Identification of YWHAE, a gene encoding 14-3-3epsilon, as a possible susceptibility gene for schizophrenia

Masashi Ikeda, Takao Hikita, Shinichiro Taya, Junko Uraguchi-asaki, Kazuhito Toyo-Oka, Anthony Wynshaw-boris, Hiroshi Ujike, Toshiya Inada, Keizo Takao, T. Tsuyoshi Miyakawa, Norio Ozaki, Kozo Kaibuchi, Nakao Iwata

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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 (Pallele = 1.01 × 10-5 and Pgenotype + 4.08 × 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.

Original languageEnglish
Pages (from-to)3212-3222
Number of pages11
JournalHuman molecular genetics
Volume17
Issue number20
DOIs
Publication statusPublished - 2008

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Ikeda, M., Hikita, T., Taya, S., Uraguchi-asaki, J., Toyo-Oka, K., Wynshaw-boris, A., Ujike, H., Inada, T., Takao, K., Miyakawa, T. T., Ozaki, N., Kaibuchi, K., & Iwata, N. (2008). Identification of YWHAE, a gene encoding 14-3-3epsilon, as a possible susceptibility gene for schizophrenia. Human molecular genetics, 17(20), 3212-3222. https://doi.org/10.1093/hmg/ddn217