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The Association Between Executive Functions and Candidate Genes of Dopaminergic and Noradrenergic Systems in Attention Deficit Hyperactivity Disorder (ADHD)

2014-08-27 03:16:32 | BioPortfolio

Summary

The ultimate goal of this study is to find specific polymorphism of candidate genes (particularly of dopaminergic and noradrenergic systems) associated with intermediate phenotypes (e.g., executive functions, IQ, and other neuropsychological function) and/or phenomenological phenotypes (subtypes, comorbidity, dimensional approach) of ADHD. We propose to replicate the analysis of the candidate genes identified by previous genetic studies and recent findings from GWAS on ADHD using the candidate gene association study design (family-based case control study using parental controls and population-based case-control study). These results may lead our research team: (1) to resolve controversies over inconsistent findings in previous genetic studies and contribute to the literature on the validity of ADHD and its subtypes using clinical and genetic data; (2) to identify potential endophenotypes for ADHD genetic studies; and (3) to identify specific polymorphism of candidate genes and gene expressions of dopaminergic and noradrenergic systems associated with executive functions measured by the CANTAB.

Description

Attention deficit hyperactivity disorder (ADHD) is a common, impairing, highly heritable, clinically heterogeneous early-onset neuropsychiatric disorder. Despite substantial evidence supporting genetic etiology of ADHD, molecular genetic studies so far have not yet provided any conclusive results using the categorical or subgroup approach of phenotype. Hence, there has been growing interest in using endophenotypes in molecular genetic studies on ADHD. Our previous studies have demonstrated significant deficits in executive functions among children with ADHD and the efficacy of methylphenidate and atomoxetine, involving dopaminergic and noradrenergic systems, in reducing ADHD core symptoms and improving executive functions. In a longitudinal follow-up family study on ADHD, we also reported that executive dysfunctions measured by the Cambridge Neuropsychological Test Automated Batteries (CANTAB) are potential endophenotypes for ADHD. Hence, identifying specific polymorphism of candidate genes of dopaminergic and noradrenergic systems associated with executive dysfunctions in Han Chinese in Taiwan is warranted.

Specific Aims:

1. To identify specific genetic polymorphism of candidate genes of dopaminergic and noradrenergic systems (e.g., DRD2, DRD4, DRD5, DAT1, NET, ADRA2A, DBH, COMT etc.) associated with executive dysfunctions measured by the CANTAB and other alternative phenotype approaches (ADHD subtypes, comorbidities, treatment effects, IQ, symptom dimensions and severity);

2. to investigate the relationship between a variety of ADHD phenotypes and endophenotypes and gene expressions of DRD2, DAT1, NET, ADRA2A, DBH, and COMT;

3. to validate executive functions and to search for other neuropsychological functioning as endophenotypes for ADHD; and

4. to determine whether ADHD is familial and identify which core symptoms of ADHD and which component of neuropsychological functioning are most familial;

Subjects and Methods: The major study design is the family-based case-control candidate gene association study. We will recruit 150 probands with ADHD, aged 7-18, and their parents (n = 300) and siblings (n= 150) and 150 school controls in three years (50, 60, and 40 families with ADHD and 50, 60, 40 school controls in the 1st, 2nd, and 3rd year, respectively). The measures include (1) interviews for psychopathology (K-SADS-E) and social functioning (SAICA), (2) self-administered questionnaires to measures ADHD symptoms (CPRS-R:S, CTRS-R:S, SNAP-IV and Adult ADHD rating scale) and comorbid conditions (ASRI and CBCL), and (3) neuropsychological tests: WISC-III-R, CPT, CANTAB, and Time Perception Tasks. The transmission/disequilibrium test (TDT) and quantitative TDT by using FBAT and FBAT-GEE, GEE, and Mixed Models will be used for data analysis.

Anticipated Results: We anticipate the establishment of clinical, neuropsychological, and genetic database of at least 350 families (150 families in this project) and 150 same-age controls, the completion of genetic analysis and gene expressions of several candidate genes including those involving dopaminergic and noradrenergic systems, and identification of genetic variants for ADHD diagnosis, symptoms, and comorbidities, executive functions, and other neurocognitive endophenotypes in a Taiwanese sample. The findings of different approaches to identify the genetic etiologies for ADHD in this study should help us determine the most promising approach for future molecular genetic studies on ADHD.

Study Design

N/A

Conditions

Attention Deficit Hyperactivity Disorder

Location

National Taiwan Univeristy Hospital
Taipei
Taiwan

Status

Not yet recruiting

Source

National Taiwan University Hospital

Results (where available)

View Results

Links

Published on BioPortfolio: 2014-08-27T03:16:32-0400

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Medical and Biotech [MESH] Definitions

A behavior disorder originating in childhood in which the essential features are signs of developmentally inappropriate inattention, impulsivity, and hyperactivity. Although most individuals have symptoms of both inattention and hyperactivity-impulsivity, one or the other pattern may be predominant. The disorder is more frequent in males than females. Onset is in childhood. Symptoms often attenuate during late adolescence although a minority experience the full complement of symptoms into mid-adulthood. (From DSM-IV)

A propylamine derivative and selective ADRENERGIC UPTAKE INHIBITOR that is used in the treatment of ATTENTION DEFICIT HYPERACTIVITY DISORDER.

A methylphenidate derivative, DOPAMINE UPTAKE INHIBITOR and CENTRAL NERVOUS SYSTEM STIMULANT that is used in the treatment of ATTENTION DEFICIT HYPERACTIVITY DISORDER.

A dextroamphetamine drug precursor that also functions as a CENTRAL NERVOUS SYSTEM STIMULANT and DOPAMINE UPTAKE INHIBITOR and is used in the treatment of ATTENTION DEFICIT HYPERACTIVITY DISORDER.

The d-form of AMPHETAMINE. It is a central nervous system stimulant and a sympathomimetic. It has also been used in the treatment of narcolepsy and of attention deficit disorders and hyperactivity in children. Dextroamphetamine has multiple mechanisms of action including blocking uptake of adrenergics and dopamine, stimulating release of monamines, and inhibiting monoamine oxidase. It is also a drug of abuse and a psychotomimetic.

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