Polygenic Scores Predict the Development of Alcohol and Nicotine Use Problems from Adolescence through Young Adulthood

Abstract

ImportanceMolecular genetic studies of alcohol and nicotine use have identified hundreds of genome-wide risk loci. Few studies have examined the influence of aggregate genetic risk on substance use trajectories over time.ObjectiveWe examined the predictive utility of drinking and smoking polygenic risk scores (PRS) for alcohol and nicotine use from late childhood to early adulthood, substance-specific versus broader-liability effects of the respective PRS, and if PRS performance varied between regular consumption versus pathological use.DesignLatent growth curve models with structured residuals were used to assess the predictive utility of drinks per week and regular smoking PRS for measures of alcohol and nicotine consumption and problematic use from age 14 to 34.SettingPRS were generated from the largest discovery sample for alcohol and nicotine use to date (i.e., GSCAN), and examined for associations with alcohol and nicotine use outcomes in the Minnesota Twin Family Study (MTFS).ParticipantsParticipants were members of the MTFS (N=3225), a longitudinal study investigating the development of substance use disorders and related conditions.Main Outcomes and MeasuresOutcomes included alcohol and nicotine use disorder symptoms as defined by the Diagnostic and Statistical Manual of Mental Disorders, measures of alcohol and nicotine consumption (i.e., drinks per occasion, cigarettes per day), and composite variables for alcohol and nicotine use problems.ResultsThe drinks per week PRS was a significant predictor of problematic alcohol use at age 14 and increases in problematic use during young adulthood. The regular smoking PRS was a significant predictor for all nicotine use outcomes. After adjusting for the effects of both PRSs, the regular smoking PRS demonstrated incremental predictive utility for most alcohol use outcomes and remained a significant predictor of nicotine use trajectories.Conclusions and RelevanceHigher PRS for drinks per week and regular smoking were each associated with more problematic levels of substance use over time. Additionally, the regular smoking PRS seems to capture both nicotine-specific and non-specific genetic liability for substance use problems, and may index genetic risk for externalizing behavior in general. Longitudinal PRS prediction approaches may inform personalized substance use intervention approaches.Key PointsQuestionDo polygenic risk scores (PRS) for drinking and smoking predict problematic alcohol and nicotine use from late childhood to early adulthood?FindingsIn the current study, drinks per week and regular smoking PRS generated from the GWAS & Sequencing Consortium of Alcohol and Nicotine use (GSCAN) were associated with higher levels of problematic alcohol and nicotine use assessed longitudinally from ages 14 to 34 in a sample of 3225 individuals.MeaningPolygenic risk scores validated within longitudinal study designs may help inform future substance use intervention and prevention efforts.

Associations between polygenic risk of substance use and use disorder and alcohol, cannabis, and nicotine use in adolescence and young adulthood in a longitudinal twin study

“…Our finding that all PGS and family history measures were associated with the use of multiple substances is in line with previous studies (e.g. Chang et al, 2019 ; Deak et al, 2020 ; Merikangas et al, 1998 ). However, we extend previous research by showing that all PGS associations remained significant even after adjusting for the corresponding family history measures.…”

“…Our finding that higher scores on multiple PGS and family history measures were associated with greater behavioral disinhibition at age 11 extends previous findings from this sample indicating that the Regular Smoking-PGS indexes broad genetic risk for multiple types of substance use and externalizing disorders (Deak et al, 2020 ; Hicks et al, 2021 ). The weaker associations with the Lifetime Cannabis Use-PGS and Nicotine Dependence-PGS that we observed could be attributable to a smaller number of pleiotropic alleles in these PGSs relative to the other polygenic risk measures, or simply to differences in sample size and heritability in the discovery GWASs used to develop each score (see Table 2 ).…”

“…alcohol) tend to predict both the use of that and other substances (e.g. cannabis and nicotine) (Chang et al, 2019 ; Deak et al, 2020 ). Thus, these putatively substance-specific scores may also capture risk mechanisms that increase the severity of multiple types of substance use simultaneously.…”