Multimodal Developmental Neurogenetics of Females with ASD

项目摘要 自闭症谱系障碍(ASD)对男性(♂)比女性(♀)的影响不成比例，可能是因为 女性保护作用(FPE)。明确FPE的特征可能有助于我们理解和治疗男女ASD。 我们的网络有助于在基因结构和基因水平上了解ASD的性别差异 表情、神经动力学、大脑功能和连通性。我们策划了一个前所未有的性别平衡， 年龄、智商和严重程度匹配的学龄儿童♂和患有自闭症、年龄和智商匹配的♀的队列 通常为发育中(TD)儿童和未受影响的兄弟姐妹(美国)。在T1，我们进行了行为表型分析和 在大脑结构、连通性、功能和时间动力学的水平上测量关键神经系统。 基因分型、全基因组测序和基因表达分析正在进行中。我们现在寻求追查 在学员过渡期间再次对他们进行评估的绝佳机会(T2) 青春期和进入青春期。我们的领域未能生成足够的知识库来帮助 为自闭症患者及其家人优化这一过渡。我们将利用我们网络的专业知识 在这一重要的转变过程中，确定ASD纵向脑发育的性别差异。我们会澄清 社会知觉、情绪调节、奖励和内隐发展的时间和空间特征 语言学习回路，除了感官习惯化的神经机制外，还创造了多维、多维的 大脑发育的水平神经信号。我们将在DNA序列和大脑发育之间架起桥梁 神经信号的行为和遗传学，以预测“真实世界”的功能，在年轻的成年人。我们将联合起来 多层次的生物学和内表型-SNV、CNV、临床测量、青春期状况、是否存在 癫痫发作/癫痫、性激素和大脑发育的多模式、纵向测量--合而为一 使用集成加权基因共表达网络分析(IWGCNA)的框架。最后，我们将延长 我们的T1系统生物学方法通过与ASD自我倡导者/参与者的合作*来评估 我们发现的经验性有效性。这项拟议的研究标志着一个新时代的开始，在这个时代， 多模式神经成像和遗传分析将演变为翻译研究链中不可或缺的一部分。 青春期和青春期ASD的新的行为疗法和药物疗法可能会进一步发展 成年后直接和更准确地评估神经损伤和变化的巨大好处 电路。通过提供有关ASD中不同的、基于性别/性别的发育途径的信息，这项研究 将确定干预/预防战略是否应包括基于性别的修改。

Project Summary Autism Spectrum Disorder (ASD) disproportionately affects males (♂) over females (♀), possibly because of a Female Protective Effect (FPE). Characterizing the FPE may help us to understand and treat ASD in both sexes. Our Network has contributed to understanding sex differences in ASD at the levels of gene structure and expression, neural dynamics, brain function and connectivity. We have curated an unprecedented sex-balanced, age-, IQ- and severity-matched cohort of cognitively-able school-age ♂, and ♀ with ASD, age- and IQ-matched typically developing (TD) children and unaffected siblings (US). At T1, we conducted behavioral phenotyping and measured key neural systems at the levels of brain structure, connectivity, function and temporal dynamics. Genotyping, whole-genome sequencing and gene expression analyses are underway. We now seek to pursue an extraordinary opportunity to assess our participants again (T2) as they make the transition through adolescence and into young adulthood. Our field has failed to generate a sufficient knowledge base to help optimize this transition for people living with ASD and their families. We will leverage the expertise of our Network to identify sex differences in ASD longitudinal brain development during this important transition. We will clarify both temporal and spatial characteristics of developing social perception, emotion regulation, reward and implicit language learning circuits, in addition to neural mechanisms for sensory habituation, creating dimensional, multi- level neural signatures of brain development. We will bridge DNA sequence and brain development and relate neural signatures to behavior and genetics to predict “real-world” functioning in young adulthood. We will combine multiple levels of biology and endophenotypes—SNVs, CNVs, clinical measures, pubertal status, presence of seizures/epilepsy, sex hormones and multimodal, longitudinal measures of brain development—into one framework using an Integrated Weighted Gene Coexpression Network Analysis (iWGCNA). Finally, we will extend our T1 systems-biology approach through a collaboration*with ASD self-advocates/participants to evaluate the experiential validity of our findings. The proposed research marks the start of a new era in which advanced multimodal neuroimaging and genetic analyses will evolve into an integral part of a translational research chain. Novel behavioral treatment and pharmacotherapies for ASD may be further developed in adolescence and young adulthood with the tremendous benefit of directly and more precisely assessing impairment and change in neural circuits. By providing information about distinct, sex/gender-based developmental pathways in ASD, this study will identify if intervention/prevention strategies should include sex-based modifications.