Examining for association between candidate gene polymorphisms in the dopamine pathway and attention-deficit hyperactivity disorder: a family-based study.
Attention-deficit hyperactivity disorder (ADHD) is a highly heritable childhood-onset psychiatric condition characterized by developmentally inappropriate inattention, hyperactivity, and impulsiveness. The pathophysiology of ADHD is currently unknown. However, the therapeutic effects of stimulant medication together with findings from animal and neuroimaging studies as well as from several molecular genetic studies of the dopamine receptor D4 gene and dopamine transporter gene have implicated involvement of the dopaminergic system. To test the dopaminergic hypothesis further, we have looked for association between ADHD and alleles of seven dopamine-related candidate genes using a family-based association approach in a sample of 150 children diagnosed with ADHD. We tested polymorphisms in genes encoding three dopamine receptors (DRD3, DRD4, and DRD5) and four dopamine-relevant enzymes: tyrosine hydroxylase [tyrosine hydroxylase (TH)], dopamine beta hydroxylase (DbetaH), catechol-O-methyltransferase (COMT), and monoamine oxidase A (MAOA). We were unable to detect a significant association with any of the polymorphisms genotyped, although there was a trend for preferential transmission of the DRD5 148 bp marker allele and the MAOA 122 bp marker allele. We conclude that none of the alleles we have tested makes a major contribution to ADHD, although much larger samples are required to exclude small effects.
Payton
A
A
ARC Epidemiology Unit, University of Manchester, Manchester, UK.
Holmes
J
J
Barrett
J H
JH
Hever
T
T
Fitzpatrick
H
H
Trumper
A L
AL
Harrington
R
R
McGuffin
P
P
O'Donovan
M
M
Owen
M
M
Ollier
W
W
Worthington
J
J
Thapar
A
A
D000293:Adolescent; D000483:Alleles; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002394:Catechol O-Methyltransferase / Q000235:genetics; D002648:Child; D004247:DNA / Q000235:genetics; D004298:Dopamine / Q000378:metabolism*; D004299:Dopamine beta-Hydroxylase / Q000235:genetics; D005192:Family Health; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008995:Monoamine Oxidase / Q000235:genetics; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D017447:Receptors, Dopamine D1 / Q000235:genetics; D017448:Receptors, Dopamine D2 / Q000235:genetics; D050637:Receptors, Dopamine D3; D050638:Receptors, Dopamine D4; D050641:Receptors, Dopamine D5; D015398:Signal Transduction; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics
C493593:DRD3 protein, human; C493599:DRD4 protein, human; C493605:DRD5 protein, human; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D050638:Receptors, Dopamine D4; D050641:Receptors, Dopamine D5; D004247:DNA; D014446:Tyrosine 3-Monooxygenase; D004299:Dopamine beta-Hydroxylase; D008995:Monoamine Oxidase; D002394:Catechol O-Methyltransferase; D004298:Dopamine