DRD3 Gene and ADHD: A Pharmaco-Behavioural Genetic Study

Abstract

Results of candidate gene investigations in ADHD have been difficult to replicate. The complexity of the phenotypes and their underlying determinants, and the relatively small effect sizes of genetic variants may, in part, be contributing to these inconsistencies. The objective of this study is to conduct an exploratory analysis using a comprehensive approach to investigate the role of candidate genes. This approach combines a dimensional behavioural approach akin to Research Domain Criteria (RDoC), a pharmaco-dynamic evaluation of behaviours relevant to ADHD, together with association and linkage testing in a large sample of children with ADHD. Parents, teachers, and research staff evaluated children with ADHD under three experimental conditions (EC): 1 week of baseline observation, followed by 1 week of methylphenidate (MPH) and 1 week of placebo, administered in a double-blind crossover order. Several quantitative behavioural and cognitive dimensions relevant for ADHD were also assessed. We combined family-based (FBAT) and quantitative trait genetic analyses (n = 575 probands with members of their nuclear families) to investigate the role of DRD3 (Ser-9-Gly) in ADHD and its relevant behavioural dimensions. Comparing the behaviours of children with different genotypes under the three EC showed a nominal association between the T allele and poorer behavioural scores during the MPH week (as assessed by teachers), particularly in boys. With the family-based analysis, the T allele showed a nominal association with increased risk for ADHD, response to placebo and MPH as assessed by research staff, and the modulation of other behavioural and cognitive dimensions. These results provide convergent, albeit preliminary evidence for the implication of the DRD3 (Ser-9-Gly) polymorphism in the aetiology of ADHD and the modulation of its various behavioural dimensions, including RDoC cognitive constructs and response to pharmacological probes. This illustrative example suggests that this research paradigm might help to reliably uncover the role of other candidate genes in ADHD.

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

“…While, to our knowledge, this is the largest study in ADHD investigating gene-by-gene interaction and included 619 children evaluated prospectively with a very stringent evaluation protocol, some of the gene-by-gene stratum contained relatively few subjects (one stratum with nine subjects was excluded from the analysis and the smallest stratum retained in the analysis contained 23 subjects). Early evidence from our group suggests a stronger effect of DRD3 in boys with ADHD (Fageera et al, 2018). However, due to the sample size, we may have insufficient statistical power to stratify the sample by gender and study the gene-gene interaction.…”

“…In a previous study, we used a comprehensive approach to investigate the role of DRD3 in ADHD (Fageera et al, 2018). The results provided some evidence on the implication of the DRD3 (Ser-9-Gly) polymorphism in the etiology of ADHD and the modulation of its various behavioral dimensions.…”

The Impact of Genetics on Cognition: Insights into Cognitive Disorders and Single Nucleotide Polymorphisms

“…The Ser9Gly polymorphism in the DRD3 gene has also been extensively studied in association with ADHD, since it is widely expressed in the mesolimbic areas, the critical regions for cognitive and emotional functions, novelty seeking, and expression of reward. It has been demonstrated that the T allele carriers are less sensitive than the C allele carriers to the effects of DA, possibly showing a lower response to methylphenidate treatment [46].…”

The Predictive Power of Attention-Deficit Hyperactivity Disorder (ADHD) Genetic Risk Factors

“…Currently, no studies have identi ed a speci c gene that causes ADHD. Part of the di culty lies in the complexity of the phenotypes and relatively small e ects of genetic variants 13 . This section will lay out and discuss the di erent genes of interest that could possibly relate to the cause of ADHD.…”