title: Genome-wide analysis of differential RNA editing in epilepsy.
abstract: The recoding of genetic information through RNA editing contributes to proteomic diversity, but the extent and significance of RNA editing in disease is poorly understood. In particular, few studies have investigated the relationship between RNA editing and disease at a genome-wide level. Here, we developed a framework for the genome-wide detection of RNA sites that are differentially edited in disease. Using RNA-sequencing data from 100 hippocampi from mice with epilepsy (pilocarpine-temporal lobe epilepsy model) and 100 healthy control hippocampi, we identified 256 RNA sites (overlapping with 87 genes) that were significantly differentially edited between epileptic cases and controls. The degree of differential RNA editing in epileptic mice correlated with frequency of seizures, and the set of genes differentially RNA-edited between case and control mice were enriched for functional terms highly relevant to epilepsy, including "neuron projection" and "seizures." Genes with differential RNA editing were preferentially enriched for genes with a genetic association to epilepsy. Indeed, we found that they are significantly enriched for genes that harbor nonsynonymous de novo mutations in patients with epileptic encephalopathy and for common susceptibility variants associated with generalized epilepsy. These analyses reveal a functional convergence between genes that are differentially RNA-edited in acquired symptomatic epilepsy and those that contribute risk for genetic epilepsy. Taken together, our results suggest a potential role for RNA editing in the epileptic hippocampus in the occurrence and severity of epileptic seizures.
authors.affiliation: Division of Brain Sciences, Imperial College Faculty of Medicine, London W12 0NN, United Kingdom.
authors.forename: Prashant Kumar
authors.initials: PK
authors.lastname: Srivastava
authors.affiliation: Centre for Complement and Inflammation Research (CCIR), Imperial College London, London W12 0NN, United Kingdom.
authors.forename: Marta
authors.initials: M
authors.lastname: Bagnati
authors.affiliation: Division of Brain Sciences, Imperial College Faculty of Medicine, London W12 0NN, United Kingdom.
authors.forename: Andree
authors.initials: A
authors.lastname: Delahaye-Duriez
authors.affiliation: Centre for Complement and Inflammation Research (CCIR), Imperial College London, London W12 0NN, United Kingdom.
authors.forename: Jeong-Hun
authors.initials: JH
authors.lastname: Ko
authors.affiliation: Institut Pasteur, Unit of Human Evolutionary Genetics, Paris 75015, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Rotival
authors.affiliation: Duke-NUS Medical School, Singapore 169857, 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 W12 0NN, United Kingdom.
authors.forename: Kirill
authors.initials: K
authors.lastname: Shkura
authors.affiliation: Neuroscience TA, UCB Pharma, 1420 Braine-l'Alleud, Belgium.
authors.forename: Manuela
authors.initials: M
authors.lastname: Mazzuferi
authors.affiliation: Neuroscience TA, UCB Pharma, 1420 Braine-l'Alleud, Belgium.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Danis
authors.affiliation: Neuroscience TA, UCB Pharma, 1420 Braine-l'Alleud, Belgium.
authors.forename: Jonathan
authors.initials: J
authors.lastname: van Eyll
authors.affiliation: Neuroscience TA, UCB Pharma, 1420 Braine-l'Alleud, Belgium.
authors.forename: Patrik
authors.initials: P
authors.lastname: Foerch
authors.affiliation: Centre for Complement and Inflammation Research (CCIR), Imperial College London, London W12 0NN, United Kingdom.
authors.forename: Jacques
authors.initials: J
authors.lastname: Behmoaras
authors.affiliation: Neuroscience TA, UCB Pharma, 1420 Braine-l'Alleud, Belgium.
authors.forename: Rafal M
authors.initials: RM
authors.lastname: Kaminski
authors.affiliation: Duke-NUS Medical School, Singapore 169857, Republic of Singapore.
authors.forename: Enrico
authors.initials: E
authors.lastname: Petretto
authors.affiliation: Division of Brain Sciences, Imperial College Faculty of Medicine, London W12 0NN, United Kingdom.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Johnson
mesh_terms: D000818:Animals; D004827:Epilepsy / Q000235:genetics*; D055106:Genome-Wide Association Study; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D051379:Mice; D017393:RNA Editing; D059467:Transcriptome