Abstract
BACKGROUND: The Philadelphia Neurodevelopmental Cohort (PNC), a community sample of ~9,500 youth (8–21 years) ascertained through pediatric services, ~1600 had neuroimaging. Psychosis spectrum (PS) symptoms at intake were associated with neurocognitive deficits and abnormalities in brain structure and function. Follow-up allows examining associations between intake parameters, environmental adversity, polygenic risk score (PRS) and outcome. METHODS: We developed an environmental risk score (ERS), which was based on geocoding and traumatic stressful events. We compared symptoms, neurocognitive and neuroimaging parameters in PS to typically developing (TD) youths in relation to PRS and ERS. We followed 639 participants with 2 sets of measures and 322 with 3. RESULTS: We divided the sample by the ERS into those who grew up in benign environment and those with adverse environment. We found that participants with PS had higher PRS only in benign environment. Adverse environment was associated with more severe psychotic symptoms, as well as greater neurocognitive deficits at intake, especially in working memory, complex cognition and social cognition. MRI showed lower gray matter volume at intake in those with persistent psychotic symptoms across cortical regions. In individuals who entered at TD, emergence of PS in follow-up was also related to intake volumes across cortical regions and thalamus. DISCUSSION: Genetic vulnerability and environmental stressors are important in the evolution of psychosis during a dynamic period of brain maturation. Genetic effects are more influential in youth growing up in a benign environment while adversity is associated with emergence of psychosis even with lower genetic vulnerability.