Associations between methamphetamine use disorder and SLC18A1, SLC18A2, BDNF, and FAAH gene sequence variants and expression levels

Abstract

Introduction: Assessing candidate gene sequence variations and expression helps to understand methamphetamine use disorder and inform potential treatments. We investigated single nucleotide polymorphisms (SNPs) and gene expression in four candidate genes: SLC18A1, SLC18A2, BDNF, and FAAH, between controls and people with methamphetamine use disorder.

Methods: Fifty-nine participants (29 people with methamphetamine use disorder and 30 controls) completed a clinical interview, cognitive tasks, and provided a blood sample. SLC18A1, SLC18A2, BDNF, and FAAH SNPs were genotyped, and gene expression was assessed with real-time quantitative PCR.

Results: SLC18A1 Pro4Thr was associated with methamphetamine use disorder (OR = 6.22; p = .007). SLC18A2 variants, rs363227 and rs363387, were negatively associated with methamphetamine use severity (p = .003) and positively associated with inhibitory control performance (p = .006), respectively. BDNF Val66Met was associated with the severity of use (p = .008). SLC18A2 and FAAH mRNA levels were lower in people who use methamphetamine relative to controls (p = .021 and .010, respectively).

Conclusions: SLC18A1 is identified for the first time to play a potential role in methamphetamine use disorder. Lower levels of blood SLC18A2 and FAAH mRNA in people with methamphetamine use disorder suggest reduced monoamine reuptake, recycling, or release, and higher anandamide levels in this clinical group, which may be potential therapeutic targets.

Keywords: Substance use disorder; VMAT; cognitive flexibility; endocannabinoid; inhibitory control; single nucleotide polymorphism.

Figure 1.

mRNA levels in people who use methamphetamine compared to controls. (A) SLC18A2: SLC18A2 mRNA levels were significantly lower in people who use methamphetamine compared to controls (*p = .021). Control n = 19; Meth n = 23 (B) FAAH: FAAH mRNA levels were significantly lower in people who use methamphetamine compared to controls (**p = .010). Control n = 19; Meth n = 23 (C) BDNF: There were no differences in BDNF mRNA levels between groups. Control n = 16; Meth n = 19. mRNA levels as a function of genotype. (D) SLC18A2: There were no differences in SLC18A2 mRNA levels between rs363276 genotypes. WT n = 24; Minor n = 14. (E) FAAH: There were no differences in FAAH mRNA levels between genotypes. WT n = 25; Minor n = 15. (F) BDNF: There was no significant difference in BDNF mRNA levels between genotypes. WT n = 19; Minor n = 13. Pearson’s correlation analyses between mRNA levels and cognition. (G) Stroop Inhibition. There was a positive association between performance in the Stroop Task (Inhibition) and FAAH mRNA qPCR cycle threshold (CT) (p = .048). (H) Stroop Switching. There was a negative association between performance in the Stroop Task (Switching) and SLC18A2 mRNA qPCR CT (p = .037). Data represented as individual values and mean ± SEM when appropriate. CT: cycle threshold; Meth: people with methamphetamine use disorder; Minor: minor allele carriers computed as heterozygous (M/m) and homozygous minor alleles (m/m); SEM: standard error of the mean; WT: wildtype (M/M).