Polymorphisms of the dopamine D4 receptor, clinical outcome, and cortical structure in attention-deficit/hyperactivity disorder.
BACKGROUND
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.


METHODS
Longitudinal cohort study.


METHODS
National Institutes of Health, Bethesda, Maryland.


METHODS
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).


METHODS
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.
Child Psychiatry Branch, Room 3N202, Bldg 10, Center Drive, National Institute of Mental Health, Bethesda, MD 20892, USA. shawp@mail.nih.gov
Philip
P
Shaw
Michele
M
Gornick
Jason
J
Lerch
Anjene
A
Addington
Jeffrey
J
Seal
Deanna
D
Greenstein
Wendy
W
Sharp
Alan
A
Evans
Jay N
JN
Giedd
F Xavier
FX
Castellanos
Judith L
JL
Rapoport
D000293:Adolescent; D001284:Atrophy; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics* / Q000473:pathology*; D002540:Cerebral Cortex / Q000254:growth & development / Q000473:pathology*; D002648:Child; D015331:Cohort Studies; D039721:Diagnostic and Statistical Manual of Mental Disorders; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D007839:Functional Laterality; D006801:Humans; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D017063:Outcome Assessment, Health Care; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011569:Psychiatric Status Rating Scales; D050638:Receptors, Dopamine D4 / Q000235:genetics*
D050483:Dopamine Plasma Membrane Transport Proteins; C493214:SLC6A3 protein, human; D050638:Receptors, Dopamine D4