TY - JOUR
T1 - Identification of YWHAE, a gene encoding 14-3-3epsilon, as a possible susceptibility gene for schizophrenia
AU - Ikeda, Masashi
AU - Hikita, Takao
AU - Taya, Shinichiro
AU - Uraguchi-asaki, Junko
AU - Toyo-Oka, Kazuhito
AU - Wynshaw-boris, Anthony
AU - Ujike, Hiroshi
AU - Inada, Toshiya
AU - Takao, Keizo
AU - Miyakawa, T. Tsuyoshi
AU - Ozaki, Norio
AU - Kaibuchi, Kozo
AU - Iwata, Nakao
N1 - Funding Information:
This research was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT), a Grant-in-Aid for Creative Scientific Research from Japan Society for the Promotion of Science, the MEXT 21st Century Center of Excellence Program, a research grant for Nervous and Mental Disorders from the Ministry of Health, Labour and Welfare, a Grant-in-Aid for Scientific Research on Pathomechanisms of Brain Disorders from the MEXT (17025021), the Japan Health Sciences Foundation (Research on Health Sciences Focusing on Drug Innovation), the Core Research for Evolutional Science and Technology, Grant-in-Aid for Scientific Research on Priority Areas— Integrative Brain Research (Shien)—from MEXT in Japan, Grant-in-Aid from Neuroinformatics Japan Center (NIJC), RIKEN and Grant-in-Aid from Institute for Bioinformatics Research and Development (BIRD) of Japan Science and Technology Agency (JST).
PY - 2008
Y1 - 2008
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/ddn217
DO - 10.1093/hmg/ddn217
M3 - Article
C2 - 18658164
AN - SCOPUS:53349156385
SN - 0964-6906
VL - 17
SP - 3212
EP - 3222
JO - Human molecular genetics
JF - Human molecular genetics
IS - 20
ER -