Neuroimaging analysis across diverse ancestries links pleiotropic genetic risk for internalizing disorders to brain development in early adolescence

Abstract \

While psychiatric disorders share genetic and neurobiological underpinnings, their manifestation during childhood and adolescence, particularly in diverse populations, remains poorly understood. Using whole-brain vertex-wise analyses in two independent pediatric cohorts representing African, Hispanic/Latinx, and European ancestries (N=8,767, with 13,769 brain scans), we investigated neurobiological signatures of pleiotropic genetic risk underlying fifteen psychiatric disorders. Higher polygenic risk for the Internalizing Factor (INTGF), capturing susceptibility to depression, anxiety, and post-traumatic stress disorder in adults, was associated with reduced cortical surface areas in the superior frontal, medial orbitofrontal, and cingulate regions, and smaller left amygdala volumes across ancestries in adolescents. At age thirteen, INTGF was associated with a broad spectrum of adolescent psychopathology, with reduced cortical surface area at age ten mediating this relationship. These findings uncover conserved neurodevelopmental pathways linking pleiotropic genetic risk to brain alterations and mental health problems detectable as early as adolescence, highlighting potential targets for early intervention across diverse populations.