F14. THE INTERPLAY OF PARENTAL MENTAL DISORDERS, CHILDHOOD ADVERSITY, AND GENETIC RISK IN PREDICTING OFFSPRING PSYCHOPATHOLOGY: A LONGITUDINAL ANALYSIS

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Background Psychiatric disorders are a leading cause of disability worldwide, arising from a complex interplay between genetic vulnerability and environmental stressors. Parental mental disorders (PMD) significantly increase offspring risk through both genetic transmission and the shaping of the child's social environment. This study investigated how PMD influences exposure to specific adversity domains—threat (events endangering physical integrity or well-being of the child) and deprivation (neglect, parental absence, and measures of material forms of deprivation)—and how these factors interact with offspring polygenic scores (PGS) for general psychopathology (p-factor) to predict longitudinal outcomes. Methods Data were drawn from the Brazilian High-Risk Cohort Study (BHRCS). PMD was assessed via the Mini-International Neuropsychiatric Interview, identifying 719 parents with psychiatric diagnoses (700 of 2,298 mothers and 19 of 105 fathers). Offspring psychopathology was measured using the Child Behavior Checklist (CBCL) across three waves: W0 (N=2,511; ages 5-14), W1 (N=2,010; ages 9-17), and W2 (N=1,801; ages 13-23). Adversity domains (threat and deprivation) were assessed through customized questionnaires and the Development and Well-Being Assessment (DAWBA). PGS for the p-factor was calculated using PRS-CS based on the most recent Cross-Disorder GWAS (Grotzinger et al., 2026). Results Both PMD and all adversity domains were robustly associated with increased offspring psychopathology across all waves (p < 0.001). Offspring of parents with PMD experienced significantly higher levels of threat and deprivation compared to controls (p < 0.001). Mothers with PMD exhibited significantly higher PGS (p < 0.001), and offspring PGS consistently predicted CBCL scores (w0: p < 0.001; w1: p=0.004; w2: p=0.017). Notably, threat and deprivation were significantly associated with offspring PGS (p < 0.001), suggesting a passive gene-environment correlation. However, stratified analyses revealed that the PGS-threat association was exclusively present in offspring of mothers without PMD. Mediation models identified divergent developmental patterns: in early childhood (W0-W1), threat fully mediated the PGS-psychopathology relationship (indirect effects: p < 0.001), while the direct genetic effect was non-significant. By W2, this mediation attenuated, and the direct effect of offspring PGS became the primary driver of psychopathology (beta=21.72, p=0.021). Conversely, deprivation showed consistent partial mediation across all waves, with the direct genetic effect remaining robust. Discussion Our findings highlight a "double hit" of inherited vulnerability and environmental stress in families with PMD. We observed a critical developmental shift: genetic risk for psychopathology appears to operate primarily through environmental "threat" exposure in childhood, whereas direct genetic influences emerge more prominently in early adulthood. The distinction between adversity domains is vital; while deprivation acts as a stable, additive risk factor, threat serves as a dynamic mediator that is most influential in early development. Notably, the moderation by maternal mental health suggests that in high-risk families, the clinical environment may overshadow individual genetic sensitivities to threat. These results emphasize the necessity of integrative models that distinguish between dimensions of adversity to uncover the mechanisms of intergenerational risk.

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