Prioritization of epileptogenic-associated genes through comparative transcriptome analyses

Background: Gene expression in the context of epilepsy syndromes has been studied in a variety of animal epilepsy models and in human patient samples. Joint analyses of this diverse range of data and the integration of transcriptomics with genetic data may identify genes involved across syndromes. These shared genes and processes present the opportunity to classify a core set of molecular pathways relevant to epileptogenesis. Methods: Here we performed a comparative analyses of organismal models covering major induction mechanisms, sequencing technologies and animal systems to identify genes common to the two principal syndrome categories of generalized and focal epilepsies, which represent distinct pathophysiological mechanisms of seizure initiation and development. We integrated the differentially expressed genes with genome-wide association studies to identify representative models, deregulated genes across epilepsy models and associations with other diseases. Results: Models for generalised epilepsies show fewer genes are differentially expressed than those for focal epilepsies. We found no overlap across all models but a group of 25 genes were detected across all focal models. Of these LRRC8B encodes a gliotransmitter previously not implicated in epileptogenesis. Integration with human genetic data highlights two models to be particularly representative for genetic generalised epilepsy. We also demonstrate the previously recognized relation with cancers across the majority of the focal models in contrast to the generalised models. Conclusions: We suggest LRRC8B as a new gene involved in the epileptogenesis of focal seizures. Our analyses highlights pathways of particular relevance in the molecular biology of epilepsy and underscores the need for further development of generalised models.