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. 2021 Jun 30:12:696591.
doi: 10.3389/fgene.2021.696591. eCollection 2021.

Identification of Atrial Fibrillation-Associated Genes ERBB2 and MYPN Using Genome-Wide Association and Transcriptome Expression Profile Data on Left-Right Atrial Appendages

Xiangguang Meng  1 , Yali Nie  2 , Keke Wang  1 , Chen Fan  3 , Juntao Zhao  4 , Yiqiang Yuan  5
Affiliations

Identification of Atrial Fibrillation-Associated Genes ERBB2 and MYPN Using Genome-Wide Association and Transcriptome Expression Profile Data on Left-Right Atrial Appendages

Xiangguang Meng et al. Front Genet. .

Abstract

More reliable methods are needed to uncover novel biomarkers associated with atrial fibrillation (AF). Our objective is to identify significant network modules and newly AF-associated genes by integrative genetic analysis approaches. The single nucleotide polymorphisms with nominal relevance significance from the AF-associated genome-wide association study (GWAS) data were converted into the GWAS discovery set using ProxyGeneLD, followed by merging with significant network modules constructed by weighted gene coexpression network analysis (WGCNA) from one expression profile data set, composed of left and right atrial appendages (LAA and RAA). In LAA, two distinct network modules were identified (blue: p = 0.0076; yellow: p = 0.023). Five AF-associated biomarkers were identified (ERBB2, HERC4, MYH7, MYPN, and PBXIP1), combined with the GWAS test set. In RAA, three distinct network modules were identified and only one AF-associated gene LOXL1 was determined. Using human LAA tissues by real-time quantitative polymerase chain reaction, the differentially expressive results of ERBB2, MYH7, and MYPN were observed (p < 0.05). This study first demonstrated the feasibility of fusing GWAS with expression profile data by ProxyGeneLD and WGCNA to explore AF-associated genes. In particular, two newly identified genes ERBB2 and MYPN via this approach contribute to further understanding the occurrence and development of AF, thereby offering preliminary data for subsequent studies.

Keywords: atrial fibrillation; genome-wide association study; single nucleotide polymorphism; systems biology; transcriptome.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
The circos diagram for GWAS and expression data sets. Two outermost tracks represent the chromosome text and banding positions. From the outside to the inside, the first and second histogram tracks represent the GWAS discovery and test sets, respectively. The red abundance value along the vertical axis represents the genes with adj p < 0.05, the first 20 of which are displayed in the first and second text tracks, and the green represents the genes with adj p > 0.05. The third and four histogram tracks represent the GS values of the expression sets of LAA and RAA, respectively. The red abundance value along the vertical axis represents the genes with GS > 2, the first 20 of which are displayed in the third and four text tracks, and the green represents the genes with GS < 2. GS, gene significance; LAA, left atrial appendage; RAA, right atrial appendage.
FIGURE 2
FIGURE 2
The principal component analysis, the calculation of power indexes, and the generation of module cluster trees on expression data sets. (A) The PCA plot is shown for determination of outlier samples in LAA. (B) The PCA plot is shown for determination of outlier samples in RAA. (C) Analysis of network topology for various soft-thresholding powers in LAA. The y-axis of the left panel represents the scale-free fit index while the x-axis indicates the soft-thresholding power. The y-axis of the right panel displays the mean connectivity and the x-axis also represents the soft-thresholding power. (D) Analysis of network topology for various soft-thresholding powers in RAA. (E) The construction of module cluster tree in LAA. In the picture, branches correspond to the coexpression modules with highly interconnected groups of genes. (F) The construction of module cluster tree in RAA. LAA, left atrial appendage; PCA, principal component analysis; RAA, right atrial appendage.
FIGURE 3
FIGURE 3
The module–trait associations of networks. (A) Module–trait associations in LAA. Row represents a module eigengene, column indicates disease status – AF or SR. Each cell contained the corresponding correlation and p-value. The table was color-coded by p-value according to the color legend. (B) Module–trait associations in RAA. LAA, left atrial appendage; RAA, right atrial appendage.
FIGURE 4
FIGURE 4
The correlation between MM and GS. (A) The correlation between MM and GS for each of two AF-associated modules in LAA. MM for each module is plotted against GS. (B) The correlation between MM and GS for each of three AF-associated modules in RAA. GS, gene significance; LAA, left atrial appendage; RAA, right atrial appendage.
FIGURE 5
FIGURE 5
The Venn plot constructed by two AF-associated modules in LAA and three AF-associated modules in RAA (GS > 2). GS, gene significance; LAA, left atrial appendage; RAA, right atrial appendage.
FIGURE 6
FIGURE 6
The enrichment pathways from GSEA. (A) The enrichment pathways from GSEA in LAA. (B) The enrichment pathways from GSEA in RAA. LAA, left atrial appendage; RAA, right atrial appendage.
FIGURE 7
FIGURE 7
The Network view from Cytoscape. (A) The Network view from Cytoscape in LAA. (B) Network view from Cytoscape in RAA. The module edge > 0.15. Green color represents downregulated genes with GS > 2, red color represents upregulated genes with GS > 2, and gray color represents the genes with GS < 2. Octagon nodes represent core genes. GS, gene significance; LAA, left atrial appendage; RAA, right atrial appendage.
FIGURE 8
FIGURE 8
The RT-qPCR results for six genes. Data are shown as mean ± SE, and each sample is in triplicate. AF, atrial fibrillation; SR, sinus rhythm. *P < 0.05.
FIGURE 9
FIGURE 9
The design scheme of this study. GS, gene significance; LAA, left atrial appendage; ME, module eigengene; MM, module membership; PCA, principal component analysis; RAA, right atrial appendage.
See this image and copyright information in PMC

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