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Posted August, 2006

Longitudinal Findings on Correlates of Three ADHD Candidate Gene Polymorphisms from Childhood to Adulthood

Using data obtained in a longitudinal study of ADHD, Russell Barkley and colleagues (2006) have tested behavioral and neuropsychological correlates of genes that have been hypothesized to be associated with ADHD. The longitudinal study began in 1978 when 158 4- to 12-year-olds identified as hyperactive and a matched community control group of 81 children were evaluated on a variety of measures. The participants were reassessed again when they were 12 to 20 years old, and again when they were 19 to 25 years old, an average of 13.8 years after their initial assessment. Blood samples were used to identify genes that have been hypothesized to be associated with ADHD. Far more numerous associations were found with one particular difference in genotypes than with the others that were tested. This was the difference between the DAT1 40 bp VNTR gene with the 9/10 allele pairing (heterozygous for the 10 repeat) versus the homozygous (10/10 repeat) pairing. Members of both the ADHD and control groups who had the 9/10 genotype obtained more adverse scores on several measures in childhood, adolescence, and young adulthood. The most consistently significant differences were found on the Externalizing scales of the CBCL completed at the childhood and adolescent assessments and of the Young Adult Behavior Checklist (YABCL, predecessor to the current ABCL) completed at the young adult assessment. Even though parents had no knowledge of the genotypes of their offspring, the effect sizes for the differences between Externalizing scores for the two genotypes more than tripled from childhood to adolescence and young adulthood. Although not so consistent across the three assessments, ratings for particular kinds of problems on other instruments and school class rankings were also significantly more adverse for participants with the 9/10 than the 10/10 genotype. On the other hand, neuropsychological tests did not show consistent differences between any of the genotypes that were tested. Barkley et al. cited findings that the "9/10 genotype is associated with greater dopamine transporter binding and better methylphenidate response in children with ADHD" (p. 494). They went on to note that, "Since most children with ADHD are positive responders to this drug, it is the 9/10 genotype that may have a greater association with clinical cases of ADHD and its severity" (p. 494). The authors also raised another important issue concerning "endophenotypes," which are conceptualized as being quantitative indices of disease liability or risk. Hypothesized endophenotypes for ADHD have previously been limited to variables assessable with neuropsychological tests or neuroimaging. Based on their findings that behavioral ratings but not neuropsychological findings were associated with genotypic differences, Barkley et al. argued that behavioral ratings should be included in the concept of an "extended phenotype" that may be more useful than concepts of endophenotypes that are inferred from neuropsychological tests and neuroimaging.

Reference: Barkley, R.A., Smith, K.M., Fischer, M., & Navia, B. (2006). An Examination of the Behavioral and Neuropsychological Correlates of Three ADHD Candidate Gene Polymorphisms (DRD4 7+, DBH TaqI A2, and DAT1 40 bp VNTR) in Hyperactive and Normal Children Followed to Adulthood. American Journal of Medical Genetics Part B (Neuropsychiatric Genetics), 141B, 487-498.