Shared Genetic Architecture of Epilepsy and Glioma Revealed by Mendelian Randomization: Identifying Prognostic...

Glioma-Related Epilepsy (GRE) is a hallmark comorbidity of Low-Grade Glioma (LGG), yet the cellular and molecular mechanisms through which germline epilepsy susceptibility converges with tumor biology to shape clinical outcomes remain poorly understood.

Genome-Wide Association Studies (GWAS), expression quantitative trait loci (eQTL) data, single-cell RNA sequencing, and spatial transcriptomics were integrated. Causal inference, phenotype-driven single-cell analyses, and machine learning were applied to identify genetically informed cellular mechanisms underlying GRE.

A total of 68 germline loci shared by glioma and epilepsy (FDRIVW < 0.05) were integrated, with microglia and excitatory neurons as the principal mediating cell types. Four seizure-associated genes (WFIKKN1, WDSUB1, SPARCL1, and CALD1) were subsequently identified in TCGA-LGG, with high-confidence enhancer-promoter support for three of them (colco.PP4 > 0.9). A four-gene signature consistently stratified overall survival across three independent cohorts (TCGA-LGG, CGGA_325, and GSE16011) and correlated with immune checkpoint gene expression. High-risk patients showed higher sensitivity to cyclopamine, according to in silico drug response.

These findings support a neuroimmune model in which pleiotropic germline variants act via microglia and excitatory neurons to link seizure biology with tumor immunity and prognosis. At the same time, in silico therapeutic predictions require functional and multi-ancestry validation.

These results reveal a common genetic architecture between glioma and epilepsy, offering candidate biomarkers and therapeutic strategies for the management of GRE.