Abstract
BackgroundThe relationship between monogenic and polygenic forms of epilepsy is poorly understood and the extent to which the genetic and acquired epilepsies share common pathways is unclear. Here, we use an integrated systems-level analysis of brain gene expression data to identify molecular networks disrupted in epilepsy.ResultsWe identified a co-expression network of 320 genes (M30), which is significantly enriched for non-synonymous de novo mutations ascertained from patients with monogenic epilepsy and for common variants associated with polygenic epilepsy. The genes in the M30 network are expressed widely in the human brain under tight developmental control and encode physically interacting proteins involved in synaptic processes. The most highly connected proteins within the M30 network were preferentially disrupted by deleterious de novo mutations for monogenic epilepsy, in line with the centrality-lethality hypothesis. Analysis of M30 expression revealed consistent downregulation in the epileptic brain in heterogeneous forms of epilepsy including human temporal lobe epilepsy, a mouse model of acquired temporal lobe epilepsy, and a mouse model of monogenic Dravet (SCN1A) disease. These results suggest functional disruption of M30 via gene mutation or altered expression as a convergent mechanism regulating susceptibility to epilepsy broadly. Using the large collection of drug-induced gene expression data from Connectivity Map, several drugs were predicted to preferentially restore the downregulation of M30 in epilepsy toward health, most notably valproic acid, whose effect on M30 expression was replicated in neurons.ConclusionsTaken together, our results suggest targeting the expression of M30 as a potential new therapeutic strategy in epilepsy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-016-1097-7) contains supplementary material, which is available to authorized users.
Highlights
The relationship between monogenic and polygenic forms of epilepsy is poorly understood and the extent to which the genetic and acquired epilepsies share common pathways is unclear
As a proof of concept, we show that among the drugs capable of inducing transcriptional changes in cells of the Connectivity map (Cmap) dataset, valproic acid (VPA), a widely used antiepileptic drugs (AEDs) with a broad spectrum of clinical efficacy, is the one that is most significantly predicted to restore the expression of M30 in epilepsy toward health
We used 88 post-mortem human brains from the UK Brain Expression Consortium (UKBEC) [29], where genome-wide gene expression had been assessed across nine brains regions: cerebellar cortex, temporal cortex, frontal cortex, occipital cortex, hippocampus, thalamus, white matter, medulla, and putamen
Summary
The relationship between monogenic and polygenic forms of epilepsy is poorly understood and the extent to which the genetic and acquired epilepsies share common pathways is unclear. Analysis of genetic epilepsy segregating in a Mendelian fashion using traditional linkage analysis led to the identification of several genes for epilepsy (reviewed in [11, 12]). The majority of these Mendelian idiopathic epilepsy genes encode ion channel subunits leading to the concept of the genetic epilepsies as ‘ion channelopathies’. The application of next-generation sequencing to the epileptic encephalopathies (EE), a group of severe childhoodonset epilepsies associated with refractory seizures and intellectual disability (ID), have underscored the importance of synaptic dysfunction in epilepsy and established de novo mutagenesis as a major genetic mechanism for EE [13, 14]
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