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).
Autism spectrum disorder (ASD) is highly heritable and marked by aberrant brain and behavioral development as early as 6 months of age, however it is unknown how genetic liability for ASD impacts infant development. This study aims to characterize how quantitative measures of genetic liability for ASD ? including heritable autistic traits in first degree relatives and polygenic risk scores in infants ? relate to trajectories of brain and behavioral development from 6 months of age through the period of early diagnosis at 24 months. Understanding the impact of genetic liability for ASD on neural and behavioral development reveals important mechanistic insight into the pathogenesis of ASD, and potentially identifies targets and timing for early intervention.
