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Replication, reanalysis, and gene expression: ME 2 and genetic generalized epilepsy
Author(s) -
Wang Meng,
Greenberg David A.,
Stewart William C. L.
Publication year - 2019
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.14654
Subject(s) - population stratification , single nucleotide polymorphism , confounding , genetics , biology , genome wide association study , genetic association , snp , population , haplotype , cohort , idiopathic generalized epilepsy , gene , psychology , epilepsy , allele , genotype , neuroscience , medicine , environmental health
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 .