Studying the Genetic Basis of Schizophrenia through Tract Alterations

描述(申请人提供)：精神分裂症是一种毁灭性的疾病，已知是由基因介导的；然而，在已发表的荟萃分析中，没有基因与疾病在全基因组水平上显著相关。精神分裂症也被认为是一种脱节综合征，大脑中异常的白质束被认为是导致疾病发展的原因之一。我们试图通过研究与精神分裂症有关的白质束的变异来阐明精神分裂症的遗传基础。为了对白质束进行研究，我们将使用弥散加权成像技术对具有详细全基因组数据的健康同卵和异卵双胞胎(N=1150)进行研究，以研究遗传多态与白质束完整性和几何形状的关系。这一独特的种群将使我们能够确定这些感兴趣区域的遗传性，或基因调节的程度。对于那些具有高度可遗传性的区域，我们将能够将这些个体的遗传多态与感兴趣的区域联系起来。然后，我们将识别出与神经束完整性和几何形状变化有关的基因，然后这些基因也将与精神分裂症有关。这将是第一个采用成像基因组学方法识别危险基因的研究：我们将调查整个基因组，以统计与感兴趣的大脑特征的关联。这项研究还将有助于提供精神分裂症的生物学机制，帮助发现治疗的新基因靶点，为精神障碍提供更准确和基于生物学的诊断标准，并提供一种方法来发现其他精神疾病的遗传基础，可被生物技术社区普遍采用。 公共卫生相关性：为了确定与这种精神分裂症相关的基因，我们将研究这种疾病的一个已知缺陷：不同大脑区域之间的异常连接。使用一种新的大脑成像技术，能够研究活着的大脑中的这些联系，并通过研究许多健康个体的整个基因组，我们将能够发现与基因组变化相关的联系中的变异。通过这一计划，我们希望发现与精神分裂症发展有关的新基因，帮助提供精神分裂症的生物机制，帮助发现治疗药物的靶点，并为精神分裂症提供更准确和基于生物学的诊断标准。

DESCRIPTION (provided by applicant): Schizophrenia is a devastating illness, known to be genetically mediated; however, no gene has been significantly associated with the illness at genome wide significance levels in published meta-analyses. Schizophrenia is also known to be a disconnection syndrome, whereby abnormal white matter tracts in the brain are thought to contribute to the development of the illness. We seek to elucidate the genetic basis of schizophrenia by studying variations in white matter tracts found to be involved in schizohprenia. In order to study the white matter tracts, we will use diffusion weighted imaging in a large sample of healthy monozygotic and dizygotic twins (N=1150) with detailed genome wide genotype data to study the relation between genetic polymorphisms and tract integrity and geometry. This unique population will allow us to determine the heritability, or the degree of genetic mediation, of these tracts of interest. For those tracts which have properties that are highly heritable, we will be able to associate genetic polymorphisms of these individuals with the tracts of interest. We will then have identified genes involved with variations of tract integrity and geometry which then will also be associated with schizophrenia. This will be the first study to take an imaging genomics approach for identifying risk genes: we will survey the entire genome for statistical association to a brain trait of interest. This study will also help provide a biological mechanism for schizophrenia, help discover novel gene targets for therapeutics, provide a more accurate and biologically based diagnostic criterion for the disorder, and provide a method to discover the genetic basis of other mental illnesses that can be generally adopted by the biotechnology community. Public Health Relevance: To identify genes associated with this schizophrenia, we will study a known deficit of the illness: aberrant connections between different brain regions. Using a new technique of brain imaging capable of studying these connections in the living brain, and by studying the entire genome of many healthy individuals, we will be able to find variations in connections that are associated with alterations in the genome. By following this plan, we expect to find novel genes involved in the development of schizophrenia, help to provide a biological mechanism for schizophrenia, help discover targets for therapeutic medications, and provide a more accurate and biologically based diagnostic criterion for the disorder.