Importance: Large consortia of genome wide association studies have yielded more accurate polygenic risk scores (PRS) that aggregate the small effects of many genetic variants to characterize the genetic architecture of disorders and provide a personalized measure of genetic risk. Objective: We examined whether a PRS for smoking measured genetic risk for general behavioral disinhibition by estimating its associations with externalizing and internalizing psychopathology and related personality traits. We examined these associations at multiple time points in adolescence using more refined phenotypes defined by stable characteristics across time and at young ages, which reduced potential confounds associated with cumulative exposure to substances and reverse causality. Methods: Random intercept panel models were fit to symptoms of conduct disorder, oppositional defiant disorder, major depressive disorder (MDD), and teacher ratings of externalizing and internalizing problems and personality traits at ages 11, 14, and 17 years-old in the Minnesota Twin Family Study (N = 3225). Results: The smoking PRS had strong associations with the random intercept factors for all the externalizing measures (mean standardized ꞵ = .27), agreeableness (ꞵ=-.22, 95% CI: -.28, -.16), and conscientiousness (ꞵ=-.19, 95% CI: -.24, -.13), but was not significantly associated with the internalizing measures (mean ꞵ = .06) or extraversion (ꞵ=.01, 95% CI: -.05, .07). After controlling for smoking at age 17, the associations with the externalizing measures (mean ꞵ = .13) and personality traits related to behavioral control (mean ꞵ = -.10) remained statistically significant. Conclusions and Relevance: The smoking PRS measures genetic influences that contribute to a spectrum of phenotypes related to behavioral disinhibition including externalizing psychopathology and normal-range personality traits related to behavioral control, but not internalizing psychopathology. Continuing to identify the correlates and delineate the mechanisms of the genetic influences associated with disinhibition could have substantial impact in mitigating a variety of public health problems (e.g., mental health, academic achievement, criminality).
