Human Molecular Genetics Advance Access originally published online on July 24, 2008
Human Molecular Genetics 2008 17(20):3212-3222; 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 2 Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Aichi 470-1192, Japan 3 Department of Cell Pharmacology 4 Department of Psychiatry, Graduate School of Medicine, Nagoya University, Nagoya 466-8550, Japan 5 Departments of Pediatrics and Medicine, UCSD School of Medicine, La Jolla, CA 92-93-0627, USA 6 Department of Neuropsychiatry, Okayama University Graduate School of Medicine and Dentistry, Okayama 700-8558, Japan 7 Neuropsychiatric Research Institute, Seiwa Hospital, Tokyo 162-0851, Japan 8 Genetic Engineering and Functional Genomics Unit, Horizontal Medical Research Organization, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan 9 CREST Japan Science and Technology Agency, 4-1-8, Honcho, Kawaguchi 332-0012, Japan
* To whom correspondence should be addressed. Tel: +81 52 744 2074; Fax: +81 52 744 2083; Email: kaibuchi{at}med.nagoya-u.ac.jp
Received April 17, 2008; Revised June 16, 2008; Accepted July 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 = 1.01 x 10–5 and Pgenotype = 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.
The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First authors.
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