Elsevier

Biological Psychiatry

Volume 62, Issue 9, 1 November 2007, Pages 985-990
Biological Psychiatry

Original Article
Partial Replication of a DRD4 Association in ADHD Individuals Using a Statistically Derived Quantitative Trait for ADHD in a Family-Based Association Test

https://doi.org/10.1016/j.biopsych.2007.03.006Get rights and content

Background

Previous research found an association between single nucleotide polymorphisms (SNPs) in the promoter region of DRD4 and statistically derived phenotypes generated from attention-deficit/hyperactivity disorder (ADHD) symptoms. We sought to replicate this finding by using the same methodology in an independent sample of ADHD individuals.

Methods

Four SNPs were genotyped in and around DRD4 in 2631 individuals in 642 families. We developed a quantitative phenotype at each SNP by weighting nine inattentive and nine hyperactive-impulsive symptoms. The weights were selected to maximize the heritability at each SNP. Once a quantitative phenotype was generated at each SNP, the screening procedure implemented in PBAT was used to select and test the five SNPs/genetic model combinations with the greatest power to detect an association for DRD4.

Results

One of the four SNPs was associated with the quantitative phenotypes generated from the ADHD symptoms (corrected p-values = .02). A rank ordering of the correlation between each of the ADHD symptoms and the quantitative phenotype suggested that hyperactive-impulsive symptoms were more strongly correlated with the phenotype; however, including inattentive symptoms was necessary to achieve a significant result.

Conclusions

This study partially replicated a previous finding by identifying an association between rs7124601 and a quantitative trait generated from ADHD symptoms. The rs7124601 is in linkage disequilibrium (LD) with the SNPs identified previously. In contrast to the previous study, this finding suggests that both hyperactive-impulsive and inattentive symptoms are important in the association.

Section snippets

Subjects and Sample Collection

The sample used in this research is a part of the International Multi-Center ADHD Genetics Project (IMAGE). Details of the subjects and sample collection for this study can be found elsewhere (20). Briefly, European Caucasian subjects were recruited from 12 specialist clinics in 8 countries: Belgium, Germany, Holland, Ireland, Israel, Spain, Switzerland, and United Kingdom. Ethical approval for this study was obtained from National Institutes of Health registered ethical review boards for each

Descriptive Statistics

The summary of the sample characteristics is given in Table 1.

FBAT-PC Analysis

Table 2 shows the five SNP/genetic model combinations selected through the screening procedure listed from highest to lowest power. Also presented are the number of informative families at each SNP, the genetic model, and the FBAT-PC p-value. SNP rs7124601 (physical location: 629273 bp [base pair]) achieves overall significance after adjusting for the five tests. The overtransmitted allele for rs7124601 was A. This SNP is located in

Discussion

Previous research used the novel analytic method, FBAT-PC, to identify an association between two SNPs in the DRD4 promoter region and heritable quantitative phenotypes based on nine inattentive and nine hyperactive-impulsive ADHD symptoms (16). Using an independent population that is substantially larger in size, we evaluated four SNPs in DRD4 using the same methodology. SNP rs7124601 was found to be associated with a phenotype generated using the FBAT-PC methodology. SNP rs7124601 is located

References (27)

  • D.P. Cantwell

    Psychiatric illness in the families of hyperactive children

    Arch Gen Psychiatry

    (1972)
  • Z. Welner et al.

    A controlled study of siblings of hyperactive children

    J Nerv Ment Dis

    (1977)
  • D.P. Cantwell

    Genetics of hyperactivity

    J Child Psychol Psychiatry

    (1975)
  • Cited by (27)

    • Conduct disorder: A neurodevelopmental perspective

      2018, Developmental Pathways to Disruptive, Impulse-Control, and Conduct Disorders
    • Biological factors underlying sex differences in neurological disorders

      2015, International Journal of Biochemistry and Cell Biology
      Citation Excerpt :

      Genome-wide association studies (GWAS) in ADHD patients have yet to successfully establish any common polymorphisms (besides copy number variants) that might be a risk factor for ADHD and/or male ADHD (Davies, 2014; Stergiakouli et al., 2012; Williams et al., 2012; Yang et al., 2013). However, GWAS and family-based association studies have reported an association between ADHD and catecholamine machinery genes such as DBH, DRD2, DDC, COMT and DRD4 (Lasky-Su et al., 2007, 2008a,b). Association studies in ADHD patients of different ethnicity indicate that catecholamine machinery gene variants DRD4, DAT1, MAO-A, COMT and DBH (Fig. 1B) are sexually dimorphic and associated with increased risk of developing ADHD in males (Biederman et al., 2008; Das Bhowmik et al., 2013; Das et al., 2006; Qian et al., 2003, 2004).

    • Case-control genome-wide association study of attention-deficit/ hyperactivity disorder

      2010, Journal of the American Academy of Child and Adolescent Psychiatry
    • Is There a Need to Reformulate Attention Deficit Hyperactivity Disorder Criteria in Future Nosologic Classifications?

      2008, Child and Adolescent Psychiatric Clinics of North America
      Citation Excerpt :

      Using modern statistical approaches and accumulating knowledge on a molecular genetics basis for ADHD, some investigators are pursuing a more causal pathway. They are departing from specific polymorphisms or haplotypes in candidate genes and trying to determine which specific aspects of the ADHD phenotype are associated with them [39,40]. Although innovative and promising, this approach needs also to document that it would be able to derive an even more heritable phenotype characterizing phenotypically a more homogeneous group of patients, presenting specific associated demographic and psychosocial factors with a more homogeneous course of symptoms and a specific pattern of response to treatment.

    View all citing articles on Scopus
    View full text