| Summary |
A polymorphism in the dopamine receptor 4 gene (DRD4) has been related to novelty seeking, Tourette's syndrome, and attention deficit hyperactivity disorder (ADHD). The variability is in a 48-bp repeat in exon 3 of the gene (a transmembrane region). This study examined the relation of the 7-repeat (ie, high-risk) allele to questionnaire-based diagnoses of ADHD (both combined type and inattentive type). Several positive findings were obtained for ADHD-inattentive type. In an association test, the 7-repeat allele occurred more frequently in children with ADHD-inattentive type than in control children. In genetically discordant sibling pairs, the sibling with a greater number of 7-repeat alleles displayed more inattentive symptoms than his/her co-sibling with fewer 7-repeat alleles. For ADHD-combined type, the 7-repeat allele frequency was greater than that in the control sample. However, a quantitative transmission disequilibrium test yielded no significant linkage of the 7-repeat allele with hyperactive-impulsive symptoms. A categorical TDT yielded no significant findings, but the number of transmissions was small, especially for ADHD-inattentive type. |
| Total Sample |
Genotypes were available for 168 children from 123 families visiting CLADD in Atlanta or a psychiatric office in Tucson and 71 children from 53 general population families. Genotyping of DRD4 was also completed on 155 mothers and 122 fathers. The sample of 71 non-referred children and siblings is hereafter identified as the control sample; the sample of 168 referred children and their siblings from psychiatric settings is hereafter identified as the clinic sample. For all 239 children (191 males, 48 females), the average age was 10 years (s.d.=2.8 years). In the clinic sample, 37 children were diagnosed with the ADHD-inattentive subtype (ADHD-IA), 11 children were diagnosed with the ADHD-hyperactive/impulsive subtype (ADHD-HI), 70 children were diagnosed with the ADHD-combined subtype (ADHD-C). The diagnosed control children were dropped from analyses that compared diagnosed clinic sample children with non-diagnosed controls. Ethnic ancestry was determined from the ancestry of the children's biological father and maternal grand-parents, as reported by the children's mother. The proportions of children with 100% ancestry were: African-USAn, 8.5%, Hispanic, 4.3%, and Caucasian, 71.8%. |
| Sample Collection |
Data were collected at two research sites: Tucson, Arizona and Atlanta, Georgia. At the Tucson site, children in the control sample were ascertained through a list of families in the general population with at least one male child 8-12 years old generated by Multi-Media, a market research firm. Any second male sibling 6-16 years old was also sampled. Clinic-referred boys in Tucson were identified through psychiatrists in private practice. Whenever possible, a brother was also sampled. At the Atlanta site, only clinic-referred children (both males and females) were sampled through the Center for Learning and Attention Deficit Disorders (CLADD) at Emory University's School of Medicine. At this site, siblings were also sampled whenever possible. |
| Diagnosis Description |
At the Tucson site, an interviewer visited each family in their homes. After obtaining informed consent, the mother was interviewed about household composition. The mother and father next received questionnaires for completion. At the Emory site, a few families were seen at CLADD, whereas the majority of families were seen in their homes. The data collection session followed much the same sequence as in Tucson. The mother provided demographic data on a short questionnaire, and both parents rated their children for behavioral problems on the Emory Diagnostic Rating Scale (viz, EDRS). This questionnaire was developed to assess symptoms of the major DSM-IV childhood disorders. Continuous symptom dimensions were constructed for DSM-IV ADHD hyperactive/impulsive and inattentive symptoms. Questionnaire-based diagnoses were derived from symptom thresholds in the DSM-IV. If a child surpassed a diagnostic threshold on the basis of either the mother's or father's ratings, a questionnaire-based diagnosis was made. |
| Technique |
Except for difficult cases genotyped with a new primer set, the DRD4 repeat polymorphism was genotyped using standard methods. Genotyping was completed at the University of Arizona's Laboratory of Molecular and Systematic Evolution, a multi-user lab facility. |
| Analysis Method |
The first strategy used in this study was to compare the frequency of the 7-repeat allele in ADHD children and controls. The second strategy was to examine within-family association and linkage. One within-family association test compared siblings discordant for the number of 7-repeat alleles. They also possessed data on parental genotypes. Thus, the second within-family analysis examined the transmission of the 7-repeat allele from heterozygous parents to their children using both categorical and quantitative transmission disequilibrium tests (TDT). Compared to the case control method, the TDT is less susceptible to biases resulting from population heterogeneity. |
| Result Description |
Between individual analyses: Too few individuals had a diagnosis of ADHD-HI type for analysis. In both the combined (n=70) and inattentive (n=37) ADHD types, the 4-repeat and 7-repeat alleles were the most common alleles. Both ADHD types had greater 7-repeat frequencies than the controls (23% and 27% vs 12.9%, respectively). In the ADHD-combined and inattentive types, the frequency of 7-repeat containing genotypes was about double (43% for both) that in the 58 controls without questionnaire-based diagnoses. The inattentive subtype also had an excess of 7/7 homozygotes (11% vs 4% in controls). The significant chi-square tests establish an association between the 7-repeat allele and the two ADHD diagnoses. The associations using the continuous symptom variables instead of the categorical diagnoses were also examined. A positive association of the 7-repeat allele and both symptom types was found in the total sample. In the sample with any ADHD diagnosis, the associations with the 7-repeat allele were stronger for inattentive than for hyperactive-impulsive symptoms. In the control sample, no associations were observed. Within-family analyses of disequilibrium: They firstly compared ADHD symptom levels in sibling pairs discordant for their DRD4 genotype. For inattentive symptoms, the mean difference was positive and statistically significant (P<0.05). For hyperactive-impulsive symptoms, the mean difference was positive but failed to reach significance. In nine of the 12 sibling pairs, the child possessing the greater number of 7-repeat alleles had the greater symptom count for inattentive symptoms. Secondly, the transmission disequilibrium test also used parental genotypes. For the categorical TDT, the number of informative families were 23 for ADHD-combined type and nine for ADHD-inattentive type. The transmission rates were: ADHD-combined type, X2=0.03; and ADHD-inattentive subtype, X2=0.7. Although for both questionnaire-based diagnoses there was an absence of linkage disequilibrium, statistical power was also low. It was especially low for inattentive symptoms, with only 13 total transmissions. In the total sample, 70 families qualified for the QTDT. This comprised 50 families in the clinic sample and 20 families in the control sample. The QTDT correlation of transmitted 7-repeat alleles with hyperactive/impulsive symptoms was near zero in the total sample and greater than zero, but not statistically significant, in the clinic sample. There was a positive correlation of 7-repeat allele transmissions with inattentive symptoms in both the total sample and clinic sample. Thus, the TDTs failed to provide unequivocal support for linkage disequilibrium between the 7-repeat allele and ADHD, but the QTDT provided evidence suggestive of linkage disequilibrium between DRD4 and inattentive symptoms of ADHD. |
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