| Summary |
Previous studies by several groups have observed a significant association of ADHD and an allele with 7 copies of the 48 base pair repeat in the third exon of the dopamine D4 receptor. The authors sought to replicate these previous findings by collecting an independent sample of families from Toronto, Ontario, Canada, and confirming this finding in an expanded sample of ADHD families collected from Irvine, California. Using the transmission disequilibrium test (TDT), the authors tested for biased transmission of the 7-repeat allele at the exon III polymorphism of the dopamine D4 receptor locus in these samples of ADHD subjects. Biased transmission of the 7-repeat allele from parents to ADHD probands and their affected siblings was observed in the 2 new samples of families collected in Toronto and Irvine (TDT one-sided P=0.050) and for these samples combined with the 52 families previously reported from Irvine (TDT one-sided P=0.006). The results of this study further support the possibility of a role of the dopamine D4 receptor locus in ADHD. |
| Total Sample |
88 children with ADHD and their parents were collected at The Hospital for Sick Children, Toronto, Ontario, Canada. Seventy-five of these families consisted of the proband and both parents, and the remainder were parent-child pairs. There were 20 affected siblings in this sample. An additional sample of 59 children and parents were collected at the Child Development Center, Irvine, California, who were not included in the previous analysis. These 59 additional families were composed of 21 families with both parents available and 38 parent-child pairs. The results from the samples were analyzed separately and then analyzed as a combined sample including the 52 families previously reported (Swanson et al., 1998) for a total sample of 199 families, 148 of which had both parental DNA samples available and 21 affected siblings. |
| Replication Size |
59 families |
| Sample Collection |
An independent sample of families from Toronto, Ontario, Canada was collected for analysis, and an expanded sample of ADHD families was collected from Irvine, California to confirme this finding. |
| Diagnosis Description |
Families from the Toronto area were recruited as part of an ongoing project to collect affected sibling pairs with ADHD. Probands and their siblings were included if they were between 7 and 16 years old and met DSM-IV criteria for 1 of the 3 ADHD subtypes (inattentive, hyperactive-impulsive, combined). Children were excluded if they scored below 80 on both the Performance and Verbal scales of the WISC-III; had evidence of neurological or chronic medical illness, Tourette's syndrome, chronic multiple tics, bipolar affective disorder, or psychotic symptoms; or had a comorbid anxiety, depressive, or developmental disorder that could better account for the behaviors (as specified by DSM-IV and emphasized in ICD-10 (Swanson et al., 1998). Children were free of medication when assessed. This protocol was approved by the Hospital Research Ethics Board. After explanation of the study, written informed consent was obtained for all participants older than the age of 16 and written assent was obtained from all participants between the ages of 7 and 15. The written consent of the parents was obtained for all subjects younger than 16. Probands identified at the University of California Irvine Child Development Center have been previously described (LaHoste et al., 1996; Swanson et al., 1998b). Briefly, subjects recruited for clinical trials were included in this study. Those subjects had a clinical diagnosis of ADHD by DSM-IV criteria confirmed by a structured interview (Shaffer et al., 1996), current treatment with clinical doses of methylphenidate, and absence of serious comorbid disorder. One sibling who was also participating in the clinical trial and who met the same criteria for ADHD was included in this study. This protocol was approved by the University of California Institutional Review Board, and written informed consent and assent were obtained for all participants prior to involvement in any study procedure. |
| Technique |
DNA was isolated from blood using the high salt extraction method of Miller et al. (1988). The 48 bp repeat polymorphism in exon III was genotyped as previously described (Lichter et al., 1993). |
| Analysis Method |
After the assignment of genotypes for each individual, statistical analysis was performed using the ETDT program (Sham and Curtis, 1995). One-sided X2 probabilities were calculated with the Chiprob program of Jurg Ott, in the LINKAGE Utilities Package (Ott, 1991). |
| Result Description |
For the TDT analyses each sample was analyzed separately and combined. One-sided test for the transmission of the 7-repeat allele reported siginficant P value in the Toronto sample. Using the TDT statistic, the transmission of the 7-repeat allele was significant in the previously reported sample from Irvine (TDT one-sided P=0.013) as expected from the haplotype relative risk analysis. The additional sample of 59 families collected from Irvine provided only 14 informative transmissions of the 7-repeat allele. For these 14 transmissions the 7-repeat allele was transmitted to the probands 7 times (TDT one-sided P=1.000). The addition of the new Irvine sample to the previously reported Irvine sample reduced the TDT X2 to 3.630; however, the result for the entire sample was still significant (one-sided P=0.028). Looking just at the new samples collected from Toronto and Irvine (including the additional sibling), the TDT was significant using the one-sided test (TDT one-sided P=0.050). When combined the results from both the Toronto and Irvine sites the results were also significant (TDT one-sided P=0.006). |
Hot Results
Basic Info
Detail Info