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.

项目摘要 自闭症谱系障碍（ASD）不成比例地影响女性（♀）的男性（♂），可能是因为 女性保护作用（FPE）。表征FPE可能会帮助我们理解和治疗两性的ASD。 我们的网络有助于理解基因结构水平上ASD的性别差异和 表达，神经动力学，大脑功能和连通性。我们已经策划了一个前所未有的性平衡， 年龄，智商和严重性匹配的认知学院时代♂，以及与ASD，年龄和IQ匹配的人群 通常是发展（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和 在大脑结构，连通性，功能和临时动力学水平上测量了关键的神经元系统。 正在进行基因分型，全基因组测序和基因表达分析。我们现在寻求购买 一个非凡的机会，可以再次评估参与者（T2），因为他们通过 青少年到成年。我们的领域未能产生足够的知识基础来帮助 为与ASD及其家人在一起的人们优化这种过渡。我们将利用网络的专业知识 在这一重要的过渡期间，确定ASD纵向大脑发育的性别差异。我们将澄清 发展社会感知，情感调节，奖励和隐式的临时和空间特征 语言学习电路，除了具有感官习惯的神经机制外，还创造了多维的多态 大脑发育的水平神经信号。我们将桥接DNA序列和大脑发育以及相关 对行为和遗传学的神经签名，以预测成年年轻人的“现实世界”功能。我们将结合 多种级别的生物学和内表型 - SNV，CNV，临床测量，青春期状态，存在 癫痫发作/癫痫，性激素和多模式，纵向测量大脑发育 - into 使用集成加权基因共表达网络分析（IWGCNA）的框架。最后，我们将扩展 我们的T1系统生物学方法通过与ASD自我顾问/参与者进行协作*评估 经验我们发现的有效性。拟议的研究标志着一个新时代的开始 多模式的神经影像学和遗传分析将演变成翻译研究链的整体部分。 在青少年和Young中，可能会进一步开发新的ASD行为治疗和药物治疗 成年，直接，更精确地评​​估神经元的损伤和变化的巨大好处 电路。通过提供有关ASD中不同性，基于性别/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。