Multicentre search for genetic susceptibility loci in sporadic epilepsy syndrome and seizure types: a case-control study.
BACKGROUND
The Epilepsy Genetics (EPIGEN) Consortium was established to undertake genetic mapping analyses with augmented statistical power to detect variants that influence the development and treatment of common forms of epilepsy.


METHODS
We examined common variations across 279 prime candidate genes in 2717 case and 1118 control samples collected at four independent research centres (in the UK, Ireland, Finland, and Australia). Single nucleotide polymorphism (SNP) and combined set-association analyses were used to examine the contribution of genetic variation in the candidate genes to various forms of epilepsy.


RESULTS
We did not identify clear, indisputable common genetic risk factors that contribute to selected epilepsy subphenotypes across multiple populations. Nor did we identify risk factors for the general all-epilepsy phenotype. However, set-association analysis on the most significant p values, assessed under permutation, suggested the contribution of numerous SNPs to disease predisposition in an apparent population-specific manner. Variations in the genes KCNAB1, GABRR2, KCNMB4, SYN2, and ALDH5A1 were most notable.


CONCLUSIONS
The underlying genetic component to sporadic epilepsy is clearly complex. Results suggest that many SNPs contribute to disease predisposition in an apparently population-specific manner. However, subtle differences in phenotyping across cohorts, combined with a poor understanding of how the underlying genetic component to epilepsy aligns with current phenotypic classifications, might also account for apparent population-specific genetic risk factors. Variations across five genes warrant further study in independent cohorts to clarify the tentative association.
Cavalleri
Gianpiero L
GL
Department of Clinical Neurological Sciences and Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland Research Institute, and Division of Neurology, Beaumont Hospital, Dublin, Ireland.
Weale
Michael E
ME
Shianna
Kevin V
KV
Singh
Rinki
R
Lynch
John M
JM
Grinton
Bronwyn
B
Szoeke
Cassandra
C
Murphy
Kevin
K
Kinirons
Peter
P
O'Rourke
Deirdre
D
Ge
Dongliang
D
Depondt
Chantal
C
Claeys
Kristl G
KG
Pandolfo
Massimo
M
Gumbs
Curtis
C
Walley
Nicole
N
McNamara
James
J
Mulley
John C
JC
Linney
Kristen N
KN
Sheffield
Leslie J
LJ
Radtke
Rodney A
RA
Tate
Sarah K
SK
Chissoe
Stephanie L
SL
Gibson
Rachel A
RA
Hosford
David
D
Stanton
Alice
A
Graves
Tracey D
TD
Hanna
Michael G
MG
Eriksson
Kai
K
Kantanen
Anne-Mari
AM
Kalviainen
Reetta
R
O'Brien
Terence J
TJ
Sander
Josemir W
JW
Duncan
John S
JS
Scheffer
Ingrid E
IE
Berkovic
Samuel F
SF
Wood
Nicholas W
NW
Doherty
Colin P
CP
Delanty
Norman
N
Sisodiya
Sanjay M
SM
Goldstein
David B
DB
D000328:Adult; D016022:Case-Control Studies; D002874:Chromosome Mapping; D015331:Cohort Studies; D004827:Epilepsy / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D051664:Kv1.3 Potassium Channel / Q000235:genetics; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B / Q000235:genetics; D012640:Seizures / Q000235:genetics*; D050644:Succinate-Semialdehyde Dehydrogenase / Q000235:genetics; D016704:Synapsins / Q000235:genetics; D013577:Syndrome
C106350:GABRR2 protein, human; C097044:KCNAB1 protein, human; C410183:KCNMB4 protein, human; D051664:Kv1.3 Potassium Channel; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; D009419:Nerve Tissue Proteins; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D016704:Synapsins; C493643:ALDH5A1 protein, human; D050644:Succinate-Semialdehyde Dehydrogenase