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

Abstract

Several candidate gene polymorphisms have been implicated in attention deficit hyperactivity disorder (ADHD), including DAT1 40bp VNTR, DRD4 7+, and DBH TaqI A2 alleles. We used the Milwaukee longitudinal study of hyperactive (N=122) and normal (N=67) children to compare participants with and without these respective polymorphisms on ADHD-related behavioral ratings at childhood, 8 years later in adolescence, and 13+ years later into young adulthood. Neuropsychological tests were given at the adolescent and young adulthood follow-up. No differences were found between the DRD4-7+ and 7-repeat polymorphism. The DBH TaqI A2 allele, when homozygous, was associated with being more hyperactive in childhood, having more pervasive behavior problems at adolescence, and earning less money on a Card Playing Task in adulthood. At adolescence, poorer test scores were also found only in the hyperactive group with homozygous for this allele. The DAT1 40bp VNTR heterozygous 9/10 repeat, however, differed from the 10/10 repeat pair in many respects, having greater ADHD and externalizing symptoms at all three follow-ups, more cross-situational behavioral problems at both childhood and adolescence, poorer mother-teen relations at adolescence, and lower class rankings in high school. Participants with the 9/10 pair in the control group also had lower work performance, a lower grade point average in high school, greater teacher rated externalizing symptoms at adolescence, and greater omission errors on a continuous performance test in adulthood. The DAT1 40bp VNTR 9/10 polymorphism pairing appears to be reliably associated with greater symptoms of ADHD and externalizing behavior from childhood to adulthood, and with family, educational, and occupational impairments. We also present a contrary view on the appropriate endophenotypes for use in behavioral genetic research on ADHD.Children with Attention Deficit Hyperactivity Disorder (ADHD), or what was previously diagnosed as Hyperactive Child Syndrome, are characterized by developmentally inappropriate levels of inattentive, impulsive, and hyperactive behavior that arise early in childhood and occur across multiple settings (American Psychiatric Association, 1968, 1980, 2001. Follow-up studies of hyperactive children suggest that from 35-80 percent of NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript cases diagnosed in childhood will persist into adolescence Gittelman et al., 1985). By adulthood, 49-66% will have significant symptoms of the disorder or meet diagnostic criteria for it (Barkley et al., 2002;Mannuzza et al., 1993Mannuzza et al., ,1998 Rasmussen & Gillberg, 2002;Weiss and Hechtman, 1993).Biological relatives of children with the disorder are more likely to have ADHD (Biederman et al. 1990, Biederman et al. 1992, Biederman et al. 1995, Maher et al. 1999, Samuel et al. 1999. Numerous twin studies found that genetic factors account for the majority of variance in this trait with an average heritability of .75-.80, with more recent studies u...

Dopamine Transporter (SLC6A3) Genotype Impacts Neurophysiological Correlates of Cognitive Response Control in an Adult Sample of Patients with ADHD

“…Regarding the genetic analyses, no significant association of SLC6A3 genotype with behavioral data was found. This is in line with the results obtained by Barkley et al (2006) who implemented a similar task, but does not replicate findings by Bellgrove et al (2005) and Loo et al (2003) who report an influence of the 3 0 UTR VNTR on behavioral measures in a Go-NoGo task, especially on response variability. In these previous studies, homozygous 10-repeat allele carriers showed poorer performance and showed greater response time variability than children with at least one nine-repeat allele.…”

“…However, Barkley et al (2006) conducted a longitudinal study on children, adolescents, and young adults with ADHD, and report greater ADHD and externalizing symptoms, as well as family, educational, and occupational impairments at all three follow-up examinations in 9/10-as compared with that in 10/10-repeat allele carriers. Also, 9/10-repeat carriers in the control group were prone to higher impairment on educational, occupational, and neurocognitive measures.…”

Molecular genetic contribution to the developmental course of attention-deficit hyperactivity disorder

“…The second study showed association between the DRD4 7-repeat allele and worse adult psychosocial outcome [27]. The third study followed 122 ADHD participants and 67 controls across three time points during childhood, adolescence and young adulthood, did not however demonstrate an association between the DRD4 7 repeat allele and ADHD at any time point (although various associations with the DAT1 480 bp VNTR were reported) [4]. Finally, a case-control study of 67 individuals with ADHD found that possession of the 7-repeat allele was associated with better clinical outcome (retaining a diagnosis of combined type ADHD) [32].…”

Multicenter Analysis of the SLC6A3/DAT1 VNTR Haplotype in Persistent ADHD Suggests Differential Involvement of the Gene in Childhood and Persistent ADHD

“…Some support for this hypothesis is provided by a prospective 13-year follow-up study indicating that more ADHD symptoms and externalizing behaviors were present in the 9/10 than in the 10/10 genotype for the group as a whole, and that the effects of the genotype became more pronounced with increasing age of the participants. Importantly, more individuals with a DSM diagnosis of ADHD in adulthood were found among those having the 9/10 genotype (53%) than among the 10/10 homozygous group (35%) (Barkley et al, 2006b). On the other hand, as dopamine transporter density decreases during life (Spencer et al, 2005) and ADHD symptoms are known to change during adolescence , the differential association of DAT1 with ADHD might reflect changing requirements on the dopaminergic system during life.…”