Genetic Determinants of Brain Structure and Disease Risk in Schizophrenia

描述（由申请人提供）：精神分裂症是一种主要的精神障碍，发生在青年成年期，遗传率为80-90%。即使采用最先进的治疗方法，精神分裂症也常常导致终身残疾，因此迫切需要描述其遗传成分，以便更好地分类、预测和治疗。尽管进行了许多基因发现研究，但精神分裂症的遗传和表型复杂性在很大程度上混淆了这些努力。为了解决这一僵局，我们将在一系列新颖而富有想象力的目标中，通过整合详尽的、高质量的基因组、表型和结构脑成像数据来研究精神分裂症的病因学。应用程序的优势在于我们样本的独特丰富性和我们调查团队的专业知识。我们汇集了不仅仅是一个，而是两个巨大的、独立的精神分裂症患者和正常对照者的样本，他们都经过高分辨率磁共振脑成像扫描，详尽地进行了表型分析，并为基因研究提供了DNA。在这些资源中，DNA尚未得到充分利用。通过使用最先进的方法和精心设计的计划分析DNA，我们将大大提高所有数据域的价值。该研究团队由在所有相关领域（精神分裂症现象学、脑成像、基因组技术和生物统计学）具有长期生产力历史的研究人员组成，他们通过富有成效的互动和合作历史联系在一起。公共卫生相关性：精神分裂症是一种主要由遗传因素引起的主要精神障碍，也与大脑结构异常有关。本研究将尝试通过使用广泛的基因组技术——微阵列技术、基因组拷贝数变异测试等——来识别精神分裂症的易感基因，并以一种整合的方式将最终的遗传数据与大脑结构体积和核心疾病本身联系起来。

DESCRIPTION (provided by applicant): Schizophrenia is a major mental disorder that strikes in young adulthood and that has a heritability of 80-90%. Even with state-of-the-art treatment, schizophrenia often produces lifelong disability, creating a pressing need to delineate the heritable components so as to enable better classification, prognostication, and treatment. Despite the performance of many gene discovery studies, the genetic and phenotypic complexities of schizophrenia have largely confounded these efforts. To address this impasse, we will examine the etiology of schizophrenia by integrating exhaustive, high-quality genomic, phenotypic, and structural brain imaging data in a set of novel and imaginative aims. The strength of the application rests on the unique richness of our samples and the expertise of our investigative team. We bring together not just one, but two large, independent samples of individuals with schizophrenia and normal controls who have been scanned with high-resolution magnetic resonance brain imaging, exhaustively phenotyped, and who have provided DNA for genetic studies. Of these resources, it is the DNA that has yet to be fully utilized. By analyzing the DNA with state-of-the-art methods and a carefully crafted plan, we will substantially enhance the value of all the data domains. The research team comprises investigators with long histories of productivity in all pertinent areas-schizophrenia phenomenology, brain imaging, genomic technology, and biostatistics-and they are linked by a history of productive interaction and collaboration. PUBLIC HEALTH RELEVANCE: Schizophrenia is a major mental disorder that is caused primarily by genetic factors and that is also associated with brain structure abnormalities. This study will attempt to identify schizophrenia susceptibility genes by using a wide array of genomic technology-microarrays, tests for genomic copy number variations, and others-and relating the resultant genetic data in an integrated fashion to both brain structure volumes and the core disorder itself.