Identifying the biological pathways underlying human focal epilepsy: from complexity to coherence to centrality

Mirza, N. et al. (2015) Identifying the biological pathways underlying human focal epilepsy: from complexity to coherence to centrality. Human Molecular Genetics, 24(15), pp. 4306-4316. (doi:10.1093/hmg/ddv163) (PMID:25941323)

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Abstract

Numerous diverse biological pathways are dysregulated in the epileptic focus. Which of these pathways are most critical in producing the biological abnormalities that lead to epilepsy? Answering this question is key to identifying the primary causes of epilepsy and for discovering new therapeutic strategies with greater efficacy than currently available antiepileptics (AEDs). We have performed the largest genome-wide transcriptomic analysis to date comparing epileptic with normal human hippocampi. We have identified 118 differentially expressed and, for the first time, differentially connected pathways in the epileptic focus. Using network mapping techniques, we have shown that these dysregulated pathways, though seemingly disparate, form a coherent interconnected central network. Using closeness centrality analysis, we have identified that the most influential hub pathways in this network are signalling through G protein-coupled receptors, in particular opioid receptors, and their downstream effectors PKA/CREB and DAG/IP3. Next, we have objectively demonstrated that genetic association of gene sets in independent genome-wide association studies (GWASs) can be used to identify causally relevant gene sets: we show that proven causal epilepsy genes, which cause familial Mendelian epilepsy syndromes, are associated in published sporadic epilepsy GWAS results. Using the same technique, we have shown that central pathways identified (opioid receptor and PKA/CREB and DAG/IP3 signalling pathways) are genetically associated with focal epilepsy and, hence, likely causal. Published functional studies in animal models provide evidence of a role for these pathways in epilepsy. Our work shows that these pathways play a central role in human focal epilepsy and that they are important currently unexploited antiepileptic drug targets.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Sills, Dr Graeme
Authors: Mirza, N., Appleton, R., Burn, S., Carr, D., Crooks, D., du Plessis, D., Duncan, R., Farah, J. O., Josan, V., Miyajima, F., Mohanraj, R., Shukralla, A., Sills, G. J., Marson, A. G., and Pirmohamed, M.
College/School:College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:Human Molecular Genetics
Publisher:Oxford University Press
ISSN:0964-6906
ISSN (Online):1460-2083
Published Online:04 May 2015

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