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

Overview

1. Department of Neurosurgery, Haiyan People's Hospital, Affiliated Haiyan Hospital of Jiaxing University, Jiaxing, China
2. Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster, UK

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper says that its authors' code is available on request: it was not published with the paper, so there is nothing to verify.

The paper's code and data availability statement is in the Data section.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none (its code is available on request), so it has no map.

Data

Datasets cited

• geo:GSE296789, at NCBI GEO; found in “DATA AVAILABILITY STATEMENT”

Data availability statement

All GWAS summary statistics used in this study are publicly available. Epilepsy GWAS summary statistics from the International League Against Epilepsy (ILAE) Consortium are available at http://www.epigad.org/. Cortical thickness GWAS summary statistics from the ENIGMA consortium are available at https://enigma.ini.usc.edu/. Cognitive function GWAS summary statistics from the COGENT consortium are available upon request from the original authors. Cell‐type‐specific expression quantitative trait loci (eQTL) data from Bryois et al. are available at https://doi.org/10.1101/2020.10.21.349415v1. Spatial transcriptomic datasets are available from the Gene Expression Omnibus (GEO) under accession numbers GSE296789 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE296789) and GSE280570 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE280570). The Mouse Organogenesis Spatiotemporal Transcriptomic Atlas (MOSTA) data are available at https://db.cngb.org/stomics/mosta/. Analysis code and processed results are available from the corresponding author upon reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 10 authors, 5 keywords, 11 MeSH terms, 1 funder, 27 references.

Cite

This paper

Zhang, D., Zhang, Q., Li, G., Yu, L., Ma, Y., Hong, X., Kui, Y., Cai, S., Sun, J., & Zhu, Z. (2026). Integrative genomic and spatial transcriptomic analysis elucidates the oligodendrocyte-mediated etiology of epileptic cortical thinning. Epilepsia open, 11(3), 895-911. https://doi.org/10.1002/epi4.70251

Similar papers

The papers with a page that share the most with this one: the tools found in their code, their categories, datasets, cited references and authors, the rarest counting most.

[1] doi:10.1093/brain/awaf259 [code]

Associations between epilepsy-related polygenic risk and brain morphology in childhood.

Journal: Brain : a journal of neurology

In common: epilepsy, structural MRI / diffusion, genetics / omics, 4 references

[2] doi:10.1177/03000605261422820 [code]

Brain tumor detection on magnetic resonance imaging scans using the artificial intelligence-based You Only Look Once algorithm.

Journal: The Journal of international medical research

In common: structural MRI / diffusion, author Shanshan Cai

[3] doi:10.1093/braincomms/fcag253 [code]

Disease detection and classification in temporal lobe epilepsy: step-wise versus simultaneous AI decision models in a multisite neuroimaging study.

Journal: Brain communications

In common: epilepsy, structural MRI / diffusion, 3 references

[4] doi:10.1111/epi.18192

The Imaging Database for Epilepsy And Surgery (IDEAS).

Journal: Epilepsia

In common: epilepsy, structural MRI / diffusion, 3 references

[5] doi:10.1038/s41467-022-30110-3 [code]

Multivariate genome-wide association study on tissue-sensitive diffusion metrics highlights pathways that shape the human brain.

Journal: Nature communications

In common: genetics / omics, 3 references

[6] doi:10.1093/brain/awab417 [code]

Topographic divergence of atypical cortical asymmetry and atrophy patterns in temporal lobe epilepsy.

Journal: Brain : a journal of neurology

In common: epilepsy, structural MRI / diffusion, 3 references

[7] doi:10.1212/nxg.0000000000200143 [code]

Dissecting the Shared Genetic Architecture of Common Epilepsies With Cortical Brain Morphology.

Journal: Neurology. Genetics

In common: epilepsy, genetics / omics, 3 references

[8] doi:10.1162/netn_a_00382 [code]

Comparison of different group-level templates in gradient-based multimodal connectivity analysis.

Journal: Network neuroscience (Cambridge, Mass.)

In common: 3 references

[9] doi:10.1002/hbm.26414 [code]

Multi-scale structural alterations of the thalamus and basal ganglia in focal epilepsy using 7T MRI.

Journal: Human brain mapping

In common: epilepsy, structural MRI / diffusion, 2 references

[10] doi:10.1016/j.biopsych.2023.06.008 [code]

Genetic Overlap Between Global Cortical Brain Structure, C-Reactive Protein, and White Blood Cell Counts.

Journal: Biological psychiatry

In common: structural MRI / diffusion, genetics / omics, cellular / molecular, 2 references

Contribute

The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.

Request its removal

To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).

Discussion: code errors and mismatches between the code and the paper about this paper and its code, from readers and its authors, beside the paper and its tracing map.

Reproductions: reports from readers who ran the authors' code and did not get the paper's result, what they ran, with which environment, commit and data.

Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.