Am. J. Hum. Genet. 56:993-998, 1995
Association of Attention-Deficit Disorder and the Dopamine Transporter Gene
Edwin H. Cook, Jr.," 23 Mark A. Stein," 3 Matthew D. Krasowski," 2 Nancy J. Cox,4 Deborah M. Olkon,' John E. Kieffer,' and Bennett L. Leventhal" 23
3Department of Pediatrics, and 4Department of Medicine, University of Chicago, Chicago
Child and Adolescent Psychiatry, Department of Psychiatry, 'Laboratory of Developmental Neuroscience, Harris Center for Developmental Studies,
Attention-deficit hyperactivity disorder (ADHD) has been shown to be familial and heritable, in previous studies. As with most psychiatric disorders, examination of pedigrees has not ...view middle of the document...
Attention-deficit disorder is a prevalent disorder, of childhood onset, characterized by attentional dysfunction. It most commonly occurs with impulsivity and hyReceived October 31, 1994; accepted for publication January 4,
Address for correspondence and reprints: Dr. Edwin H. Cook, Jr., MC 3077, 5841 South Maryland Avenue, Chicago, IL 60637. © 1995 by The American Society of Human Genetics. All rights reserved.
peractivity, in the form of attention-deficit hyperactivity disorder (ADHD) (American Psychiatric Association 1994). ADHD often persists into adulthood and is a risk factor for development of antisocial and drug-abuse disorders (Mannuzza et al. 1993). Family/genetic studies of ADHD have revealed an increased prevalence of ADHD in relatives of probands with ADHD, compared with relatives of normal or psychiatric controls (Cantwell 1972; Biederman et al. 1990, 1992). There is an increase in attentional dysfunction in genetic parents of probands with hyperactivity, compared with adoptive parents of probands with hyperactivity (Alberts-Corush et al. 1986). In addition, twin studies are consistent with moderate-to-high heritability of attentional dysfunction (Stevenson 1992). Previously, ADHD was found to be more common in subjects with generalized resistance to thyroid hormone (GRTH), compared with controls (Hauser et al. 1993). However, the prevalence of GRTH in ADHD has been found to be extremely rare (Weiss et al. 1993), and subsequent studies have not supported genetic linkage of ADHD and GRTH (Weiss et al. 1994). The most commonly used and well-studied treatment approach for ADHD is pharmacotherapy, which is effective in most children with ADHD (reviewed in Greenhill 1992). Pharmacological agents that inhibit the dopamine transporter (including methylphenidate, dextroamphetamine, pemoline, and bupropion) have been shown in numerous, double-blind trials to be effective in the treatment of attentional dysfunction, hyperactivity, and impulsivity of ADHD (Casat et al. 1987; Zametkin and Rapoport 1987; Greenhill 1992; Hechtman 1994; Rapport et al. 1994). This led us to consider the dopamine transporter locus (DAT1) as a primary candidate gene in ADHD. Although diagnosis of ADHD in probands is reliable after decades of refinement, relatives of probands with ADHD are at increased risk for several disorders other than ADHD (Biederman et al. 1990). For example, in the genetic analysis of ADHD, one is left with the question of whether to consider relatives to be affected or unaffected if they have conduct disorder, mood disorder,
Am. J. Hum. Genet. 56:993 -998, 1995
or alcoholism but do not have a clinical diagnosis of ADHD. Nonparametric methods of genetic analysis have the advantage of not requiring pedigrees with several affected members. Association studies in which affected individuals are compared with controls suffer from the potential pitfall of sampling...