Wednesday, February 5, 2025
2/5/2025
PROJECT SUMMARY The Penn-CHOP proposal builds on collaborations and complementary expertise in phenomics and genomics. The 22q11.2 deletion syndrome (22qDS) is associated with high risk for neuropsychiatric disorders across the lifespan. The clinical presentation and course are markedly heterogeneous, with a range of developmental neuropsychiatric disorders, including ADHD, Anxiety, ASD, and Psychosis Spectrum Disorders. Notably, presentation and course resemble idiopathic disorders. Therefore, beyond the specific genetic syndrome investigated, the proposed accelerated longitudinal design will identify convergent risk mechanisms for developmental trajectories of neuropsychiatric disorders in the broader population. We are uniquely positioned to establish developmental trajectories during a critical period, adolescence and emerging adulthood. Lacking in the literature of 22qDS is a systematic examination of environmental exposures, which play an important role in psychopathology and neurocognition in the general population. The nature and degree of medical burden have likewise not been examined in 22qDS. Taking a ‘genetics first’ approach of ascertainment based on a known deletion will allow us to overcome barriers posed by the genetic and phenotypic complexity of idiopathic developmental neuropsychiatric disorders. We postulate that 22q11.2 deletion exerts a large main and multifactorial effects on psychopathology, with contributions from multifaceted environmental exposures and common and rare genetic variants. Dissecting these effects with dimensional measures of psychopathology and neurocognition can elucidate the combined contribution of genetic and environmental mechanisms to psychiatric conditions and build models of risk prediction. Our ability to pursue such a large-scale study capitalizes on our existing successful collaborations, complementary expertise, and institutional commitments to achieve these goals. We propose to parse dimensional measures of psychopathology, neurocognition, and environmental exposures, to elucidate the architecture of risk for neuropsychiatric disorders in 22qDS focusing on the emergence of psychosis. Prospective evaluation with dimensional measures relevant to neuropsychiatric disorders will be applied to a cohort of 300 individuals with 22qDS and their parents, establishing trios. Thus, we will examine family and environmental factors that can contribute to the heterogeneity of presentation and developmental course in 22qDS. Recruitment for longitudinal prospective phenotyping will leverage an existing large cohort with a wealth of clinical data, many of whom have already been ascertained and comprehensively characterized with a range of phenotypic measures. We will also utilize existing genetic data from the largest available case-control samples in the PGC to generate polygenic risk scores for the most common neuropsychiatric disorders evident in 22qDS and examine their relation to outcome. This project will contribute to common phenomic and genomic resources established for data sharing.
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