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）生物标志物的发现和验证以及特定的挑战主题03- mh -101*精神障碍中的生物标志物。具体来说，我们计划结合使用遗传和神经影像学工具来识别精神分裂症患者临床严重程度的新生物标志物。精神分裂症是一种慢性和严重使人衰弱的精神障碍，影响着大约1%的世界人口。涉及多种神经递质系统，以及灰质和白质异常。这些结构改变被认为是局部神经元回路突触沟通错误和分布的大脑区域之间功能断开的基础。考虑到髓磷脂在亚服务快速长距离通信中的作用，有人提出少突胶质细胞功能和髓磷脂完整性的破坏可能导致这种疾病的一些症状。越来越多的神经病理学、神经影像学和分子遗传学研究支持这一观点，证明精神分裂症患者存在白质病理学。虽然精神分裂症不是一种髓鞘异常疾病，但需要注意的是：a)症状的发作通常与额叶和颞叶髓鞘形成的高峰同时发生；b)精神分裂症患者通常表现出与这些脑区白质体积受损相关的年龄增加；c)在这一关键时期髓鞘结构的特异性破坏通常与精神分裂症样症状有关。在过去的5年中，有超过90篇文章使用弥散张量成像（DTI）来描述慢性和首发患者的白质异常。研究表明髓鞘完整性缺陷存在于皮层下白质，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，并且在确定的白质病理的位置和程度上存在一些差异，关于髓磷脂病理在患者群体中的患病率仍存在几个问题。此外，基因对这些改变的贡献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遗传变异对精神分裂症不同症状的影响。特定基因多态性对白质完整性测量的贡献将在500名患者和对照受试者中进行评估。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：利用在250例特征明确的精神分裂症患者和健康对照中收集的可用DTI数据和DNA样本，确定白质束异常的假定遗传基础，并将其与临床严重程度的几种测量相关联。这些数据和样本是在两个地点收集的，作为以前和现在资助的研究的一部分：精神研究网络（MRN）和奥林神经精神病学研究中心（ONRC）。目标2：使用在两个地点收集的额外数据（N=250）进行验证性分析，验证目标1下的观察结果。我们还将向社区发布一套软件工具。为什么挑战资助机制是理想的提议的研究？1)我们的目标是使用创新的方法来识别适合后续验证工作的精神障碍候选生物标志物，这与本RFA的目标相匹配。遗传、神经成像和统计工具的建议使用也与RFA中描述的技术方法相匹配，代表了该领域的新方向。目前还没有可靠的精神分裂症生物标志物，因此寻找可以预测疾病严重程度的生物标志物的建议具有很高的影响。2)两年的资助奖是理想的提议的工作。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方式（fMRI和EEG）。因此，本项目将侧重于基因分型和DTI分析以及寻找特异性生物标志物的统计方法。3)我们已经组建了一支具有独特专业知识和过去有效合作记录的研究团队来进行这些研究。我们计划雇用和培训新人员，并使用美国公司（如Illumina， Inc.）采用独特的基因组和生物信息学技术，这将对刺激经济产生额外的好处。

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.