Genetic Liability for Autism and Infant Brain and Behavioral Development

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的研究项目， 神经成像、行为分析和遗传学，以研究形成易感性的个人因素 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 现场工作，通过阐明致病原因，告知早期干预的时间和性质 机制及其发展的时间进程。 研究项目：ASD是高度可遗传的，大多数ASD病例是由于遗传， 常见的多基因变异。对患有自闭症的大龄儿童的婴儿兄弟姐妹进行的前瞻性研究 ASD自身发展的可能性增加，有详细的异常大脑和行为轨迹 早在6个月大的时候就开始出现ASD(20%)和30%的高危婴儿 未发展为自闭症的婴儿。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，到目前为止，还没有关于可量化基因的研究 自闭症对婴儿发育的责任。鉴于生命的第一年标志着大脑的高度可塑性时期 在ASD诊断特征出现之前的发展，决定了作用机制 而针对这一发育期的干预措施可能会产生最佳结果。当前的目标是 该项目旨在确定婴儿和蹒跚学步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数量自闭症特征(QAT)来衡量 反映与ASD相关的累积风险基因的婴儿多基因风险评分(PR)。此外，自然界 6个月至24个月龄的大脑和行为中间ASD表型的相关性 将被描述为。具体目标：(1)确定ASD的遗传易感性是否与婴儿大脑有关 以及使用(1a)一级亲属的QAT和(1b)PR，以及(2)定义 在早期发育中，中间脑和行为表型之间的关联。 职业发展：这个K01奖项将在以下方面为我提供必要的培训 遗传流行病学和分子遗传学，这是我在过渡到独立职业之前需要的。 导师：共同导师：约瑟夫·皮文博士(系和约翰·康斯坦蒂诺博士(系)。的 华盛顿大学精神病学)。顾问：Jason Stein博士(遗传学，北卡罗来纳大学)，Danielle Fallin博士 约翰斯·霍普金斯大学的流行病学博士、北卡罗来纳大学儿科学学院的辛西娅·鲍威尔博士和生物统计学学院的张进博士。

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).