Background: Adolescent suicide is a global health crisis, and familial risk is a primary, yet poorly understood contributor. Integrating molecular genetics with developmental psychopathology is crucial for identifying transmission mechanisms across generations, but this has been lacking, hindering effective, mechanism-based prevention.


Methods: Combining molecular, familial, and behavioral data across cultures, we analyzed longitudinal data from 11,867 U.S. adolescents (ABCD Study®, 5 years) and 94,412 Chinese adolescents (self-established A-HELP cohort, 2 years). We defined intergenerational (parent-to-child), cross-generational (grandparent-to-grandchild), and multi-generational (three consecutive generations) pathways based on family history of suicide (FHoS). We then tested a mechanistic model where polygenic risk scores (PRSs) and early psychopathology mediate the link between FHoS and adolescent suicidal behavior.


Results: Over half of adolescents with FHoS reported suicidal behaviors (ABCD: 53.9%; A-HELP: 52.0%). Parental suicidal behavior was the strongest predictor of offspring risk, with a sensitive period for transmission emerging between ages 9-15. FHoS was significantly associated with PRSs for six psychiatric disorders, including major depressive disorder (MDD), bipolar disorder (BD), and ever self-harm (ESH). We identified a core biological mechanism: polygenic liability for MDD significantly mediated all transmission pathways. This genetic vulnerability was expressed through emotional problems, which also served as powerful mediators. This entire mechanistic cascade was buffered by a key environmental factor: protective parental monitoring, a finding replicated across both cohorts.


Conclusions: Our findings reveal a developmental cascade for the familial transmission of suicide, where inherited polygenic liability for depression contributes to early-onset psychopathology, elevating suicide risk. This work provides a novel framework for risk stratification by integrating FHoS and PRS, and identifies parental monitoring as a potent, scalable intervention target to disrupt the multi-generational cycle of suicide.