Structural and Functional Characteristics of XYY - Relationship to ASD

XYY 的结构和功能特征 - 与 ASD 的关系

• 批准号: 9254609
• 负责人: Timothy P Roberts
• 金额: $ 20.6万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-11 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9254609
• 关键词: 16 year old; Acoustics; Address; Affect; Age; Anisotropy; Auditory; Auditory area; Autacoids; Autistic Disorder; Behavior; Behavior Disorders; Behavioral; Behavioral Symptoms; Biological; Biological Markers; Brain; Characteristics; Child; Child health care; Clinical; Cognitive; Coupled; Data; Data Collection; Data Set; Development; Developmental Delay Disorders; Diagnosis; Diagnostic; Diffuse; Diffusion Magnetic Resonance Imaging; Disease; Dissociation; Etiology; Fragile X Syndrome; Future; Gene Dosage; Genes; Genetic; Genetic Determinism; Genetic Heterogeneity; Genetic Models; Genetic Predisposition to Disease; Glutamates; Goals; Hereditary Disease; Heritability; Heterogeneity; Image; Intercept; Intervention; Link; Magnetic Resonance Spectroscopy; Magnetoencephalography; Matched Group; Measures; Methods; Modality; Modeling; Multivariate Analysis; Neurobiology; Neurodevelopmental Disorder; Neurotransmitters; Pathogenesis; Pathway interactions; Phase; Phenotype; Population; Radiation; Rett Syndrome; Risk; Role; Sex Chromosome Disorders; Sex Chromosomes; Social Interaction; Specificity; Subgroup; Superior temporal gyrus; Synapses; Syndrome; XYY Karyotype; Y Chromosome; autism spectrum disorder; boys; clinical biomarkers; clinical phenotype; cohort; communication behavior; design; disorder risk; efficacy study; falls; gamma-Aminobutyric Acid; genetic risk factor; improved; innovation; male; meetings; multidisciplinary; neural correlate; neurochemistry; neuroimaging; neurophysiology; overexpression; phenotypic biomarker; postnatal; public health relevance; repetitive behavior; sex; synaptic function; synergism; white matter

 DESCRIPTION (provided by applicant): This proposal addresses two challenges of great importance to child health: defining genetic etiologies of autism spectrum disorders (ASD) and establishing clinical-pathophysiological mechanisms in ASD. Autism is common in the US, affecting ~1% of the population, and is heterogeneous with regard to etiology, pathogenesis, and clinical presentation. A known, genetic risk factor for ASD is the male sex chromosome disorder, 47,XYY syndrome (XYY). Approximately one third of males with XYY satisfy diagnostic criteria for ASD, and XYY is significantly overrepresented in autism cohorts; yet this significant association is understudied. Coupled with the 4:1 male predominance for ASD, the increased risk for ASD in XYY suggests the involvement of sex-linked genes (i.e. increased Y chromosome gene copy number in XYY leads to over- expression of Y-linked genes related to brain development and function, thereby increasing ASD risk). The overarching goals of this proposal are to 1) better understand the particular role of the Y-chromosome in ASD, given the male preponderance and likely involvement of sex-linked genes, 2) to improve understanding of the neuroanatomic and neurophysiologic correlates of ASD in this relatively genetically homogeneous model of autism 3) to enlighten our understanding of convergent pathophysiological mechanisms that may generalize to the broader autism spectrum, and 4) to characterize the neural correlates of behavioral symptoms in boys with XYY, leading towards future targeted treatments and interventions. To accomplish these goals, we will contrast the clinical, behavioral and neurophysiological markers of ASD in four groups (20 per group) of age-matched (6-16 yrs) boys: XYY with ASD (XYY+ASD), XYY without ASD (XYY-ASD), ASD-Idiopathic (ASD-I) and typically developing (TD) controls. An existing well-characterized dataset will be used for ASD-I and TD cohorts. Cognitive and behavioral phenotypes will be obtained from 80 boys with XYY to yield 40 (20 XYY+ASD / 20 XYY-ASD) subjects suitable for imaging. Aims 1 and 2 seek to establish commonalities between the XYY+ASD and ASD-I populations as well as specificities of the ASD phenotype within the XYY population (XYY+ASD vs XYY-ASD) by comparing clinical/behavioral markers of ASD (in Aim 1) and local cortical neurophysiologic (magnetoencephalography) markers (in Aim 2) in the four groups. The mechanisms underlying the neurophysiologic measures will be probed in Aim 3, via the neuro- chemical magnetic resonance spectroscopy of key neurotransmitters GABA and glutamate and quantitative diffusion MRI. Aim 4 examines interactions between clinical/behavioral phenotypic markers and neurophys- iological, neurochemical and neuroimaging measures and will demonstrate that ASD in XYY+ASD shares a neurobiological basis with ASD-I. This innovative study takes advantage of the methodical ASD characteriza- tion of the unique XYY cohort (Dr. Ross), extensive ASD-I neuroimaging expertise (Dr. Roberts), compelling synergies of the multidisciplinary team, multi-modal data collection, and sophisticated multivariate analysis.

