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

Abstract

Background Recent well-powered genome-wide association studies have enhanced prediction of substance use outcomes via polygenic scores (PGSs). Here, we test (1) whether these scores contribute to prediction over-and-above family history, (2) the extent to which PGS prediction reflects inherited genetic variation v. demography (population stratification and assortative mating) and indirect genetic effects of parents (genetic nurture), and (3) whether PGS prediction is mediated by behavioral disinhibition prior to substance use onset. Methods PGSs for alcohol, cannabis, and nicotine use/use disorder were calculated for Minnesota Twin Family Study participants (N = 2483, 1565 monozygotic/918 dizygotic). Twins' parents were assessed for histories of substance use disorder. Twins were assessed for behavioral disinhibition at age 11 and substance use from ages 14 to 24. PGS prediction of substance use was examined using linear mixed-effects, within-twin pair, and structural equation models. Results Nearly all PGS measures were associated with multiple types of substance use independently of family history. However, most within-pair PGS prediction estimates were substantially smaller than the corresponding between-pair estimates, suggesting that prediction is driven in part by demography and indirect genetic effects of parents. Path analyses indicated the effects of both PGSs and family history on substance use were mediated via disinhibition in preadolescence. Conclusions PGSs capturing risk of substance use and use disorder can be combined with family history measures to augment prediction of substance use outcomes. Results highlight indirect sources of genetic associations and preadolescent elevations in behavioral disinhibition as two routes through which these scores may relate to substance use.

Phenome-wide association analysis of substance use disorders in a deeply phenotyped sample

“…Such relationships are expected as these variables capture aspects of family history of substance use. However, although a family history of a SUD is associated with many substance use outcomes, it is not wholly overlapping with genetic risk and it has been argued that these 2 sources of information should be used together to provide a fuller measure of risk (44). These findings raise an important theoretical question that cannot be answered with the data available here: namely, do associations of PRS with features such as trauma, truancy, educational, and parental substance reflect intergenerational effects (i.e., "genetic nurture"?)…”

Developmental genetic effects on externalizing behavior and alcohol use: Examination across two longitudinal samples

“…We examined this research question using two mediation models in which the AUD-PGS predicted externalizing behavior ("a" path) and alcohol use ("c" path), and externalizing behavior predicted alcohol use ("b" path). This conceptual framework is in-line with past research examining polygenic prediction of substance use via earlier behavior and allows us to examine genetic prediction of both externalizing behavior and alcohol use while examining for genetically mediated effects (e.g., Li et al, 2017;Schaefer et al, 2021;Trucco, Villafuerte, et al, 2014, Trucco et al, 2016. In Model 1, the AUD-PGS was considered a predictor of externalizing behavior in early adolescence and alcohol use in adolescence, and externalizing behavior a predictor of alcohol use.…”

“…When examining polygenic scores, genetic predisposition for smoking has been associated with externalizing at ages 11, 14, and 17 (Hicks et al, 2021). In a related study, polygenic scores for alcohol, cannabis, and smoking were broadly associated with alcohol use, cannabis use, nicotine use, and a broader substance use factor, cumulatively measured from ages 14 to 24 (Schaefer et al, 2021). When examining this issue in a longitudinal model, cannabis use disorder and regular smoking polygenic scores were associated with behavioral disinhibition at age 11, which predicted latent substance use across age 14 to 24.…”

“…In the current study, we created polygenic scores for alcohol use disorder (AUD-PGS) using summary statistics from two large genome-wide association studies (GWAS) on alcohol use disorder in African Americans (AAs) and European Americans (EAs) (Kranzler et al, 2019), allowing for investigation of developmental associations in distinct ethnic subgroups. We chose to examine polygenic scores for alcohol use disorder given previous evidence that polygenic scores for various substance use disorders and problematic substance use predict subclinical substance use, externalizing and impulsive behavior, and sensation seeking in adolescence and early adulthood, possibly because they better capture genetic signals across constructs and developmental periods (Johnson et al, 2021;Li et al, 2017;Salvatore et al, 2015;Schaefer et al, 2021).…”

Clinical, Environmental, and Genetic Risk Factors for Substance Use Disorders: Characterizing Combined Effects across Multiple Cohorts

“…More recently, polygenic scores (PGS), which aggregate risk for a trait across the genome using information from genome-wide association studies (GWAS), were robustly associated with substance use 12 and substance related problems 13 across adolescence and into young adulthood. However, though robustly associated, current PGS do poorly in identifying individuals affected by SUDs 14 .…”