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。将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。患者及其兄弟姐妹的皮质功能将使用功能磁共振成像、磁共振波谱和神经心理测试进行量化。使用这些方法的结果将与遗传数据相结合，以寻找影响大脑功能和增加精神分裂症易感性的基因。经过仔细诊断的患者将从当地和国家来源招募。先证者的诊断是根据以前的精神病记录和结构化的诊断性面谈确定的。兄弟姐妹和对照受试者同样通过结构化面试进行评估。所有受试者都要提供血液样本进行基因分析。使用功能磁共振成像和神经心理测试对皮质功能进行评估。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。其中两种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。这项研究的结果之所以引人注目，有两个原因。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。

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 to be 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 will be quantified using functional MRI, MR Spectroscopy and neuropsychological testing. Results using these methods will be combined with genetic data to look for genes that affect brain function and increase susceptibility to schizophrenia. Carefully diagnosed patients will recruited from local and national sources. Diagnosis of probands is established from previous psychiatric records and a structured diagnostic interview. Siblings and control subjects likewise are evaluated with a structured interview. All subjects give a blood sample for genetic analysis. Evaluation of cortical function is performed using functional MRI and neuropsychological testing. These procedures have been 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 is 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 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 overactivating cortical regions responsible for processing information related to fear. The results of this study are notable for two 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.