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Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies

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Title: Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies
Authors: The International League Against Epilepsy Consortium on Complex Epilepsies
Item Type: Journal Article
Abstract: The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology.
Issue Date: 31-Dec-2018
Date of Acceptance: 30-Oct-2018
URI: http://hdl.handle.net/10044/1/65058
DOI: https://dx.doi.org/10.1038/s41467-018-07524-z
ISSN: 2041-1723
Publisher: Nature Research (part of Springer Nature)
Journal / Book Title: Nature Communications
Volume: 9
Issue: 1
Copyright Statement: © 2018 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Sponsor/Funder: Wellcome Trust
GlaxoSmithKline Services Unlimited
Commission of the European Communities
Medical Research Council (MRC)
Imperial College Healthcare NHS Trust- BRC Funding
Funder's Grant Number: 066056/Z/01/Z
Keywords: MD Multidisciplinary
Publication Status: Published
Article Number: 5269
Online Publication Date: 2018-12-10
Appears in Collections:Department of Medicine (up to 2019)