Combined polygenic risk scores of different psychiatric traits predict general and specific psychopathology in childhood

Background: Polygenic risk scores (PRSs) are increasingly used in psychiatric research to operationalize genetic propensity towards a particular mental disorder. PRSs hold promise as early predictors of psychiatric symptoms in clinical settings, but, before a PRS can be clinically used, their specificity towards a psychiatric domain needs to be evaluated and their explanatory power increased. In this study we tested whether PRSs associate more with general or specific psychopathology in school-aged children. In addition, we tested whether psychiatric PRSs can be combined into a multi-PRS score for improved performance. Methods: We computed 16 PRSs based on GWASs of psychiatric outcomes, but also neuroticism and cognitive ability. Study participants were 9267 school-aged children from three population-based cohorts of the DREAM-BIG consortium: ALSPAC (England), The Generation R Study (the Netherlands) and MAVAN (Canada). We associated each PRS with general and specific psychopathology factors, derived from a bifactor model based on self-, parental-, teacher-, and observer reports. After fitting each PRS in separate models, we also tested a multi-PRS model, in which all PRSs are entered simultaneously as predictors of the general psychopathology factor. Results: Seven PRSs were associated with the general psychopathology factor after multiple testing adjustment, two with specific externalizing and four with specific internalizing psychopathology. PRSs predicted general psychopathology independent of each other, with the exception of depression and depressive symptom PRSs. Each PRS associated with a specific psychopathology domain, was also associated with general child psychopathology. Conclusions: The results suggest that PRSs based on current GWASs of psychiatric outcomes tend to be associated with general psychopathology, or both general and specific psychiatric symptoms, but not with one specific psychopathology domain only. Furthermore, PRSs can be combined to improve predictive ability. PRS users should therefore be conscious of non-specificity and consider using multiple PRS simultaneously, when predicting psychiatric disorders.