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: 9750806
• 负责人: Kevin A Pelphrey
• 金额: $ 231.59万
• 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/9750806
• 关键词: Adolescence; Adult; Advocate; Affect; Age; Base of the Brain; Behavior Therapy; Behavioral; Behavioral Genetics; Biological Markers; Biology; Brain; Brain Diseases; Brain region; Brothers; Candidate Disease Gene; Characteristics; Child; Clinical; Cognitive; Collaborations; Comorbidity; 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; Nucleotides; 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; Sister; Social Perception; Social status; Structural Genes; Structure; Symptoms; System; Systems Biology; Techniques; Translational Research; Variant; Work; autism spectrum disorder; autistic; base; boys; cognitive interview; cohort; 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）对男性的影响不成比例地超过女性，可能是因为 女性保护作用（FPE）描述FPE可能有助于我们理解和治疗两性ASD。 我们的网络为了解ASD在基因结构水平上的性别差异做出了贡献， 表达、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期认知能力正常的ASD患者和ASD患者队列，年龄和智商匹配 正常发育（TD）儿童和未受影响的兄弟姐妹（US）。在T1，我们进行了行为表型分析， 在大脑结构、连通性、功能和时间动力学等层面测量了关键神经系统。 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 这是一个非常好的机会，可以在参与者完成过渡时再次评估他们（T2）， 从青春期到青年期。我们的领域未能产生足够的知识基础来帮助 为ASD患者及其家人优化这种过渡。我们将利用我们网络的专业知识 以确定在这一重要转变过程中ASD纵向大脑发育的性别差异。我们将澄清 社会知觉、情绪调节、奖赏和内隐认知发展的时空特征 语言学习回路，除了感官习惯化的神经机制，创造维度，多- 大脑发育的水平神经信号。我们将连接DNA序列和大脑发育， 行为和遗传学的神经信号来预测年轻成年人的“现实世界”功能。我们将联合收割机 多水平的生物学和内表型-SNV、CNV、临床测量、青春期状态、 癫痫发作/癫痫，性激素和多模式，大脑发育的纵向措施-合二为一 使用集成加权基因共表达网络分析（iWGCNA）的框架。最后，我们将扩展 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 *， 我们发现的经验有效性。这项拟议中的研究标志着一个新时代的开始， 多模式神经成像和遗传分析将发展成为转化研究链的一个组成部分。 ASD的新型行为治疗和药物治疗可能会在青少年和年轻人中进一步发展 直接和更精确地评估神经系统的损伤和变化的巨大好处 电路.通过提供关于ASD中不同的、基于性别的发育途径的信息，本研究 将确定干预/预防战略是否应包括基于性别的修改。