| Summary |
The relationship of the DRD2 TaqI-A1 allele to hyperactive/impulsive and inattentive symptoms of attention deficit hyperactivity disorder (ADHD) in children and adolescents was examined in a sample of clinic-referred children and their siblings, and control children and their siblings (n=236). The contribution of genetic dominance and additivity to mean differences among the A2A2, A1A2, and A1A1 genotypes was estimated using structural equation modeling. The effect of genetic additivity was statistically significant for both traits in an analysis of all children. The heritability from the DRD2 locus was estimated at 4.27% for hyperactive-impulsive symptoms and 2.12% for inattentive symptoms. Children with the A2A2 genotype had the highest mean level of symptoms. To control for any possible effects of population stratification, this analysis was repeated with parental genotypes as controls. In this smaller sample, although the direction of the effect was the same as that in the whole sample, the genotypic differences failed to reach conventional significance levels and the effect sizes were smaller (h2=1.62% and 0.79%, respectively). Furthermore, a genotype relative risk test of children who had questionnaire-based diagnoses of ADHD also failed to yield evidence of either association or linkage. Given that the A1 allele was expected to be the high risk allele, and that results were non-significant in tests that controlled for population heterogeneity, they doubt that this DRD2 polymorphism influences symptoms of ADHD in childhood. |
| Total Sample |
DRD2 genotypes were determined for 164 children from 125 families visiting the Center for Learning and Attention Deficit Disorders in Atlanta or a psychiatric office in Tucson and 72 children from 53 general population families. Genotyping of DRD2 was also completed on 161 mothers and 121 fathers. The sample of 72 non-referred children and siblings is hereafter identified as the control sample; the sample of 164 referred children and their siblings from psychiatric settings is hereafter identified as the clinic sample. For all 236 children (192 males, 44 females), the average age was 10 years (SD = 2.8 years). Their genotypic frequencies were A1A1 0.017 (n = 4), A1A2 0.326 (n = 77), and A2A2 0.657 (n = 155). The frequency of the A1 allele was 0.18. |
| 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¨C12 years old generated by Multi-Media. Any male sibling 6-16 years old was also sampled. Clinic-referred boys in Tucson were identified through psychiatrists in private practice. 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 also were sampled whenever possible. |
| Diagnosis Description |
At the Tucson site, an interviewer visited each family in their homes. The mother was interviewed about household composition. The mother and father next completed questionnaires on demographic characteristics and behavior problems in their children. At the Emory site, a few families were seen at CLADD, although the majority of families were seen in their homes. The data collection sessions 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 (EDRS). This questionnaire was developed to assess symptoms of the major DSM-IV childhood disorders. In this study, scores on the hyperactive-impulsive and inattentive symptom dimensions of ADHD were analyzed. The EDRS also yields questionnaire-based diagnoses of the ADHD subtype disorders in addition to the continuous symptom-scales. A diagnosis was assigned if a child surpassed the standard diagnostic thresholds (ie, >=6 of 9 symptoms) on the inattention and/or hyperactivity symptom dimensions. Children were given an ADHD diagnosis if they surpassed the diagnostic threshold on inattention symptoms, hyperactive-impulsive symptoms, or on both types of symptoms. |
| Technique |
Buccal cell samples from family members were returned to University of Arizona's Laboratory of Molecular and Systematic Evolution, a multi-user lab facility. DNA was extracted using a low/high salt procedure. Genotyping of the DRD2 TaqI polymorphism was completed followed a standard protocol. For genotyping, DNA stained with ETBr was visualized on agarose gels. |
| Analysis Method |
The X2 difference tests which examined whether the genotype effects were significant. For the situation with parental mating types as controls, the quantitative test used was the genotype relative risk method (GRR). This method tests two relative risks for a trait: (1) the relative risk for homozygotes with two copies of a candidate gene vs the homozygote without the candidate gene; and (2) the relative risk of heterozygotes with one copy of the candidate gene vs the homozygote without the candidate gene. |
| Result Description |
The means of the ADHD symptom counts for the 236 children tended to decrease with an increase in the number of A1 alleles. This indicated that the high risk A1 allele was associated with lower instead of higher symptom counts. This trend was also present for different genotypes within the same mating type group. The parameter estimates and heritability due to the DRD2 polymorphism in the sample of clinic-referred and control children indicated that the A1 allele was associated with lower symptom counts. In all situations the dominance score was very small. The heritabilities were larger for Hyperactive-Impulsive than for Inattentive symptoms. For the tests that used parental mating types as controls, heritabilities were consistently smaller. Most X2 tests were not significant. An exception was the test for Hyperactive-Impulsive symptoms in the situation without parents as controls, where the test for the additive genetic parameter as well as the over-all test were significant. By the way, the test was performed for total genetic effects with two degrees of freedom. With one degree of freedom the result for additive genetic effects on Inattentive symptoms in the situation without parental mating types as controls was also significant. The GRR method was applied only to children in the clinic sample with a diagnosis of ADHD, with at least one parent who was a DRD2 heterozygote, and with genotypes available for both parents (n = 26). Results showed that the test that constrained both relative risks as well as the TDT that involved one relative risk were not significant. None of the results with the test that included parental mating types as controls were significant. |
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