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

Yu B, Chang N, Lu Y, Ma H, Liu N, Guo Q

Scientific Reports 2017 Apr 27;7(1):1226. doi: 10.1038/s41598-017-01403-1

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.

Commentary by Konstantinos Kamperis

Is a dopamine receptor D4 promoter polymorphism predisposing to enuresis in children?

It is beyond any doubt that nocturnal enuresis is a genetic disorder but the responsible sites in our genome that predispose to bedwetting are yet to be identified. This possibly reflects the complex pathophysiological background of the condition as well as the variability in the phenotype with some children suffering nocturnal polyuria whereas in others bladder dysfunction is evident. One of the current hypotheses is that the condition is the result of a central nervous system defect and the dopamine D4 receptor promoter has previously been associated with the condition. In this paper the authors take a step further and try to correlate a polymorphism in the promoter region of the gene with ability to arouse form sleep and resting functional connectivity in the brain in children with enuresis and controls. Functional MR studies were performed and the authors seem able to demonstrate that children with the C-alleles are more difficult to awake and share decreased functional connectivity within the thalamus an important part of the brain participating in sleep and wakefulness processes. The authors hypothesize that this polymorphism may predispose to the inability to awaken to the stimuli of a full bladder, leading thus to bedwetting. Although the study provides evidence of D4 receptor promoter gene polymorphism being a susceptibility gene for nocturnal enuresis this needs to be confirmed in large scale studies and possibly in different subpopulations of children with enuresis as we do know that there is a significant phenotypic variability in the condition.  

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Consensus Guidelines

Practical consensus guidelines for the management of enuresis. 
Evaluation and management of enuresis, a common condition, is not a priority in training programs for medical doctors (MDs), despite being a common condition. 

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Diagnosis and Treatment of Nocturnal Enuresis developed by the Working Group of Nocturnal Enuresis Belgium.