Moderator effects of working memory on the stability of ADHD symptoms by dopamine receptor gene polymorphisms during development.
- Authors
- Trampush, Joey W; Jacobs, Michelle M; Hurd, Yasmin L; Newcorn, Jeffrey H; Halperin, Jeffrey M
- Year
- 2014
- Journal
- Developmental science
- PMID
- 24410775
- DOI
- 10.1111/desc.12131
- PMCID
- PMC4069210
We tested the hypothesis that dopamine D1 and D2 receptor gene (DRD1 and DRD2, respectively) polymorphisms and the development of working memory skills can interact to influence symptom change over 10 years in children with attention-deficit/hyperactivity disorder (ADHD). Specifically, we examined whether improvements in working memory maintenance and manipulation from childhood to early adulthood predicted the reduction of ADHD symptoms as a function of allelic variation in DRD1 and DRD2. Participants were 76 7-11-year-old children with ADHD who were genotyped and prospectively followed for almost 10 years. ADHD symptoms were rated using the Attention Problems scale on the Child Behavior Checklist, and verbal working memory maintenance and manipulation, measured by Digit Span forward and backward, respectively, were assessed at baseline and follow-up. After correction for multiple testing, improvements in working memory manipulation, not maintenance, predicted reduction of symptomatology over development and was moderated by major allele homozygosity in two DRD1 polymorphisms (rs4532 and rs265978) previously linked with variation in D1 receptor expression. Depending on genetic background, developmental factors including age-dependent variation in DRD1 penetrance may facilitate the link between improvements in higher-order working memory and the remission of symptoms in individuals with childhood-diagnosed ADHD. Furthermore, the current findings suggest that DRD1 might contribute minimally to the emergence of symptoms and cognitive difficulties associated with ADHD in childhood, but may act as a modifier gene of these clinical features and outcome during later development for those with ADHD.
Haploview-generated linkage disequilibrium patterns of the (a) four DRD1 and (b) four DRD2 single nucleotide variants examined in this study. D′ values (x100) are noted at the intersection of each SNP pair. ‘Decreased’ shades of red in each box represent decreasing linkage disequilibrium values.
Simple slope plots as a function of genotype for the two DRD1 SNPs (a) rs265978 and (b) rs4532 that evidenced a significant moderation effect. The y-axis spans the range of residualized CBCL attention problems change scores from baseline to follow-up. Negative scores are indicative of greater relative reduction in ADHD symptoms over time. The x-axis shows one standard deviation above and below the mean of the residualized digit span backward change score from baseline to follow-up. Positive scores are indicative of relative improvement in digit span backward performance over time (i.e. improvements in working memory manipulation). The lines represent the relationship between ADHD symptom reduction and working memory manipulation improvement as a function of genotype. As can be seen, symptoms significantly improved (p = .008–.015) in individuals with the common TT genotype if improvement in digit span backward was above average. Conversely, symptoms did not improve if digit span backward was below average, nor for carriers of the minor C allele irrespective of digit span backward score.
| Name | Type |
|---|---|
| ADHD | phenotype |
| ADHD probands local | cohort |
| ADHD-related phenotypes local | phenotype |
| ADHD symptom change local | phenotype |
| ADHD symptoms | phenotype |
| ADHD youth cohort local | cohort |
| adolescents | cohort |
| Adolescents and young adults with childhood-diagnosed ADHD local | cohort |
| age-corrected z-scores local | phenotype |
| ANKK1 | gene |
| attentional control | phenotype |
| Attention problem change local | phenotype |
| attention problems | phenotype |
| autism | phenotype |
| Axis-I psychiatric disorders local | phenotype |
| Behaviorally dysregulated phenotype local | phenotype |
| BrainCloud | cohort |
| CBCL-AP local | phenotype |
| CBCL-AP scores local | phenotype |
| CBCL attention problems local | phenotype |
| CBCL attention problems T-scores local | phenotype |
| Childhood-diagnosed ADHD local | cohort |
| childhood-diagnosed ADHD cohort local | cohort |
| childhood-onset ADHD local | phenotype |
| childhood sample local | cohort |
| children diagnosed with ADHD local | cohort |
| children with ADHD local | cohort |
| cognitive growth local | phenotype |
| cortex | anatomy |
| digit span backward | phenotype |
| digit span forward local | phenotype |
| Digit Span forward local | phenotype |
| dopamine | drug |
| dopamine gene local | gene |
| dopamine SNP local | variant |
| dorsolateral prefrontal cortex | anatomy |
| DRD1 | gene |
| DRD1 SNPs local | variant |
| DRD1 variant local | variant |
| DRD2 | gene |
| DRD2 SNPs local | variant |
| frontal cortex | anatomy |
| general population | cohort |
| genetic liability for ADHD local | phenotype |
| Halperin 2008 cohort local | cohort |
| Higher-order neurocognitive development local | phenotype |
| hyperactivity | phenotype |
| Impulsive response local | phenotype |
| impulsivity | phenotype |
| inattention | phenotype |
| Inattention/Overactivity local | phenotype |
| inner-city individuals of lower SES local | cohort |
| intermediate cognitive and behavioral phenotypes local | phenotype |
| low IQ | phenotype |
| maintenance local | phenotype |
| manipulation local | phenotype |
| minority groups local | cohort |
| neural activity patterns local | phenotype |
| neurological disorders | phenotype |
| nicotine | drug |
| nicotine dependence | phenotype |
| non-ADHD comparison/control group local | cohort |
| non-ADHD comparison group local | cohort |
| non-ADHD controls local | cohort |
| original cohort (Halperin et al., 2008) local | cohort |
| parent and teacher ratings of child behavior local | phenotype |
| participants | cohort |
| Post-1994 cohort local | cohort |
| Pre-1994 cohort local | cohort |
| prefrontal cortex | anatomy |
| Preschoolers with ADHD local | cohort |
| psychosis | phenotype |
| rats | cohort |
| Remission of ADHD symptoms local | phenotype |
| rs1076560 | variant |
| rs12364283 local | variant |
| rs1800497 | variant |
| rs2283265 | variant |
| rs265978 local | variant |
| rs265978 major allele local | variant |
| rs4532 local | variant |
| rs4532 major allele local | variant |
| rs686 local | variant |
| SNP | cohort |
| SNP genotype local | variant |
| stimulant medication local | drug |
| striatum | anatomy |
| symptom remission | phenotype |
| Twin cohort | cohort |
| typically developing children local | cohort |
| unaffected siblings of children diagnosed with ADHD local | cohort |
| ventrolateral prefrontal cortex | anatomy |
| WISC-III local | phenotype |
| WISC-R local | phenotype |
| working memory | phenotype |
| working memory maintenance local | phenotype |
| young adults | cohort |
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| The Role of DRD1 and DRD2 Receptors for Response Selection Under Varying Complexity Levels: Implications for Metacontrol Processes. | Zink N et al. | — | 2019 | → |
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| Ventral striatal regulation of CREM mediates impulsive action and drug addiction vulnerability. | Miller ML et al. | — | 2018 | → |
| Synaptosome-related (SNARE) genes and their interactions contribute to the susceptibility and working memory of attention-deficit/hyperactivity disorder in males. | Gao Q et al. | — | 2015 | → |
| DRD1 and DRD2 genotypes modulate processing modes of goal activation processes during action cascading. | Stock AK et al. | — | 2014 | → |