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.
Highlights
Substance use disorders (SUDs) are heritable psychiatric disorders [Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5); American Psychiatric Association, 2013] that are influenced by both environmental and genetic factors
We cover SUD epidemiology, conclusions from twin and family studies of SUDs, and findings from more recent molecular genetic studies1; we summarize the current state of the field and suggest future directions
Epidemiological estimates suggest that up to 29.1% and 27.9% of individuals will meet the criteria for alcohol use disorder (AUD) and nicotine use disorder (NicUD), respectively, in their lifetime, with lower lifetime prevalence rates for cannabis use disorder (CanUD) (6.3%), opioid use disorder (OUD) (2.1%), and cocaine use disorder (CocUD) (2.4%) (Grant et al, 2016)
Summary
Substance use disorders (SUDs) are heritable psychiatric disorders [Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5); American Psychiatric Association, 2013] that are influenced by both environmental and genetic factors. Recent studies have demonstrated that, similar to other complex traits, larger sample sizes have aided the successful detection of loci influencing AUD and alcohol-related outcomes (reviewed in Deak, Miller, & Gizer, 2019; Sanchez-Roige, Palmer, & Clarke, 2020) These have replicated genome-wide significant (GWS) associations for loci in the ADH1B gene (e.g. rs1229984 and rs2066702) with AUD (Gelernter et al, 2014a; Kranzler et al, 2019; Walters et al, 2018; Zhou et al, 2020a, b) and with various measures of alcohol use and consumption (Clarke et al, 2017; Gelernter et al, 2019; Kranzler et al, 2019; Liu et al, 2019; Sanchez-Roige et al, 2019a, b; Xu et al, 2015). That was associated with ND in an earlier GWAS (Hancock et al., 2015)
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