32^nd European Neurology Congress

Genetic generalized epilepsy (GGE) is a highly heritable condition (h2=66%) consisting of epileptic syndromes with overlapping symptoms. Previous studies (both linkage and association) identified malic enzyme 2 (ME2) as a candidate susceptibility gene for adolescent-onset GGE. To definitively test ME2’s infl uence on GGE, we used three different approaches. First, we compared a newly recruited GGE cohort with an ethnically matched reference sample from 1000 genomes, using an efficient test of association (POPFAM+). Second, in a previously collected data set, we replaced the original controls with ethnically matched reference samples to minimize the confounding effect of population stratification and we used POPFAM+ in the re-analysis. Third, in a post hoc analysis of healthy human pre-frontal cortex, we identified single nucleotide polymorphisms (SNPs) influencing ME2 messenger RNA (mRNA) expression and then, we tested those same SNPs for association with GGE in a large case control cohort. In the analysis of our newly-recruited GGE Cohort, we found a strong association between an ME2 SNP and GGE (p =0.0006 at rs608781). In the re-analysis of previously collected data, we confirmed the Greenberg et al., (2005) finding of a GGE associated ME2 risk haplotype. Finally, in the post hoc ME2 expression analysis, we found evidence for a possible link between GGE and ME2 gene expression in human brain. Overall, our research (and the research of others) provides compelling evidence that ME2 influences adolescent onset GGE susceptibility.