Investigation on candidate genes involved in pathophysiology of schizophrenia

根据精神分裂症的低谷氨酸能假说，对VGLUT1/2基因进行病例对照关联研究。在VGLUT1基因区检测到LD阻断，单倍型分析显示有显著关联(P=0.06)。IVS2+87A&GT；G与偏执型精神分裂症显著相关(P=0.01)。在VGLUT2基因区检测到两个LD区块，但单倍型频率在病例组和对照组之间无显着差异。IVS2-49G&gt；A与女性精神分裂症显著相关(P=0.02)。在Bonfferoni矫正后，这些关联并不显著。几条证据支持GFAP功能障碍参与精神分裂症发展的观点。因此，我们对GFAP基因进行了研究，发现3个SNP与精神分裂症显著相关(P&lt；0.01)。这些数据表明，神经元-神经胶质细胞相互作用的功能障碍可能在精神分裂症的易感性中起到作用。去年我们发现Reelin基因与精神分裂症呈正相关。SNPs位于内含子/外显子边界附近，可能与剪接变异有关。我们对位于SNPs附近的Reelin外显子进行了RT-PCR，检测到了新的跳跃外显子9的剪接变异体。实时定量聚合酶链式反应显示，与对照组相比，精神分裂症患者外显子9的mRNA跳跃水平升高。

We performed case-control association study for VGLUT1/2 gene based upon the hypoglutamatergic hypothesis of schizophrenia. A LD block was detected in VGLUT1 gene region and haplotype analysis showed nominally significant association (P=0.06). IVS2+87A>G displayed significant association with paranoid type schizophrenia (P=0.01). Two LD blocks were detected in VGLUT2 gene region but haplytype frequencies showed no significant different between cases and controls. IVS2-49G>A was significantly associated with female schizophrenia (P=0.02). Those associations were not significant after Bonfferoni's correction.Several lines of evidence support idea that functional disturbance of GFAP is involved in development of schizophrenia. We therefore investigated GFAP gene and 3 SNPs were significantly associated with schizophrenia (P<0.01). The data suggested that dysfunction of neuron-glia interaction could play a role in vulnerability of schizophrenia.We detected positive association between Reelin gene and schizophrenia last year. SNPs which showed significant association could be related to splicing variations since they were located near intron/exon boundary. We performed RT-PCR for the exons of Reelin near the SNPs and detected novel spliced variant skipping exon9. Real-time PCR revealed mRNA skipping exon9 was elevated in schizophrenia compared to control brains.