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: 8385755
• 负责人: Kevin A Pelphrey
• 金额: $ 311.9万
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8385755
• 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; Heterogeneity; Image; Language; Language Development; Measures; Methods; Metric; 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; Variant; Work; autism spectrum disorder; base; cohort; developmental disease; disorder risk; endophenotype; exome; experience; genome-wide; high risk; male; neural circuit; neurogenetics; neuroimaging; novel; relating to nervous system; response; reward circuitry; 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. PUBLIC HEALTH RELEVANCE: Project Narrative In this project, we will pool together our interdisciplinary expertise and recruitment efforts across four leading Centers for the study of autism spectrum disorder (Yale, UCLA, Harvard, and University of Washington) in an effort to: 1) Identify difference between boys and girls in brain mechanisms underlying autism spectrum disorder; 2) Search for relationships between brain mechanisms and underlying genetic differences; 3) Discover the brain and genetic mechanisms underlying heterogeneity in the presentation and severity of autism spectrum disorder in boys and girls.

描述（由申请人提供）：项目摘要一词自闭症 - 谱系疾病（ASD）典型地说明了这种发育障碍在表型和潜在的遗传水平上的巨大异质性。反复观察到，相对于女性（@），ASD不成比例地影响男性（b）。尽管许多假设试图解释这种偏见，但由于不一致和不完整的表型和小样本量而没有出现明确的答案。我们建议利用网络的跨学科优势和招募力量来通过深层表型和ASD参与者的基因分型来研究性别差异。我们将招募ASD的性平衡队列（n = 125 B n = 125 @），并匹配通常开发（TD）比较参与者（n = 125 B，n = 125 @），以及一组不受影响的兄弟姐妹（US; n = 63 @，n = 62 B）。我们将在大脑结构（SMRI），连通性（DTI和FMRI），功能（基于任务和静止状态fMRI）和时间动力学（EEG）（EEG）的水平（SMRI），连接性（DTI和fMRI），功能（dTI和fMRI），功能（DTI和fMRI），函数（DTI和fMRI）上进行定量表型多个行为域，并测量几个关键的与ASD相关的神经系统。此外，我们将为这些参与者及其父母测量拷贝数变化（CNV）和单核苷酸变化（SNV），使我们能够测试五个候选ASD基因的性别和电路特异性基因型 - 基因型 - 表型假设，并最终将我们的方法扩展到搜索新颖的性别特异性和高风险基因。我们的具体目的是：1）确定ASD中大脑结构，功能，连通性和时间动态方面的性别差异。 2）表征DNA序列与副本编号变体以及@ASD和@TD对BASD和BTD的关联。 3）将大脑的结构，功能和时间动力学之间的差异与ASD行为和遗传学的异质性联系在一起。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来帮助理解ASD中的巨大异质性。因此，我们将使用综合网络分析IWGCNA将多种水平的生物学和内型 - SNV，CNV，行为指标以及静止状态成像和电生理测量指标的静止状态成像和电生理测量方法结合在一起。 公共卫生相关性：该项目的项目叙述，我们将在四个主要的自闭症谱系障碍研究中心（耶鲁大学，加州大学洛杉矶分校，哈佛大学和华盛顿大学）中汇集跨学科专业知识和招聘工作，以：1）确定男孩和女孩在自闭症谱系下的男孩和女孩之间的差异； 2）寻找大脑机制和潜在的遗传差异之间的关系； 3）发现男孩和女孩自闭症谱系障碍的表现和严重程度中的异质性的大脑和遗传机制。