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。要使用的方法是受影响的兄弟姐妹配对范式。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。仔细诊断的先证者将从我们现有的慢性精神分裂症患者群体中招募。其他先驱是通过媒体和全国精神疾病联盟招募的。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，是因为人们已经知道，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，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，从而表明他们在表型上类似于他们患病的兄弟姐妹，尽管他们没有证据(在测试时)全面发展的综合症。这项研究和遗传分析的方法是独一无二的，因为它不使用诊断作为识别变量。相反，我们关注的是中间的生物变量。我们预计这将增加发现精神分裂症基因的统计能力。在这方面，我们的初步结果非常有希望。22号染色体上的一个特殊基因，称为COMT，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。我们最近发现，COMT基因的一种变体会损害工作记忆和执行功能，这样做会略微增加患精神分裂症的风险。

The purpose of this project is to find genes that impair cortical function and, in doing so, increase the risk for developing schizophrenia. The method to be used is the affected sibling pair paradigm. 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 probands will recruited from our existing in patient population of persons with chronic schizophrenia. Other probands are recruited through the media and the National Alliance for the Mentally Ill. 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 done using functional MRI and neuropsychological testing. These procedures have been chosen because it is already known that persons with schizophrenia demonstrate some abnormality compared to normal controls. We have recently shown that subsets of the siblings show one or more abnormal traits on these tests, thus suggesting that they are phenotypically similar to their ill sibling even though they do not evidence (at the time of testing) the full blown syndrome. This study and the method of genetic analysis is unique in that it does not use diagnosis as the identifying variable. Instead, we look at intermediate biological variables. We anticipate that this will increase the statistical power to find schizophrenia genes. Our initial results have been very promising in this regard. A specific 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 refered to as working memory and executive function, are impaired in patients with schizophrenia. We have recently shown that a variant of the COMT gene impairs working memory and executive function and, in doing so, slightly increases risk for developing schizophrenia.