Genetic markers of white matter integrity in schizophrenia: Relationship to clini

描述(由申请人提供)：本申请涉及广泛的挑战领域(03)生物标记物的发现和验证以及特定的挑战主题03-MH-101*精神疾病中的生物标记物。具体地说，我们计划使用遗传和神经成像工具的组合来识别精神分裂症患者临床严重程度的新生物标记物。精神分裂症是一种慢性和严重衰弱的精神疾病，影响着大约1%的世界人口。多种神经递质系统以及灰质和白质的异常都与此有关。这些结构的改变被认为是局部神经元回路上的突触沟通错误和分布的大脑区域之间的功能中断的基础。鉴于髓鞘在亚服务快速远距离通讯中的作用，有人认为少突胶质细胞功能和髓鞘完整性的破坏可能是导致这种疾病的一些症状的原因。支持这一观点的是，越来越多的神经病理学、神经成像和分子遗传学研究证明精神分裂症患者中存在白质病理。虽然精神分裂症不是一种髓鞘障碍，但必须注意的是：a)症状的出现通常与额叶和颞叶的髓鞘形成高峰期一致，b)精神分裂症患者的脑白质体积通常随着年龄的增长而受损，c)在这一关键时期髓鞘结构的特定破坏通常与精神分裂症样症状有关。在过去的5年中，有90多篇文章使用弥散张量成像(DTI)来表征慢性和首发患者的脑白质异常。研究表明，皮质下白质中存在髓鞘完整性缺陷，尤其是额叶和颞叶。然而，考虑到这些研究是在少数患者中进行的，而且对于所确定的白质病理的位置和程度存在一些差异，关于髓鞘病理在患者群体中的流行率仍然存在几个问题。此外，这些改变的遗传因素以及白质病理对临床严重程度的意义仍有待确定。如上图所示，在这项挑战拨款中，我们建议评估白质改变和基因变异对精神分裂症不同症状的影响。我们将使用500名患者和对照受试者来评估特定基因多态对白质完整性测量的贡献。这些测量将使用PI开发的多变量统计方法与疾病严重程度相关联。具体来说，我们计划：目标1：利用现有的DTI数据和DNA样本，从250名特征良好的精神分裂症患者和健康对照中收集，以确定白质束异常的假定遗传基础，并将这些与临床严重程度的几个测量相关联。这些数据和样本是作为之前和目前在两个网站资助的研究的一部分收集的：精神研究网络(MRN)和奥林神经精神病学研究中心(ONRC)。目标2：使用在两个站点(N=250)收集的额外数据进行验证性分析，以验证根据目标1所做的观察。我们还将向社区发布一套软件工具。为什么挑战资助机制对于拟议的研究是理想的？1)我们的目标是使用创新的方法来确定适用于后续验证工作的精神障碍候选生物标记物，这与本RFA的目标相匹配。拟议使用的遗传、神经成像和统计工具也符合《区域评估》中所述的技术方法，代表了该领域的一个新方向。目前还没有可靠的精神分裂症生物标记物，因此拟议中的寻找可以预测疾病严重程度的生物标记物的影响很大。2)对于拟议的工作，两年的拨款奖励是理想的。我们已经获得了大部分MRI数据，并收集了唾液样本，作为NIH资助的其他研究的一部分，这些研究在同一组患者中使用了不同的成像模式(fMRI和EEG)。因此，该项目将重点放在基因分型和DTI分析以及寻找特定生物标志物的统计方法上。3)我们已经组建了一支拥有独特专业知识和过去有效合作记录的调查团队来进行这些研究。我们计划招聘和培训新的人员，并使用Illumina，Inc.等总部设在美国的公司采用独特的全基因组和生物信息学技术，这将增加刺激经济的好处。 公共卫生相关性：这项挑战拨款申请的目标是确定精神分裂症患者临床严重程度的新生物标记物。目前还没有可靠的精神分裂症生物标记物，因此提议使用复杂的基因分型、神经成像和生物统计学工具在两个大的患者队列中搜索可以预测疾病严重程度的生物标记物具有很高的临床影响。这些生物标志物的识别不仅将增加我们对精神分裂症的病理生理学的了解，而且最重要的是，甚至可能有助于在症状出现之前预测这种疾病的风险增加。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (03) Biomarker Discovery and Validation and specific Challenge Topic 03-MH-101* Biomarkers in Mental Disorders. Specifically, we plan to use a combination of genetic and neuroimaging tools to identify novel biomarkers of clinical severity in patients with schizophrenia. Schizophrenia is a chronic and severely debilitating mental disorder affecting approximately 1% of the world's population. Multiple neurotransmitter systems have been implicated, as well as both gray and white matter abnormalities. These structural alterations are thought to underlie both synaptic miscommunication at local neuronal circuits and functional disconnectivity among distributed brain regions. Given the role of myelin in sub-serving rapid long-distance communication, it has been proposed that a disruption of oligodendrocyte function and myelin integrity may contribute to some of the symptoms of this illness. Supporting this idea, an increasing number of neuropathological, neuroimaging and molecular genetic studies demonstrate the presence of white matter pathology in patients with schizophrenia. Although schizophrenia is not a dysmyelinating disorder, it is important to note that: a) the onset of symptoms usually coincides with the peak of myelination in the frontal and temporal lobes, b) patients with schizophrenia often show an impaired age- related increase in white matter volumes in the these brain regions and c) specific disruption of myelin structure during this critical period is often associated with schizophrenia-like symptoms. Over 90 articles in the past 5 years have used diffusion tensor imaging (DTI) to characterize white matter abnormalities in chronic and first episode patients. The studies demonstrated myelin integrity defects in the subcortical white matter, particularly in the frontal and temporal lobes. However given that