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

The International League Against Epilepsy Consortium on Complex Epilepsies

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Article number5269
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

Fingerprint

epilepsy
genome
loci
Epilepsy
Genes
Genome
genes
Vitamin B 6
Ion Channels
Metabolism
Gene expression
Anticonvulsants
Generalized Epilepsy
Brain
vitamins
Transcription Factors
Gene Expression Regulation
gene expression
Epigenomics
metabolism

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies. / The International League Against Epilepsy Consortium on Complex Epilepsies.

In: Nature Communications, Vol. 9, No. 1, 5269, 01.12.2018.

Research output: Contribution to journalArticle

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. In: Nature Communications. 2018 ; Vol. 9, No. 1.
@article{5046818ab41d45a78f611e9c99b7ea0b,
title = "Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies",
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.",
author = "{The International League Against Epilepsy Consortium on Complex Epilepsies} and Bassel Abou-Khalil and Pauls Auce and Andreja Avbersek and Melanie Bahlo and Balding, {David J.} and Thomas Bast and Larry Baum and Becker, {Albert J.} and Felicitas Becker and Bianca Berghuis and Berkovic, {Samuel F.} and Boysen, {Katja E.} and Bradfield, {Jonathan P.} and Brody, {Lawrence C.} and Buono, {Russell J.} and Ellen Campbell and Cascino, {Gregory D.} and Catarino, {Claudia B.} and Cavalleri, {Gianpiero L.} and Cherny, {Stacey S.} and Krishna Chinthapalli and Coffey, {Alison J.} and Alastair Compston and Antonietta Coppola and Patrick Cossette and Craig, {John J.} and {de Haan}, {Gerrit Jan} and {De Jonghe}, Peter and {de Kovel}, {Carolien G.F.} and Norman Delanty and Chantal Depondt and Orrin Devinsky and Dlugos, {Dennis J.} and Doherty, {Colin P.} and Elger, {Christian E.} and Eriksson, {Johan G.} and Ferraro, {Thomas N.} and Martha Feucht and Ben Francis and Andre Franke and French, {Jacqueline A.} and Saskia Freytag and Verena Gaus and Geller, {Eric B.} and Christian Gieger and Tracy Glauser and Simon Glynn and Goldstein, {David B.} and Hongsheng Gui and Haut, {Sheryl R.}",
year = "2018",
month = "12",
day = "1",
doi = "10.1038/s41467-018-07524-z",
language = "English (US)",
volume = "9",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

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 - Haut, Sheryl R.

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.

UR - http://www.scopus.com/inward/record.url?scp=85058169154&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85058169154&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-07524-z

DO - 10.1038/s41467-018-07524-z

M3 - Article

C2 - 30531953

AN - SCOPUS:85058169154

VL - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 5269

ER -