Imaging the Impact of Glutamate Liability Genes in Schizophrenia

描述(申请人提供)：为了揭示候选基因对精神分裂症患者大脑功能的影响，我们将采用两个阶段的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。使用一种内表型驱动的方法，我们将确定谷氨酸能基因突变是否支持精神分裂症的神经和认知风险。1)第一阶段将在一个大的总体样本中检验5个谷氨酸调节基因(RGS4、DTNBP1、GRM3、NRG1和DAOA)是否与背景加工的个体差异有关。我们还将使用重新采样技术来探索七个不太成熟的谷氨酸调节基因(GRIA2、EPSIN 4、PPP3CC、GRIN、DAO、PROSH和YWHAH)是否有助于上下文处理，以及谷氨酸多态是否与COMT的精神分裂症风险等位基因相互作用。2)第二阶段将评估普通人群中与语境加工相关的谷氨酸调节基因是否与精神分裂症患者及其亲缘关系中的语境加工缺陷有关。3)最后，为了了解谷氨酸多态与脑功能障碍之间的关系，我们将使用功能磁共振成像(FMRI)来检测精神分裂症患者和对照组在执行背景处理任务时的健康亲属的前额叶皮质活动。这个项目属于R21机制的范围，因为对普通人群和精神分裂症的研究是建立和资助的。R21基金将支持行为表型和基因分型，但不支持功能磁共振扫描、招募或额外的血液采样成本。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大脑功能的影响，我们将采用两个阶段的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大型普通人群注册表中上下文处理的个体差异有关。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亲属的上下文处理缺陷有关，并确定这些基因是否与亲属和对照的脑功能功能磁共振测量有关。

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.