Different effects of the DRD4 genotype on intrinsic brain network connectivity strength in drug-na\xefve children with ADHD and healthy controls

Chuqi Fu,Jiance Li,Andan Qian,Meihao Wang,Shuangli Chen,Chuang Yang,Xiaoqi Huang,Ronghui Zhou,Jiejie Tao,Jiejie Zhou,Qingxia Lin

doi:10.1007/s11682-021-00521-9

Abstract

The dopamine D4 receptor gene (DRD4) has been consistently reported to be associated with attention-deficit/hyperactivity disorder (ADHD). Recent studies have linked DRD4 to functional connectivity among specific brain regions. The current study aimed to compare the effects of the DRD4 genotype on functional integrity in drug-naïve ADHD children and healthy children. Resting-state functional MRI images were acquired from 49 children with ADHD and 37 healthy controls (HCs). We investigated the effects of the 2-repeat allele of DRD4 on brain network connectivity in both groups using a parameter called the degree of centrality (DC), which indexes local functional relationships across the entire brain connectome. A voxel-wise two-way ANCOVA was performed to examine the diagnosis-by-genotype interactions on DC maps. Significant diagnosis-by-genotype interactions with DC were found in the temporal lobe, including the left inferior temporal gyrus (ITG) and bilateral middle temporal gyrus (MTG) (GRF corrected at voxel level p < 0.001 and cluster level p < 0.05, two-tailed). With the further subdivision of the DC network according to anatomical distance, additional brain regions with significant interactions were found in the long-range DC network, including the left superior parietal gyrus (SPG) and right middle frontal gyrus (MFG). The post-hoc pairwise analysis found that altered network centrality related to DRD4 differed according to diagnostic status (p < 0.05). This genetic imaging study suggests that the DRD4 genotype regulates the functional integration of brain networks in children with ADHD and HCs differently. This may have important implications for our understanding of the role of DRD4 in altering functional connectivity in ADHD subjects.

Highlights

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent and highly heritable childhood-onset neurodevelopmental disorder characterized by age-inappropriate levels of inattention, hyperactivity, and/or impulsivity (Apa, 2013)
The analysis further revealed that the left inferior temporal gyrus (ITG) and bilateral middle temporal gyrus (MTG) exhibited significantly higher Degree centrality (DC) values in the attention-deficit/hyperactivity disorder (ADHD) subjects with the DRD4 2R genotype (p < 0.05)
Using resting-state functional MRI (fMRI) and a network centrality approach, we found the first evidence of a significant interaction of DRD4 diagnosis-by-genotype on the brain functional architecture of the ITG and MTG

Summary

Introduction

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent and highly heritable childhood-onset neurodevelopmental disorder characterized by age-inappropriate levels of inattention, hyperactivity, and/or impulsivity (Apa, 2013). Most of the candidate genes associated with ADHD belong to the dopaminergic system (Gizer et al, 2009). Several meta-analyses have shown that the DRD4 7-repeat (7R) allele is mostly associated with ADHD It has been reported that the 2-repeat (2R) allele of DRD4 is an ADHD-risk allele in the Asian population (Hong et al, 2018; Leung et al, 2005). Implications of the genotype DRD4 2R allele in predicting more severe symptoms and poor ADHD treatment outcomes exist (Cheon et al, 2007). An association between DRD4 and some certain behavioral traits has gained conflicting evidence. Because DRD4 appears to be associated with both adverse and advantageous outcomes, some researchers have proposed that the 7R variant (or the 2R variant) of DRD4 functions as a plasticity allele, which is highly sensitive to environmental influence.

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