Studying the Genetic Basis of Schizophrenia through Tract Alterations

描述（由申请人提供）：精神分裂症是一种毁灭性的疾病，已知由基因介导；然而，在已发表的荟萃分析中，没有基因在全基因组显著水平上与该疾病显著相关。精神分裂症也被认为是一种断开综合症，因此大脑中异常的白质束被认为是导致这种疾病发展的原因。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。为了研究白质束，我们将在健康的单卵双胞胎和异卵双胞胎（N=1150）的大样本中使用扩散加权成像，并提供详细的全基因组基因型数据，以研究遗传多态性与白质束完整性和几何形状之间的关系。这个独特的种群将使我们能够确定这些感兴趣的区域的遗传能力，或遗传中介的程度。对于那些具有高度遗传特性的束，我们将能够将这些个体的遗传多态性与感兴趣的束联系起来。然后，我们将确定与神经束完整性和几何形状变化有关的基因，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来识别风险基因的研究：我们将调查整个基因组，以寻找与感兴趣的大脑特征的统计关联。这项研究还将有助于提供精神分裂症的生物学机制，帮助发现新的治疗基因靶点，为精神分裂症提供更准确和基于生物学的诊断标准，并为发现其他精神疾病的遗传基础提供一种方法，这种方法可以被生物技术界普遍采用。

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.