COMT by DRD3 Epistatic Interaction in Modulating Behaviors in Children with ADHD: A Pharmaco-Dynamic Behavioral Approach

Abstract

Objective: Examining the joint effect of two functional variants in two dopamine-related genes ( DRD3 and COMT) on ADHD-relevant behaviors under three experimental conditions (EC). Method: 362 children with ADHD were assessed by parents and teachers during a week of baseline evaluation, followed by 1 week of MPH and placebo, administered in a double-blind crossover design. Results: Statistically significant 3-way ( DRD3-by- COMT-by-EC; p = .004) and 2-way interactions ( COMT by EC; p = .002) were observed on Conners’-Teachers scores. Children with the COMT Met/Met genotype had lower scores at baseline and on placebo compared to the other genotype groups. Furthermore, stratifying the children according to their COMT genotypes helped to detect statistically significant and biologically meaningful effects of DRD3 genotype. Conclusions: These findings suggest that COMT and DRD3 genetic variants may together play a role in ADHD symptomatology and response to treatment through gene-gene interaction.

Dopamine Related Genes Differentially Affect Declarative Long-Term Memory in Healthy Humans

“…Indeed, in a previous study, reward-related hemodynamic activity in the ventral striatum could be related to the combination of DAT and COMT polymorphisms (Yacubian et al, 2007 ). More recent work has confirmed such epistatic gene-gene interactions, for instance, by showing that COMT and DRD3 together modulate behavior in children with ADHD (Fageera et al, 2020 ) and that DRD4 in combination with COMT modulate the clinical responses to clozapine in schizophrenia patients (Rajagopal et al, 2018 ). In our study, the most apparent link to the investigated polymorphisms is their impact on dopaminergic neuromodulation.…”

Developmental dyslexia genes are selectively targeted by diverse environmental pollutants

“…There were also 18 dyslexia susceptibility genes, two of which were concurrently susceptible. For example, DRD3 gene may be related to the clinical significance of ASD and ADHD [ 64 , 65 ]. Genes related to dyslexia and neurodevelopment usually share a common mechanism in influencing brain development, including synaptic plasticity, neuronal migration, and neurotransmitter transmission [ 66 ].…”

ADHD co-morbidities: A review of implication of gene × environment effects with dopamine-related genes

“…Inclusion of 36,989 patients and 113,075 control cases helped to demonstrate that DRD2 is associated with schizophrenia (Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014) that is a highly heritable disorder and exclusively treated with drugs that bind to dopamine D2 receptor. In pathogenesis, many hidden G × G interactions are likely to occur (e.g., Fageera et al, 2020), and each gene variation has a potential to be included in several pathogenetic pathways at the individual level. Altogether this means that dopamine-related genes may have each a small effect in general but a large effect together, shaping the overall activity of the dopaminergic system.…”