RESUMO
Though most genetic studies of substance use focus on specific substances in isolation or generalized vulnerability across multiple substances, few studies to date focus on the concurrent use of two or more substances within a specified time frame (i.e., polysubstance use; PSU). We evaluated whether distinct genetic factors underlying internalizing and externalizing traits were associated with past 30-day PSU above variance shared across general psychopathology and substance use (SU). Using Genomic Structural Equation Modeling, we constructed theory-driven, multivariate genetic factors of 16 internalizing, externalizing, and SU traits using genome-wide association studies (GWAS) summary statistics. Next, we fit a model with a higher order SU-related psychopathology factor as well as genetic variance specific to externalizing and internalizing (i.e., residual genetic variance not explained by SU or general psychopathology). GWAS-by-subtraction was used to obtain single nucleotide polymorphism effects on each of these factors. Polygenic scores (PGS) were then created in an independent target sample with data on PSU, the National Longitudinal Study of Adolescent to Adult Health. To evaluate the effect of genetic variance due to internalizing and externalizing traits independent of variance related to SU, we regressed PSU on the PGSs, controlling for sex, age, and genetic principal components. PGSs for SU-related psychopathology and non-SU externalizing traits were associated with higher PSU factor scores, while the non-SU internalizing PGS was not significantly associated with PSU. In total, the three PGSs accounted for an additional 4% of the variance in PSU above and beyond a null model with only age, sex, and genetic principal components as predictors. These findings suggest that there may be unique genetic variance in externalizing traits contributing to liability for PSU that is independent of the genetic variance shared with SU.
RESUMO
BACKGROUND: Studies suggest a broad spectrum of behaviors associated with drinking. Consequently, it is unclear whether patterns of familial risk for psychopathology are directly or indirectly related to patterns of alcohol use and problems in late adolescence or mediated by behavioral characteristics, such as temperament, mood. OBJECTIVES: We examined direct and indirect effects of perceived family history of psychopathology on pre-collegiate alcohol use and problems via the Transmissible Liability Index (TLI). METHODS: Participants (N = 302; 29.6% male) provided self-report data on age of onset of drinking, past 90-day frequency of alcohol use and problems (AUP), family history of internalizing and alcohol and illicit substance use, and TLI. RESULTS: Approximately 21% of participants reported having at least one relative with a history of regular and/or problematic alcohol use, compared to 12% for illicit substance use, and -55% for internalizing problems. Higher TLI scores were associated with increased family history of substance use, alcohol use, and internalizing problems, as well as earlier age of onset of drinking. Family history of internalizing problems was the most robust indicator of AUP (ß = 0.20 [95% CI = 0.04-0.36], P = .01). Path analyses suggested that the individual-level behaviors that comprise TLI mediate the effects of family history on age of initiation and regular alcohol consumption. CONCLUSIONS: Family history of internalizing, drinking, and illicit substance use reflect generalized risk for a broad set of behaviors associated with risk for alcohol initiation and use during the transition from high school to college.
