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: 10227950
• 负责人: Kevin A Pelphrey
• 金额: $ 228.13万
• 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 2022-09-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227950
• 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; 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; preventive intervention; 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.

项目总结