Identification of YWHAE, a gene encoding 14-3-3epsilon, as a possible susceptibility gene for schizophrenia
Identification of YWHAE, a gene encoding 14-3-3epsilon, as a possible susceptibility gene for schizophrenia
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DOI：
10.1093/hmg/ddn217
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发表时间：
2008-10-15
影响因子：
3.5
通讯作者：
Iwata, Nakao
中科院分区：
文献类型：
--
作者：
Ikeda, Masashi;Hikita, Takao;Iwata, Nakao
精神分裂症是一种复杂的精神障碍，具有相当高的遗传性。虽然精神分裂症的病因尚不清楚，但现在广泛认为它是一种神经发育和神经退行性疾病，涉及突触的断开和紊乱。DISC 1基因是一个很有前途的候选易感基因，参与神经发育，包括大脑皮层的成熟。为了确定精神分裂症的其他易感基因，我们筛选了DISC 1相互作用分子[NudE样（NUDEL），Lissencephaly-1（LIS 1），14-3- 3 β（YWHAE），生长因子受体结合蛋白2（GRB 2）和Kinesen 1的驱动蛋白家族5A（KIF 5A）]，评估了日本人群中总共25个标签单核苷酸多态性（SNP）。我们鉴定了一个YWHAE SNP（rs 28365859），该SNP在病例和对照样本之间显示出高度显著性差异，在对照中具有更高的次要等位基因频率（在1429例病例和1728例对照中，P（等位基因）= 1.01 x 10（-5），P（基因型）= 4.08 x 10（-5））。与纯合主要等位基因受试者相比，在携带杂合和纯合次要等位基因的健康对照受试者的淋巴细胞中，14-3- 3 β的信使RNA转录和蛋白表达也增加。为了进一步研究YWHAE在精神分裂症中的潜在作用，我们研究了Ywhae（+/-）小鼠，其中14-3- 3R蛋白水平降低至野生型同窝出生小鼠的50%。这些小鼠在八臂放射状迷宫中表现出弱的工作记忆缺陷，在高架十字迷宫中表现出中度增强的焦虑样行为。我们的研究结果表明，YWHAE是一个可能的易感基因，在精神分裂症中起保护作用。
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 (P(allele) = 1.01 x 10(-5) and P(genotype) = 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.