作者：魏冕1，张亚恒2，韩亚2，齐俊丽3

单位：

1.471000河南省洛阳市，河南科技大学第一附属医院神经内科　2.471000河南省洛阳市，河南科技大学第二附属医院神经内科3.471000河南省洛阳市，洛阳职业技术学院康复医学院

Units：

1.Department of Neurology, the First Affiliated Hospital of Henan University of Science and Technology, Luoyang 471000,China2.Department of Neurology, the Second Affiliated Hospital of Henan University of Science and Technology, Luoyang 471000,China3.Rehabilitation Medical College of Luoyang Polytechnic, Luoyang 471000, China

关键词：

阿尔茨海默病；加权基因共表达网络分析；血液；基因

Keywords：

Alzheimer's disease; Weighted gene co-expression network analysis; Blood; Genes

CLC：

R 745.7

DOI：

10.12114/j.issn.1008-5971.2022.00.285

Funds：

河南省医学科技攻关计划（联合共建）项目（LHGJ20200598）

摘要：

目的　基于加权基因共表达网络分析（WGCNA）筛选阿尔茨海默病（AD）的血液关键基因。方法　2021年5—7月，利用美国国家生物技术信息中心基因表达综合数据库收集AD相关数据，以AD患者为实验组，以年龄匹配的健康老年人为对照组。采用WGCNA构建差异基因的共表达网络，以进一步筛选与临床特征相关性较高的基因模块。利用注释、可视化和集成发现的数据库（DAVID）对基因模块进行GO富集分析和KEGG通路富集分析。以基因显著性（GS）＞0.9和模块身份（MM）＞0.9为临界标准筛选模块中的核心基因，再使用Cytoscape的cytoHubba插件筛选蛋白-蛋白相互作用（PPI）网络中的关键基因。结果　本研究数据集为GSE97760队列的19个血液样本，其中实验组10个血液样本、对照组9个血液样本。最终拆分出4个基因共表达模块，结果显示，黑色模块与AD呈正相关（r =0.89），绿色模块与AD呈负相关（r =-0.90）。GO富集分析结果显示，黑色模块和绿色模块基因的生物学功能主要富集于转录、参与泛素依赖性蛋白质分解代谢过程的蛋白质泛素化，细胞组成主要富集于核、核质，分子功能主要富集于蛋白质结合、DNA结合、泛素蛋白转移酶活性。KEGG通路富集分析结果显示，黑色模块和绿色模块基因主要调节途径包括PI3K-Akt信号通路、MAPK信号通路。在黑色模块中共得到4个关键基因（CUL5、RBM25、SRSF10、SRSF2），其中CUL5的最大团中心性（MCC）、最大相邻成分（MNC）、节点连接度（degree）、边缘渗滤分量（EPC）均最大。结论　CUL5是AD的血液关键基因，其可调控PI3K-Akt、MAPK信号通路，并有望成为AD潜在的诊断和治疗靶点。

Abstract：

Objective　To screen the key genes in Alzheimer's disease (AD) blood by weighted gene co-expressionnetwork analysis (WGCNA) . Methods　From May to July 2021, AD-related data were collected using the National Center forBiotechnology Information Gene Expression Comprehensive Database. AD patients were used as the experimental group, and agematchedhealthy elderly people were used as the control group. The co-expression network of differential genes was constructedby WGCNA to further screen the gene modules with high correlation with clinical features. GO enrichment analysis and KEGGpathway enrichment analysis of gene modules were performed using the the database for annotation，visualization and integrateddiscovery (DAVID) . The core genes in the module were screened with gene significance (GS) > 0.9 and module identity (MM) >0.9 as the critical criteria, and then the cytoHubba plug-in of Cytoscape was used to screen the key genes in the protein-proteininteraction (PPI) network. Results　The data set of this study was 19 blood samples from the GSE97760 cohort, including 10blood samples in the experimental group and 9 blood samples in the control group. Finally, four gene co-expression moduleswere separated. The results showed that the black module was positively correlated with AD (r =0.89) , and the green module wasnegatively correlated with AD (r =-0.90) . The results of GO enrichment analysis showed that the biological functions of blackand green module genes were mainly enriched in transcription, protein ubiquitination involved in ubiquitin-dependent proteincatabolism, cell composition was mainly enriched in nucleus and nucleoplasm, and molecular functions were mainly enrichedin protein binding, DNA binding and ubiquitin protein transferase activity. KEGG pathway enrichment analysis showed that themain regulatory pathways of black and green module genes included PI3K-Akt signaling pathway and MAPK signaling pathway.A total of four key genes (CUL5, RBM25, SRSF10, SRSF2) were obtained in the black module, among which the maximal cliquecentrality (MCC) , maximum neighborhood component (MNC) , degree, and edge percolated component (EPC) of CUL5 were thelargest. Conclusion　CUL5 is a key gene in the blood of AD, which can regulate PI3K-Akt and MAPK signaling pathways, and isexpected to become a potential diagnostic and therapeutic target for AD.

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