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

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.

A Meta-Analysis Approach to Gene Regulatory Network Inference Identifies Key Regulators of Cardiovascular Diseases

“…PBXIP1 has been shown to be an AF-associated biomarker in human left atrial appendages [93]. In our analysis, we further observed an increased activity of this transcription factor in patients with heart failure compared to healthy individuals and a decreased activity in patients with hypertrophic cardiomyopathy, as reported in Figure 5A.…”

Comparison of whole transcriptome sequencing of fresh, frozen, and formalin-fixed, paraffin-embedded cardiac tissue

“…The introduction of next-generation sequencing (NGS) has enabled large-scale genetic, epigenetic, and gene expression analyses. The potential use of high-throughput RNA-sequencing to uncover molecular mechanisms of human cardiac diseases has been acknowledged [1][2][3][4][5]. However, due to the tissue-specific nature of gene expression, a major limitation of RNAsequencing in the investigation of cardiac diseases is the limited availability of cardiac tissue.…”

Decreased FAM13B Expression Increases Atrial Fibrillation Susceptibility by Regulating Sodium Current and Calcium Handling

“…ERBB2 was previously identified as an AF-associated biomarker. 29 Of interest because FAM13B is in the RhoGAP gene family, there were also 3 Rho GTPase activation gene sets among the top 86 sets. Two gene sets containing SCN2B (Reactome: Phase 0 Rapid Depolarization and Reactome: Sensory Perception) were among the top sets.…”