| Summary |
They recruited an additional sample and, overall, in the combined sample of 178 triads they observe using the transmission disequilibrium test, preferential transmission of the short allele of DRD4. Additionally, they now report the effect of the DRD4 repeat region on the Test Of Variables of Attention (TOVA), a widely used computerized continuous performance test. Probands with the short exon III repeat performed significantly worse on the TOVA measured both by errors of commission and response time variable. Intriguingly, a 'dose effect' was observed. Increasing repeat size is accompanied by a reduced number of errors of commission and a significant difference is observed between the 2 vs 7 repeats. On the whole, the results lend credence to the notion that the relationship between the DRD4 receptor and ADHD is complex and may be reflecting linkage disequilibrium between the 7 or long DRD4 exon III repeats and a 'true' risk allele in this gene or a neighboring locus. |
| Total Sample |
76 families were independently recruited from Petak Tikvah. Combined sample of 178 recruited ADHD families (from Jerusalem and Petak Tikvah) was also used for family-based analysis. The distribution of the DRD4 exon III polymorphism was also analyzed by case control design comparing 180 ADHD probands to a large group of control subjects which have genotyped for studies of normal personality. The percentage of probands with ADHD combined type was 68.2%, inattentive 30.6% and 1.2% impulsive. Twenty-seven percent of the probands had comorbid ODD/CD. The Jerusalem cohort has been previously described. |
| Sample Collection |
ADHD cases and parents were recruited from the greater Tel-Aviv (Petak Tikvah) and Jerusalem municipal areas. Subjects were all clinical referrals from hospital neurologists, school psychologists and parents. Families included all diagnosed ADHD children who had two biological parents. The Ethics Committee of the Israeli Health Ministry approved this study and written informed consent was obtained from participating subjects. |
| Diagnosis Description |
ADHD criteria followed DSM-IV guidelines that recognize three types of ADHD: ADHD-Predominantly Inattentive (Type I), ADHD-Predominantly Hyperactive Impulsive (Type II), and ADHD-Combined Type (III). Informants were the parents, the teacher, and the proband. The parents and the proband underwent a thorough, albeit not standardized, clinical interview, which included as a separate item all DSM-IV criteria for ADHD and Conduct Disorder. Two scales, the abbreviated Conners Rating Scales and the Child Behavior Checklist, were also employed. Consensus diagnoses were made according to DSM-IV ADHD or either with or without comorbidity. These DSM-IV diagnoses were based on all available clinical information and the Child Behaviour Checklist and the Conners Parents and Teachers Rating Scales. When the Conners Teachers Scale was not available, teachers were contacted by telephone and interviewed. The ADHD subjects were also administered the Test Of Variables of Attention (TOVA). In the Ritalin phase subjects received 0.3 mg kg-1 of the medication. Cases were excluded with a primary diagnosis of Pervasive Developmental Disorder, physical handicap, psychosis, mental retardation, epilepsy, hyperthyroidism, evidence or history of child abuse, or adoption. Children with an IQ less than 80 were excluded. IQ was assessed using the Wechsler Intelligence Scale for Children-Revised. |
| Technique |
DNA was extracted from frozen blood samples using the phenolchloroform procedure or from fresh blood using a MasterPure kit (Epicentre Technologies, Madison, WI, USA). For some individuals, from whom a blood sample could not be obtained, DNA was obtained from buccal smears, again using the MasterPure kit. The DRD4 exon III repeat region was characterized as previously described. |
| Analysis Method |
The transmission disequilibrium test was used to analyze transmission from heterozygote parents to ADHD probands. The Kruskal¨CWallis one-way ANOVA is the distribution-free (or nonparametric) analogue of the parametric ANOVA and was used to group TOVA scores by genotype. The distributions of allele frequencies of the DRD4 repeat polymorphism in the ADHD probands were 2 repeat=5.6%; 3=0.8%; 4=76.9%; 5=1.1%; 7=15.3%; 8=0.3%). Using the long vs short scheme or the 7 repeat vs non-7 repeat therefore makes little difference in this cohort, since almost all the 'long' repeats are 7 (there was one proband with an 8 allele). |
| Result Description |
Preferential transmission of the short repeat alleles from heterozygous parents to the ADHD proband in the Petak Tikvah cohort was observed in the independently recruited sample of 76 families. In the combined Petak Tikvah sample preferential transmission of the short DRD4 repeat was also observed. Combining all 178 recruited ADHD families (from both Jerusalem and Petak Tikvah), preferential transmission of the short alleles is observed from heterozygote parents to the ADHD proband. Similar to the results obtained by family-based design, there is a small but significant excess of the short DRD4 repeat in the ADHD probands compared to the control subjects in the case-control design comparing 180 ADHD probands to a large group of control subjects. A significant effect of the long DRD4 repeat was observed on errors of commission (measure of impulsivity) and the response time variable. Children with the long DRD4 repeat did significantly better on these two TOVA paradigms than children with the short allele. There was also a trend for improved performance on errors of omission in those children carrying the long repeat. There is a 'dose effect' of DRD4 repeat allele length and TOVA performance. Increasing repeat size is accompanied by reduced number of errors of commission and a significant difference was observed between the 2 vs 7 repeats. In the presence of Ritalin, however, there was no effect of the DRD4 gene on any of the TOVA variables. |
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