Genetic Basis Of Cortical Malfunction In Schizophrenia

我们继续扩大我们对精神分裂症患者和他们健康兄弟姐妹的皮质处理的研究，以努力进一步完善这一与皮质功能相关的风险增加特征的现象学。这些研究涉及1)对涉及记忆和认知控制的子过程进行更精细的分析，2)功能磁共振信号分析的新方法，以及3)继续获取大脑处理数据。我们使用与精神分裂症风险相关的基因来了解与疾病的关键生物学方面相关的分子和神经系统机制。利用来自认知、成像和基础科学方法的融合数据，我们希望基于经过验证的神经机制来确定新的治疗方法。精神分裂症基因相关性的验证提供了生物学证据，表明精神分裂症相关风险等位基因对通过认知和神经成像方法在健康和疾病受试者中分析的大脑发育和功能的相关测量产生影响。我们的理论基础是，精神疾病易感基因的发现代表了这些疾病病因的第一个客观线索，将导致确定致病机制和新的治疗方法。然而，临床相关性的统计证据是一个不确定的起点，因为统计证据不能证明因果关系。我们不是专注于发现风险相关基因，而是基于知情的兴趣基因来生成生物假设和检验。为了发现新的治疗靶点，必须将遗传关联转化为涉及分子网络/途径和神经系统的生物机制。 我们的研究人员已经证明，与精神分裂症有关的多个基因聚集在认知模式和相关的脑处理模式上，这些模式已被确定为与精神分裂症遗传风险相关的中间表型。这些发现有助于将细胞水平的致病机制(即基因)转化为涉及临床状态的神经系统水平的病理生理机制(即异常的皮质信息处理)。这些结果表明，可能有许多分子途径导致该病的生物学和临床特征。这些发现的研究影响体现在世界范围内迅速增长的研究兴趣，即将精神疾病风险相关基因的影响映射到与这些疾病的生物学有关的大脑结构和功能的各个方面。 CBDB的研究证实和阐明的遗传关联也构成了与基因、认知和精神病计划(GCAP)基础研究人员合作的基础，以高危等位基因和易感基因单倍型或与风险相关等位基因相关的组织中改变的基因处理或表达模式为基础，开发细胞和转基因动物模型。这些研究的目的是阐明从基因功能到细胞生物学再到神经系统功能的多个生物学水平上的风险相关机制。这种对生物关联进行分层和收敛假设检验的系统生物学方法已经确定了至少五个新的潜在治疗靶点，这些靶点正在作为我们未来治疗试验工作的主要重点。

We have continued to extend our studies of cortical processing in patients with schizophrenia and their healthy siblings in an effort to further refine the phenomenology of this increased risk trait related to cortical function. These studies have involved 1) a more refined analysis of subprocesses involved in memory and cognitive control, 2) novel approaches to fMRI signal analysis, and 3) the continued acquisition of brain processing data. We use genes associated with risk for schizophrenia to learn about molecular and neural system mechanisms related to key biologic aspects of the illness. Using convergent data from cognitive, imaging and basic science methods, we hope to identify new approaches to treatment based on validated neural mechanisms. Validation of genetic association with schizophrenia provides biologic evidence of the effect of schizophrenia-associated risk alleles on relevant measures of brain development and function assayed with cognitive and neuroimaging approaches in healthy and ill subjects. Our rationale is that the discovery of susceptibility genes for psychiatric disorders, which represent the first objective clues to the etiologies of these conditions, will lead to identifying pathogenic mechanisms and new therapies. However, the statistical evidence of clinical association is an uncertain starting point, as statistical evidence cannot prove causation. We are not focused on discovering risk-associated genes, but on generating biologic hypothesis and testing based on genes of informed interest. Genetic association must be translated into biologic mechanisms involving molecular networks/pathways and neural systems for the discovery of new therapeutic targets. Our investigators have demonstrated that multiple genes implicated in schizophrenia converge on patterns of cognition and related brain processing that have been identified as intermediate phenotypes related to genetic risk for schizophrenia. These findings help translate causative mechanisms at the cellular levels (i.e. genes) into pathophysiologic mechanisms at the level of neural systems involved in the clinical state (i.e. abnormal cortical information processing). These results indicate that there are likely many molecular pathways to the biological and clinical features of the disorder. The investigative impact of these findings is illustrated in the rapidly growing worldwide research interest in mapping effects of psychiatric risk-associated genes onto aspects of brain structure and function related to the biology of these disorders. Genetic associations confirmed and elucidated by studies in CBDB also form the basis for collaborations with basic researchers in the Genes, Cognition and Psychosis Program (GCAP) to develop cellular and transgenic animal models based on high-risk alleles and haplotypes of susceptibility genes or on altered gene processing or expression patterns in tissue related to risk-associated alleles. The goal of these studies is to elucidate risk-associated mechanisms at multiple levels of biology, from gene function, to cell biology, to neural systems function. This systems biology approach of hierarchical and convergent hypothesis testing of biological association has led to the identification of at least five novel potential therapeutic targets that are being pursued as a major emphasis of our future work towards therapeutic trials.