Multimodal Developmental Neurogenetics of Females with ASD

描述（由申请人提供）：项目摘要术语自闭症谱系障碍（ASD）说明了这种发育障碍在表型和潜在遗传水平上的巨大异质性。已经反复观察到ASD相对于女性（@）不成比例地影响男性（B）。尽管许多假说试图解释这种偏倚，但由于表型不一致和不完整以及样本量小，没有明确的答案。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参与者进行深度表型和基因分型来研究性别特异性差异。我们将招募一个性别平衡的ASD队列（N=125 B N=125 @）和匹配的典型发育（TD）对照参与者（N=125 B，N=125 @），以及一组未受影响的兄弟姐妹（US; N=63 @，N=62 B）。我们将定量表型多个行为域和测量几个关键的ASD相关的神经系统在脑结构（sMRI），连接（DTI和fMRI），功能（基于任务和静息状态的fMRI）和时间动力学（EEG）的水平。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基因的性别和电路特异性基因型-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ASD中大脑结构，功能，连接和时间动力学的性别差异。2)描述@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)将大脑在结构、功能和时间动力学方面的差异与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ASD的巨大异质性。因此，我们将联合收割机多层次的生物学和内表型-SNV，CNV，行为指标，静息状态成像和电生理学措施-到一个框架中受影响的和未受影响的同胞和控制使用集成的网络分析，iWGCNA。

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.