TY - JOUR
T1 - Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies
AU - The International League Against Epilepsy Consortium on Complex Epilepsies
AU - Abou-Khalil, Bassel
AU - Auce, Pauls
AU - Avbersek, Andreja
AU - Bahlo, Melanie
AU - Balding, David J.
AU - Bast, Thomas
AU - Baum, Larry
AU - Becker, Albert J.
AU - Becker, Felicitas
AU - Berghuis, Bianca
AU - Berkovic, Samuel F.
AU - Boysen, Katja E.
AU - Bradfield, Jonathan P.
AU - Brody, Lawrence C.
AU - Buono, Russell J.
AU - Campbell, Ellen
AU - Cascino, Gregory D.
AU - Catarino, Claudia B.
AU - Cavalleri, Gianpiero L.
AU - Cherny, Stacey S.
AU - Chinthapalli, Krishna
AU - Coffey, Alison J.
AU - Compston, Alastair
AU - Coppola, Antonietta
AU - Cossette, Patrick
AU - Craig, John J.
AU - de Haan, Gerrit Jan
AU - De Jonghe, Peter
AU - de Kovel, Carolien G.F.
AU - Delanty, Norman
AU - Depondt, Chantal
AU - Devinsky, Orrin
AU - Dlugos, Dennis J.
AU - Doherty, Colin P.
AU - Elger, Christian E.
AU - Eriksson, Johan G.
AU - Ferraro, Thomas N.
AU - Feucht, Martha
AU - Francis, Ben
AU - Franke, Andre
AU - French, Jacqueline A.
AU - Freytag, Saskia
AU - Gaus, Verena
AU - Geller, Eric B.
AU - Gieger, Christian
AU - Glauser, Tracy
AU - Glynn, Simon
AU - Goldstein, David B.
AU - Gui, Hongsheng
AU - Vining, Eileen P.G.
N1 - Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-018-07524-z
DO - 10.1038/s41467-018-07524-z
M3 - Article
C2 - 30531953
AN - SCOPUS:85136267598
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5269
ER -