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DRD4 Variants Moderate the Impact of Parental Characteristics on Child Attention-Deficit Hyperactivity Disorder: Exploratory Evidence from a Multiplex Family Design.

ABSTRACT: Parental ADHD symptomatology and related impairments have been robustly associated with youth ADHD across decades of work. Notably, these factors may impede typical development of child self-regulation capabilities through both neurobiological and interpersonal processes. High heritability of estimates for the disorder further suggest that these effects are likely genetically-mediated, at least in part. Variation within the dopamine D4 receptor gene (DRD4) has been shown to moderate parental influences on youth ADHD. Use of a multiplex family design (i.e., samples of families that included multiple affected members) may facilitate identification of additional gene variants of interest and advance understanding of gene-environment interplay in regard to parenting. Thirty multiplex families consisting of 114 individuals (66 youth, 48 parents) completed a multi-stage, multi-informant diagnostic and neurocognitive assessment, measures of parenting, and provided saliva samples for DNA analyses. Sanger sequencing of the DRD4 gene yielded 16 rare variants; a polygenic risk score was computed for both parents and youth. Generalized estimating equations (GEE) examined the predictive effects of parental ADHD symptoms, parental neurocognitive functioning, and poor parenting dimensions on youth ADHD as well as moderation of these effects by parental and youth DRD4 variants. Findings indicated that parental DRD4 variants moderated the impact of parental ADHD and neurocognitive functioning on youth ADHD symptoms. Youth DRD4 variants moderated the impact of parental inconsistent discipline on child ADHD. In all cases, stronger associations were observed for those individuals with more risk variants. These exploratory findings highlight the potential utility of a multiplex family design for examining the interplay between parent and child characteristics in predicting youth outcomes.

SUBMITTER: Nikolas MA

PROVIDER: S-EPMC5648541 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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DRD4 Variants Moderate the Impact of Parental Characteristics on Child Attention-Deficit Hyperactivity Disorder: Exploratory Evidence from a Multiplex Family Design.

Nikolas Molly A MA Momany Allison M AM

Journal of abnormal child psychology 20170401 3

Parental ADHD symptomatology and related impairments have been robustly associated with youth ADHD across decades of work. Notably, these factors may impede typical development of child self-regulation capabilities through both neurobiological and interpersonal processes. High heritability of estimates for the disorder further suggest that these effects are likely genetically-mediated, at least in part. Variation within the dopamine D4 receptor gene (DRD4) has been shown to moderate parental inf ...[more]

PMID: 28138806

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Project description:Objectives: To investigate child and parental characteristics of medication use for attention-deficit/hyperactivity disorder (ADHD). Methods: Participants were part of the prospective population-based Norwegian Mother, Father and Child Cohort study (MoBa) (n = 114,500 children, 95,000 mothers, and 75,000 fathers). This cohort was linked to the Norwegian Prescription Database (NorPD) and the Norwegian Patient Registry (NPR) to compare child and parental characteristics in children medicated and not medicated for ADHD during years 2008-2013. Results: One thousand seven hundred and sixty-four children (74% boys) with ADHD (International Classification of Diseases [ICD-10]: F90 and F98.8) were identified. One thousand three hundred and sixty-two (77%) used medication. Boys and girls did not differ in the use of ADHD medication (both 77%). Mean age at first prescription was 9 years in both boys and girls, and age at ADHD diagnosis was 8 years in medicated and unmedicated children. Significantly more hyperkinetic conduct disorders (F90.1), and significantly fewer with attention-deficit disorder (F98.8) were found among the medicated children compared to the unmedicated children. The medicated children also had a significantly lower global functioning (Child Global Assessment Scale). Child disruptive symptoms reported in the MoBa child age 3 year questionnaire were significantly higher in children who used medication compared to the nonusers (t = 2.2, p = 0.03), and group differences in ADHD symptoms at age 3 years were close to significant (t = 1.8, p = 0.07). Other preschool child and parental characteristics were not significantly different in the two groups. Conclusion: In this large birth cohort study, where a great majority of children with ADHD used medication, only child characteristics were significantly associated with the use of medication. We could not replicate previous findings suggesting that "environmental factors," such as parental education and psychopathology, drive medication use. The small differences between medicated and unmedicated children in this cohort study, where a majority used medication, might be due to strong established clinical practices where medication is offered as a treatment option, particularly for hyperkinetic conduct disorder in an egalitarian high-income society.

Project description:The 48-basepair (48-bp) variable number tandem repeat (VNTR) polymorphism in exon 3 of the dopamine receptor D4 gene (DRD4) is implicated in the etiology of attention-deficit/ hyperactivity disorder (ADHD). In particular, ADHD in European-ancestry population is associated with an increased prevalence of the 7-repeat (7R) allele of the exon 3 VNTR. However, it is intriguing to note that the 7R allele has been found to be of very low prevalence in the Chinese general population. In a previous case-control study, our research team had found that the 7R allele was similarly absent in Chinese ADHD children in Hong Kong. Instead, there was an increased prevalence of the 2R allele in Chinese ADHD children. Interestingly, in Asian samples, the 2R allele had been found to be an evolutionary derivative of the 7R allele with equivalent biochemical functionality. So, the finding of an association between ADHD and 2R allele in Chinese population does not exactly contradict the original 7R allele finding in European-ancestry population. However, given the potential pitfall of population stratification in the previous case-control design, this current study tested the 2R allele and ADHD association using a methodologically more rigorous family-based approach on 33 Chinese ADHD probands who had favorable clinical responses to stimulant medication (methylphenidate). Haplotype Relative Risk (HRR) analysis and Transmission Disequilibrium Test (TDT) both showed a significant preferential transmission of the 2R allele from the biological parents to ADHD probands (pone-tailed = 0.038, OR = 2.04; pone-tailed = 0.048, OR = 2.29, respectively). A second hypothesis speculates that it is the deviation, including 7R and 2R alleles, from the conserved ancestral 4R allele which confers risk to ADHD. Thus, a preferential transmission of non-4R alleles, against the 4R allele, from biological parents to their ADHD probands is predicted. Both HRR analysis and TDT confirmed such prediction (pone-tailed = 0.029, OR = 2.07; pone-tailed = 0.032, OR = 2.43, respectively). This study re-confirmed the original finding of a previous study that in Chinese population, the 2R allele of the DRD4 exon 3 VNTR was related to ADHD. This endorses the general thesis that DRD4 exon 3 VNTR polymorphism is related to ADHD, despite that the exact length or number of repeats of the associated alleles varies across ethnicity. This in turn supports the dopamine dysregulation theory of ADHD.

