Mapping Genotype to Developmental Course Across an Autism-Schizophrenia Gradient

Autism spectrum disorders (ASD) and schizophrenia (SCZ) are highly heritable neuropsychiatric disorders associated with substantial phenotypic heterogeneity in developmental course. Across both disorders, while some individuals struggle with developmental delays and have co-occurring intellectual disability (ID) from a young age, others attain milestones without difficulty and show few challenges until later in life. This heterogeneity in developmental course has challenged efforts to predict clinical prognosis, discover biological mechanisms, and develop personalized treatments. Both disorders are also associated with genetic risk factors and gene expression patterns that suggest a possible genetically-associated neurodevelopmental gradient from ID to ASD to SCZ. To assess how well this gradient maps on to developmental course in ASD and SCZ, the PI will analyze phenotypic, genetic, and neurobiological data from over 43,000 participants (including over 35,000 ASD children and 8,000 SCZ adults) and over 1,900 postmortem human brain tissue donors (including over 290 fetal donors and 1,600 adult donors). Genetic variation associated with ID, ASD, and/or SCZ will act as a bridge between phenotype and biology in this research. In Aim 1, the PI will distinguish subgroups of ASD children based on behavioral trajectories and subgroups of SCZ adults based on diagnostic trajectories, then compare the subgroups by key clinical outcomes. In Aim 2, the PI will characterize trajectory subgroups by average common and rare genetic burdens associated with ID, ASD, and SCZ, and average social-environmental exposure to childhood adversity, then test additive and non-additive risk models predicting subgroup membership. In Aim 3, the PI will evaluate the expression consequences of common variation associated with ID, ASD, and SCZ in neuropsychiatric risk genes across distinct developmental timepoints and cortical cell types. Altogether, ID/ASD/SCZ-associated genetic variation may show consistent associations across phenotype and biology, which can highlight putative biological candidates for further inquiry. To support her research aims and training goals, the PI has assembled an interdisciplinary committee of eminent scientists including Jordan Smoller (primary mentor), Elise Robinson (co-mentor), Michael Talkowski, Caroline Uhler, Aarno Palotie, Michael Gandal, Somer Bishop, and Evan Macosko. Building on her strong foundation in psychology, genetics, and neuroscience, the PI will deepen her statistical training in large- scale phenotyping approaches, statistical genetics methods, and functional genomics tools, and broaden her professional skills to prepare her for a faculty position. Her career development will be further bolstered by the highly collaborative training environments and extensive research infrastructures at the MGH Center for Genomic Medicine and the Broad Institute of MIT and Harvard. The PI’s completion of this proposal will inform biological mechanisms contributing to developmental course, developmental time windows for targeting therapeutic interventions, and personalized treatments tailored to genetic and environmental risk profiles. Project Number: 1K99MH137253-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Szu-Yu Susan Kuo | Institution: MASSACHUSETTS GENERAL HOSPITAL, BOSTON, MA | Award Amount: $129,290 | Activity Code: K99 | Study Section: Special Emphasis Panel[ZMH1 ERB-M (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11137297