Genetic Basis Of Cortical Malfunction In Schizophrenia

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。采用功能磁共振成像（fMRI）、磁共振波谱（mri）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。使用这些方法的结果与遗传数据相结合，寻找影响脑功能和增加精神分裂症易感性的基因。采用功能磁共振成像和神经心理测试评估皮质功能。选择这些方法是因为精神分裂症患者与正常对照相比表现出一些异常。我们最近发现，他们的健康兄弟姐妹的亚群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。

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.