SEX-SPECIFIC ASSOCIATION BETWEEN POLYGENIC RISKS FOR MAJOR DEPRESSIVE DISORDER, PERINATAL ADVERSITY, BRAIN MATURATION AND ADOLESCENT INTERNALIZING SYMPTOMS

Severe forms of mood disorders (MD) with adolescent onset exhibit atypical sulcation patterns. These cortical anomalies reflect altered perinatal brain maturation, suggesting perinatal origins in these forms of MD. Sex differences exist both in perinatal brain maturation and in psychopathology of MD. Thus, understanding how sex moderates the association between perinatal factors and MD onset could facilitate earlier diagnosis. Using ABCD study longitudinal data (N=7,031, ages 9–11), we analyzed annual Child Behavior Checklist assessments of internalizing symptoms (anxiety, depression, withdrawal, ruminations) over four years, defining three trajectories: controls (never clinical), early-onset persistent, and early remitters (early onset then remit). Sulcal morphometry was extracted from baseline sMRI. We computed PRS to assess genetic vulnerability for major psychiatric disorders. Mixed models compared groups to controls, adjusting for site, scanner, age, race/ethnicity, and stratifying analysis by sex. Early remitters were 71.9% boys, while sex-distribution was balanced in other groups. For boys only, early-onset and early-remitter children exhibited reduced global sulcal surface as compared to controls. These groups showed higher perinatal complications in both sexes. For the early-onset group only, Major Depressive Disorder PRS was elevated compared to controls. Finally, early-onset internalizing symptoms likely stem from joint genetic vulnerability and adverse perinatal events, but differences in perinatal brain maturation appear only among boys. This aligns with previous work suggesting girls’ maturing brains benefit from a greater protection against perinatal insults. Early remitters, predominantly boys, share perinatal risks with early-onset children, underscoring the need to identify factors driving their apparent remission.