| Summary |
As a follow up to a pilot study [see Castellanos et al. 1998; Mol Psychiatry 3:431-434] consisting of 41 probands and 56 controls which found no significant association between the DRD4 7-repeat allele in exon 3 and ADHD, a greatly expanded study sample (cases n=166 and controls n=282) and long term follow-up (n=107, baseline mean age n=9, follow-up mean age of n=15) prompted reexamination of this gene. The DRD4 7-repeat allele was significantly more frequent in ADHD cases than controls. Further, within the ADHD group, the 7-repeat allele was associated with better cognitive performance (measured by the WISC-III) as well as a trend for association with better long-term outcome. This provides further evidence of the role of the DRD4 7-repeat allele in the etiology of ADHD and suggests that this allele may be associated with a more benign form of the disorder. |
| Total Sample |
166 children and adolescents with ADHD were recruited. 94% percent of the patients were diagnosed with ADHD combined type and the remaining 6% were diagnosed with primary inattentive type. For the family-based analyses, 87 trios and 26 dyads were available. Forty-one of the original probands from the previously reported genetics study were included in the analysis [see Castellanos et al., 1998]. Healthy subjects were recruited from the local community and nationally with no personal or family history of psychiatric or neurological disorders. All subjects were given age-appropriate versions of the WISC, and comprised 82% Caucasian, 10% African USAn, 3% Hispanic, 3% Asian, and 2% mixed or other ethnicities. |
| Sample Collection |
Children and adolescents with ADHD were recruited locally. The majority of sample was Caucasian (75% Caucasian, 12% African USAn, 10% Hispanic, 2% Asian and 1% other) |
| Diagnosis Description |
Children and adolescents meeting criteria for Diagnostic Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) [USAn Psychiatric Association, 1994] ADHD were recruited for this study. Exclusion criteria included a full-scale WISC-III IQ less than 80, significant medical or neurological disorders, or other primary axis I psychiatric disorder. Comorbidity for learning disability, oppositional defiant disorder, and anxiety were permitted. Patients meeting DSM-IV diagnosis of ADHD were administered a Diagnostic Interview for Children and Adolescents (DICA)-Child, Adolescent and Parent versions. Other measures included the Conners Parent and Teacher Rating Scales, Child Behavior Checklist, Teacher Report Form, Full Scale Wechsler Intelligence Scale for Children, Third Edition (WISC-III), a computerized response inhibition task, and an anatomic brain MRI scan [see Castellanos et al., 2002 for details]. |
| Technique |
Genomic DNA was extracted from immortalized lymphoblastoid cells using the QIAamp DNA Extraction Kit (Qiagen, Inc., Valencia, CA) and saliva samples using PUREGENE. |
| Analysis Method |
COCAPHASE was used to compare allele frequencies in cases and controls [Dudbridge, 2003]. TDTPHASE was used for family-based TDT analyses. QTPHASE was used to examine genetic associations with quantitative phenotypes among the ADHD probands.One-tailed asymptotic P-values are reported for alleles that were previously reported to be associated in other studies. |
| Result Description |
ADHD patients had a higher frequency of the 7-repeat allele as compared to controls. Conversely, the controls had a higher frequency of the 4-repeat allele, consistent with previous reports. This association was not confirmed in the TDT analyses,which assesses transmissions from parents to affected offspring. There was evidence for significant association with three subscales of the WISC and the 7-repeat allele within the ADHD group. Specifically, probands with a 7-repeat allele had higher scores on the information, and vocabulary, and a trend for association with the similarities, subscales of the WISC. They categorized the follow-up sample as having good or poor outcome based on a median split of scores at follow-up on the Children's Global Assessment Scale (CGAS). There was a higher frequency of the 7-repeat allele in the good outcome group as compared to the poor outcome group, though this difference did not reach statistical significance, likely due to the small sample size. |
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