Imaging the Impact of Glutamate Liability Genes in Schizophrenia

谷氨酸责任基因对精神分裂症的影响成像

• 批准号: 7470504
• 负责人: ANGUS W MACDONALD
• 金额: $ 29.9万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-08 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7470504
• 关键词: Address; Adult; Alleles; Animals; Behavioral; Biological; Blood specimen; Brain; Build-it; COMT gene; Candidate Disease Gene; Catechol O-Methyltransferase; Characteristics; Cognitive; DNA; Diagnosis; Disease; Dopamine; Environment; Etiology; Expectancy; Exploratory/Developmental Grant; Family Study; Functional Magnetic Resonance Imaging; Functional disorder; Funding; General Population; Genes; Genetic; Genetic Polymorphism; Genomics; Genotype; Glutamates; Health behavior; Image; Individual Differences; Lead; MRI Scans; Magnetic Resonance Imaging; Measures; Medical center; Molecular Genetics; Mutation; NRG1 gene; Neuregulin 1; Numbers; PLAB Protein; PPP3CC gene; Patients; Pattern; Performance; Phenotype; Population; Prefrontal Cortex; Process; Psychotic Disorders; Public Health; Registries; Relative (related person); Research; Risk; Risk Factors; Role; Sampling; Savings; Schizophrenia; Science; Screening procedure; Staging; Stratification; Symptoms; Techniques; Testing; Thinking; Work; base; cost; design; endophenotype; epsin; falls; gene discovery; human PPP3CC protein; insight; neuromechanism; programs; relating to nervous system; theories

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.

描述（由申请人提供）：为了揭示候选基因对精神分裂症大脑功能的影响，我们将采用两阶段筛选过程来测试基因与情境处理缺陷和前额皮质功能障碍的关联。使用内表型驱动的方法，我们将确定谷氨酸能基因的突变是否会导致精神分裂症的神经和认知风险。 1) 第一阶段将测试五个谷氨酸调节基因（RGS4、DTNBP1、GRM3、NRG1 和 DAOA）是否与大型一般人群样本中上下文处理的个体差异相关。我们还将使用重采样技术来探索七个尚未建立的谷氨酸调节基因（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）第二阶段将评估一般人群中与情境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情境处理缺陷有关。 3）最后，为了了解谷氨酸多态性与脑功能障碍之间的关系，我们将使用功能磁共振成像（fMRI）来检查精神分裂症患者和对照组的健康亲属在执行情境处理任务期间的前额皮质活动。该项目属于 R21 机制的范围，因为针对普通人群和精神分裂症的研究已经建立并得到资助。 R21 资金将支持行为表型和基因分型，但不支持功能磁共振成像扫描、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。公共健康相关性：为了揭示候选基因对精神分裂症大脑功能的影响，我们将采用两阶段筛选过程来测试基因与情境处理缺陷和前额皮质功能障碍的关联。第一阶段将测试谷氨酸调节基因是否与大型普通人群登记中情境处理的个体差异相关。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情境处理缺陷有关，并确定这些基因是否与亲属和对照的脑功能功能磁共振成像测量有关。