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: 10000140
• 负责人: Kevin A Pelphrey
• 金额: $ 229.91万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-31 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10000140
• 关键词: Adolescence; Adult; Advocate; Affect; Age; Base of the Brain; Behavior Therapy; Behavioral Genetics; Biological Markers; Biology; Brain; Brain Diseases; Brain region; Brothers; Candidate Disease Gene; Characteristics; Child; Clinical; Cognitive; Collaborations; Copy Number Polymorphism; DNA Sequence; Data; Data Set; Development; Diagnostic; Diffusion Magnetic Resonance Imaging; Dimensions; Dose; Electroencephalography; Epilepsy; Event-Related Potentials; Exhibits; Family; Female; Friendships; Functional Magnetic Resonance Imaging; Gender; Gene Expression; Gene Expression Profiling; Gene Structure; Genes; Genetic; Genetic Load; Genotype; Gonadal Steroid Hormones; Impairment; Intervention; Language Development; Magnetic Resonance Imaging; Measurement; Measures; Modification; Participant; Pathway Analysis; Pathway interactions; Pattern; Pharmacology; Pharmacotherapy; Phenotype; Preventive Intervention; Q-Sort; Quality of life; Research; Rest; Rewards; Sampling; School-Age Population; Seizures; Sensory; Severities; Sex Differences; Siblings; Single Nucleotide Polymorphism; Sister; Social Perception; Social status; Structure; Symptoms; System; Systems Biology; Techniques; Translational Research; Variant; Work; autism spectrum disorder; autistic; base; behavior measurement; behavioral phenotyping; boys; cognitive interview; cohort; comorbidity; disorder risk; emotion regulation; endophenotype; executive function; experience; gender difference; genetic analysis; genome sequencing; girls; habituation; indexing; insight; knowledge base; male; multimodality; neural circuit; neurogenetics; neuroimaging; neuromechanism; novel; pleiotropism; protective effect; relating to nervous system; resilience; reward circuitry; risk variant; sensory mechanism; sex; sexual dimorphism; social; symptomatology; tetrahydrobiopterin; trait; whole genome; young adult

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.

项目概要 自闭症谱系障碍 (ASD) 对男性 (♂) 的影响超过对女性 (♀) 的影响，可能是因为 女性保护作用（FPE）。描述 FPE 的特征可能有助于我们理解和治疗两性自闭症谱系障碍 (ASD)。 我们的网络有助于在基因结构和水平上了解自闭症谱系障碍的性别差异 表达、神经动力学、大脑功能和连接性。我们策划了前所未有的性别平衡， 年龄、智商和严重程度匹配的具有认知能力的学龄♂和♀患有自闭症谱系障碍的队列，年龄和智商匹配 典型发育中（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 在大脑结构、连接性、功能和时间动态层面测量关键神经系统。 基因分型、全基因组测序和基因表达分析正在进行中。我们现在寻求追求 这是一个绝佳的机会，可以在参与者进行过渡时再次评估他们（T2） 青春期和青年期。我们的领域未能产生足够的知识库来帮助 为自闭症谱系障碍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 以确定这一重要转变期间自闭症谱系障碍纵向大脑发育的性别差异。我们将澄清 发展社会感知、情绪调节、奖励和内隐的时间和空间特征 语言学习回路，除了感觉习惯化的神经机制之外，还创造了维度、多维度的 大脑发育水平的神经特征。我们将连接 DNA 序列和大脑发育并将其联系起来 行为和遗传学的神经特征可以预测成年早期的“现实世界”功能。我们将结合 生物学和内表型的多个水平——SNV、CNV、临床测量、青春期状态、存在 癫痫发作/癫痫、性激素和大脑发育的多模式纵向测量——合二为一 使用综合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/参与者合作*来评估 我们的研究结果的经验有效性。拟议的研究标志着一个新时代的开始，其中先进的 多模式神经影像和遗传分析将演变成转化研究链不可或缺的一部分。 针对自闭症谱系障碍的新型行为治疗和药物疗法可能会在青春期和年轻人中得到进一步开发 成年期的巨大好处是可以直接、更准确地评估神经损伤和变化 电路。通过提供有关自闭症谱系障碍 (ASD) 中不同的、基于性别的发展途径的信息，本研究 将确定干预/预防策略是否应包括基于性别的修改。