ArticleEpilepsia open2026
Integrative genomic and spatial transcriptomic analysis elucidates the oligodendrocyte-mediated etiology of epileptic cortical thinning.
Article in Epilepsia open, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
objectiveFocal 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.
methodsWe 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.
resultsFocal 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 SIGNIFICANCE: 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. PLAIN LANGUAGE SUMMARY: 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.
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