The association of DAT gene methylation with striatal DAT availability in healthy subjects

Abstract

Background DNA methylation inhibits gene expression by preventing transcription factors from binding to DNA. Functioning of nigrostriatal dopaminergic neurons is influenced by the expression of the dopamine transporter (DAT), and genetic variations in the gene encoding DAT contribute to differences in reward processing. We aimed to investigate the action of DAT methylation on DAT protein expression measured by positron emission tomography (PET). Methods The emission data were acquired over 90 min with 50 frames after injection of 18F-FP-CIT using PET. Binding potentials (BPNDs) of ventral striatum, caudate nucleus, putamen were measured with the simplified reference tissue method. Genomic DNA was extracted from subjects’ blood sampling. Methylation of 4 regions in SLC6A3 gene was assessed using bisulfite pyrosequencing. The mean percentage of methylation (%) for each cluster was calculated by taking the average of all CpG site methylation levels measured within the cluster. Subjects were assessed with the Generalized Reward and Punishment Expectancy Scales (GRAPES) that consists of 30 items related with the reward and punishment that individuals expect for their behaviors. Results Thirty-five healthy males, with an age range between 20 and 30 years, and a mean age of 24.4 ± 2.7 years, were included in this study. The mean percentage of methylation (%) from cluster C showed a trend of positive correlation with DAT availability of ventral striatum (rho = 0.3712, p = 0.0281), not significant after correction for multiple comparisons, and a significant correlation with GRAPES A: reward expectancy scale (rho = 0.7178, p < 0.0001). Conclusion DAT methylation from peripheral blood showed a trend of positive correlation with DAT availability of ventral striatum in healthy subjects; however, it was not significant after correction for multiple comparison. The degrees of methylation from cluster C of DAT in peripheral blood were significantly correlated with reward scales of GRAPES A: reward expectancy scale. The association between DAT methylation and DAT expression needs to be investigated further.

Epigenetic Analysis of the Dopamine Transporter Gene DAT1 with a Focus on Personality Traits in Athletes

“…Previous studies found that DAT1 methylation derived from blood correlated with symptoms of hyperactivity and impulsivity in children and adolescents with ADHD [63] and with impulsivity (and basal ganglia DAT availability) in monkeys [64]; alcohol dependency and alcohol craving [65], nicotine [66] and cannabis [67] dependency in humans. Moreover, DAT methylation from peripheral blood showed a positive correlation with DAT availability of ventral striatum in healthy subjects [68].…”

Dopamine receptor D2 (DRD2) and dopamine transporter (DAT) gene promoter methylation and hyperphagia-related behavior in Prader-Willi syndrome

“…Regarding DRD2 gene, there is less evidence in this respect. It should also be mentioned that not all studies indicate an inverse relationship of DAT promoter methylation and DAT expression as for example Pak et al suggested a positive correlation, which, however, represented only a trend but not a signi cant effect [33]. Overall, it must be stated that the functional relationship between promoter methylation and gene expression is poorly understood for DAT, but especially for DRD2.…”

DAT1 5′-Un-Translated-Region Methylation Patterns as Bio-Markers of ADHD Psycho-Pathology: Contribution to Disease Prognosis and to Monitoring of a Successful Therapy

“…On the other hand, the same fate can be observed at CpG 2 and 3 (correlation; [ 10 , 14 ], both following CpG 1) when the stressed father has real discomfort with the child, so that ADHD remains severe. DA levels in the mesolimbic pathway, which in turn may predispose children to impulsive behavior, may be fine-tuned by DAT1 expression, which in turn could be modulated by altering CpG 2 vs. 3 dynamics [ 19 ]. Fathers could thus cause emotional and behavioral dysregulations in children via an influence on the 5′-UTR of DAT1 .…”