Polygenic scores for psychiatric traits mediate the impact of multigenerational history for depression on offspring psychopathology.

A family history of depression is a well-documented risk factor for offspring psychopathology. However, the genetic mechanisms underlying the intergenerational transmission of depression remain unclear. We used genetic, family history, and diagnostic data from 11,875 9-10 year-old children from the Adolescent Brain Cognitive Development study. We estimated and investigated the children's polygenic scores (PGSs) for 30 distinct traits and their association with a family history of depression (including grandparents and parents) and the children's overall psychopathology through logistic regression analyses. We assessed the role of polygenic risk for psychiatric disorders in mediating the transmission of depression from one generation to the next. Among 11,875 multi-ancestry children, 8111 participants had matching phenotypic and genotypic data (3832 female [47.2%]; mean (SD) age, 9.5 (0.5) years), including 6151 [71.4%] of European-ancestry). Greater PGSs for depression (estimate = 0.129, 95% CI = 0.070-0.187) and bipolar disorder (estimate = 0.109, 95% CI = 0.051-0.168) were significantly associated with higher family history of depression (Bonferroni-corrected P < 0.05). Depression PGS was the only PGS that significantly associated with both family risk and offspring's psychopathology, and robustly mediated the impact of family history of depression on several youth psychopathologies including anxiety disorders, suicidal ideation, and any psychiatric disorder (proportions mediated 1.39-5.87% of the total effect on psychopathology; FDR-corrected P < 0.05). These findings suggest that increased polygenic risk for depression partially mediates the associations between family risk for depression and offspring psychopathology, showing a genetic basis for intergenerational transmission of depression. Future approaches that combine assessments of family risk with polygenic profiles may offer a more accurate method for identifying children at elevated risk.