Molecular Studies on the Candidate Genes of Dopaminergic and Noradrenergic Systems in 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
      associated with endophenotypes and/or phenomenological phenotypes of ADHD. We propose to
      replicate the analysis of the candidate genes identified by previous genetic studies on ADHD
      using the candidate gene association study design (family-based case control study using
      parental controls) to validate the findings from other research groups. These results will
      lead our team: (1) to resolve controversies over inconsistent findings in previous genetic
      studies and contribute to the literature on the validity of ASD using clinical and genetic
      data; (2) to study the pathogenetic process of abnormal genes in abnormal neuropsychological
      and neurobiological functions of ADHD; (3) to delineate the nature and the effect of
      gene-gene interaction in the etiology of ADHD.
    

Detailed description: 
      Attention deficit hyperactivity disorder (ADHD), characterized by inattention, hyperactivity
      and impulsivity, is an early onset, highly heritable, clinically heterogeneous, long-term
      impairing disorder with tremendous impact on individuals, families, and societies. It affects
      5-10% of school-aged children worldwide (7.5% in Taiwan) and 2-4% of adults.
      Neuropsychological deficits related to executive functions, state regulation, and delay
      aversion show heritability, replicated association with ADHD, and familial-genetic overlap
      with ADHD, are suitable for biomarkers for ADHD. Despite the abundance of molecular genetic
      studies on ADHD, the genetic etiologies of ADHD have been non-conclusive, and there is
      limited information about the expressions, neuropsychological deficits, and genetic variants
      for ADHD in Chinese population. This present study, a family-based parental control
      association study, aims to identify the genetic markers of dopaminergic and noradrenergic
      systems for ADHD using the dichotomous categorization of affected and non-affected,
      quantitative phenotypes (symptom dimension and severity of ADHD) and endophenotype
      (neuropsychological measures) as well.

      Specific Aims:

        1. to determine the components of ADHD and neuropsychological deficits with the greatest
           familial recurrence risks;

        2. to replicate studies with positive genetic findings from literature by performing
           candidate gene analysis such as DRD4, DRD2, DRD5, DAT1, DBH, ADRA2C, ADRA1C, and SLC6A2;

        3. to identify the potential genetic variants using haplotype tagSNPs for the following
           candidate genes, MAO-A and ADRA2A and any updated genetic findings.

      In addition to a sample of 200 ADHD families (200 probands, 400 parents, and 150 siblings)
      being recruited in a parallel study (NSC96-2628-B-002-069 -MY3), we will recruit another 100
      probands with ADHD, aged 7-18, and their parents (n = 200) and siblings (n= 75) in this
      project. The phenotype measures include (1) interviews for psychopathology (K-SADS-E) and
      social functioning (SAICA), (2) self-administered questionnaires to measures ADHD symptoms
      (SNAP-IV and Adult ADHD rating scale) and comorbid conditions (ASRI and CBCL), and (3)
      Neuropsychological tests: WISC-III, CPT, CANTAB, and Time Perception Tasks. The DNA will be
      collected and analyzed. The transmission/disequilibrium test (TDT) and quantitative TDT will
      be used in data analysis.

      We anticipate the establishment of clinical, neuropsychological, and genetic database of 300
      ADHD families (200 in NSC96-2628-B-002-069-MY3 and 100 in this project), completion of the
      screening of several candidate genes, and identification of potential genetic variants for
      ADHD, and determination of their association with ADHD diagnosis and symptoms and its
      endophenotype in a Taiwanese sample. The long-term objectives are to identify the behavioral
      phenotypes and endophenotypes that are close to the biological expression of genes underlying
      ADHD. The findings of different approaches to identify the genetic etiologies for ADHD in
      this pilot study should help us to determine the most promising approach for future molecular
      genetic and pharmacogenetic study on ADHD.
    

Observational model: Family-Based
Time perspective: Other
Sampling method: Non-Probability Sample
Study population: 
        The sample will consist of 100 probands with ADHD, aged 7-18. Their biological parents (n =
        200) and siblings (estimated number = 75) born to the same biological parents will be
        recruited as the parent controls and sibling controls, respectively, for the family-based
        case control study.
      
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; dopaminergic; noradrenergic; endophenotype; molecular genetics; candidate gene; Family-based Association study