Prenatal maternal stress is a known risk factor for later emotional problems, yet not all exposed offspring develop psychopathology. Executive functioning and prefrontal cortex structure and activity may buffer these effects, but it remains unclear whether genetic predispositions in these domains moderate associations with adolescent internalizing symptoms.

We examined 3,111 adolescents (1,881 females, 1,230 males). Prenatal stress was measured via a cumulative index across four domains. Internalizing symptoms were self-reported at ages 14 and 16. Genetic predisposition for executive functioning was indexed using a polygenic score (PGS) derived from adult samples, applied here to estimate genetic predisposition for executive functioning in adolescence. We also estimated a prefrontal cortex PGS based on cortical thickness and activation in six prefrontal regions, with a composite index derived from the first principal axis summarizing these measures.

Higher prenatal stress was significantly associated with more internalizing symptoms in adolescence. Female sex and maternal genetic risk for internalizing symptoms were also associated with higher symptom levels. Neither genetic disposition for executive functioning nor prefrontal cortex moderated this association overall. However, a weak interaction emerged at age 16, indicating that a genetic disposition for higher executive functioning was associated with greater internalizing symptoms under high stress exposure.

Prenatal maternal stress predicted increased adolescent internalizing symptoms, with limited evidence for moderation by genetic predisposition for executive functioning. Higher genetic potential for executive functioning may confer increased sensitivity to early stress under certain developmental conditions.