Replication, reanalysis, and gene expression: ME 2 and genetic generalized epilepsy

Summary Objective Genetic generalized epilepsy ( GGE ) consists of epileptic syndromes with overlapping symptoms and is considered to be largely genetic. Previous cosegregation and association studies have pointed to malic enzyme 2 ( ME 2 ) as a candidate susceptibility gene for adolescent‐onset GGE . In this article, we present new evidence supporting ME 2 's involvement in GGE . Methods To definitively test ME 2's influence on GGE , we used 3 different approaches. First, we compared a newly recruited GGE cohort with an ethnically matched reference sample from 1000 Genomes Project, using an efficient test of association ( POPFAM +). Second, we used POPFAM+ to reanalyze a previously collected data set, wherein the original controls were replaced with ethnically matched reference samples to minimize the confounding effect of population stratification. Third, in a post hoc analysis of expression data from healthy human prefrontal cortex, we identified single nucleotide polymorphisms ( SNP s) influencing ME 2 messenger RNA ( mRNA ) expression; and then we tested those same SNP s for association with GGE in a large case‐control cohort. Results First, in the analysis of our newly recruited GGE Cohort, we found a strong association between an ME 2 SNP and GGE ( P  =   0.0006 at rs608781). Second, in the reanalysis of previously collected data, we confirmed the Greenberg et al (2005) finding of a GGE ‐associated ME 2 risk haplotype. Third, in the post hoc ME 2 expression analysis, we found evidence for a possible link between GGE and ME 2 gene expression in human brain. Significance Overall, our research, and the research of others, provides compelling evidence that ME 2 influences susceptibility to adolescent‐onset GGE .