of system biology based on the approach of pathway and network.On the other hand,considering the co-occurrence of severe depression and Alzheimer’s disease,the study compared the biochemical processes and pathways involved in the two disease-related susceptibility genes using the methods of pathway and network analysis,The relationship between them was explored at the molecular level.Method: 1.The susceptibility genes The susceptibility genes associated with MDD were determined by the study of human genetic association.The susceptibility gene set (Major depressive disorder gene set;MDDgene).Related to severe depression was identified by search and literature review with specific keywords.Alzheimer’s disease-related susceptibility gene set(Alzheimer’s disease gene set;ADgene)is based on the existing set of genes to complement new genes.2.Functional enrichment analysis of susceptibility genes for major depression In order to reveal the main biological characteristics of MDD-related genes,we analyzed their functional characteristics.We first analyze the Gene Ontology(GO)class of MDD susceptible genes,then merge and delete redundant entries,and finally obtain a list of MDD-related GO Biological Process entries.3.Biological pathway analysis and pathway serialization analysis By analyzing the biological pathways of MDD-related susceptible genes and the cross-talk networks formed by the related pathways,the main pathways related to MDD and the relationship between them were determined.We further summarize the main biological module systems related to MDD and explore the pathogeny of the disease at the macro level.4.Protein interaction network analysis In view of the extensive influence of protein interaction(PPIs)in complex biological processes,we constructed the protein interaction network of MDD susceptible genes and analyzed the topological characteristics of the network.Cluster analysis of the constructed protein network was carried out to explore the main disease modules and biological functions.5.Construct a specific subnetwork related to major depression In this study,the node-weighted Steiner minimum tree algorithm was used to extract the specific disease sub-network of MDD from the human PPI background network,and the potential risk genes associated with severe depression were predicted by analyzing the heterozygote network.6.Analysis of major depression and Alzheimer’s disease based on network and pathway methods By means of correlation analysis tools for pathway analysis and protein interaction network analysis,MDDgene and ADgene data sets were compared to construct important biological pathway crosstalk networks between them,and to explore the co-pathogenesis of the two data sets at the molecular level.Predict the risk-prone genes of the two genes.Results: 1.Disease susceptibility gene set By screening and viewing 1514 studies related to human MDD studies,The AD gene set is composed of 255 disease susceptibility genes that have a significant association with MDD,and the AD gene set integrates the disease genes identified by previous researchers and the newly added genetic association study of 157 disease genes,and the AD gene set is composed of two genes,one is the disease susceptibility gene,the other is the AD gene set.Finally 587 AD susceptibility genes were collected.2.GO BP enrichment analysis Significantly enriched GO entries in MDD-related genes are mainly distributed in cellular signal transduction,synaptic transmission,cellular transport,endocrine system or response to stimuli.Typical items include stress,trauma and pain responses,dopamine transport,dopamine metabolism,neuronal apoptosis and hormone secretion.3.Biological pathways and crosstalk network analysis 73 significantly enriched pathways were identified by the enrichment analysis of the MDD susceptible gene,including pathways associated with neurotransmission or neural function regulation,such as the neuroactive ligand-receptor interaction,the glutamate-capable synapse,the 5-hydroxytryptamine-capable synapse,the dopaminergic synapse,GABAergic synapses,cholinergic synapses and retrograde endogenous cannabinoid signaling;some of the pathways involved in cell signaling cascades are also enriched,such as the c AMP signal transduction pathway,the MAPK signal transduction pathway and the calcium signaling pathway.In addition,biological pathways associated with nervous system disorders and immune responses are also included in the enriched pathways.These significantly enriched pathways,after cross-talk analysis,form three major modules,a cell signal transduction and endocrine control module,a module associated with neurotransmission,neurological disorders and endocrine metabolism,and a module associated with the immune system.4.PPIN and specific subnetwork analysis By analyzing the topological characteristics of the constructed MDD-specific subnets,it is found that the coverage of MDD gene in the sub-network is relatively high and the distribution of the network node degree is clearly right-biased.Comparing it with the gene sets of AD and Cancer,it is found that MDD and AD are closer to each other at the network level,indicating that there is a significant difference between nervous system diseases and cancer.Subsequently,35 new genes outside the MDD-related genes were introduced into the MDD-specific molecular network.It was found that these new genes were closely associated with the MDD-related genes,indicating that they might be associated with the pathological process of the disease.In addition,through the analysis of these 35 genes,we identified 6 key genes,including GRB2,APP and HSP90AB1,which may be related to the development of MDD.5.Analysis of major depressive disorder and Alzheimer’s disease based on network and pathway methods By comparing the gene sets,pathways and network topology parameters related to MDD and AD,we get 45 important paths in common,and construct a cross-talk network based on common paths.It is found that these pathways are more closely related to MDD,suggesting that MDD may play a dominant role in the concomitant state of the two diseases.By analyzing the topological features of the network,it is found that at least at the network level,the characteristics of MDD and AD are relatively similar,which are obviously different from those of cancer.Conclusions: 1.MDD is a complex multi-gene mental system disease,the pathogenesis of which involves many biological processes and biochemical pathways,in which,the immune system of the body.The common disorder of nervous system and endocrine system may cause the occurrence and development of disease.2.Compared with the analytical network of cancer,MDD and AD are close to each other,reflecting the obvious difference between nervous system diseases and cancer.3.Six key genes,APP,HSP90AB1,PRKACA,GRB2,PRKCA and SP1,which were screened by specific sub-networks,may play an important role in the development of MDD.4.Through the construction and analysis of the disease protein network,it is concluded that there may be potentially susceptible genes at the same time with MDD and AD.These genes provide valuable results and new research directions for future co-disease studies of the two diseases.5.The results of functional and pathway enrichment analysis in this study are consistent with those of previous studies and databases,indicating that the susceptible gene sets of MDD and AD are more reliable.It provides a valuable reference for future experimental research and database construction of major depressive disorder and Alzheimer’s disease. |
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