Genetics of methamphetamine use disorder: A systematic review and meta-analyses of gene association studies
Introduction
Amphetamine-like stimulants are the second most used illicit drug in the world, behind cannabis (UNODC, 2017a). Among amphetamines, methamphetamine (meth) represents the greatest global health threat, with a rapidly increasing market and number of users worldwide (UNODC, 2017b). In their most recent report, the U.S. Substance Abuse and Mental Health Services Administration (SAMHSA) estimated that 13 million people in the U.S. used meth in their lifetime (∼4% of the total population), with 569,000 people using meth in the past month (SAMHSA, 2015). Meth use appears to be increasing globally, most likely due to expanding markets (UNODC, 2017b), highlighting the need to better understand meth use disorder.
Evidence from family, twin and adoption studies suggests substantial heritability for substance use disorders (for comprehensive reviews see Ducci and Goldman, 2012; Goldman et al., 2005; Vanyukov and Tarter, 2000). Substance use disorders are regarded as highly polygenic, with many hundreds of genes likely contributing to their heritability, each of which contribute a miniscule fraction of the overall risk (Ducci and Goldman, 2012). While the heritability of stimulant use disorders is estimated to be close to 40 % (Goldman et al., 2005), no twin or family studies have been conducted in people with meth use disorder, making it challenging to uncover the heritability of risk for this particular drug. Notably, that 40 % figure seems consistent across numerous classes of abused drugs including stimulants, cannabinoids, opioids, nicotine and alcohol.
Another approach to investigate the heritability of disorders are genome-wide association studies (GWASs). To date, only three GWASs have been conducted in people with meth use disorder (Ikeda et al., 2013; Sun et al., 2019; Uhl et al., 2008b). While Uhl et al. (2008b) and Ikeda et al. (2013) did not detect significant genome-wide single nucleotide polymorphism (SNP) associations, Sun et al. (2019) more recently reported an association between meth use disorder and three SNPs. It should be noted that the first two studies used overlapping samples, and all three studies were gravely under-powered for GWASs. Specifically, study with the largest sample size included 1750 people with meth use disorder, compared to the tens or even hundreds of thousands of participants required for reliable genetic findings for similarly polygenic complex psychiatric disorders. Of note, the three studies exclusively recruited people of Han Chinese or Japanese ethnicity. There is preliminary evidence of ethnic divergence of gene variants for meth use disorder (Bousman et al., 2010).
While twin studies have been lacking and GWAS results have been inconclusive, there has been an accumulation of candidate gene association studies in people with meth use disorder over the past two decades. Though not without important limitations, candidate gene studies can identify specific sequence variations in genes of interest and point towards potential molecular pathways affected to inform future research. While an association of genetic variants of a given candidate gene with some functional endpoint can potentially teach us about the biological effects of that gene and its naturally occurring sequence variations, this is very different from claiming that those gene variants contribute to heritable risk for a given psychiatric disorder. The latter claim can only be verified with rigorous genome-wide approaches or the careful study of large family pedigrees.
The first aim of the present study was therefore to systematically review gene association studies in people with meth use disorder to identify any promising targets and possible pathways underlying meth use disorder. Genotype, allele frequencies, and haplotypes were assessed. For specific markers with 3 or more studies available, meta-analyses were also conducted. Importantly, risk of bias assessment was conducted as a quality measure for each study using the National Heart, Lung, and Blood Institute Quality Assessment of Case-Control studies (NHLBI, 2020).
Candidate gene studies can be classified into two broad categories: those that examine possible influencing factors predisposing to the development of substance use disorders, (e.g., poor inhibition and impulse control), and those that specifically examine putative genetic variants in neurotransmitter and receptor systems involved in the substance use disorder of interest. In addition, Uhl et al. (2008a) suggested that the genetics of substance use vulnerability can either be due to individual differences in specific drug targets, or individual differences in receptor drug responses which may be shared across different class of substances (Uhl et al., 2008a). In that regard, the second aim of this review was to examine genetic contribution of broad substance use in meth use disorder to understand polysubstance use. We also systematically reviewed other secondary outcomes that the genetic association studies explored, including sex differences and age of first meth use.
Section snippets
Literature search
This systematic review was conducted following the PRISMA guidelines (Moher et al., 2009). The protocol was registered with PROSPERO (CRD42020177826) after preliminary searches were conducted, but before literature search. The entire PubMed, EMBASE, PsycINFO and MEDLINE databases were searched for studies from their date of inception to April 10, 2020. The following search terms were used: “methamphetamine” OR “methylamphetamine”; and a combination of the following terms: “gene” OR “allele” OR
Study selection and quality assessment
From the 2330 studies identified through database search, 1065 remained following removal of duplicates (Fig. 1). Following title and abstract screening by two independent assessors, 239 articles underwent full-text assessment for eligibility. In total, 79 studies met the inclusion criteria, for a total of 44,184 participants (17,682 cases and 26,502 controls). Three studies were GWASs, and 76 studies were hypothesis-driven candidate gene studies, investigating 75 unique genes (Supplementary
Discussion
The present study systematically reviewed gene association studies in people with meth use disorder. A previous systematic review uncovered 38 studies and provided a thorough examination of the field from 2000 to 2009 (Bousman et al., 2009). In the present review, we provide a significant update of this expanding field and reviewed a total of 79 studies. While the number of candidate gene studies has almost doubled in the past decade, there is still a clear lack of twin and family studies, as
Conclusion
In this study we systematically reviewed gene association studies in people with meth use disorder to identify any promising targets and pathways underlying the disorder. We assessed the quality and risk of bias of each study and calculated the power of each association. In addition, a meta-analytic approach was conducted when three or more studies were available for any given marker. We found that most significant associations were identified in neurotransmitter-related genes, with functional
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgements
This work was supported by Melbourne Research Scholarship from the University of Melbourne (AAG); National Institutes of Health GrantP01DA047233 (EJN); NHMRC Senior Principal Research Fellowship1059660 and 1156072 (MB); NHMRC Principal Research Fellowship1116930 (AJL); NHMRC Senior Research Fellowship1154651 (SR); and Brain and Behavior Research Foundation NARSAD young Investigator Award (JHK). We also acknowledge the Victorian State Government Operational Infrastructure Scheme.
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