| Summary |
They have initiated genetic studies in a unique cohort of 158 ADHD and 81 control adult subjects who have been followed longitudinally since childhood in the MilwaUnited Kingdomee study of ADHD. From this cohort, genetic analysis was performed in 105 Caucasian subjects with ADHD and 68 age and ethnicity-matched controls for the DRD4 exon 3 VNTR, the SLC6A3 (DAT1) 3' UTR VNTR, dopamine beta hydroxylase (DBH) TaqI A polymorphism, and the DBH GT microsatellite repeat polymorphism that has been quantitatively associated with serum levels of DBH activity, but not previously studied in ADHD. Results indicate a significant association between the DBH TaqI A1 allele and ADHD (P=0.018) with a relative risk of 1.33. The DBH GT repeat 4 allele, which is associated with high serum levels of DBH, occurred more frequently in the ADHD group than controls, but the difference did not reach statistical significance. Associations were not found with the SLC6A3 10 repeat or DRD4 7 repeat alleles. |
| Total Sample |
Of the 158 original study participants with ADHD and 81 age, sex, and ethnicity matched control subjects; genotyping was performed on 105 Caucasian ADHD subjects and 68 Caucasian control subjects. |
| Sample Collection |
A detailed description of this case control cohort can be found in articles by Barkley et al. [1990, 2002]. The hyperactive group was recruited from consecutive referrals to a child psychology service specializing in the treatment of hyperactive children at MilwaUnited Kingdomee Children's Hospital. The community control children were recruited using a 'snowball' technique. |
| Diagnosis Description |
Diagnostic criteria for hyperactivity were based on the following: (1) scores on two commonly used rating scales assessing hyperactiveimpulsive behavior that exceeded two standard deviations above the mean for severity for same age, same sex normal children; (2) cross-situational symptoms as assessed by the Home situations questionnaire [Barkley and Murphy, 1998] with significant behavioral problems in at least six or more of the 14 problem situations on this scale (a score exceeding the 93rd percentile); (3) parent and/or teacher complaints (as reported by parent) of poor sustained attention, poor impulse control, and excessive activity level; (4) the onset of behavior problems prior to 6 years of age; (5) behavior problems present for at least 12 months; and (6) no indication of autism, psychosis, thought disorder, epilepsy, gross brain damage, or mental retardation. In view of these selection criteria and the close convergence of rating scale diagnoses with the clinical diagnosis of ADHD [Edelbrock and Costello, 1988], these subjects would likely have met DSM-IV criteria for ADHD combined or hyperactive types [USAn Psychiatric Association, 1994]. At present, the subjects from both groups are 25¨C32 years of age and are undergoing re-evaluation in a follow-up phase of this project. |
| Technique |
Genomic DNA was extracted from peripheral blood lymphocytes of study subjects using the Puregene DNA isolation kit (Gentra Systems, Minneapolis, MN). The DRD4 48 bp VNTR allele status was determined according to the procedure described by Lichter et al. [1993], with some minor modifications. The 40 bp VNTR in the 3' untranslated region of the SLC6A3 allele was genotyped according to the protocol described by Cook et al. [1995]. The GT microsatellite repeat in the 5' promoter region of the DBH gene was amplified according to the protocol described by Wei et al. [1997]. The TaqI A allele, in intron 5 of the DBH gene, was genotyped according to the procedure reported by Daly et al. [1999]. |
| Analysis Method |
Differences in allele frequencies between the ADHD and control subjects were calculated with a chi-squared test. To detect possible associations between the presence of a particular DBH allele and the presence of ADHD, they carried out a logistic-regression analysis where presence or absence of each allele was the potential predictive (independent) variable and ADHD status (ADHD versus control) was the outcome (dependent variable). |
| Result Description |
Results indicate a significant association between the DBH TaqI A1 allele and ADHD (P=0.018) with a relative risk of 1.33. The DBH GT repeat 4 allele, which is associated with high serum levels of DBH, occurred more frequently in the ADHD group than controls, but the difference did not reach statistical significance. Associations were not found with the SLC6A3 10 repeat or DRD4 7 repeat alleles. These results indicate that the DBH TaqI A allele, or another polymorphism in linkage disequilibrium with this allele, may confer increased susceptibility towards ADHD. |
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