Endophenotype, Molecular Genetic Study on Attention-Deficit/Hyperactivity Disorder
Condition: Attention Deficit Hyperactivity Disorder
MeSH terms: Hyperkinesis; Attention Deficit Disorder with Hyperactivity
Study type: Observational

Summary: 
      The ultimate goals of this study are to identify patterns of familial aggregation with
      regards to categorical and dimensional approaches of ADHD and neuropsychological measures, to
      validate the phenotypes and endophenotypes that are close to biological expression of genders
      underlying ADHD, and to identify the genetic variants close to the etiological genes of ADHD
      in Taiwanese sample. 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. With the accomplishment of these goals, this study will resolve
      controversies over inconsistent findings in previous genetic studies and contribute to the
      literature on the validity of ASD using clinical and genetic data.
    

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, endophenotypes, and genetic variants for ADHD in
      Chinese population. This polite study, a family-based parental control association study,
      aims to identify the genetic markers for ADHD using the dichotomous categorization of
      affected and non-affected, quantitative phenotypes (symptoms dimension and severity of ADHD)
      and endophenotype (neuropsychological measures) as well.

      Specific Aims:

        1. to determine the components of ADHD and neuropsychological deficit with the greatest
           familial recurrence risks;

        2. to replicate studies with positive genetic findings from literature by performing
           candidate gene analysis such as DRD4, DAT1, DRD5, HTR1B, SNPA-25, 5-HTT, DBH, CHRNA4,
           CHRNA7 etc;

        3. to identify the potential genetic variants using haplotype tag SNPs for the following
           candidate genes, CHRNA4 and CHRNA7 and any updated genetic findings.

      We will recruit 200 probands with ADHD, aged 7-18, and their parents (n = 400) and siblings
      (n= 150) in three years (50, 100, and 50 families with ADHD 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, 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 200
      ADHD families, 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 study on ADHD.
    

Observational model: Family-Based
Time perspective: Other
Sampling method: Non-Probability Sample
Study population: 
        The sample will consist of 200 children and adolescents with ADHD, aged 7-18.
      
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; neuropsychological deficits; endophenotype; molecular genetics; candidate gene; family-based association study