Skip to main content
Journal cover image

Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies.

Publication ,  Journal Article
International League Against Epilepsy Consortium on Complex Epilepsies. Electronic address: epilepsy-austin@unimelb.edu.au,
Published in: Lancet Neurol
September 2014

BACKGROUND: The epilepsies are a clinically heterogeneous group of neurological disorders. Despite strong evidence for heritability, genome-wide association studies have had little success in identification of risk loci associated with epilepsy, probably because of relatively small sample sizes and insufficient power. We aimed to identify risk loci through meta-analyses of genome-wide association studies for all epilepsy and the two largest clinical subtypes (genetic generalised epilepsy and focal epilepsy). METHODS: We combined genome-wide association data from 12 cohorts of individuals with epilepsy and controls from population-based datasets. Controls were ethnically matched with cases. We phenotyped individuals with epilepsy into categories of genetic generalised epilepsy, focal epilepsy, or unclassified epilepsy. After standardised filtering for quality control and imputation to account for different genotyping platforms across sites, investigators at each site conducted a linear mixed-model association analysis for each dataset. Combining summary statistics, we conducted fixed-effects meta-analyses of all epilepsy, focal epilepsy, and genetic generalised epilepsy. We set the genome-wide significance threshold at p<1·66 × 10(-8). FINDINGS: We included 8696 cases and 26 157 controls in our analysis. Meta-analysis of the all-epilepsy cohort identified loci at 2q24.3 (p=8·71 × 10(-10)), implicating SCN1A, and at 4p15.1 (p=5·44 × 10(-9)), harbouring PCDH7, which encodes a protocadherin molecule not previously implicated in epilepsy. For the cohort of genetic generalised epilepsy, we noted a single signal at 2p16.1 (p=9·99 × 10(-9)), implicating VRK2 or FANCL. No single nucleotide polymorphism achieved genome-wide significance for focal epilepsy. INTERPRETATION: This meta-analysis describes a new locus not previously implicated in epilepsy and provides further evidence about the genetic architecture of these disorders, with the ultimate aim of assisting in disease classification and prognosis. The data suggest that specific loci can act pleiotropically raising risk for epilepsy broadly, or can have effects limited to a specific epilepsy subtype. Future genetic analyses might benefit from both lumping (ie, grouping of epilepsy types together) or splitting (ie, analysis of specific clinical subtypes). FUNDING: International League Against Epilepsy and multiple governmental and philanthropic agencies.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Lancet Neurol

DOI

EISSN

1474-4465

Publication Date

September 2014

Volume

13

Issue

9

Start / End Page

893 / 903

Location

England

Related Subject Headings

  • Neurology & Neurosurgery
  • Humans
  • Genome-Wide Association Study
  • Epilepsy
  • 3209 Neurosciences
  • 3202 Clinical sciences
  • 1109 Neurosciences
  • 1103 Clinical Sciences
 

Citation

APA
Chicago
ICMJE
MLA
NLM
International League Against Epilepsy Consortium on Complex Epilepsies. Electronic address: epilepsy-austin@unimelb.edu.au, . (2014). Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies. Lancet Neurol, 13(9), 893–903. https://doi.org/10.1016/S1474-4422(14)70171-1
International League Against Epilepsy Consortium on Complex Epilepsies. Electronic address: epilepsy-austin@unimelb.edu.au, L. “Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies.Lancet Neurol 13, no. 9 (September 2014): 893–903. https://doi.org/10.1016/S1474-4422(14)70171-1.
International League Against Epilepsy Consortium on Complex Epilepsies. Electronic address: epilepsy-austin@unimelb.edu.au. Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies. Lancet Neurol. 2014 Sep;13(9):893–903.
International League Against Epilepsy Consortium on Complex Epilepsies. Electronic address: epilepsy-austin@unimelb.edu.au, L. “Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies.Lancet Neurol, vol. 13, no. 9, Sept. 2014, pp. 893–903. Pubmed, doi:10.1016/S1474-4422(14)70171-1.
International League Against Epilepsy Consortium on Complex Epilepsies. Electronic address: epilepsy-austin@unimelb.edu.au. Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies. Lancet Neurol. 2014 Sep;13(9):893–903.
Journal cover image

Published In

Lancet Neurol

DOI

EISSN

1474-4465

Publication Date

September 2014

Volume

13

Issue

9

Start / End Page

893 / 903

Location

England

Related Subject Headings

  • Neurology & Neurosurgery
  • Humans
  • Genome-Wide Association Study
  • Epilepsy
  • 3209 Neurosciences
  • 3202 Clinical sciences
  • 1109 Neurosciences
  • 1103 Clinical Sciences