期刊
HUMAN MOLECULAR GENETICS
卷 17, 期 20, 页码 3212-3222出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddn217
关键词
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资金
- Ministry of Education, Culture, Sports, Science and Technology of Japan [17025021]
- Japan Society for the Promotion of Science
- 21st Century Center of Excellence Program
- Ministry of Health, Labour and Welfare
- Japan Health Sciences Foundation (Research on Health Sciences Focusing on Drug Innovation)
- Neuroinformatics Japan Center (NIJC), RIKEN
- nstitute for Bioinformatics Research and Development (BIRD)
- Japan Science and Technology Agency (JST)
- Grants-in-Aid for Scientific Research [17025021] Funding Source: KAKEN
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.
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