Integrative genomic and spatial transcriptomic analysis elucidates the oligodendrocyte‐mediated etiology of epileptic cortical thinning

Zhang, Dingyuan and Zhang, Qianqian and Li, Guangming and Yu, Lingting and Ma, Yanling and Hong, Xiaoli and Kui, Yujie and Cai, Shanshan and Sun, Jianguang and Zhu, Zechao (2026) Integrative genomic and spatial transcriptomic analysis elucidates the oligodendrocyte‐mediated etiology of epileptic cortical thinning. Epilepsia Open. ISSN 2470-9239

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Abstract

Objective: 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. Methods: 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. Results: 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. 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.