Identification of YWHAE, a gene encoding 14-3-3epsilon, as a possible susceptibility gene for schizophrenia.
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.
Ikeda
Masashi
M
Department of Psychiatry, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan.
Hikita
Takao
T
Taya
Shinichiro
S
Uraguchi-Asaki
Junko
J
Toyo-oka
Kazuhito
K
Wynshaw-Boris
Anthony
A
Ujike
Hiroshi
H
Inada
Toshiya
T
Takao
Keizo
K
Miyakawa
Tsuyoshi
T
Ozaki
Norio
N
Kaibuchi
Kozo
K
Iwata
Nakao
N
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*
D048948:14-3-3 Proteins; C412476:DISC1 protein, human; D009419:Nerve Tissue Proteins; C482983:YWHAE protein, human