these studies were performed using a small number of patients, and there were some discrepancies about the location and extent of white matter pathology identified, several questions remain about the prevalence of myelin pathology in the patient population. Furthermore, the genetic contributions to these alterations and the significance of white matter pathology to clinical severity remain to be established. As shown in the diagram above, in this challenge grant, we propose to assess influence of white matter alterations and genetic variation to the different symptoms of schizophrenia. The contributions of specific gene polymorphisms to measurements of white matter integrity will be evaluated using 500 patients and control subjects. These measurements will be correlated with disease severity using multivariate statistical methods developed by the PI. Specifically we plan to: Aim 1: Employ available DTI data and DNA samples, collected in 250 well-characterized schizophrenia patients and healthy controls, to identify the putative genetic underpinnings of white matter tract abnormalities and correlate these with several measurements of clinical severity. The data and samples have been collected as part of previously and currently funded studies at two sites: The Mind Research Network (MRN) and the Olin Neuropsychiatry Research Center (ONRC). Aim 2: Use additional data collected at both sites (N=250) to perform a confirmatory analysis validating the observations made under Aim 1. We will also release a set of software tools to the community. Why is a Challenge grant mechanism ideal for the proposed research? 1) Our goal of using innovative approaches to identify candidate biomarkers for mental disorders that are suitable for subsequent validation efforts matches the goals of this RFA. The proposed use of genetic, neuroimaging and statistical tools also matches the technological approaches described in the RFA and represents a new direction in the field. There are currently no reliable biomarkers for schizophrenia, so the proposed search for biomarkers that can predict disease severity is of high impact. 2) A two year grant award is ideal for the proposed work. We have already acquired most of the MRI data and collected saliva samples as part of other NIH funded studies that used different imaging modalities (fMRI and EEG) in the same groups of patients. Therefore, the project will focus on the genotyping and DTI analyses and the statistical methods to search for specific biomarkers. 3) We have assembled a team of investigators with unique expertise and an excellent record of effective past collaborations to pursue these studies. Our plan to hire and train new personnel, and to employ unique genome wide and bioinformatics technologies using US-based companies such as Illumina, Inc., will have the added benefit of stimulating the economy. PUBLIC HEALTH RELEVANCE: The goal of this Challenge grant application is to identify novel biomarkers of clinical severity in patients with schizophrenia. There are currently no reliable biomarkers for schizophrenia, so the proposed use of sophisticated genotyping, neuroimaging and biostatistical tools for searching biomarkers that can predict disease severity in two large cohorts of patient has a high clinical impact. The identification of such biomarkers will not only increase our knowledge of the pathophysiology of schizophrenia but also, and most importantly, may help predict an increased risk for this illness even before the onset of symptoms.