Identification of YWHAE, a gene encoding 14-3-3epsilon, as a possible susceptibility gene for schizophrenia
| Autor: | Hiroshi Ujike, Takao Hikita, Junko Uraguchi-Asaki, Toshiya Inada, Keizo Takao, Masashi Ikeda, Tsuyoshi Miyakawa, Nakao Iwata, Anthony Wynshaw-Boris, Kazuhito Toyo-oka, Norio Ozaki, Shinichiro Taya, Kozo Kaibuchi |
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| Rok vydání: | 2008 |
| Předmět: |
Heterozygote
Psychosis Gene Expression Nerve Tissue Proteins Single-nucleotide polymorphism CHO Cells Anxiety Biology Polymorphism Single Nucleotide Linkage Disequilibrium Mice DISC1 Cricetulus Gene Frequency Japan Cricetinae Chlorocebus aethiops Genotype Genetics medicine Animals Humans Genetic Predisposition to Disease Allele Maze Learning Promoter Regions Genetic Molecular Biology YWHAE Causes of schizophrenia Alleles Genetics (clinical) Mice Knockout Homozygote General Medicine medicine.disease Minor allele frequency Disease Models Animal 14-3-3 Proteins Case-Control Studies COS Cells Schizophrenia biology.protein |
| Zdroj: | Human Molecular Genetics. 17:3212-3222 |
| ISSN: | 1460-2083 0964-6906 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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