[en] Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6 and 90 of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.
Centre de recherche :
Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Disciplines :
Génétique & processus génétiques Neurologie
Auteur, co-auteur :
Stevelink, Remi
Campbell, Ciarán
Chen, Siwei
Abou-Khalil, Bassel
Adesoji, Oluyomi M.
Afawi, Zaid
Amadori, Elisabetta
Anderson, Alison
Anderson, Joseph
Andrade, Danielle M.
Annesi, Grazia
Auce, Pauls
Avbersek, Andreja
Bahlo, Melanie
Baker, Mark D.
Balagura, Ganna
Balestrini, Simona
Barba, Carmen
Barboza, Karen
Bartolomei, Fabrice
Bast, Thomas
Baum, Larry
Baumgartner, Tobias
Baykan, Betül
Bebek, Nerses
Becker, Albert J.
Becker, Felicitas
Bennett, Caitlin A.
Berghuis, Bianca
Berkovic, Samuel F.
Beydoun, Ahmad
Bianchini, Claudia
Bisulli, Francesca
Blatt, Ilan
BOBBILI, Dheeraj Reddy ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
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