Background: Recent epidemiological evidence links early-life obesity and metabolic dysregulation to adult psychosis vulnerability, though a causal relationship remains unclear. Establishing causality in highly heritable psychotic disorders requires 1) demonstrating that early-life metabolic factors mediate between genetic vulnerability and psychosis trajectory, 2) dissecting mechanisms leading to early-life obesity in genetically vulnerable individuals, and 3) clarifying downstream neurodevelopmental pathways linking early-life obesity to psychosis symptoms.

Methods: Here we investigated bidirectional pathways linking behavioral, body mass index (BMI), and neurodevelopmental trajectories in a unique longitudinal cohort of 184 individuals at high genetic risk for psychosis, due to 22q11.2 deletion syndrome (22q11DS), and 182 neurotypical control individuals, followed-up since childhood. We combined repeated BMI measurements with clinical/neurocognitive phenotyping and neuroimaging. We investigated the relationship between BMI trajectories with risk of psychosis and tested whether altered cortical or cerebellar development could underlie this association.

Results: Childhood behavioral impulsivity predicted early and progressive deviations in BMI trajectories, mediating the effects of 22q11DS vulnerability to early-life obesity. Chronic BMI increases manifesting during childhood predicted the subsequent emergence of psychosis during late adolescence/early adulthood, mediating the effects of behavioral impulsivity. A dose-effect relationship linked duration of increased BMI status to worsening of motor and cognitive disorganization, a key schizophrenia symptom domain, which was mediated by progressive gray matter volume reductions in posterior-inferior cerebellum.

Conclusions: These findings suggest that metabolic dysregulation associated with obesity may link childhood behavioral impulsivity to psychosis vulnerability in 22q11DS by influencing cerebellar maturation. These findings might support preventive interventions targeting early-life metabolic trajectories in individuals at risk of psychosis.