3/3 - A Neurobehavioral Family Study of Schizophrenia

描述（由申请人提供）：精神分裂症神经行为家族研究是一项多代调查（MGI），涉及三个协作ro1，结合遗传学和神经生物学范式，以促进对精神分裂症（SCZ）易感性调节基因的发病机制和检测。复杂的遗传机制是SCZ易感性的基础。与遗传学的进展平行，神经生物学研究已经确定了可以为集中研究提供病理生理基础的神经系统。我们建立了一个多代多重家族样本，对其进行了确定、表型表征和基因分型，用于全基因组连锁分析。该样本用计算机化的神经认知电池进行检查，该电池为诊断提供了互补的定量表型。我们观察到几个神经认知领域的显著遗传性以及联系的证据。我们更新申请的目标是利用这个独特的样本，并通过磁共振成像（MRI）获得大脑结构和功能的神经成像表型。我们将使用基于体积的形态测量和弥散张量成像（DTI）的连通性来检查大脑结构。功能性核磁共振成像（fMRI）研究将检查大脑回路对神经行为探针的反应。我们将对MGI样本中的300人进行神经成像研究。我们还将确定300个社区对照的新的基于人群的样本（具体目标1）。我们将把神经影像学表型的遗传性与症状和神经行为测量联系起来，并进行多变量定量遗传分析，以确定受相同基因影响的定量表型（具体目标2）。为了建立产生神经行为和神经影像学表型的遗传机制，我们将通过全基因组关联（GWA）分析定位新的数量性状位点，并跟踪显著连锁和GWA分析信号，以及通过正在进行的关联研究确定的候选基因（Specific Aim 3）。标本将被送到NIMH仓库进行转化和DNA提取。将保持数据收集和质量控制，并定期将经核实的数据上传到NIMH存储库（具体目标4）。MGI增加了其他可用的样本，采用类似的措施来确认和扩展目前的发现。此外，参与者的神经行为和神经影像学数据的表型特征将有助于评估遗传对神经生物学异常和临床表现的影响之间的关系。发现遗传易感性的其他潜在定量标记可以提高我们对大脑发育和调节相关基因如何与环境相互作用以赋予SCZ易感性的理解。这些努力将加强人类和动物研究中神经生物学和遗传学范式的整合。反过来，这可能为风险预测和更好的治疗铺平道路。公共卫生相关性：精神分裂症是一种复杂的脑部疾病，通常出现在青春期和成年早期，对个人和家庭具有破坏性影响。了解脑功能缺陷的遗传基础是早期发现和推进治疗以改善结果的关键。精神分裂症联合多代调查的目标是在高危家庭中整合神经行为和神经影像学方法，这将为该领域的进展提供所需的数据。

DESCRIPTION (provided by applicant): Neurobehavioral Family Study of Schizophrenia is a Multiplex Multigenerational Investigation (MGI) of three collaborative RO1s that combine genetic and neurobiologic paradigms to advance the understanding of pathogenesis and detection of genes that modulate susceptibility to schizophrenia (SCZ). Complex genetic mechanisms underlie the susceptibility to SCZ. Paralleling the progress in genetics, neurobiologic studies have identified neural systems that could provide pathophysiologic substrates for focused investigations. We have established a sample of multigenerational multiplex families that were ascertained, phenotypically characterized and genotyped for genome-wide linkage analyses. This sample was examined with a computerized neurocognitive battery that provides complementary quantitative phenotypes to diagnosis. We observed significant heritability for several neurocognitive domains as well as evidence for linkage. Our goal for the renewal application is to capitalize on this unique sample and obtain neuroimaging phenotypes of brain structure and function with Magnetic Resonance Imaging (MRI). We will examine brain structure using volume-based morphometry and connectivity with Diffusion Tensor Imaging (DTI). Functional MRI (fMRI) studies will examine brain circuitry activated in response to neurobehavioral probes. We will follow 300 individuals from the MGI sample for neuroimaging studies. We will also ascertain a new population-based sample of 300 community controls (Specific Aim 1). We will relate the heritability of neuroimaging phenotypes to symptom and neurobehavioral measures and perform multivariate quantitative genetic analyses to identify quantitative phenotypes influenced by the same genes (Specific Aim 2). To establish genetic mechanisms producing the neurobehavioral and neuroimaging phenotypes we will localize new quantitative trait loci through genome-wide association (GWA) analyses and follow-up significant linkage and GWA analysis signals as well as candidate genes identified through ongoing association studies (Specific Aim 3). Specimens will be sent to the NIMH repository for transformation and DNA extraction. Data collection and quality control will be maintained and verified data will be regularly uploaded to the NIMH repository (Specific Aim 4). The MGI augments other samples available with similar measures to confirm and extend present findings. In addition, the phenotypic characterization of participants with neurobehavioral and neuroimaging data will enable evaluation of the relation between genetic influences on neurobiological abnormalities and clinical manifestations. Finding additional potential quantitative markers for genetic vulnerability could improve our understanding of how genes related to brain development and regulation interact with environment in conferring SCZ susceptibility. Such efforts will enhance the integration of neurobiologic and genetic paradigms in human and animal research. In turn, this may pave the way for risk prediction and better treatment. PUBLIC HEALTH RELEVANCE: Schizophrenia is a complex brain disorder that commonly emerges in adolescence and early adulthood and has devastating effects on the individual and family. Understanding the genetic basis of the deficits in brain function is key to early detection and to advance treatments that may improve outcome. The goal of the Multiplex Multigenerational Investigation of the schizophrenia consortium is to integrate neurobehavioral and neuroimaging methods in high-risk families that will yield the data needed for progress in the field.