Journal Article

Identification of <i>YWHAE</i>, 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, Tsuyoshi Miyakawa, Norio Ozaki, Kozo Kaibuchi and Nakao Iwata

in Human Molecular Genetics

Volume 17, issue 20, pages 3212-3222
Published in print October 2008 | ISSN: 0964-6906
Published online July 2008 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddn217
Identification of YWHAE, a gene encoding 14-3-3epsilon, as a possible susceptibility gene for schizophrenia

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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.

Journal Article.  6314 words.  Illustrated.

Subjects: Genetics and Genomics

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