Genetics of substance use disorders: a review

Abstract

Substance use disorders (SUDs) are prevalent and result in an array of negative consequences. They are influenced by genetic factors (h2 = ~50%). Recent years have brought substantial progress in our understanding of the genetic etiology of SUDs and related traits. The present review covers the current state of the field for SUD genetics, including the epidemiology and genetic epidemiology of SUDs, findings from the first-generation of SUD genome-wide association studies (GWAS), cautions about translating GWAS findings to clinical settings, and suggested prioritizations for the next wave of SUD genetics efforts. Recent advances in SUD genetics have been facilitated by the assembly of large GWAS samples, and the development of state-of-the-art methods modeling the aggregate effect of genome-wide variation. These advances have confirmed that SUDs are highly polygenic with many variants across the genome conferring risk, the vast majority of which are of small effect. Downstream analyses have enabled finer resolution of the genetic architecture of SUDs and revealed insights into their genetic relationship with other psychiatric disorders. Recent efforts have also prioritized a closer examination of GWAS findings that have suggested non-uniform genetic influences across measures of substance use (e.g. consumption) and problematic use (e.g. SUD). Additional highlights from recent SUD GWAS include the robust confirmation of loci in alcohol metabolizing genes (e.g. ADH1B and ALDH2) affecting alcohol-related traits, and loci within the CHRNA5-CHRNA3-CHRNB4 gene cluster influencing nicotine-related traits. Similar successes are expected for cannabis, opioid, and cocaine use disorders as sample sizes approach those assembled for alcohol and nicotine.

Child Maltreatment and Substance Use: A Behavior Genetic Analysis

“…The nonshared environment (plus error) accounted for the majority of observed variance in cigarette use but genetic factors still accounted for almost a quarter of the variance. These results are in line with previous behavior genetic research on adolescent substance use where the heritability of tobacco and illicit substance use such as marijuana are estimated to be between 40-50% (McGue et al, 2000;Young et al, 2006; for a review see Deak & Johnson, 2021). With respect to child maltreatment, the reported findings are in line with an emerging body of work suggesting that variation in selfreported child maltreatment (Pezzoli et al, 2019) as well as adverse childhood experiences (Connolly, 2020;Schwartz et al, 2019) are explained by a combination of genetic and environmental factors.…”

Genome-wide association study and multi-trait analysis of opioid use disorder identifies novel associations in 639,709 individuals of European and African ancestry

“…Compared to other complex traits in psychiatry, there are comparatively small samples available for genetic analysis of individuals with drug use disorders, particularly those involving illegal substances (heroin, cocaine) (8,9). Thus, a strategy that increases statistical power by incorporating other sets of samples-for example, from GWAS of closely-related but nonidentical traits such as other SUDs-could help advance our understanding of the genetic architecture of OUD.…”

“…Although opioid misuse and progression to OUD(2) are influenced by heritable factors, discovery of OUD risk loci has been limited (3)(4)(5)(6)(7). Difficulties in advancing OUD genetic discovery are largely due to lack of adequately powered cohorts of genetically informative samples (8,9). Existing genome-wide association studies (GWAS) of OUD have been underpowered (8,9).…”

“…Difficulties in advancing OUD genetic discovery are largely due to lack of adequately powered cohorts of genetically informative samples (8,9). Existing genome-wide association studies (GWAS) of OUD have been underpowered (8,9). This poses challenges in understanding the genetic and neurobiological factors that influence risk for OUD and related traits.…”

Back-translating GWAS findings to animal models reveals a role for Hgfac and Slc39a8 in alcohol and nicotine consumption

“…These GWAS findings also demonstrate that alcohol and tobacco use are highly polygenic, composed of a large number of implicated variants and loci, each with small effect. Nonetheless, large-scale GWAS of alcohol and tobacco use phenotypes to date have yielded significant associations for variants and loci in genes with clear biological relevance for addiction, such as those involved in substance metabolism, neural targets, and dopaminergic neurotransmission (for recent reviews of notable SUD GWAS findings, see 9 , 11 , 12 ). Many genetic loci that are identified are novel targets for AUD and/or TUD related biology, representing untapped potential in further understanding addiction biology and for developing novel therapies.…”