RGS4 Polymorphisms and Neurobiology of Schizophrenia

描述（由申请人提供）：本研究职业发展计划提出了一个培训和研究项目，旨在阐明精神分裂症患者、精神分裂症风险个体和匹配的健康受试者中g蛋白信号传导亚型4 （RGS4）多态性基因编码调节因子变异的体内生物学影响。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。RGS4在精神分裂症患者的背外侧前额叶皮层（DLPFC）中表达不足。随后，在美国、欧洲、印度和巴西的7个独立确定的人群中报道了RGS4基因与精神分裂症的关联。我们的初步研究表明，精神分裂症患者的DLPFC较小，与SNP4的等位基因T和SNP18的等位基因A纯合，但在健康受试者中没有，这表明与其他疾病相关变量相互作用。根据精神分裂症的神经发育假说，发病过程早于临床症状的出现。因此，研究尚未表现出精神分裂症的精神分裂症遗传高风险人群的大脑变化，可以最大限度地减少因疾病引起的混淆。在精神分裂症患者中也观察到较小的DLPFC， COMT基因Val等位基因纯合子也与精神分裂症有关。拟议的研究计划利用结构MRI和磷磁共振波谱来表征这些研究组中与RGS4变异相关的形态学和膜化学（磷酸单酯和磷酸二酯）浓度的差异。我们将探讨这些成像措施与COMT多态性的关系。利用“交叉纵向”设计表征中间表型有助于描述遗传多态性的大脑相关物的纵向轨迹，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.