Human Molecular Genetics Advance Access published online on July 24, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn217
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Identification of YWHAE, a gene encoding 14-3-3epsilon, as a possible susceptibility gene for schizophrenia
1 Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi 470-1192, Japan 2 Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan 3 Departments of Pediatrics and Medicine, UCSD School of Medicine, La Jolla, California 92-93-0627, USA. 4 Department of Neuropsychiatry, Okayama University Graduate School of Medicine and Dentistry, Okayama, 700-8558, Japan 5 Neuropsychiatric Research Institute, Seiwa Hospital, Tokyo, 162-0851, Japan 6 Genetic Engineering and Functional Genomics Unit, Horizontal Medical Research Organization, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan 7 Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan 8 Department of Psychiatry, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan 9 CREST Japan Science and Technology Agency, 4-1-8, Honcho, Kawaguchi, 332-0012 Japan
* Correspondence and proofs: Kozo Kaibuchi Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan Tel: +81-52-744-2076; Fax: +81-52-744-2083 E-mail: kaibuchi{at}med.nagoya-u.ac.jp
Received April 17, 2008; Revised June 16, 2008; Accepted June 23, 2008
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=1.01x10–5 and Pgenotype=4.08x10–5 in 1,429 cases and 1,728 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.
The first three authors should be regarded as joint first authors.
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