The Association Between Executive Functions and Candidate Genes of Dopaminergic and Noradrenergic Systems in Attention Deficit Hyperactivity Disorder (ADHD)
Condition: Attention Deficit Hyperactivity Disorder
MeSH terms: Hyperkinesis; Attention Deficit Disorder with Hyperactivity
Study type: Observational

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.
    

Detailed 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.
    

Observational model: Other
Time perspective: Other
Sampling method: Non-Probability Sample
Study population: 
        The proband sample will consist of at least 150 drug-naïve children and adolescents with
        ADHD, aged 7-18 (who are able to perform the CANTAB and time tasks) from Department of
        Psychiatry, National Taiwan University Hospital (NTUH). Their biological parents (n = 300)
        and siblings (estimated number = 150) born to the same biological parents will be recruited
        as the parent controls and sibling controls, respectively, for the family-based case
        control study. We will recruit 150 school controls without lifetime diagnosis of ADHD in
        the same school districts and with similar age and gender distributions of the probands
        with ADHD.
      
Biospecimen description: 
      The subjects will receive blood withdrawal. The blood sample will be used for establishing
      lymphoblastoid cell lines, which will be used for molecular genetic experiments.
    
Keywords: Attention-deficit/hyperactivity disorder; executive function; endophenotype; dopaminergic system; noradrenergic system; candidate gene; Family-based association study