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已经将精神分裂症确定为神经发育障碍。鉴于精神分裂症的高遗传率估计（>80%），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。我们研究了编码神经营养因子如脑源性神经营养因子（brain-derived neurotrophic factor，BDNF）和胶质细胞源性神经营养因子（glial-cell derived neurotrophic factor，GDNF）的基因的可能作用。我们在BDNF基因中检测到一个单核苷酸取代（G758 A），导致氨基酸变化（瓦尔/Met）。然后，我们在日本的316名精神分裂症患者和343名对照样本中研究了这种多态性与精神分裂症的关联。两组的基因型和等位基因分布差异无统计学意义，提示G758 A多态性对精神分裂症的易感性无显著影响。此外，我们不能检测到任何显着的影响，这一多态性对脑室-脑或脑室-脑MRI测量的15例精神分裂症患者的样本中的比例。关于GDNF基因，我们研究了（AGG）n三联重复多态性在3'非翻译区的可能作用，在精神分裂症的发病机制。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>在精神分裂症组（N=99）中比对照组（N=98）显著（p&lt;0.05）更常见，提示三联体重复多态性与精神分裂症易感性可能相关。由于显着性水平不是很高，进一步的研究，在更大的样本量，需要得出结论，这种多态性在精神分裂症的发病机制可能参与。

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.