Genetic influences for distinct impulsivity domains are differentially associated with early substance use initiation: Results from the ABCD Study

Background Impulsivity is among the strongest correlates of substance involvement (i.e. a broad continuum of substance-related behaviors), and distinct domains (e.g. sensation seeking [SS] and urgency) are differentially correlated, phenotypically and genetically, with unique substance involvement stages. Examining whether polygenic influences for distinct impulsivity domains are differentially predictive of early substance use initiation - a major risk factor for later problematic use - may improve our understanding of the role of impulsivity in addiction etiology. Methods Data collected from participants of genetically inferred European ancestry enrolled in the Adolescent Brain Cognitive Development Study^SM (n = 4,808) were used to estimate associations between polygenic scores (PGSs) for UPPS-P impulsivity domains (i.e. SS, lack of premeditation [LPREMED]/perseverance [LPERSEV], and negative/positive urgency [NU/PU]) and substance (i.e. any, alcohol, nicotine, and cannabis) use initiation by age 15 years. Mediation models examined whether child impulsivity (ages 9-11 years) mediated links between PGSs and substance use initiation. Results SS-PGS was significantly associated with any substance and alcohol use initiation (odds ratio [ORs] > 1.10, psFDR < 0.05). LPERSEV and NU/PU PGSs were nominally associated with alcohol and nicotine use initiation, respectively (ORs > 1.06, ps < 0.05, psFDR > 0.05). No significant associations were observed for LPREMED-PGS or cannabis use initiation. Measured impulsivity domains accounted for 5-9% of associations between UPPS-P PGSs and substance use initiation. Conclusions Genetic influences for distinct impulsivity domains have differential associations with early substance use initiation, with SS showing the most robust associations, highlighting valuable etiological insight into the earliest stages of substance involvement that may be leveraged to improve prevention and intervention strategies.