Abstract
This paper aimed to explore the genome-wide DNA methylation status of methamphetamine (MA) abusers with different qualities to addiction and to identify differentially methylated candidate genes. A total of 207 male MA abusers with an MA abuse frequency of ≥10 times and an MA abuse duration of ≥1 year were assigned to the high MA addiction quality group (HMAQ group; 168 subjects who met the diagnostic criteria for MA dependence according to the DSM-IV) or to the low MA addictive quality group (LMAQ group; 39 subjects who did not meet the criteria for MA dependence). In addition 105 healthy controls were recruited. Eight HMAQ subjects, eight LMAQ subjects, and eight healthy controls underwent genome-wide DNA methylation scans with an Infinium Human Methylation 450 array (Illumina). The differentially methylated region (DMR) data were entered into pathway analysis, and the differentially methylated position (DMP) data were screened for candidate genes and verified by MethyLight qPCR with all samples. Seven specific pathways with an abnormal methylation status were identified, including the circadian entrainment, cholinergic synapse, glutamatergic synapse, retrograde endocannabinoid signaling, GABAergic synapse, morphine addiction and PI3K-Akt signaling pathways. SLC1A6, BHLHB9, LYNX1, CAV2, and PCSK9 showed differences in their methylation levels in the three groups. Only the number of methylated copies of CAV2 was significantly higher in the LMAQ group than in the HMAQ group. Our findings suggest that the circadian entrainment pathway and the caveolin-2 gene may play key roles in MA addiction quality. Further studies on their functions and mechanisms will help us to better understand the pathogenesis of MA addiction and to explore new targets for drug intervention.
Highlights
Methamphetamine (MA) is an amphetamine-type stimulant drug with a strong propensity for abuse, and it promotes the release of monoamine neurotransmitters in the central and peripheral systems [1]
Our findings suggest that the circadian entrainment pathway and the caveolin-2 gene may play key roles in MA addiction quality
After all differentially methylated region (DMR) in the pairwise comparisons of the three groups were entered into the Gene Ontology (GO) analysis and KEGG pathway analysis, the top 30 categories of the GO analysis and enrichment analysis results of methylation chip data are shown in Figures 2, 3
Summary
Methamphetamine (MA) is an amphetamine-type stimulant drug with a strong propensity for abuse, and it promotes the release of monoamine neurotransmitters in the central and peripheral systems [1]. A low dose of MA can induce a series of short-term effects, including euphoria, an increase in energy, positive emotions, increases in heart rate and blood pressure, mydriasis, peripheral high fever, a loss of appetite and weight, improvements in mental acuity, and social and sexual disinhibition [2]. According to the 2017 Report on Drug Control in China, by the end of 2017, more than 1.54 million individuals abused synthetic drugs (especially MA), accounting for 60.2% of drug abusers, which did not include double hidden drug users [5]. 0.54 million individuals ( ∼0.2% of the population aged 12 years or older, roughly close to the proportion of the individuals using MA in the past month) in the United States in 2012 met the diagnostic criteria for stimulant drug abuse or dependence according to the DSM-IV [6]
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