Interaction between DRD4 and MAOA genetic polymorphisms on static and dynamic regional coherence in the prefrontal cortex of drug-naive children with ADHD

The aim of this study was to explore the genetic association between DRD4 and MAOA genotypes and local functional connectivity in drug-naive children with ADHD. We investigated the effects of individual genotypes and gene × gene interactions between DRD4 and MAOA variants on local functional connectivity in 94 children with ADHD, using both the mean static regional homogeneity (sReHo) and the coefficient of variation (CV) of dynamic ReHo (dReHo). Additionally, correlation and mediation analyses were conducted to explore the relationships between dopamine-related genes, regional brain function, and neurocognitive alterations. There was a significant genetic epistasis between DRD4 and MAOA variants affecting both sReHo and dReHo in the right orbital part of the middle frontal gyrus (MFG.R), belonging to prefrontal cortex (PFC). Post-hoc pairwise analysis revealed the altered intrinsic brain connectivity related to DRD4 varied according to MAOA genotype. Furthermore, the sReHo value in MFG.R was negatively correlated with the Hyperactivity index of the Conners scale in ADHD group. Mediation analysis suggested that the relationship between the DRD4 × MAOA gene interaction and the Hyperactivity index was mediated by the regional coherence of MFG.R in the PFC. These results suggest that alterations in the dopamine system in ADHD may contribute to abnormalities in both static and dynamic local functional connectivity. Disruptions in DA homeostasis within the synaptic cleft of the prefrontal cortex could lead to changes in intrinsic regional neural coherence. Our findings may help clarify the genetic basis of dopaminergic mechanisms underlying prefrontal dysfunction in ADHD.