Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies.
journal contributionposted on 2022-04-01, 14:55 authored by Gianpiero CavalleriGianpiero Cavalleri, Norman DelantyNorman Delanty, Christopher D. Whelan, Mark McCormack, Colin P. Doherty, Lisa Slattery, The International League Against Epilepsy Consortium on Complex Epilepsies
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.
European Union’s Horizon 2020 (Marie Skłodowska-Curie grant agreement No 751761); Health Research Board of Ireland (C.D.W.) (Translational Research Scholars award); Science Foundation Ireland (SFI) (16/RC/3948 and X); European Regional Development Fund; FutureNeuro industry partners; Wellcome Trust (grant 084730); Epilepsy Society, UK. NIHR (08-08-SCC); NIH R01-NS-49306-01; NIH R01-NS-053998; NIH R01-NS-064154-01; NIH: UL1TR001070; Development Fund from The Children’s Hospital of Philadelphia NHMRC Program Grant ID: 1091593; The Royal Melbourne Hospital Foundation Lottery Grant; The RMH Neuroscience Foundation; European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 279062 (EpiPGX) and 602102; Department of Health’s NIHR Biomedical Research Centers funding scheme; European Community (EC: FP6 project EPICURE: LSHM-CT-2006-037315); German Research Foundation (DFG: SA434/4-1/4-26-1, WE4896/3-1); EuroEPINOMICS Consortium (European Science Foundation/DFG: SA434/5-1, NU50/8-1, LE1030/11-1, HE5415/3-1, RO 3396/2-1); German Federal Ministry of Education and Research; National Genome Research Network (NGFNplus/EMINet: 01GS08120, and 01GS08123. IntenC, TUR 09/I10 ); The Netherlands National Epilepsy Fund (grant 04-08); EC (FP7 project EpiPGX 279062); Research Grants Council of the Hong Kong Special Administrative Region, China project numbers HKU7623/08M, HKU7747/ 07M and CUHK4466/06M; Fonds National de la Recherche Scientifique; Fondation Erasme; Université Libre de Bruxelles; GlaxoSmithKline; Nationwide Children’s hospital in Columbus, Ohio, USA; The Wellcome Trust (WT066056); The NIHR Biomedical Research Centres Scheme (P31753); Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Contract: N01HD33348); German Ministry for Education and Research (01EY1103), High Performance Center of the University of Luxembourg and Elixir-Luxembourg; Helmholtz Zentrum München – Ger
CommentsThe original article is available at www.nature.com
Published CitationCavalleri GL, Delanty N, Whelan CD, McCormack M, The International League Against Epilepsy Consortium on Complex Epilepsies. Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies. Nature Communications. 2018;9(1):5269.
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