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

• DOI: 10.1007/s00787-017-1040-9
• Publication Date: 2017-08-18T07:59:10Z
• Authors: Walter Adriani; Emilia Romano; Mariangela Pucci; Esterina Pascale; Luca Cerniglia; Silvia Cimino; Renata Tambelli; Paolo Curatolo; Oleg Granstrem; Mauro Maccarrone; Giovanni Laviola; Claudio D’Addario
• Keywords: 9-Repeat allele; Male; 0301 basic medicine; Polymorphism, Genetic; OCD; Adolescent; Genotype; 10-Repeat allele 9-Repeat allele Auto-antibodies (aAbs) to neuro-receptors CGAS scal eConners’ scales Dopamine transporter (DAT) Epigenetics in neuro-psychiatry OCD Tourette’s; Conners’ scale; 03 medical and health sciences; Settore MED/39 - NEUROPSICHIATRIA INFANTILE; 10-Repeat allele; 9-Repeat allele; Auto-antibodies (aAbs) to neuro-receptors; CGAS scale; Conners’ scales; Dopamine transporter (DAT); Epigenetics in neuro-psychiatry; OCD; Tourette’s; Attention Deficit Disorder with Hyperactivity; Auto-antibodies (aAbs) to neuro-receptor; 616; CGAS scale; Humans; Dopamine transporter (DAT); Female; Child; 10-Repeat allele; Epigenetics in neuro-psychiatry; Tourette’s; attention deficit disorder with hyperactivity; genes; transporter gene

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.