Integrative genomic and spatial transcriptomic analysis elucidates the oligodendrocyte-mediated etiology of epileptic...

Focal epilepsy is characterized by progressive cortical thinning, particularly within limbic structures; however, whether this atrophy reflects acquired seizure-induced damage or shared genetic predisposition remains unresolved.

We integrated genome-wide association study (GWAS) summary statistics from the ILAE Consortium (focal epilepsy: 15212 cases; 29 677 controls), ENIGMA (cortical thickness: N = 33 992), and COGENT (cognitive function: N = 257 841) using linkage disequilibrium score regression and genomic structural equation modeling (Genomic SEM). A latent cortical factor (F-EpiCortex) was derived and interrogated through MAGMA gene-based analysis, cell-type-specific Mendelian randomization (csMR) using brain single-cell expression quantitative trait loci, and spatial transcriptomic mapping (gsMap) across mouse embryonic and human cortical datasets.

Focal epilepsy exhibited significant negative genetic correlations with cingulate cortical thickness (rg = -0.23 to -0.27; p < 0.05). Genomic SEM identified a well-fitting two-factor model (CFI = 0.916) wherein focal epilepsy genetic liability was associated with reduced cortical thickness (β = -0.30; p = 0.02), while cognitive function showed a protective association (β = 0.10; p = 0.04). GWAS of the F-EpiCortex latent factor identified nine genome-wide significant loci, with DPYSL5 (p = 1.88 × 10^-11) as the lead signal. Cell-type-specific analysis revealed oligodendrocytes as the predominant cellular mediator, with DPYSL5 (β = -0.21; p = 1.3 × 10^-10) and SLC16A8 (β = -0.28; p = 8.9 × 10^-8) exhibiting robust protective effects predominantly within the oligodendrocyte lineage. Spatial transcriptomic validation confirmed oligodendrocyte enrichment across human cingulate and temporal cortices, with 70% concordance between csMR predictions and spatial expression patterns. Experimental validation in human oligodendrocytes under glutamate-induced excitotoxic stress demonstrated significant downregulation of the prioritized protective proteins, providing functional evidence for their susceptibility to epilepsy-associated injury.

These findings implicate oligodendrocyte dysfunction as a shared genetic component linking focal epilepsy to cortical atrophy. This extends the "scars of seizures" paradigm by supporting a complementary neurodevelopmental origin model, with implications for neuroprotective therapeutic strategies.

Focal epilepsy is often accompanied by a progressive thinning of the brain's cortex, which has traditionally been viewed purely as cumulative damage from repeated seizures. In this study, we investigated whether an underlying genetic predisposition also plays a role. By analyzing large-scale genetic and brain imaging datasets, we discovered a shared genetic link between focal epilepsy and cortical thinning. Furthermore, we traced this genetic vulnerability specifically to oligodendrocytes-the cells responsible for supporting and insulating nerve fibers. Our findings suggest that cortical thinning is not merely a "scar" from seizures, but partly a preexisting structural vulnerability driven by reduced protective functions of specific genes (such as DPYSL5 and SLC16A8) in these support cells. This offers a new perspective on preventing brain structural changes in epilepsy.