Imaging the Impact of Glutamate Liability Genes in Schizophrenia

描述（由申请人提供）：为了揭示候选基因对精神分裂症患者脑功能的影响，我们将采用两阶段筛选过程来测试与上下文处理缺陷和前额叶皮质功能障碍相关的基因。使用内表型驱动的方法，我们将确定是否在神经和认知风险的精神分裂症的神经元能基因突变的基础。1)第一阶段将测试五个谷氨酸调节基因（RGS4，DTNBP1，GRM3，NRG 1和DAOA）是否与大规模一般人群样本中上下文处理的个体差异相关。我们还将使用恢复技术来探索7个不太确定的谷氨酸调节基因（GRIA2，EPSIN 4，PPP3CC，GRIN，DAO，PRODH和YWHAH）是否有助于上下文处理，以及谷氨酸多态性是否与COMT的精神分裂症风险等位基因相互作用。2)第二阶段将评估与一般人群中的背景处理相关的谷氨酸调节基因是否与精神分裂症患者及其生物学亲属的背景处理缺陷相关。3)最后，为了了解谷氨酸多态性和脑功能障碍之间的关系，我们将使用功能性磁共振成像（fMRI）检查精神分裂症患者和对照组的健康亲属在执行上下文处理任务时的前额叶皮层活动。该项目福尔斯属于R21机制的范围，因为已经建立并资助了对一般人群和精神分裂症的研究。R21基金将支持行为表型和基因分型，但不支持fMRI扫描、招募或额外的血液采样费用。目前的研究有可能证实谷氨酸调节基因在精神分裂症病因学中的重要性，并强调这些基因导致疾病表现的中间机制。公共卫生相关性：为了揭示候选基因对精神分裂症患者脑功能的影响，我们将采用两阶段筛选过程来测试与上下文处理缺陷和前额叶皮质功能障碍相关的基因。第一阶段将测试谷氨酸调节基因是否与背景处理中的个体差异相关。第二阶段将评估阳性筛选的谷氨酸基因是否与精神分裂症患者及其生物学亲属的背景处理缺陷相关，并确定这些基因是否与亲属和对照组的脑功能fMRI测量相关。

DESCRIPTION (provided by applicant): To reveal the effects of candidate genes on brain function in schizophrenia, we will employ a two-stage screening process to test genes for association with context processing deficits and prefrontal cortical dysfunction. Using an endophenotype-driven approach, we will determine whether mutations in glutamatergic genes underpin neural and cognitive risk for schizophrenia. 1) The first stage will test whether five glutamate moderating genes (RGS4, DTNBP1, GRM3, NRG1, and DAOA) are associated with individual differences in context processing in a large general population sample. We will also use resampling techniques to explore whether seven less established glutamate moderating genes (GRIA2, EPSIN 4, PPP3CC, GRIN, DAO, PRODH and YWHAH) contribute to context processing, and whether glutamate polymorphisms interact with the schizophrenia risk allele of COMT. 2) The second stage will evaluate whether glutamate modulating genes associated with context processing in the general population are related to context processing deficits in schizophrenia patients and their biological relatives. 3) Finally, to understand the relationship between glutamate polymorphisms and brain dysfunction, we will use functional magnetic resonance imaging (fMRI) to examine prefrontal cortical activity in healthy relatives of schizophrenia patients and controls during performance of a context processing task. This project falls within the scope of the R21 mechanism because studies in the general population and schizophrenia are established and funded. R21 funding will support behavioral phenotyping and genotyping, but not fMRI scanning, recruitment, or additional blood sampling costs. The current study has the potential to confirm the importance of glutamate modulating genes in the etiology of schizophrenia and highlight the intermediate mechanisms through which these genes lead to disease manifestation. PUBLIC HEALTH RELEVANCE: To reveal the effects of candidate genes on brain function in schizophrenia, we will employ a two-stage screening process to test genes for association with context processing deficits and prefrontal cortical dysfunction. The first stage will test whether glutamate moderating genes are associated with individual differences in context processing in a large general population registry. The second stage will evaluate whether positively screened glutamate genes are related to context processing deficits in schizophrenia patients and their biological relatives, and determine whether these genes are related to fMRI measures of brain function in relatives and controls.