Genetic Basis Of Cortical Malfunction In Schizophrenia

精神分裂症皮质功能障碍的遗传基础

• 批准号: 7136266
• 负责人: Daniel Martin Weinberger
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7136266
• 关键词: behavioral /social science research tag; behavioral genetics; brain derived neurotrophic factor; catechol methyltransferase; depression; functional magnetic resonance imaging; gene expression; genetic mapping; genetic susceptibility; human subject; human tissue; memory; neural information processing; neurogenetics; neurophysiology; neuropsychological tests; neurotransmitter transport; nuclear magnetic resonance spectroscopy; prefrontal lobe /cortex; schizophrenia; serotonin; statistics /biometry

The purpose of this project is to find genes that impair cortical function and, in doing so, increase the risk for developing Schizophrenia. The methods used include family based and case control comparisons. Abnormalities of cortical function appear to be core features of chronic Schizophrenia. Cortical function of patients and their siblings were quantified using functional Magnetic Resonance Imaging (fMRI), Magnetic Resonance Spectroscopy and neuropsychological testing. Results using these methods were with genetic data to look for genes that affect brain function and increase susceptibility to Schizophrenia. Evaluation of cortical function was performed using fMRI and neuropsychological testing. These procedures were chosen because patients with Schizophrenia demonstrate some abnormality compared to normal controls. We have recently shown that subsets of their healthy siblings show one or more abnormal traits on these tests, suggesting these measures may be useful measures for detecting genes that increase risk for schizophrenia. This study and the methods used are unique in focusing on such biological variables. We anticipate that this will increase the statistical power to find schizophrenia genes. Our initial results have been very promising. We have found evidence that four genes affect cortical processing. Two of these genes also increase risk for developing schizophrenia. First, a gene on chromosome 22, called COMT, is important in regulating prefrontal dopamine metabolism and cognitive processes subserved by the prefrontal cortex. These cognitive processes generically referred to as working memory and executive function, are impaired in patients with schizophrenia. We have shown in this study that a variant of the COMT gene impairs working memory and executive function and, in doing so, slightly increases risk for developing schizophrenia. Second, we have recently replicated findings of other researchers by showing that a gene on chromosome 6, called dysbindin, increases risk for schizophrenia. We have extended these findings by showing that this gene may exert its effects by slowing processing time and slightly reducing IQ. Third, a gene called BDNF, known to be critically involved in memory in many other animal species, has a recent human mutation (called val66met). Our results show this mutation impairs cortical function and memory by changing how the protein is processed. This memory gene may have deleterious effects in other illnesses where memory is impaired. Finally, a gene that increases risk for depression and anxiety, the serotonin transporter, may exert its effects by over-activating cortical regions responsible for processing information related to fear. More recent data has implicated 7 additional genes in the risk for schizophrenia. These include DISC1, G72, neuregulin, GRM3, MRDS1, and GAD1. We have found additional supportive evidence that these genes increase risk for schizophrenia and/or cognitive deficits typically found in schizophrenia. For example, DISC1, which is highly expressed in hippocampus, appears to have subtle deleterious effects on long term memory in patients as well as hippocampal physiological responses. GRM3, which regulates synaptic glutamate, has similar deleterious effects on both hippocampal and prefrontal physiological responses and related cognitive processes. Furthermore, evidence that it increases risk for schizophrenia was detected in three separate cohorts. The results of this study are notable for three reasons. First, they begin to put together some of the pieces in the very complex disorder of schizophrenia and suggest potential new treatments, such as COMT inhibitors. Second, they show how this combination of clinical, physiological, and molecular techniques can produce compelling, convergent results showing how genes affect brain physiology and risk for mental illness. Finally, they offer a new opportunity to study, in animal models, how various combinations of these deleterious genes can impact downstream molecular processes that might mediate their psychogenic effects.

这个项目的目的是找到损害皮质功能的基因，这样做会增加患精神分裂症的风险。使用的方法包括基于家庭的比较和病例对照比较。皮质功能异常似乎是慢性精神分裂症的核心特征。使用功能磁共振成像(FMRI)、磁共振波谱和神经心理测试对患者及其兄弟姐妹的皮质功能进行量化。结果使用这些方法可以利用遗传数据寻找影响大脑功能和增加精神分裂症易感性的基因。使用功能磁共振成像和神经心理测试进行皮质功能评估。之所以选择这些手术，是因为与正常对照组相比，精神分裂症患者表现出一些异常。我们最近发现，他们健康的兄弟姐妹的子集在这些测试中显示出一个或多个异常特征，这表明这些措施可能是检测增加精神分裂症风险的基因的有用措施。这项研究和使用的方法在关注这些生物变量方面是独一无二的。我们预计这将增加发现精神分裂症基因的统计能力。 我们的初步结果是非常有希望的。我们发现了四个基因影响大脑皮层处理的证据。其中两个基因也会增加患精神分裂症的风险。首先，22号染色体上名为COMT的基因在调节前额叶多巴胺代谢和前额叶皮质辅助的认知过程中起着重要作用。这些认知过程通常被称为工作记忆和执行功能，在精神分裂症患者中受到损害。我们在这项研究中已经表明，COMT基因的一个变体会损害工作记忆和执行功能，并在这样做的过程中，略微增加患精神分裂症的风险。其次，我们最近复制了其他研究人员的发现，表明6号染色体上的一种名为dybindin的基因会增加患精神分裂症的风险。我们扩展了这些发现，表明该基因可能通过减缓加工时间和略微降低智商来发挥作用。第三，已知在许多其他动物物种中与记忆密切相关的一种名为BDNF的基因，最近发现了一种人类突变(称为Val66Met)。我们的结果表明，这种突变通过改变蛋白质的处理方式损害了皮质功能和记忆。这种记忆基因可能会对其他记忆受损的疾病产生有害影响。最后，一种增加抑郁和焦虑风险的基因--5-羟色胺转运体--可能会通过过度激活负责处理与恐惧相关的信息的皮质区域来发挥作用。 最近的数据表明，另外7个基因与精神分裂症的风险有关。这些基因包括DISC1、G72、NeuRegin、GRM3、MRDS1和GAD1。我们发现了更多的支持性证据，表明这些基因会增加精神分裂症和/或通常在精神分裂症中发现的认知缺陷的风险。例如，在海马区高表达的DISC1似乎对患者的长期记忆和海马区的生理反应有微妙的有害影响。调节突触谷氨酸的GRM3对海马区和前额叶的生理反应以及相关的认知过程都有类似的有害影响。此外，在三个不同的队列中发现了它增加精神分裂症风险的证据。 这项研究的结果之所以引人注目，有三个原因。首先，他们开始将精神分裂症这一非常复杂的疾病的一些片段组合在一起，并提出了潜在的新治疗方法，如COMT抑制剂。其次，他们展示了这种临床、生理和分子技术的结合如何产生令人信服的、收敛的结果，表明基因如何影响大脑生理和精神疾病的风险。最后，他们提供了一个在动物模型中研究这些有害基因的不同组合如何影响下游分子过程的新机会，这些下游分子过程可能调节它们的心理效应。