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

Epigenetic modifications, such as changes in DNA methylation, have been linked to several diseases in recent years. The purpose of our study was to search for biomarkers that (using non-invasive techniques) could assist the clinician in the prognosis of infant/adolescent psychopathology. We previously showed that changes in methylation of the 5'-UTR in the DAT1/SLC6A3 gene can be used as a biomarker for the prognosis of initial severe ADHD: treatment-resistant severe ADHD children were characterized by methylated CpG 1 in particular, while methylated CpGs 2 and 6 were then found in children who improved after the therapy. Further, we confirmed these outcomes and provided the hypothesis that symptomatology might be influenced by the children's genotype and family environment. In particular, levels of CpG 3 methylation in the heterozygous ADHD children were associated with high paternal own risk or stress. Eventually, we found that the same biomarkers are more broadly useful in the field of internalizing or externalizing symptoms (when a certain vulnerability is already present in the child). In particular, it was seen how inheriting specific 9-repeat or 10-repeat VNTR alleles from the mother or from the father could modify the pattern of methylation at the 5'-UTR of the DAT1 gene. A specific pattern of methylations (with CpG 2 following either CpGs 1 + 3 or CpG 6 at the DAT1 5'-UTR) has been associated, therefore, with the likelihood of an internalizing or externalizing developmental trajectory entailing ADHD-like psycho-pathological characteristics. Since each individual responds differently to a specific treatment, we suggest that these methylation patterns may be used as biomarkers to monitor the outcome and/or predict the success of a given therapy (personalized medicine).