title: Malic enzyme 2 may underlie susceptibility to adolescent-onset idiopathic generalized epilepsy.
abstract: Idiopathic generalized epilepsy (IGE) is a class of genetically determined, phenotypically related epilepsy syndromes. Linkage analysis identified a chromosome 18 locus predisposing to a number of adolescent-onset IGEs. We report a single-nucleotide polymorphism (SNP) association analysis of the region around the marker locus with the high LOD score. This analysis, which used both case-control and family-based association methods, yielded strong evidence that malic enzyme 2 (ME2) is the gene predisposing to IGE. We also observed association among subgroups of IGE syndromes. An ME2-centered nine-SNP haplotype, when present homozygously, increases the risk for IGE (odds ratio 6.1; 95% confidence interval 2.9-12.7) compared with any other genotype. Both the linkage analysis and the association analysis support recessive inheritance for the locus, which is compatible with the fact that ME2 is an enzyme. ME2 is a genome-coded mitochondrial enzyme that converts malate to pyruvate and is involved in neuronal synthesis of the neurotransmitter gamma-aminobutyric acid (GABA). The results suggest that GABA synthesis disruption predisposes to common IGE and that clinical seizures are triggered when mutations at other genes, or perhaps other insults, are present.
authors.affiliation: Division of Statistical Genetics, Department of Psychiatry, and Columbia University Genome Center, Columbia University, 722 West 168th Street, New York, NY 10032, USA. dag2005@columbia.edu
authors.forename: David A
authors.initials: DA
authors.lastname: Greenberg
authors.forename: Eftihia
authors.initials: E
authors.lastname: Cayanis
authors.forename: Lisa
authors.initials: L
authors.lastname: Strug
authors.forename: Sudhir
authors.initials: S
authors.lastname: Marathe
authors.forename: Martina
authors.initials: M
authors.lastname: Durner
authors.forename: Deb K
authors.initials: DK
authors.lastname: Pal
authors.forename: Gabriele B
authors.initials: GB
authors.lastname: Alvin
authors.forename: Irene
authors.initials: I
authors.lastname: Klotz
authors.forename: Elisa
authors.initials: E
authors.lastname: Dicker
authors.forename: Shlomo
authors.initials: S
authors.lastname: Shinnar
authors.forename: Edward B
authors.initials: EB
authors.lastname: Bromfield
authors.forename: Stanley
authors.initials: S
authors.lastname: Resor
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Cohen
authors.forename: Solomon L
authors.initials: SL
authors.lastname: Moshe
authors.forename: Cynthia
authors.initials: C
authors.lastname: Harden
authors.forename: Harriet
authors.initials: H
authors.lastname: Kang
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D002874:Chromosome Mapping; D002887:Chromosomes, Human, Pair 18; D004829:Epilepsy, Generalized / Q000235:genetics*; D005808:Genes, Recessive; D020022:Genetic Predisposition to Disease; D006801:Humans; D008126:Lod Score; D008291:Malate Dehydrogenase / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D008291:Malate Dehydrogenase; C495394:malic enzyme 2; human