Genetic association studies of methamphetamine use disorders: A systematic review and synthesis

Abstract

Efforts to understand the biological processes that increase susceptibility to methamphetamine (METH) use disorders (i.e., abuse, dependence, and psychosis) have uncovered several putative genotypic variants. However, to date a synthesis of this information has not been conducted. Thus, systematic searches of the current literature were undertaken for genetic-association studies of METH use disorders. Each gene's chromosomal location, function, and examined polymorphic markers were extracted. Frequencies, odds ratios and 95% confidence intervals for risk alleles, as well as sample size and power, were calculated. We uncovered 38 studies examining 39 genes, of which 18 were found to have a significant genotypic, allelic, and/or haplotypic association with METH use disorders. Three genes (COMT, DRD4, and GABRA1) were associated with METH abuse, nine (ARRB2, BDNF, CYP2D6, GLYT1, GSTM1, GSTP1, PDYN, PICK1, and SLC22A3) with METH dependence, two (AKT1 and GABRG2) with METH abuse/dependence, and four (DTNBP1, OPRM1, SNCA, and SOD2) with METH psychosis. Limitations related to phenotypic classification, statistical power, and potential publication bias in the current literature were noted. Similar to other behavioral, psychiatric, and substance use disorders, the genetic epidemiology of METH use disorders is complex and likely polygenic. National and international collaborative efforts are needed to increase the availability of large population-based samples and improve upon the power to detect genetic associations of small magnitude. Further, replication of the findings reviewed here along with further development of more rigorous methodologies and reporting protocols will aid in delineating the complex genetic epidemiology of METH use disorders.

Dopamine receptor D4 promoter hypermethylation increases the risk of drug addiction

“…Similar to heroin addiction, the etiology of METH abuse is complex. The association between DRD4 and METH abuse was determined by a previous study (30). In the present study, increased methylation levels of DRD4 promoter were detected in METH addicts compared with normal controls.…”

BDNF (Val66Met) Genetic Polymorphism is Associated with Vulnerability for Methamphetamine Dependence

“…While rs6265 has the strongest evidence for functional effects, there may be other polymorphisms in the BDNF gene that could influence BDNF function [25][26][27]; furthermore, future studies need to assess the possible effects of, and interactions with, polymorphisms in other risk genes [28]. Thus, a more comprehensive investigation of common BDNF polymorphisms in a larger sample, powered adequately to assess interaction with other putative risk genes, would provide a valuable assessment of the importance of BDNF and its relation to other genetic risk factors in the development of METH dependence and its associated psychosis.…”

Preliminary evidence of ethnic divergence in associations of putative genetic variants for methamphetamine dependence

“…Twin studies have shown significantly high heritability of stimulant use disorders (Tsuang et al, 1996; Tsuang et al, 1998; Kendler et al, 2003); thus, the search for risk genes underlying these disorders is warranted. Some progress in identifying risk genes for METH dependence has been made, but almost exclusively in Asian populations (for reviews see (Barr et al, 2006; Bousman et al, 2009). In these studies, several genes have been implicated across several biological pathways, ranging from dopamine-metabolism and signaling to neuronal survival factors.…”