RGS4 Polymorphisms and Neurobiology of Schizophrenia

描述(由申请人提供)：这项研究职业发展计划提出了一项培训和研究计划，旨在阐明精神分裂症患者、精神分裂症高危人群和匹配的健康受试者中G蛋白信号亚型4(RGS4)基因编码调节器的变异对体内生物学的影响。证明遗传变异和中间表型之间的关联为遗传关联提供了重要的额外支持。报道了RGS4在精神分裂症患者背外侧前额叶皮质(DLPFC)的低表达。随后，在美国、欧洲、印度和巴西的7个独立确定的人群中，RGS4基因与精神分裂症的关联被报道。我们的初步研究表明，精神分裂症患者的DLPFC较小，SNP4的等位基因T和SNP18的等位基因A纯合，但在健康受试者中不存在，提示与其他疾病相关变量存在交互作用。根据精神分裂症的神经发育假说，发病过程在临床症状出现之前就开始了。因此，研究尚未表现出精神分裂症的遗传高危人群的大脑变化可以将疾病造成的混乱降至最低。在COMT基因Val等位基因纯合的精神分裂症患者中也观察到较小的DLPFC，该基因也与精神分裂症有关。这项拟议的研究计划利用结构磁共振和磷磁共振光谱来表征这些研究组中与RGS4变异相关的形态计量和膜化学(磷单酯和磷二酯)浓度的差异。我们将探索这些成像方法与COMT基因多态之间的关系。使用“交叉纵向”设计描述中间表型有助于描绘大脑遗传多态相关者的纵向轨迹，设计新的药物和早期检测。

DESCRIPTION (provided by applicant): This Research Career Development plan proposes a program of training and research designed to clarify the in vivo biological impact of variations in the gene encoding regulator of G-protein signaling subtype 4 (RGS4) polymorphisms in schizophrenia patients, individuals at risk for schizophrenia and matched healthy subjects. Demonstrating an association between genetic variations and intermediate phenotypes provides an important additional support for genetic association. RGS4 underexpression in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia patients is reported. Subsequently, an association of RGS4 gene with schizophrenia has been reported in 7 independently ascertained populations in USA, Europe, india and Brazil. Our preliminary studies showed smaller DLPFC in schizophrenia patients homozygous for allele T of SNP4 and allele A of SNP18 but not in healthy subjects suggesting an interaction with other illness related variables. According to the neurodevelopmental hypothesis of schizophrenia pathogenic process starts prior to the emergence of clinical symptoms. Therefore, studying cerebral changes in persons at genetically high risk for developing schizophrenia who have not yet manifested the illness could minimize the confounds due to the illness. Smaller DLPFC was also observed in schizophrenia subjects homozygous for Val allele of the COMT gene that has also been associated with schizophrenia. The proposed study plans to utilize structural MRI and phosphorus magnetic resonance spectroscopy to characterize the differences in morphometry and membrane chemical (phosphomonoesters and phosphodiesters) concentrations associated with RGS4 variations in these study groups. We will explore the associations of these imaging measures with COMT polymorphisms. Characterizing intermediate phenotypes using "cross-longitudinal" design helps in delineating longitudinal trajectory of cerebral correlates of genetic polymorphisms, designing novel medications and early detection.