Multimodal Developmental Neurogenetics of Females with ASD

女性自闭症谱系障碍的多模式发育神经遗传学

• 批准号: 8885900
• 负责人: Kevin A Pelphrey
• 金额: $ 270.31万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-04 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8885900
• 关键词: Affect; Age; Attention; Behavior; Behavioral; Behavioral Genetics; Biology; Brain; Child; Copy Number Polymorphism; Cues; DNA Sequence; Data; Development; Disease; Electroencephalography; Electrophysiology (science); Emotional; Equation; Equilibrium; Etiology; Exhibits; Female; Functional Magnetic Resonance Imaging; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Health; Heterogeneity; Image; Language; Language Development; Measures; Methods; Modeling; Nucleotides; Parents; Participant; Pathway Analysis; Phenotype; Process; Psychological reinforcement; Recruitment Activity; Regulation; Relative (related person); Rest; Rewards; Sample Size; Severities; Sex Characteristics; Siblings; Site; Social Development; Structure; System; Testing; Time; Universities; Variant; Washington; Work; autism spectrum disorder; base; boys; cohort; developmental disease; disorder risk; endophenotype; exome; experience; genome-wide; girls; high risk; male; neural circuit; neurogenetics; neuroimaging; novel; pleiotropism; relating to nervous system; response; reward circuitry; risk variant; sex; social

DESCRIPTION (provided by applicant): Project Summary The term autism-spectrum disorders (ASD) exemplifies the tremendous heterogeneity in this developmental disorder at both the phenotypic and underlying genetic levels. It has repeatedly been observed that ASD disproportionately affects males (B) relative to females (@). Although many hypotheses attempt to explain this bias, no clear answers have emerged because of inconsistent and incomplete phenotyping and small sample sizes. We propose to leverage the interdisciplinary strengths and recruiting power of our network to study sex- specific differences by deep phenotyping and genotyping of ASD participants. We will recruit a sex-balanced cohort of ASD (N=125 B N=125 @) and matched typically developing (TD) comparison participants (N=125 B, N=125 @), as well as a set of unaffected siblings (US; N=63 @, N=62 B). We will quantitatively phenotype multiple behavioral domains and measure several key ASD-related neural systems at the level of brain structure (sMRI), connectivity (DTI and fMRI), function (task based and resting state fMRI), and temporal dynamics (EEG). Additionally, we will measure copy number variation (CNV) and single nucleotide variation (SNV) for these participants and their parents, allowing us to test sex- and circuit-specific genotype-phenotype hypotheses for five candidate ASD genes and ultimately extend our methods to a search for novel sex-specific and high-risk genes. Our Specific Aims are to: 1) Identify sex differences in brain structure, function, connectivity, and temporal dynamics in ASD. 2) Characterize associations between DNA sequence and copy number variants and brain structure and function in @ASD and @TD versus BASD and BTD. 3) Relate brain differences in structure, function, and temporal dynamics to heterogeneity in ASD behavior and genetics. We hypothesize that advanced network methods can aid in understanding the tremendous heterogeneity in ASD by connecting different levels of phenotype with genetic variation. We will therefore combine multiple levels of biology and endophenotypes - SNVs, CNVs, behavioral metrics, and resting state imaging and electrophysiology measures - into one framework across affected and unaffected siblings and controls using an integrated network analysis, iWGCNA.

描述（由申请人提供）：项目摘要 自闭症谱系障碍 (ASD) 一词例证了这种发育障碍在表型和潜在遗传水平上的巨大异质性。反复观察发现，相对于女性 (@)，自闭症谱系障碍 (ASD) 对男性 (B) 的影响不成比例。尽管许多假设试图解释这种偏差，但由于表型不一致和不完整以及样本量较小，尚未出现明确的答案。我们建议利用我们网络的跨学科优势和招募能力，通过对 ASD 参与者进行深入的表型和基因分型来研究性别特异性差异。我们将招募性别平衡的 ASD 队列 (N=125 B N=125 @) 和匹配的典型发育 (TD) 比较参与者 (N=125 B, N=125 @)，以及一组未受影响的兄弟姐妹 (美国；N=63@，N=62B)。我们将定量表型多个行为领域，并在大脑结构 (sMRI)、连通性（DTI 和 fMRI）、功能（基于任务和静息状态 fMRI）和时间动态 (EEG) 水平上测量几个关键的 ASD 相关神经系统。此外，我们将测量这些参与者及其父母的拷贝数变异（CNV）和单核苷酸变异（SNV），使我们能够测试五个候选 ASD 基因的性别和回路特异性基因型表型假设，并最终将我们的方法扩展到寻找新的性别特异性和高风险基因。我们的具体目标是： 1) 确定自闭症谱系障碍患者大脑结构、功能、连接性和时间动态方面的性别差异。 2) 表征@ASD 和@TD 与BASD 和BTD 中DNA 序列和拷贝数变异与大脑结构和功能之间的关联。 3) 将大脑结构、功能和时间动态的差异与 ASD 行为和遗传学的异质性联系起来。我们假设先进的网络方法可以通过将不同水平的表型与遗传变异联系起来，帮助理解自闭症谱系障碍的巨大异质性。因此，我们将使用集成网络分析 iWGCNA，将多个层面的生物学和内表型（SNV、CNV、行为指标以及静息态成像和电生理学测量）结合到一个框架中，涵盖受影响和未受影响的兄弟姐妹和对照。