Exploring Molecular Pathways Underlying Epilepsy Development in Intellectual Disability

Abstract

Background

Intellectual disability (ID) and epilepsy are often comorbid, but the pathways that lead to epilepsy in individuals with ID remain unclear. This study aims to explore the molecular pathways linked to epilepsy development in ID, providing insights into shared genetic mechanisms.

Methods

Definitive ID-related genes were extracted from the SysNDD database, and their association with epilepsy pathways was assessed using gene set overrepresentation analysis. Enrichment was performed using Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Disease Ontology (DO) terms. Pathways were classified based on their relevance to epilepsy, and the involvement of specific genes was analyzed.

Results

Approximately 75% of ID-related genes were associated with epilepsy. Enriched pathways in ID-related epilepsy genes included neurotransmitter signaling, ion channel regulation, and metabolic pathways such as “nicotine addiction” and “thermogenesis.” Key genes like GRIN2A, CACNA1A, and PIGB were found to be involved in multiple pathways, suggesting their potential as therapeutic targets. DO and GO terms indicated shared and distinct mechanisms between ID and epilepsy, with significant overlap in pathways such as “intellectual disability.”

Conclusion

We performed overrepresentation analyses on curated gene sets; the results are descriptive and hypothesis-generating rather than causal. These insights provide potential targets for therapeutic interventions and highlight the need for further research into the genetic underpinnings of epilepsy in this population.

Keywords

intellectual disability - epilepsy - overrepresentation analysis - neurotransmitter signaling - pathway analysis

Contributors' Statement

All authors have seen and approved the final version of the main text.

Ethical Approval

This study was approved by the Dokuz Eylul University Faculty of Medicine Ethics Committee.

Publikationsverlauf

Eingereicht: 17. August 2025

Angenommen: 04. Dezember 2025

Accepted Manuscript online:
11. Dezember 2025

Artikel online veröffentlicht:
24. Dezember 2025

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