Effect of DRD4 receptor -616 C/G polymorphism on brain structure and functional connectivity density in pediatric primary nocturnal enuresis patients

Abstract

The dopamine D4 receptor (DRD4) promoter (-616; rs747302) has been associated with primary nocturnal enuresis (PNE); however, its relationship with neuroimaging has not been investigated. Therefore, we assessed the effects of the DRD4 -616 C/G single nucleotide polymorphism on the gray matter volume (GMV) and functional connectivity density (FCD) during resting-state functional magnetic resonance imaging in children with PNE using voxel-based morphometry and FCD methods. Genomic and imaging data were obtained from 97 children with PNE and 105 healthy controls. DRD4 -616 C/G was genotyped. Arousal from sleep (AS) was assessed on a scale of 1-8. Both the main effect of genotype and the group (PNE/control)-by-genotype interaction on GMV and FCD were calculated. Our results showed that C-allele carriers were associated with a higher AS, decreased GMV and FCD in the pregenual anterior cingulate cortex; children with PNE carrying the C allele exhibit decreased GMV and FCD in the thalamus; however, controls carrying the C allele exhibit increased FCD in the posterior cingulate cortex. These effects of genetic variation of the DRD4 locus may help us understand the genetic susceptibility of the DRD4 -616 C allele to PNE.

Figure 1

Association between DRD4 −616 C/G and AS and GMV. (A) Comparisons of AS scores in different genotypes and groups. (B) Whole-brain thalamic VBM analysis demonstrates a significant main effect of genotype in the pregenual ACC. (C) Whole-brain thalamic VBM analysis demonstrates a significant interaction between genotype and group in the thalamus. (D) PNE C-allele carriers exhibited a significantly decreased GMV in the pregenual ACC compared to the PNE G-allele homozygotes.

Figure 2

Association between DRD4 −616 C/G, AS and FCD. (A) A main effect of genotype on the FCD was found in the pregenual ACC. (B) FCD analysis demonstrates a group-genotype interaction in the thalamus. (C) FCD analysis demonstrates a group-genotype interaction in the PCC. (D) Post-hoc testing demonstrated that the C-allele carriers in the PNE group had a significantly decreased FCD in the thalamus. (E) Post-hoc testing revealed that controls carrying the C allele exhibited increased FCD in the PCC. (F) The FCD of the thalamus also showed a significant negative correlation with the AS scores in C-allele carriers of the PNE group.