Patterns of DNA methylation at specific loci of the dopamine transporter 1 gene and psychopathological risk in trios of mothers, fathers and children

While accumulating literature is demonstrating the role of the dopamine transporter (DAT) in predicting emotional–behavioural difficulties in adults of at risk populations, only few studies have focused on the possible association between the methylation status of the DAT promoter and the psychopathological risk of mothers, fathers and children in normative samples. The pattern of methylation of M1-M7 loci present in the 5′-untranslated promoter region (5′-UTR) of DAT1, and parental and offspring psychopathological risk were assessed in a sample of 152 families with 5-year-old-children, employing principal components (PCAs) and cluster analyses. Parents’ psychopathological symptoms were assessed through SCL-90/R; children’s emotional-behavioural functioning was evaluated through C-TRF. Cluster analysis allowed to form three clusters; cluster 1 is primarily composed by children with low-/middle-risk profiles; most of children with high-risk are in this cluster, and had parents with mild/high psychopathological risk; children in cluster 2 showed low-risk profiles and their parents had low/mild psychopathological risk; children in cluster 3 were predominantly at middle risk and had parents with low psychopathological risk. Analysis of results shows that DNA methylation occurs in different loci of DAT1 according to patterns of psychopathology and that psychopathological risk is specifically associated with hyper-methylation or hypo-methylation of these loci

Potential for diagnosis versus therapy monitoring of attention deficit hyperactivity disorder: a new epigenetic biomarker interacting with both genotype and auto-immunity

In view of the need for easily accessible biomarkers, we evaluated in ADHD children the epigenetic status of the 5'-untranslated region (UTR) in the SLC6A3 gene, coding for human dopamine transporter (DAT). We analysed buccal swabs and sera from 30 children who met DSM-IV-TR criteria for ADHD, assigned to treatment according to severity. Methylation levels at six-selected CpG sites (among which, a CGGCGGCGG and a CGCG motif), alone or in combination with serum titers in auto-antibodies against dopamine transporter (DAT aAbs), were analysed for correlation with CGAS scores (by clinicians) and Conners' scales (by parents), collected at recruitment and after 6 weeks. In addition, we characterized the DAT genotype, i.e., the variable number tandem repeat (VNTR) polymorphisms at the 3'-UTR of the gene. DAT methylation levels were greatly reduced in ADHD patients compared to control, healthy children. Within patients carrying at least one DAT 9 allele (DAT 9/x), methylation at positions CpG2 and/or CpG6 correlated with recovery, as evident from delta-CGAS scores as well as delta Conners' scales ('inattentive' and 'hyperactive' subscales). Moreover, hypermethylation at CpG1 position denoted severity, specifically for those patients carrying a DAT 10/10 genotype. Intriguingly, high serum DAT-aAbs titers appeared to corroborate indications from high CpG1 versus high CpG2/CpG6 levels, likewise denoting severity versus recovery in DAT 10/10 versus 9/x patients, respectively. These profiles suggest that DAT 5'UTR epigenetics plus serum aAbs can serve as suitable biomarkers, to confirm ADHD diagnosis and/or to predict the efficacy of treatment