Blunted maturation of inhibitory control circuits in the NAC-shell underlies genetic vulnerability to early-life obesity and impulsivity

Obesity and behavioral impulsivity are highly heritable traits that share overlapping genetic risk and often co-occur in childhood. This study investigates whether maturation of the nucleus accumbens shell (NAC-shell) inhibitory-control circuit mediates shared vulnerability to both traits. Using state-of-the-art dynamic fMRI, we mapped NAC-shell development across 460 longitudinal assessments from childhood to adulthood, in 136 healthy controls and 126 individuals with 22q11.2 deletion syndrome (22q11DS), a genetic model conferring high risk for obesity and impulsivity. Blunted NAC-shell maturation predicted steeper BMI increases and persistent neurocognitive impulsivity, consistently mediating their association in both HC and 22q11DS populations. NAC-shell development explained both impulsivity/obesity genetic vulnerability linked to 22q11DS and familial correlations between affected/unaffected siblings. These findings propose NAC-shell maturation as a transdiagnostic endophenotype underlying obesity and self-regulation, bridging neurodevelopment, genetics, and behavior. They could inform future early-screening and precision preventive strategies for youth at risk of obesity and other impulsivity-related phenotypes.