Examining the role of common genetic variation in the gamma2 subunit of the GABA(A) receptor in epilepsy using tagging SNPs.
BACKGROUND
Mutations in the gamma2 subunit gene of the GABA(A) receptor, GABRG2, have been shown to cause generalised epilepsy syndromes in rare familial cases. Here we set out to examine whether common variation in GABRG2 predisposes to the development of common, complex forms of epilepsy in two large independent cohorts.


METHODS
We have applied a tagging single nucleotide polymorphism (tSNP) technique allowing us to satisfactorily represent common variation in the gene. However, to ensure maximal representation of functional variation and in particular in cases of low minor allele frequency (MAF), we have identified and forced known functional variation as tagging SNPs. We examined the association between tagging SNPs and subtypes of epilepsy in two independent cohorts; the first consisted of 677 cases and 384 healthy controls, the second of 684 cases and 277 healthy controls.


RESULTS
We failed to detect any variation that conferred an increased risk of disease development in both cohorts.


CONCLUSIONS
Our results suggest that common variants of strong effect in GABRG2 do not appear to play a role in the development of common, complex forms of epilepsy. This report illustrates a number of important features of study design in genetic association studies, including the simultaneous use of map and sequence-based techniques and the necessity of replication before robust conclusions can be drawn from results.
Kinirons
Peter
P
Department of Clinical Neurological Sciences, Royal College of Surgeons in Ireland, Division of Neurology, Beaumont Hospital, Dublin 9, Ireland. petkiniron@rcsi.ie
Cavalleri
Gianpiero L
GL
Shahwan
Amre
A
Wood
Nicholas W
NW
Goldstein
David B
DB
Sisodiya
Sanjay M
SM
Delanty
Norman
N
Doherty
Colin P
CP
D000483:Alleles; D004827:Epilepsy / Q000145:classification / Q000235:genetics*; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011963:Receptors, GABA-A / Q000235:genetics*
C546279:GABRG2 protein, human; D011963:Receptors, GABA-A