Genetics of methamphetamine use disorder: A systematic review and meta-analyses of gene association studies

Abstract

Genetic susceptibility to methamphetamine use disorder is poorly understood. No twin or adequately powered genome-wide association studies (GWASs) have been conducted. However, there are a large number of hypothesis-driven candidate gene association studies, which were systematically reviewed herein. Seventy-six studies were identified, investigating markers of 75 different genes. Allele frequencies, odds ratios, 95 % confidence intervals and power were calculated. Risk of bias was also assessed as a quality measure. Meta-analyses were conducted for gene markers if three or more studies were available. Eleven markers from adequately powered studies were significantly associated with methamphetamine use disorder, with Fatty Acid Amide Hydrolase (FAAH) and Brain Derived Neurotrophic Factor (BDNF) representing promising targets. Limitations of these studies include unclear rationale for candidate gene selection, low power and high risk of bias. Future research should include replications to enable more meta-analyses, well-powered GWASs or whole exome or genome sequencing, as well as twin and family studies to further complement the findings of this review to uncover genetic contributions toward methamphetamine use disorder.

Keywords: Abuse; Addiction; BDNF; Dependence; FAAH; Gene-association studies; Meta-analysis; Methamphetamine; Neuroscience; Psychiatry; Single-nucleotide polymorphism.

Fig. 1.

PRISMA Diagram illustrating stages of article processing for the systematic review.

Fig. 2.

Key characteristics of included studies. A. Diagnostic criteria. Studies predominantly used the ICD-10 and DSM-IV criteria. B. Comorbidities. Comorbidities were reported in 71 % of studies, with polysubstance use disorder and meth-induced psychosis the most common. C. Ethnicities. Participants of Japanese and Han Chinese descent were the most studied. Some studies belonged to more than 1 category. D. Sex. Most studies included both male and female participants, but 14 studies only included males. Three studies did not report participant sex. Numbers on each wedge represent the number of studies with the characteristic of interest.

Fig. 3.

BDNF rs6265. A. Schematic representation of BDNF and the location of rs6265. Numbers represent exons. Lighter shaded boxes represent non-coding regions. B. Forrest plot of the association between the rs6265 variant of BDNF and meth use disorder. There was a significant overall effect (p < 0.0001) of the variant, with the minor allele associated with protection against meth use disorder (OR = 0.78). Event = number of minor alleles; OR = odds ratio.

Fig. 4.

Makers in dopamine-related genes. A. Schematic representation of DRD2 and the location of rs1800497. Numbers represent exons. Lighter shaded boxes represent non-coding regions. B. Forrest plot of the association between the rs1800497 variant of DRD2 and meth use disorder. C. Schematic representation of DKD4 and the location of the exon 3 VNTR. D. Forrest plot of the association between the exon 3 VNTR of DKD4 and meth use disorder. E. Schematic representation of COMT and the location of rs4680. F. Forrest plot of the association between the rs4680 variant of COMT and meth use disorder. G. Schematic representation of SLC6A3 and the location of the 3′ VNTR. H. Forrest plot of the association between the 3′ VNTR of SLC6A3 and meth use disorder. There was no significant overall effect (ps > 0.05) of any of the variants on meth use disorder. Event = number of minor alleles; VNTR = variable number tandem repeat.

Fig. 5.

A. SLC6A4 LPR. Schematic representation of SLC6A4 and the location of the LPR. Numbers represent exons. Lighter shaded boxes represent non-coding regions. B. Forrest plot of the association between the LPR variant of SLC6A4 and meth use disorder. There was a moderate overall effect (p = 0.04) of the variant, with the minor allele associated with protection against meth use disorder (OR = 0.78). Event = number of minor alleles; LPR = linked polymorphic region; OR = odds ratio.

Fig. 6.

A. FAAH rs324420. Schematic representation of FAAH and the location of rs324420. Numbers represent exons. Lighter shaded boxes represent non-coding regions. B. Forrest plot of the association between the rs324420 variant of FAAH and meth use disorder. There was a significant overall effect (p < 0.00001) of the variant, with the minor allele associated with a risk for meth use disorder (OR = 1.64). Event = number of minor alleles; OR = odds ratio.