Project description:The identification of biomarkers to support the diagnosis and prediction of treatment response for attention-deficit/hyperactivity disorder (ADHD) is still a challenge. Our previous works highlighted the DRD4 (dopamine receptor D4) as the best potential genetic marker for childhood diagnosis and methylphenidate (MPH) response. Here, we aimed to provide additional evidence on biomarkers for ADHD diagnosis and treatment response, by using more specific approaches such as meta-analytic and bioinformatics tools. Via meta-analytic approaches including over 3000 cases and 16,000 controls, we demonstrated that, among the different variants studied in DRD4 gene, the 48-base pair, Variable Tandem Repeat Polymorphism, VNTR in exon 3 showed an age/population-specificity and an allelic heterogeneity. In particular, the 7R/"long" allele was identified as an ADHD risk factor in European-Caucasian populations (d = 1.31, 95%CI: 1.17-1.47, Z = 4.70/d = 1.36, 95%CI: 1.20-1.55, Z = 4.78, respectively), also, from the results of last meta-analysis, linked to the poor MPH efficacy. The 4R/"short" allele was a protective factor in European-Caucasian and South American populations (d = 0.83, 95%CI: 0.75-0.92, Z = 3.58), and was also associated to positive MPH response. These results refer to children with ADHD. No evidence of such associations was detected for adults with persistent ADHD (data from the last meta-analysis). Moreover, we found evidence that the 4R allele leads to higher receptor expression and increased sensitivity to dopamine, as compared with the 7R allele (d = 1.20, 95%CI: 0.71-1.69, Z = 4.81), and this is consistent with the ADHD protection/susceptibility effects of the respective alleles. Using bioinformatics tools, based on the latest genome-wide association (GWAS) meta-analysis of the Psychiatry Genomic Consortium (PGC), we demonstrated that the 48 bp VNTR is not in Linkage Disequilibrium with the DRD4 SNPs (Single Nucleotide Polymorphisms), which were not found to be associated with ADHD. Moreover, a DRD4 expression downregulation was found in ADHD specific brain regions (Putamen, Z score = -3.02, P = 0.00252). Overall, our results suggest that DRD4 48 bp VNTR variants should be considered as biomarkers to support the diagnosis of ADHD and to predict MPH response, although the accuracy of such a biomarker remains to be further elucidated.

Project description:Background and objectiveMounting evidence showed that lead exposure increased the risk of child attention-deficit-hyperactivity disorder (ADHD). Epidemiologic studies have typically used the blood-lead as a biomarker of lead exposure; blood-lead levels mostly reflect recent lead exposure. However, few studies have examined the relationship between bone-lead, a biomarker of cumulative exposure, and ADHD. Therefore, we aimed to compare the associations of bone-lead vs blood-lead levels with child ADHD symptoms and comorbidities.MethodsA total of 164 children aged 3-15 years were enrolled during 2014-2015. The Vanderbilt-ADHD-Diagnostic-Parent-Rating Scale (VADPRS) was used to evaluate the children's ADHD symptoms and comorbidities. Children's blood and bone lead concentrations were assessed, the latter using a non-invasive K-X-ray-fluorescence technique. According to blood-lead levels, children were classified into high (blood-lead ≥ 10.0 μg/dL) and low (blood-lead < 10.0 μg/dL) blood-lead groups. According to bone-lead levels, children were classified into high (bone-lead ≥ 2.66 μg/g) and low (bone-lead < 2.66 μg/g) bone-lead groups. We associated blood/bone lead with VADPRS data using multi-variable binary logistic regression models.ResultsChildren in the high blood-lead group had higher hyperactivity/impulsivity (P = 0.02) scores than the corresponding low blood-lead group. Children in the high bone-lead group had higher hyperactivity/impulsivity (P = 0.02) and oppositional-defiant-disorder (ODD) (P = 0.03) scores than the corresponding low bone-lead group. After adjusting for relevant confounders, children in the high bone-lead group were more likely to have ODD-behavior than the low group (OR = 6.7, 95%CI: 1.2-36.5). However, no adjusted association was observed between blood-lead and any ADHD-domain score.ConclusionHigh levels of cumulative lead exposure in children may be an independent risk factor of ODD-behavior.

Dataset Information

DRD4 Variants Moderate the Impact of Parental Characteristics on Child Attention-Deficit Hyperactivity Disorder: Exploratory Evidence from a Multiplex Family Design.

Publications

DRD4 Variants Moderate the Impact of Parental Characteristics on Child Attention-Deficit Hyperactivity Disorder: Exploratory Evidence from a Multiplex Family Design.

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