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: 10598198
• 负责人: Jessica Bullins Girault
• 金额: $ 5.4万
• 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: 2020-04-20 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598198
• 关键词: Age-Months; Area; Behavioral; Biometry; Brain; Child; Development; Diagnostic; Early Diagnosis; Early Intervention; Epidemiology; First Degree Relative; Genetic; Goals; Heritability; Individual; Infant; Infant Development; Inherited; Intervention; Life; Measures; Mentored Research Scientist Development Award; Mentors; Mentorship; Molecular Genetics; Nature; Neurodevelopmental Disorder; Neurosciences; Outcome; Parents; Pathogenesis; Pathogenicity; Pediatrics; Phenotype; Prospective Studies; Psychiatry; Research; Research Project Grants; Risk; Shapes; Siblings; Time; Training; Universities; Variant; Washington; Work; autism spectrum disorder; autistic; autistic children; behavioral phenotyping; career; career development; genetic epidemiology; improved outcome; infancy; insight; neuroimaging; polygenic risk score; proband; programs; relating to nervous system; risk variant; trait

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， 神经成像，行为分析和遗传学，以研究塑造脆弱性的个体因素， 神经发育障碍和表型表达的变异性。最终，我希望改善结果 在患有神经发育障碍的儿童中，重点是自闭症谱系障碍（ASD）， 通过阐明病原体，告知早期干预的时间和性质的现场工作 机制及其发展的时间进程。 研究项目：ASD是高度遗传的，大多数ASD病例是由于遗传， 常见的多基因变异对年龄较大的ASD儿童的婴儿兄弟姐妹进行的前瞻性研究， 他们自己发展ASD的可能性增加，有详细的异常大脑和行为轨迹， 最早在6个月大的婴儿中开始，继续发展为ASD（20%）和30%的高危婴儿 未患ASD的婴儿。这表明ASD的遗传易感性可能会影响大脑和行为 以分级的方式发展;然而，迄今为止，还没有关于可量化的遗传学的研究。 ASD对婴儿发育的影响鉴于生命的第一年标志着大脑的高度可塑期 在ASD诊断特征出现之前的发展，决定作用机制 针对这一发展阶段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因素的影响， ASD的易感性，通过父母和老年先证者的遗传性定量自闭症特征（QAT）来衡量， 婴儿多基因风险评分（PRS）反映与ASD相关的累积风险基因。此外，性质 从6个月到24个月大的大脑和行为中间ASD表型之间的关联 将被定性。具体目的：（1）确定ASD的遗传易感性是否与婴儿大脑有关 和行为发展使用（1a）QAT在一级亲属和（1b）PRS，和（2）定义 在早期发育过程中，中间脑和行为表型之间的关联。 职业发展：这个K 01奖项将为我提供以下领域的必要培训： 遗传流行病学和分子遗传学，我需要在过渡到一个独立的职业生涯。 导师：共同导师：约瑟夫·皮文博士（部门。约翰·康斯坦丁诺博士（John Constantino）的 精神病学，华盛顿大学）。顾问：Jason Stein博士（遗传学，遗传学），Danielle Fallin博士 （流行病学，约翰·霍普金斯大学）、Cynthia Powell博士（儿科，北卡罗来纳大学）和Kinh Truong博士（生物统计学，北卡罗来纳大学）。