Identifying the biological pathways underlying human focal epilepsy: from complexity to coherence to centrality.
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.
Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3GL, UK, nasir.mirza@liv.ac.uk.
Nasir
N
Mirza
The Roald Dahl EEG Unit, Paediatric Neurosciences Foundation, Alder Hey Children's NHS Foundation Trust, Liverpool L12 2AP, UK.
Richard
R
Appleton
Department of Neurosurgery, Alder Hey Children's NHS Foundation Trust, Liverpool L12 2AP, UK.
Sasha
S
Burn
Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3GL, UK.
Daniel
D
Carr
Department of Neuropathology, the Walton Centre NHS Foundation Trust, Liverpool L9 7LJ, UK.
Daniel
D
Crooks
Department of Cellular Pathology, Salford Royal NHS Foundation Trust, Salford M6 8HD, UK.
Daniel
D
du Plessis
Department of Neurology, Christchurch Hospital, Private Bag 4710, Christchurch 8140, New Zealand.
Roderick
R
Duncan
Department of Neurosurgery, the Walton Centre NHS Foundation Trust, Liverpool L9 7LJ, UK.
Jibril Osman
JO
Farah
Department of Neurosurgery, Salford Royal NHS Foundation Trust, Salford M6 8HD, UK and.
Vivek
V
Josan
Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3GL, UK.
Fabio
F
Miyajima
Department of Neurology, Salford Royal NHS Foundation Trust, Salford M6 8HD, UK.
Rajiv
R
Mohanraj
Department of Neurology, Salford Royal NHS Foundation Trust, Salford M6 8HD, UK.
Arif
A
Shukralla
Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3GL, UK.
Graeme J
GJ
Sills
Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3GL, UK.
Anthony G
AG
Marson
Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3GL, UK.
Munir
M
Pirmohamed
D004828:Epilepsies, Partial / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015398:Signal Transduction