Genetic Liability for Autism and Infant Brain and Behavioral Development

自闭症和婴儿大脑和行为发育的遗传责任

• 批准号: 10596107
• 负责人: Jessica Bullins Girault
• 金额: $ 16.9万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10596107
• 关键词: Age Months; Area; Attention; Behavioral; Biometry; Brain; Brain imaging; Child; Clinical; Complex; Data; Development; Diagnosis; Diagnostic; Disease; Early Diagnosis; Early Intervention; Epidemiology; Family; Family member; First Degree Relative; Genes; Genetic; Genetic Diseases; Genetic Variation; Goals; Heritability; Human; Individual; Individual Differences; Infant; Infant Development; Inherited; Intervention; Joints; Knowledge acquisition; Language; Learning; Life; Link; Measures; Mental disorders; Mentored Research Scientist Development Award; Mentors; Mentorship; Methods; Molecular Genetics; Nature; Neurodevelopmental Disorder; Neurosciences; Outcome; Parents; Pathogenesis; Pathogenicity; Pattern; Pediatrics; Phenotype; Population; Positioning Attribute; Postdoctoral Fellow; Process; Prospective Studies; Psychiatry; Quantitative Genetics; Research; Research Personnel; Research Project Grants; Research Proposals; Risk; Shapes; Siblings; Site; Surface; Symptoms; Time; Training; Universities; Variant; Washington; Work; autism spectrum disorder; autistic; autistic children; behavioral phenotyping; brain behavior; career; career development; clinical practice; de novo mutation; experience; genetic epidemiology; imaging study; improved outcome; indexing; infancy; insight; neural; neuroimaging; neuropsychiatric disorder; novel strategies; phenotypic data; polygenic risk score; proband; programs; risk variant; tool; training opportunity; trait; white matter

PROJECT ABSTRACT CAREER GOAL: My long-term goal is to build a program of research integrating neuroscience, neuroimaging, behavioral analysis, and genetics to study individual factors that shape vulnerability for neurodevelopmental disorders and variability in phenotypic expression. Ultimately, I wish to improve outcomes in children with neurodevelopmental disorders, with a focus on autism spectrum disorder (ASD), by contributing work to the field that informs the timing and nature of early interventions through elucidation of pathogenic mechanisms and their developmental time course. RESEARCH PROJECT: ASD is highly heritable and the majority of ASD cases are due to inherited, common polygenic variation. Prospective studies following infant-siblings of older children with ASD, who are at an increased likelihood of developing ASD themselves, have detailed aberrant brain and behavioral trajectories beginning as early as 6 months of age in both infants that go on to develop ASD (20%) and 30% of the at-risk infants who do not develop ASD. This suggests that genetic liability for ASD likely influences brain and behavioral development in a graded fashion; however, to date, there have been no studies relating quantifiable genetic liability for ASD to infant development. Given that the first year of life marks a highly plastic period of brain development that precedes the emergence of the diagnostic features of ASD, determining mechanisms of action and targeting interventions to this developmental period could yield optimal outcomes. The goal of the current project is to determine if brain and behavioral development in infancy and toddlerhood are impacted by genetic liability for ASD, as measured by inherited quantitative autistic traits (QAT) in parents and older probands and infant polygenic risk scores (PRS) reflecting cumulative risk genes associated with ASD. Additionally, the nature of associations between brain and behavioral intermediate ASD phenotypes from 6 months to 24 months of age will be characterized. Specific Aims: (1) To determine if genetic liability for ASD is associated with infant brain and behavioral development using both (1a) QAT in first-degree relatives and (1b) PRS, and (2) To define associations between intermediate brain and behavioral phenotypes across early development. CAREER DEVELOPMENT: This K01 award will provide me with the necessary training in the areas of genetic epidemiology and molecular genetics that I require before transitioning to an independent career. Mentorship: Co-mentors: Dr. Joseph Piven (Dept. of Psychiatry, UNC) and Dr. John Constantino (Dept. of Psychiatry, Washington University). Advisors: Dr. Jason Stein (Genetics, UNC), Dr. Danielle Fallin (Epidemiology, Johns Hopkins), Dr. Cynthia Powell (Pediatrics, UNC), and Dr. Kinh Truong (Biostatistics, UNC).

项目摘要 职业目标：我的长期目标是建立一个整合神经科学、 神经影像学、行为分析和遗传学来研究影响脆弱性的个体因素 神经发育障碍和表型表达的变异。最终，我希望改善结果 在患有神经发育障碍的儿童中，重点关注自闭症谱系障碍（ASD），通过贡献 通过阐明致病因素，了解早期干预措施的时间和性质的领域的工作 机制及其发展时间过程。 研究项目：自闭症谱系障碍具有高度遗传性，大多数自闭症谱系障碍病例是由于遗传、 常见的多基因变异。对年龄较大的自闭症谱系障碍儿童的婴儿兄弟姐妹进行的前瞻性研究 本身患自闭症谱系障碍的可能性增加，有详细的异常大脑和行为轨迹 早在 6 个月大时就开始出现自闭症谱系障碍 (ASD) 的婴儿 (20%) 和 30% 的高危婴儿 未患自闭症谱系障碍 (ASD) 的婴儿。这表明自闭症谱系障碍的遗传倾向可能会影响大脑和行为 分级发展；然而，迄今为止，还没有关于可量化遗传的研究 ASD 对婴儿发育的责任。鉴于生命的第一年标志着大脑的高度可塑期 ASD 诊断特征出现之前的发展，决定了作用机制 针对这一发展时期的干预措施可能会产生最佳结果。当前的目标 该项目旨在确定婴儿期和幼儿期的大脑和行为发育是否受到遗传的影响 自闭症谱系障碍的责任，通过父母和年长先证者遗传的自闭症数量特征（QAT）来衡量 婴儿多基因风险评分（PRS）反映了与 ASD 相关的累积风险基因。此外，大自然 6 个月至 24 个月龄大脑与行为中间 ASD 表型之间的关联 将被表征。具体目标：(1) 确定 ASD 的遗传倾向是否与婴儿大脑相关 和行为发展，同时使用 (1a) 一级亲属的 QAT 和 (1b) PRS，以及 (2) 定义 早期发育过程中的中间大脑和行为表型之间的关联。 职业发展：这个 K01 奖项将为我提供以下领域的必要培训 在转向独立职业之前我需要遗传流行病学和分子遗传学。 导师：共同导师：Joseph Piven 博士（北卡罗来纳大学精神病学系）和 John Constantino 博士（北卡罗来纳大学精神病学系） 精神病学，华盛顿大学）。顾问：Jason Stein 博士（北卡罗来纳大学遗传学）、Danielle Fallin 博士 （约翰·霍普金斯大学流行病学）、Cynthia Powell 博士（北卡罗来纳大学儿科）和 Kinh Truong 博士（北卡罗来纳大学生物统计学）。