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WGCNA combined with GSVA to explore biomarkers of refractory neocortical epilepsy
Rui Zhang1, Yan Chen1, Jia He1
1Department of Epilepsy and Sleep Disorder, Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, 150086, Harbin, China.
Abstract:
About two-thirds of epilepsy patients relapse within five years after surgery. It is significant to note that the limitations of current treatments stem from a lack of understanding of molecular mechanisms. In this study, Weighted Gene Co-expression Network Analysis (WGCNA) and Gene set variation analysis (GSVA) methods were used to analyze the total RNA data from 20 surgical removal samples (epileptogenic zone and irritative zone, EZ and IZ) of 10 Chinese patients with refractory neocortical epilepsy downloaded from the original microarray dataset (GSE31718) of the National Center for Biological Information -Gene Expression Omnibus database (NCBI-GEO). The late stages of the estrogen response pathway, the IL6-JAK-STAT3-signal pathway and G2 checkpoints are correlated with the EZ, whereas the early stages of the estrogen response pathway and TGF-β signal are more strongly expressed in the IZ. The allogeneic rejection, apical surface and the TGF-β signal are relevant to the high seizure frequency, the unfolded protein response and MYC-target are mostly expressed in patients with low-frequency seizures. Genes with high gene significance(GS) values that were correlated with seizure frequency include OSR2, CABP4, CAPSL, CYP4F8, and FRK in the pink module, and SH3GLB2, CHAC1 and DDX23 in the yellow module. The occurrence of EZ and IZ act on different biological mechanisms. The upregulated genes associated with seizure frequency include OSR2, CABP4, CAPSL, CYP4F8, and FRK, and the downregulated genes include SH3GLB2, CHAC1 and DDX23. The evidence of key genes and differential pathways obtained by WGCNA and GSVA may be biomarkers for novel preventive and pharmacological interventions in clinical practice.
Insights
Epilepsy surgery relapse is high due to unknown molecular causes. This study identified key genes and pathways in epilepsy zones linked to seizure frequency, offering potential biomarkers for new treatments.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Epilepsy surgery has a high relapse rate, often linked to an incomplete understanding of underlying molecular mechanisms.
- Current treatments for refractory epilepsy are limited by a lack of knowledge regarding the specific biological pathways involved.
Purpose of the Study:
- To identify molecular differences between the epileptogenic zone (EZ) and irritative zone (IZ) in refractory neocortical epilepsy.
- To uncover key genes and biological pathways associated with seizure frequency in epilepsy patients.
Main Methods:
- Weighted Gene Co-expression Network Analysis (WGCNA) and Gene Set Variation Analysis (GSVA) were applied to RNA sequencing data from 20 surgical samples.
- Analysis focused on differentiating molecular signatures between EZ and IZ, and correlating gene expression with seizure frequency.
Main Results:
- Distinct molecular pathways were identified in the EZ (late estrogen response, IL6-JAK-STAT3, G2 checkpoints) and IZ (early estrogen response, TGF-β).
- Allogeneic rejection and TGF-β signaling correlated with high seizure frequency, while unfolded protein response and MYC-target were linked to low seizure frequency.
- Specific genes (OSR2, CABP4, CAPSL, CYP4F8, FRK, SH3GLB2, CHAC1, DDX23) were identified as significantly correlated with seizure frequency.
Conclusions:
- The epileptogenic zone and irritative zone exhibit distinct molecular mechanisms.
- Identified genes and pathways serve as potential biomarkers for developing novel preventive and pharmacological interventions for epilepsy.
