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Philip Shaw, MD, PhD; Michele Gornick, BS; Jason Lerch, PhD; Anjene Addington, PhD; Jeffrey Seal, BS; Deanna Greenstein, PhD; Wendy Sharp, MSW; Alan Evans, PhD; Jay N. Giedd, MD; F. Xavier Castellanos, MD; Judith L. Rapoport, MD

Arch Gen Psychiatry. 2007;64(8):921-931.

Context  Attention-deficit/hyperactivity disorder (ADHD) is one of the most heritable neuropsychiatric disorders, and a polymorphism within the dopamine D₄ receptor (DRD4) gene has been frequently implicated in its pathogenesis.

Objective  To examine the effects of the 7-repeat microsatellite in the DRD4 gene on clinical outcome and cortical development in ADHD. We drew comparisons with a single nucleotide polymorphism in the dopamine D₁ receptor (DRD1) gene, which was associated with ADHD within our cohort, and a polymorphism within the dopamine transporter (DAT1) gene, reported to have additive effects with the DRD4 7-repeat allele.

Design  Longitudinal cohort study.

Setting  National Institutes of Health, Bethesda, Maryland.

Participants  One hundred five children (with 222 neuroanatomical magnetic resonance images) with ADHD (mean age at entry, 10.1 years) and 103 healthy controls (total of 220 magnetic resonance images). Sixty-seven subjects with ADHD (64%) had follow-up clinical evaluations (mean follow-up, 6 years).

Main Outcome Measures  Cortical thickness across the cerebrum and presence of DSM-IV–defined ADHD at follow-up.

Results  Possession of the DRD4 7-repeat allele was associated with a thinner right orbitofrontal/inferior prefrontal and posterior parietal cortex. This overlapped with regions that were generally thinner in subjects with ADHD compared with controls. Participants with ADHD carrying the DRD4 7-repeat allele had a better clinical outcome and a distinct trajectory of cortical development. This group showed normalization of the right parietal cortical region, a pattern that we have previously linked with better clinical outcome. By contrast, there were no significant effects of the DRD1 or DAT1 polymorphisms on clinical outcome or cortical development.

Conclusions  The DRD4 7-repeat allele, which is widely associated with a diagnosis of ADHD, and in our cohort with better clinical outcome, is associated with cortical thinning in regions important in attentional control. This regional thinning is most apparent in childhood and largely resolves during adolescence.

Author Affiliations: Child Psychiatry Branch, National Institute of Mental Health, Bethesda, Maryland (Drs Shaw, Gornick, Lerch, Addington, Seal, Greenstein, Sharp, Giedd, and Rapoport); Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada (Dr Evans); and New York University Child Study Center, New York (Dr Castellanos).