 描述（由应用程序提供）：该提案解决了对儿童健康重大重要性的两个挑战：定义自闭症谱系障碍的遗传病因（ASD）并在ASD中建立临床病理生理机制。自闭症在美国很常见，影响约1％的人口，并且在病因，发病机理和临床表现方面是异质的。 ASD的已知遗传危险因素是男性性染色体疾病，47，XYY综合征（XYY）。 XYY的男性中约有三分之一满足ASD的诊断标准，而XYY在自闭症队列中的代表性大大过多。然而，这种重要的关联已被理解。再加上ASD的4：1男性占主导地位，XYY中ASD的风险增加表明了性别连接基因的参与（即，XYY中Y染色体基因拷贝数的增加导致与大脑发育相关的Y链接基因过度表达与大脑发育和功能相关，从而增加了ASD风险）。该提案的首要目标是1）更好地了解Y染色体在ASD中的特殊作用，鉴于男性的优势和可能与性别联系的基因的参与，2），2），以提高对神经解剖学和神经生理学的理解，在ASD中，ASD的神经生理学相关性在此相对普遍的同性恋模型中，可以使我们的自动化概念性促进，3）促进了我们的促进的趋势3）更广泛的自闭症谱系和4）表征了XYY男孩的行为症状的神经元相关性，导致未来的目标治疗和干预措施。为了实现这些目标，我们将以四组（每​​组20）年龄匹配（6-16岁）的男孩与ASD（XYY+ASD）（XYY+ASD），无ASD（XYY-ASD），ASD-IDIIPARTAIC（ASD-IDIOPATHIC（ASD-I）和典型的（TED）（TEND）（TEND）（TEND）（TEND）（TED）（XYY），将ASD的临床，行为和神经生理标记与ASD的临床，行为和神经生理标记对比。现有的良好特征数据集将用于ASD-I和TD队列。认知和行为表型将从80名具有XYY的男孩获得40名（20 XYY+ASD / 20 XYY-ASD）受试者，适合成像。目的1和2试图在XYY+ASD和ASD-I种群之间建立共同点，以及XYY人群（XYY+ASD vs XYY-ASD）内ASD表型的规格，通过比较ASD的临床/行为标记（在AIM 1）（在AIM 1）和局部cortical cortical cortical cortical cortical cortical cortical cortical cortical corporphyolophyolophyolophyolophyolophyolophyolophyolophyolophyolophyolophyology（Magnetetecorphalogementagraphal）中（AIM）（in AIM）（在AIM）中（AIM）。神经生理测量的基础机制将在AIM 3中通过关键神经递质GABA和谷氨酸的神经化学磁共振光谱以及定量扩散MRI进行探测。 AIM 4检查临床/行为表型标记与神经植物，神经化学和神经影像学措施之间的相互作用，并将证明XYY+ASD中的ASD与ASD-I共享神经生物学基础。这项创新的研究利用了独特的XYY队列（Ross博士）的有条理的ASD特征，广泛的ASD-I神经影像学专业知识（Roberts博士），多模式数据收集的多学科团队的引人注目的协同作用，以及成熟的多变量分析。