Role of neurotrophic factors in the susceptibility to schizophrenia and its brain abnormalities

神经营养因子在精神分裂症及其脑异常易感性中的作用

• 批准号: 11670966
• 负责人: KUNUGI Hiroshi
• 金额: $ 2.24万
• 依托单位: Teikyo University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670966/
• 关键词: Schizophrenia; Neurodevelopment; Neueotrophic factor; Brain-derived neurotrophic factor; Glial cell derived neurotrophic factor; single nucleotide polymorphism; Hippocampus; Ventricular enlargement; 分子遺伝学

Several lines of evidence from neuroimaging and neuropathological studies have formulated schizophrenia as a neurodevelopmental disorder. Given the high heritability estimate of schizophrenia (>80%), genes which play an important role in neurodevelopment might be involved in the pathogenesis of the illness. We have examined the possible role of genes encoding neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and glial-cell derived neurotrophic factor (GDNF).We searched for polymorphisms in the exonic region of the BDNF gene with polymerase chain reaction and single strand conformational polymorphism analysis. We detected a single nucleotide substitution (G758A) in the BDNF gene which results in an amino acid change (Val/Met). Then we examined this polymorphism for an association with schizophrenia in a Japanese sample of 316 patients with schizophrenia and 343 controls. There was no significant difference in the genotypic or allelic distribution between the two groups, suggesting that the G758A polymorphism has no major effect on the susceptibility to schizophrenia. Furthermore, we could not detect any significant effect of this polymorphism on ventricular-brain or hippocampus-brain ratio measured with MRI in a sample of 15 schizophrenics.With regard to the GDNF gene, we examined the (AGG)n triplet repeat polymorphism in the 3' untranslated region for the possible role in the pathogenesis of schizophrenia. Although we did not find an unusually expanded allele, the 10-repeat allele (AGG)_<10> was significantly (p<0.05) more common in the schizophrenics (N=99) than in the controls (N=98), suggesting the possible relevance of the triplet repeat polymorphism to susceptibility to schizophrenia. Since the level of significance was not very high, further studies in larger sample sizes are required to conclude the possible involvement of this polymorphism in the pathogenesis of schizophrenia.

来自神经影像学和神经病理学研究的几条证据已将精神分裂症定义为一种神经发育障碍。鉴于精神分裂症的高遗传力估计（>80%），在神经发育中发挥重要作用的基因可能参与该疾病的发病机制。我们研究了编码脑源性神经营养因子（BDNF）和胶质细胞源性神经营养因子（GDNF）等神经营养因子的基因的可能作用。我们通过聚合酶链反应和单链构象多态性分析来寻找BDNF基因外显子区域的多态性。我们在 BDNF 基因中检测到单核苷酸取代 (G758A)，这会导致氨基酸变化 (Val/Met)。然后，我们在由 316 名精神分裂症患者和 343 名对照者组成的日本样本中检查了这种多态性与精神分裂症的关联。两组之间的基因型或等位基因分布没有显着差异，表明G758A多态性对精神分裂症的易感性没有重大影响。此外，我们在 15 名精神分裂症患者样本中通过 MRI 测量，未检测到该多态性对心室-大脑或海马-大脑比率有任何显着影响。关于 GDNF 基因，我们检查了 3' 非翻译区的 (AGG)n 三联体重复多态性，以了解其在精神分裂症发病机制中的可能作用。尽管我们没有发现异常扩展的等位基因，但 10 重复等位基因 (AGG)_<10> 在精神分裂症患者 (N=99) 中比在对照组 (N=98) 中显着更常见 (p<0.05)，这表明三联体重复多态性与精神分裂症易感性可能存在相关性。由于显着性水平不是很高，需要更大样本量的进一步研究来得出这种多态性可能参与精神分裂症发病机制的结论。