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. 2021 Dec 20;41(12):1752-1762.
doi: 10.12122/j.issn.1673-4254.2021.12.01.

[Identification of potential hub genes of Alzheimer's disease by weighted gene co-expression network analysis]

[Article in Chinese]
J Xue  1 , J Liu  2 , M Geng  2 , J Yue  1 , H He  1 , J Fan  2
Affiliations

[Identification of potential hub genes of Alzheimer's disease by weighted gene co-expression network analysis]

[Article in Chinese]
J Xue et al. Nan Fang Yi Ke Da Xue Xue Bao. .

Abstract
in English, Chinese

Objective: To investigate the differential expression gene modules and hub genes associated with Alzheimer's disease (AD) by weighted gene co-expression network analysis (WGCNA) and annotate the biological functions of these modules.

Methods: We downloaded transcriptome sequencing data from the GEO database, and according to the correlation of the genes, a gene co-expression network was constructed with the parameter setting of β=8 and a correlation coefficient threshold of 0.85. Pearson correlation test was used to calculate the correlation between the module genes and clinical traits to screen the gene modules significantly associated with AD and identify the hub genes according to the connectivity within modules. GO functional enrichment analysis and KEGG pathway analysis were used to annotate the functions of the modules. A cell model of AD was established in SH-SY5Y cells by Aβ1-42 treatment, and the mRNA expression levels of the hub genes were compared between the Aβ1-42-treated cells and the control cells.

Results: Ten gene co-expression modules were constructed based on the correlations of gene expression, in which the brown (r=0.66, P < 0.001) and turquoise modules (r=-0.68, P < 0.001) were significantly correlated with the AD group. Forty-eight genes were identified as the hub genes in the co-expression network. Function annotation revealed that the genes in both modules were mainly enriched in DNA damage and repair pathways and metabolism-related pathways. Differential expression analysis of the genes revealed that the genes DNASE1, TEKT2 and MTSS1L were highly expressed while ACP2, LANCL2 and GMPR2 were lowly expressed in AD group. The results of cell experiment confirmed the up-regulation of DNASE1, TEKT2 and MTSS1L genes and the down-regulation of ACP2, LANCL2, and GMPR2 in Aβ1-42-treated SH-SY5Y cells (P < 0.01).

Conclusion: The brown and turquoise modules are closely correlated with AD. The hub genes including MTSS1L, GMPR2, ACP2, ACTG1 and LANCL2 selected from the modules may participate in AD pathogenesis by regulating DNA damage and repair.

目的: 采用加权基因共表达网络分析（WGCNA）探索阿尔茨海默病（AD）相关的差异基因模块及其枢纽基因，并对差异基因模块进行生物功能注释。

方法: 从GEO数据库下载转录组测序数据，根据基因的相关性，当关联系数阈值设定为0.85时，参数β=8，以此构建基因共表达网络；采用Pearson相关性检验计算模块基因与临床表型相关性，筛选出与AD显著相关的基因模块，根据模块内的连接性筛选枢纽基因；利用GO功能富集分析和KEGG通路分析对模块进行功能注释。进一步建立β-淀粉样蛋白（Aβ1-42）诱导SH-SY5Y细胞损伤模型，在模型组和对照组中检测枢纽基因的表达水平。结果根据基因表达的相关性，共构建了10个基因共表达模块，其中brown和turquoise模块与AD组显著相关（brown：r=0.66，p < 0.001；turquoise：r=-0.68，P < 0.001）；

结果: 显示48个基因在共表达网络中处于核心地位；通过生物注释功能发现，两模块中的基因主要富集在DNA损伤修复通路和代谢相关通路等生物学过程中。基因的差异表达分析显示，DNASE1、TEKT2、MTSS1L等基因在AD组中高表达，ACP2、LANCL2、GMPR2等基因在AD组中低表达；体外实验进一步验证了在Aβ1-42诱导的SH-SY5Y细胞损伤过程中DNASE1、TEKT2、MTSS1L表达上调（P < 0.01），ACP2、LANCL2、GMPR2表达下调（P < 0.01）。

结论: brown和turquoise模块与AD高度相关，并从模块中筛选出MTSS1L、GMPR2、ACP2、ACTG1、LANCL2等枢纽基因，可能通过调节DNA损伤和修复参与AD发病机制。

Keywords: Alzheimer's disease; DNA damage and repair; hub genes; weighted gene co-expression network analysis.

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Figures

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差异表达的火山图和韦恩图 Volcano and Wayne diagrams of the differentially expressed genes (DEGs). A: Volcano diagram of the DEGs between AD group and normal-old group. B: Volcano diagram of the DEGs between AD group and normal-young group. C: Wayne diagram of the DEGs between AD group and normal-old group and between AD and normal-young group.
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共表达网络的构建 Construction of the co-expression network. A: Sample clustering and removal of outlier samples. The sample-22 with the height greater than 150 000 was excluded. B: Sample dendrogram and its trait heatmap after removal of the outlier samples. C: Selection of the best soft-threshold value. The best power value with scale-free topological index of 0.85 or more and good average connectivity was calculated with β=8. D: Cluster dendrogram and module partitioning of the co-expression gene modules. The 9 colors indicate the corresponding gene co-expression modules.
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共表达模块与临床表型的相关性分析 Correlation between co-expression modules and clinical traits. A: Relationship heatmap between modules and clinical traits. B: Hierarchical clustering tree and relationship heatmap within the modules.
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brown和turquoise模块与AD表型的相关性分析 Correlation between brown and turquoise modules with AD. A: Scatter plot of GS and MM in brown module. B: Scatter plot of GS and MM in turquoise module. C: Heatmap of gene expression in brown module. D: Heatmap of gene expression in turquoise module. E: Heatmap and clustering map of the traits in brown module. F: Heatmap and clustering map of traits in turquoise module.
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模块基因与临床表型聚类热图及各模块的连通性 Heatmap of module gene clustering between module genes and clinical traits and connectivity of each module.
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枢纽基因连接图 Hub gene map of the brown module (A) and turquoise module (B).
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brown和turquoise模块的GO和KEGG富集分析 GO and KEGG enrichment analysis of the brown and turquoise modules. A: GO function enrichment analysis of brown module. B: GO function enrichment analysis of turquoise module. C: KEGG pathway analysis of brown module. D: KEGG pathway analysis of turquoise module. The size of the dots represents the number of genes, and the color of the dots represents the -log10(P) value; the x-axis represents the RichFactor of genes.
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枢纽基因在不同组别中的差异表达情况 Differential expressions of the hub genes in Aβ1-42-induced SH-SY5Y cell model of AD. A: Differential expression of genes among groups (AD, normal-old, normal-young) on the original RNA-seq dataset. B: mRNA relative expression of genes among Aβ1-42-treatment cells and control cells. *P < 0.05, **P < 0.01, ***P < 0.001.
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枢纽基因共表达相关性热图 Heatmap of co-expression correlation between the hub genes. A: Heatmap of co-expression correlation between hub genes in brown module. B: Heatmap of co-expression correlation between hub genes in turquoise module. A darker bluecolor in the upper right part indicates a stronger correlation, and the data in the lower left part are the correlation coefficients.
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北京市自然科学基金（5214028）；国家自然科学基金（82070447）