The dopamine transporter gene SLC6A3: multidisease risks

The human dopamine transporter gene SLC6A3 has been consistently implicated in several neuropsychiatric diseases but the disease mechanism remains elusive. In this risk synthesis, we have concluded that SLC6A3 represents an increasingly recognized risk with a growing number of familial mutants associated with neuropsychiatric and neurological disorders. At least five loci were related to common and severe diseases including alcohol use disorder (high activity variant), attention-deficit/hyperactivity disorder (low activity variant), autism (familial proteins with mutated networking) and movement disorders (both regulatory variants and familial mutations). Association signals depended on genetic markers used as well as ethnicity examined. Strong haplotype selection and gene-wide epistases support multimarker assessment of functional variations and phenotype associations. Inclusion of its promoter region’s functional markers such as DNPi (rs67175440) and 5’VNTR (rs70957367) may help delineate condensate-based risk action, testing a locus-pathway-phenotype hypothesis for one gene-multidisease etiology.

Associations Between Physical Effort and DNA Methylation in the Promotor Region of the Dopamine Transporter Gene (DAT1)

The purpose of this study was to investigate the association between physical effort and DNA methylation in the promoter region of the dopamine transporter gene (DAT1). The research group included 100 athletes (mean age = 22.88, SD = 6.35), whereas the control group were 239 healthy male volunteers matched for age (mean age = 21.69, SD = 3.39). Both, the control and the research group, included individuals with Caucasian origin from the same region of Poland. DNA was extracted from peripheral blood leukocytes using a DNA isolation kit (A&A Biotechnology, Gdynia, Poland). Bisulfite modification of 250 ng DNA was performed using the EZ DNA Methylation Kit (Zymo Research, Orange, CA, USA), according to manufacturer's instructions. The methylation-specific PCR assay was carried out in a Mastercycler epgradient S (Eppendorf, Germany). We observed that the level of general methylation of the CpG island was similar for both groups. Further exploration of individual CpG sites allowed to notice that there were significant differences in methylation status in specific positions. Nonetheless, there was no rule that would indicate either higher or lower methylation of individual sites, four of them were methylated at a higher level (positions 1, 4, 5, 7, 8, 9, 10, 11, 12, 13, 16, 17, 18, 23, 25, 26, 27, 29 and 30), while one showed an inverse trend (position 3). More precise analysis with the usage of Bonferroni correction for multiple tests indicated that differences in CpG site methylation were mainly increased in several positions and decreased in position 3.

Smoking Genes: A Case–Control Study of Dopamine Transporter Gene (SLC6A3) and Dopamine Receptor Genes (DRD1, DRD2 and DRD3) Polymorphisms and Smoking Behaviour in a Malay Male Cohort

Dopamine receptor and dopamine transporter genes polymorphisms have been associated with cigarette smoking behaviour in different populations. The aim of this case–control study was to evaluate polymorphisms in the dopamine transporter gene (SLC6A3 (rs27072)) and the dopamine receptor genes (DRD1 (rs686), DRD2 (rs1800497) and DRD3 (rs7653787)) and their contribution to smoking behaviour in a Malay male population. We identified 476 participants over the age of 18 years comprising 238 smokers and 238 non-smokers. Information such as age, height, weight, body mass index, systolic and diastolic blood pressures, marital status, and smoking status of close family members were taken. For the genetic study, we genotyped four genes (SLC6A3 (rs27072), DRD1 (rs686), DRD2 (rs1800497) and DRD3 (rs7653787)) using the polymerase chain reaction–restriction fragment length polymorphism method and further confirmed our findings with sequencing. Dopamine receptor genes (DRD1, DRD2 and DRD3) were found to be associated with smoking behaviour in a Malay male population. The dopamine transporter gene (SLC6A3) did not show this association. Significant differences were observed between smokers’ and non-smokers’ age, systolic blood pressure, marital status and family members who smoke. Smoking behaviour is significantly influenced by genetic variations of DRD1, DRD2 and DRD3 in a Malay male population.

Contribution of Dopamine Transporter Gene Methylation Status to Cannabis Dependency

The susceptibility to cannabis dependency results from the influence of numerous factors such as social, genetic, as well as epigenetic factors. Many studies have attempted to discover a molecular basis for this disease. However, our study aimed at evaluating the connection between altered methylation of the dopamine transporter gene (DAT1) promoter CpG sites and cannabis dependency. In the cases of some DNA sequences, including the DAT1 gene region, their methylation status in blood cells may reflect a systemic modulation in the whole organism. Consequently, we isolated the DNA from the peripheral blood cells from a group of 201 cannabis-dependent patients and 285 controls who were healthy volunteers and who were matched for age and sex. The DNA was subjected to bisulfite conversion and sequencing. Our analysis revealed no statistical differences in the general methylation status of the DAT1 gene promoter CpG island between the patients and controls. Yet, the analysis of individual CpG sites where methylation occurred indicated significant differences. These sites are known to be bound by transcription factors (e.g., SP1, p53, PAX5, or GR), which, apart from other functions, were shown to play a role in the development of the nervous system. Therefore, DAT1 gene promoter methylation studies may provide important insight into the mechanism of cannabis dependency.

Genes of dopamine receptors and transporter in patients with schizophrenia: associations with the clinical characteristics of the disorder

Genotyping of 28 polymorphisms of 5 dopamine receptor genes and 12 polymorphisms of dopamine transporter gene was performed in 475 schizophrenia patients and 135 healthy individuals. Associations of several polymorphisms of the DRD2, DRD3 and SLC6A3 genes were identified with leading symptoms and late debut of schizophrenia.