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

来自神经影像学和神经病理学研究的几条证据表明，精神分裂症是一种神经发育障碍。鉴于精神分裂症的高遗传率估计（bbb80 %），在神经发育中起重要作用的基因可能参与疾病的发病机制。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可能的作用。我们利用聚合酶链反应和单链构象多态性分析在BDNF基因外显子区寻找多态性。我们在BDNF基因中检测到一个单核苷酸替换（G758A），导致氨基酸变化（Val/Met）。然后，我们在316名精神分裂症患者和343名对照组的日本样本中检测了这种多态性与精神分裂症的关联。两组间基因型及等位基因分布均无显著差异，提示G758A多态性对精神分裂症易感性无重大影响。此外，在15名精神分裂症患者的MRI样本中，我们没有发现这种多态性对脑室-脑或海马体-脑比值的显著影响。关于GDNF基因，我们检测了3'非翻译区（AGG）n三联体重复多态性在精神分裂症发病机制中的可能作用。虽然我们没有发现异常扩增的等位基因，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）中更常见（p<0.05），提示三联体重复多态性可能与精神分裂症易感性相关。由于显著性水平不是很高，需要进一步的更大样本量的研究来得出这种多态性在精神分裂症发病机制中的可能参与。

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.