Abstracts

Mutations in the gamma 2 subunit of the GABA A receptor (GABAG2) have been reported to cause familial epilepsy syndromes, including febrile seizures, childhood absence epilepsy and generalised epilepsy with febrile seizures plus (GEFS+). We wanted to investigate the role of polymorphic variation in this gene in sporadic epilepsy patients. However, frustrated with published association studies using small cohorts and limited single nucleotide polymorhisms (SNPS) which have since failed replication, we wanted to design a study that would conclusively prove or reject our hypothesis.We therefore used haplotype tagging SNPS to capture all common variation in the gene and performed the analysis in one large cohort before replicating any positive findings in a second large cohort. Over 1300 patients were enrolled from the epilepsy clinics at the two centres along with almost 800 controls. Phenotypic information was recorded and stored in a secure linked anonymized database. We identified 6 tagging SNPS sufficient to capture common variation across the gene. We first genotyped these SNPS in the Irish cohort and looked for association with disease at a single SNP and haplotype level. Positive results were then carried forward for analysis in the UK cohort A trend towards significance was observed for two loci (p between 0.15 and 0.01) and one common haplotype (p=0.13) in Irish patients with idiopathic generalized epilepsy. No significant associations were obseved for other types of epilepsy, including patients with febrile seizures. However when we performed the analysis in the UK cohort we were unable to replicate these trends. In fact the risk allele of one SNP in the Irish cohort appeared to be protective in the UK cohort. We therefore consider the findings in the Irish cohorts false positives. This study illustrates the importance of study design in genetic assocaition studies. Large cohorts of well phenotyped cases and controls are required and replication of positive findings prior to publication is essential to avoid unnecessary cost and effort by other groups. Based on this study we can conclude that polymorphic variation in this gene does not play a significant role in the development of sporadic epilepsy.