title: DAT1 and DRD4 genes involved in key dimensions of adult ADHD.
abstract: Attention-deficit hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder often persisting in adulthood. Genetic studies of ADHD mainly focused on the Dopamine Transporter (DAT1) and the Dopamine Receptor 4 (DRD4) genes. Nevertheless, polymorphisms of these genes explain only a small fraction of the assigned risk, suggesting that intermediate dimensions and environmental factors should also be considered. We investigated in 77 adult ADHD subjects compared to 474 controls, how polymorphisms within the genes coding for DAT1 (40-bp VNTR in 3'UTR), the Dopamine Receptor 2 (DRD2) (rs1799732) and DRD4 (48-bp VNTR in exon 3), may modulate the expression of the disorder. By genotyping DAT1, we detected a new 9.5R allele showing a deletion of 40 bp and also an insertion of 19 bp compared to the 10R allele. This novel allele was found to be significantly protective for ADHD (p < 0.0001). Another significant difference was found in the distribution of DRD4 48-bp VNTR 6R allele when comparing patients and controls (p = 0.0007). In addition significant results were also found for DAT1 9.5R allele, which was associated with impulsiveness (p = 1.98 × 10(-4)) and trait anger scores (p = 7.66 × 10(-4)). Moreover, impulsiveness scores were partly modulated by an interaction between the DRD4 48-bp VNTR 6R allele and childhood maltreatment (p = 0.01), however, this result did not resist correction for multiple comparisons. Altogether, our results show the putative involvement of DAT1 and DRD4 genes in the aetiology of ADHD with a main role in modulation of key dimensions of the disorder.
authors.affiliation: Department of Psychiatry, University of Geneva, Geneva, Switzerland, roland.hasler@hcuge.ch.
authors.forename: R
authors.initials: R
authors.lastname: Hasler
authors.forename: A
authors.initials: A
authors.lastname: Salzmann
authors.forename: T
authors.initials: T
authors.lastname: Bolzan
authors.forename: J
authors.initials: J
authors.lastname: Zimmermann
authors.forename: P
authors.initials: P
authors.lastname: Baud
authors.forename: P
authors.initials: P
authors.lastname: Giannakopoulos
authors.forename: N
authors.initials: N
authors.lastname: Perroud
mesh_terms: D000328:Adult; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D011954:Receptors, Dopamine / Q000235:genetics; D050638:Receptors, Dopamine D4 / Q000235:genetics*
chemical_list: C493599:DRD4 protein, human; D050483:Dopamine Plasma Membrane Transport Proteins; D011954:Receptors, Dopamine; C493214:SLC6A3 protein, human; D050638:Receptors, Dopamine D4