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

Abstract

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.

Association of norepinephrine transporter methylation with in vivo NET expression and hyperactivity–impulsivity symptoms in ADHD measured with PET

“…They found that less methylation was associated with greater MPH response [12]. Another study detected negative association between DAT1 methylation and scores of hyperactivity [44].…”

Association between DNA methylation and ADHD symptoms from birth to school age: A prospective meta-analysis

“…4,10 Consequently, candidate studies have primarily focused on genes related to dopamine function. For instance, DNA methylation alterations in DRD4 [11][12][13] , DRD5 12 , and DAT1 12,14 genes have been associated with ADHD diagnoses or symptoms, though not consistently 15 . Beyond the candidate gene approach, three studies tested DNA methylation across the whole genome.…”

Epigenetics applied to psychiatry: Clinical opportunities and future challenges

“…A longitudinal study has shown association between SP6 gene DNA methylation, amygdala/hippocampal volume ratio, and psychopathology, supporting the role of DNA methylation as a longitudinal epigenetic predictor. Moreover, blood methylation levels of 5‐HTT and/or BDNF genes have been suggested as promising biomarkers for prediction of pharmacological or psychotherapeutic treatment response in patients suffering from MDD, BD, BPD, PTSD, SCZ and ADHD . In addition to these genes, recent studies have reported a four‐locus model involving the CYP3A4 gene that significantly alters risperidone treatment response of SCZ patients .…”

“…Moreover, blood methylation levels of 5-HTT and/or BDNF genes have been suggested as promising biomarkers for prediction of pharmacological or psychotherapeutic treatment response in patients suffering from MDD, 69 BD, BPD, 70 PTSD, 71 SCZ 72 and ADHD. 73 In addition to these genes, recent studies have reported a four-locus model involving the CYP3A4 gene that significantly alters risperidone treatment response of SCZ patients. 74 Finally, the generation of a DNA methylation biosignature in blood or © 2018 The Authors Psychiatry and Clinical Neurosciences © 2018 Japanese Society of Psychiatry and Neurology saliva has been shown to improve a suicide-prediction model.…”