An emerging literature has demonstrated an association between the dopamine D4 receptor (DRD4) gene and volumetric brain abnormalities in children with ADHD. However, these results have not been extended to adults and have not addressed the impact of comorbidity. Our objective was to examine the DRD4 7R gene and volumetric brain abnormalities in adults with ADHD while accounting for comorbidity with bipolar disorder (BPD). Subjects were male and female adult outpatient referrals stratified into two diagnostic groups: 24 with ADHD, 19 with ADHD and BPD, as well as 20 male and female adult community controls without ADHD or BPD. We measured volumes (cm(3)) of a priori selected brain regions (superior frontal, middle frontal, anterior cingulate, and cerebellum cortices) by structural magnetic resonance imaging. Among adults with ADHD, subjects with the 7-repeat allele of the DRD4 gene had a significantly smaller mean volume in the superior frontal cortex and cerebellum cortex compared to subjects without this allele. In contrast, no such effects were detected in the adults with ADHD + BPD or controls. Our findings suggest that volumetric abnormalities in the dorsolateral prefrontal cortex and cerebellum may represent an intermediate neuroanatomical phenotype between DRD4 genotype and the clinical expression of ADHD in adults, but only in ADHD subjects without comorbid BPD. These result support the heterogeneity of ADHD and provides insights as to its underlying pathophysiology.
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