title: Rare and common epilepsies converge on a shared gene regulatory network providing opportunities for novel antiepileptic drug discovery.
abstract: 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. Here, we use an integrated systems-level analysis of brain gene expression data to identify molecular networks disrupted in epilepsy.
  
  
  
  We 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.
  
  
  
  Taken together, our results suggest targeting the expression of M30 as a potential new therapeutic strategy in epilepsy.
authors.affiliation: Division of Brain Sciences, Imperial College Faculty of Medicine, London, UK. a.delahaye-duriez@imperial.ac.uk.|MRC Clinical Sciences Centre, Imperial College London, London, UK. a.delahaye-duriez@imperial.ac.uk.|Université Paris 13, Sorbonne Paris Cité, UFR de Santé, Médecine et Biologie Humaine, Paris, France. a.delahaye-duriez@imperial.ac.uk.|PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France. a.delahaye-duriez@imperial.ac.uk.
authors.forename: Andree
authors.identifier: 0000-0003-4324-7372
authors.initials: A
authors.lastname: Delahaye-Duriez
authors.affiliation: Division of Brain Sciences, Imperial College Faculty of Medicine, London, UK.
authors.forename: Prashant
authors.initials: P
authors.lastname: Srivastava
authors.affiliation: Division of Brain Sciences, Imperial College Faculty of Medicine, London, UK.
authors.forename: Kirill
authors.initials: K
authors.lastname: Shkura
authors.affiliation: Division of Brain Sciences, Imperial College Faculty of Medicine, London, UK.|Duke-NUS Medical School, 8 College Road, 169857, Singapore, Republic of Singapore.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Langley
authors.affiliation: Division of Brain Sciences, Imperial College Faculty of Medicine, London, UK.
authors.forename: Liisi
authors.initials: L
authors.lastname: Laaniste
authors.affiliation: MRC Clinical Sciences Centre, Imperial College London, London, UK.|Duke-NUS Medical School, 8 College Road, 169857, Singapore, Republic of Singapore.
authors.forename: Aida
authors.initials: A
authors.lastname: Moreno-Moral
authors.affiliation: Neuroscience TA, UCB Pharma, S.A, Allée de la Recherche, 60, 1070, Brussels, Belgium.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Danis
authors.affiliation: Neuroscience TA, UCB Pharma, S.A, Allée de la Recherche, 60, 1070, Brussels, Belgium.
authors.forename: Manuela
authors.initials: M
authors.lastname: Mazzuferi
authors.affiliation: Neuroscience TA, UCB Pharma, S.A, Allée de la Recherche, 60, 1070, Brussels, Belgium.
authors.forename: Patrik
authors.initials: P
authors.lastname: Foerch
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, 3052, Australia.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Gazina
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, 3052, Australia.
authors.forename: Kay
authors.initials: K
authors.lastname: Richards
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, 3052, Australia.|The Centre for Neural Engineering, The Department of Electrical Engineering, The University of Melbourne, Parkville, Victoria, 3052, Australia.|The Australian Research Council Centre of Excellence for Integrative Brain Function, Parkville, Victoria, 3052, Australia.
authors.forename: Steven
authors.initials: S
authors.lastname: Petrou
authors.affiliation: Neuroscience TA, UCB Pharma, S.A, Allée de la Recherche, 60, 1070, Brussels, Belgium.
authors.forename: Rafal M
authors.initials: RM
authors.lastname: Kaminski
authors.affiliation: MRC Clinical Sciences Centre, Imperial College London, London, UK. enrico.petretto@duke-nus.edu.sg.|Duke-NUS Medical School, 8 College Road, 169857, Singapore, Republic of Singapore. enrico.petretto@duke-nus.edu.sg.
authors.forename: Enrico
authors.initials: E
authors.lastname: Petretto
authors.affiliation: Division of Brain Sciences, Imperial College Faculty of Medicine, London, UK. m.johnson@imperial.ac.uk.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Johnson
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use; D004195:Disease Models, Animal; D055808:Drug Discovery; D004827:Epilepsy / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D004833:Epilepsy, Temporal Lobe / Q000235:genetics* / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics; D053263:Gene Regulatory Networks / Q000235:genetics*; D006801:Humans; D051379:Mice; D020412:Multifactorial Inheritance / Q000235:genetics; D009154:Mutation; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics
chemical_list: D000927:Anticonvulsants; D062550:NAV1.1 Voltage-Gated Sodium Channel; C568249:Scn1a protein, mouse
keywords: Co-expression; Epilepsy; Epileptic encephalopathy; Protein-protein interactions; Regulatory network; SCN1A; Systems genetics; Valproic acid