title: Identification of YWHAE, a gene encoding 14-3-3epsilon, as a possible susceptibility gene for schizophrenia.
abstract: Schizophrenia is a complex mental disorder with a fairly high degree of heritability. Although the causes of schizophrenia remain unclear, it is now widely accepted that it is a neurodevelopmental and neurodegenerative disorder involving disconnectivity and disorder of the synapses. Disrupted-in-schizophrenia 1 (DISC1) is a promising candidate susceptibility gene involved in neurodevelopment, including maturation of the cerebral cortex. To identify other susceptibility genes for schizophrenia, we screened for DISC1-interacting molecules [NudE-like (NUDEL), Lissencephaly-1 (LIS1), 14-3-3epsilon (YWHAE), growth factor receptor bound protein 2 (GRB2) and Kinesin family 5A of Kinesen1 (KIF5A)], assessing a total of 25 tagging single-nucleotide polymorphisms (SNPs) in a Japanese population. We identified a YWHAE SNP (rs28365859) that showed a highly significant difference between case and control samples, with higher minor allele frequencies in controls (P(allele) = 1.01 x 10(-5) and P(genotype) = 4.08 x 10(-5) in 1429 cases and 1728 controls). Both messenger RNA transcription and protein expression of 14-3-3epsilon were also increased in the lymphocytes of healthy control subjects harboring heterozygous and homozygous minor alleles compared with homozygous major allele subjects. To further investigate a potential role for YWHAE in schizophrenia, we studied Ywhae(+/-) mice in which the level of 14-3-3epsilon protein is reduced to 50% of that in wild-type littermates. These mice displayed weak defects in working memory in the eight-arm radial maze and moderately enhanced anxiety-like behavior in the elevated plus-maze. Our results suggest that YWHAE is a possible susceptibility gene that functions protectively in schizophrenia.
authors.affiliation: Department of Psychiatry, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Ikeda
authors.forename: Takao
authors.initials: T
authors.lastname: Hikita
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Taya
authors.forename: Junko
authors.initials: J
authors.lastname: Uraguchi-Asaki
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Toyo-oka
authors.forename: Anthony
authors.initials: A
authors.lastname: Wynshaw-Boris
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ujike
authors.forename: Toshiya
authors.initials: T
authors.lastname: Inada
authors.forename: Keizo
authors.initials: K
authors.lastname: Takao
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Miyakawa
authors.forename: Norio
authors.initials: N
authors.lastname: Ozaki
authors.forename: Kozo
authors.initials: K
authors.lastname: Kaibuchi
authors.forename: Nakao
authors.initials: N
authors.lastname: Iwata
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics* / Q000502:physiology; D000483:Alleles; D000818:Animals; D001007:Anxiety / Q000235:genetics; D016466:CHO Cells; D019556:COS Cells; D016022:Case-Control Studies; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D015870:Gene Expression; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007564:Japan; D015810:Linkage Disequilibrium; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012559:Schizophrenia / Q000209:etiology / Q000235:genetics*
chemical_list: D048948:14-3-3 Proteins; C412476:DISC1 protein, human; D009419:Nerve Tissue Proteins; C482983:YWHAE protein, human