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 - 13-10-2008

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Schizophrenia
Genes
14-3-3 Proteins
Single Nucleotide Polymorphism
GRB2 Adaptor Protein
Classical Lissencephalies and Subcortical Band Heterotopias
Alleles
Kinesin
Short-Term Memory
Gene Frequency
Mental Disorders
Neurodegenerative Diseases
Cerebral Cortex
Synapses
Healthy Volunteers
Anxiety
Lymphocytes
Messenger RNA
Population

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Ikeda, Masashi ; Hikita, Takao ; Taya, Shinichiro ; Uraguchi-asaki, Junko ; Toyo-Oka, Kazuhito ; Wynshaw-boris, Anthony ; Ujike, Hiroshi ; Inada, Toshiya ; Takao, Keizo ; Miyakawa, T. Tsuyoshi ; Ozaki, Norio ; Kaibuchi, Kozo ; Iwata, Nakao. / Identification of YWHAE, a gene encoding 14-3-3epsilon, as a possible susceptibility gene for schizophrenia. In: Human molecular genetics. 2008 ; Vol. 17, No. 20. pp. 3212-3222.
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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.",
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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, TT, 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, vol. 17, no. 20, pp. 3212-3222. https://doi.org/10.1093/hmg/ddn217

Identification of YWHAE, a gene encoding 14-3-3epsilon, as a possible susceptibility gene for schizophrenia. / Ikeda, Masashi; Hikita, Takao; Taya, Shinichiro; Uraguchi-asaki, Junko; Toyo-Oka, Kazuhito; Wynshaw-boris, Anthony; Ujike, Hiroshi; Inada, Toshiya; Takao, Keizo; Miyakawa, T. Tsuyoshi; Ozaki, Norio; Kaibuchi, Kozo; Iwata, Nakao.

In: Human molecular genetics, Vol. 17, No. 20, 13.10.2008, p. 3212-3222.

Research output: Contribution to journalArticle

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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

PY - 2008/10/13

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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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