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.

Jonathan D Schaefer,Seon-Kyeong Jang,Scott I Vrieze,Joseph D Deak,William G Iacono,D Angus Clark,Matt Mcgue,Brian M Hicks,Mengzhen Liu,Sylia Wilson

doi:10.1017/s0033291721004116

Abstract

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. 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. 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. 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.

Highlights

Substance use disorders (SUDs) are one of the most common and disabling behavioral health problems (Whiteford et al, 2013), with lifetime prevalence estimates from longitudinal studies coalescing around 40% (Angst et al, 2016; Hamdi & Iacono, 2014; Schaefer et al, 2017)
History of SUDs was common in our sample, with 62, 36, and 63% of participants with parent data having at least one parent who met criteria for a lifetime alcohol use disorder, cannabis use disorder, or nicotine dependence diagnosis, respectively
The only exceptions to this pattern were the Drinks Per WeekPGS, which was not significantly associated with cannabis use, and the Nicotine Dependence-polygenic scores (PGSs), which was significantly associated with nicotine use only

Summary

Introduction

Substance use disorders (SUDs) are one of the most common and disabling behavioral health problems (Whiteford et al, 2013), with lifetime prevalence estimates from longitudinal studies coalescing around 40% (Angst et al, 2016; Hamdi & Iacono, 2014; Schaefer et al, 2017). A recent influx of well-powered genome-wide association studies (GWASs) has led to substantial increases in the ability to predict substance use and use disorder via polygenic scores (PGSs). PGSs place individuals somewhere along a continuum of risk by taking the sum of the total number of trait-associated alleles across the genome, weighted by risk allele effect sizes from the corresponding GWASs (Choi, Mak, & O’Reilly, 2020) These scores generally explain only a few percent of the variance in their respective phenotypes, PGSs have been used for a range of purposes in the biomedical and social sciences to date, including identifying shared etiology among traits, testing for genome-wide gene-by-environment interaction, and – when combined with other clinical and demographic information – patient stratification (Hoffmann et al, 2017; Torkamani, Wineinger, & Topol, 2018; Wray et al, 2018). 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

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