title: Multiple marker analysis at the promoter region of the DRD4 gene and ADHD: evidence of linkage and association with the SNP -616.
abstract: Abnormalities of dopamine neurotransmission have been hypothesized to play an important role in the pathophysiology of attention deficit hyperactivity disorder (ADHD). Support for this has come from numerous association studies on candidate genes including the dopamine D4 receptor gene (DRD4). One of the most replicated associations between ADHD and the dopaminergic system is the 7-repeat allele of the VNTR polymorphism of this gene. A lack of association between this marker and ADHD has also been reported in several investigations. In the absence of a firm link between the number of the VNTR repeats and the function of the gene, we sought to investigate several additional markers at the 5'-end of the gene with potential influence on the expression of the DRD4. We observed a significant over transmission of single nucleotide polymorphism (SNP) (chi(2) = 7.45, P = 0.008, OR = 1.63). In addition, an excess transmission of the A allele of the -521 SNP was observed, although it did not attain statistical significance (chi(2) = 2.14, P = 0.17, OR = 1.25). Linkage disequilibrium (LD) analysis demonstrated a weak level of D' between any of the tested markers implying that this may be a region of high recombination. It also raises the possibility that the new association with ADHD may be independent of the 7-repeat allele. Further analyses, preferably in samples demonstrating association with the VNTR, or in other ethnic groups, are required to confirm these observations.
authors.affiliation: Departments of Genetics and Psychiatry, Trinity College, Dublin, Ireland.
authors.forename: Naomi
authors.initials: N
authors.lastname: Lowe
authors.forename: Aiveen
authors.initials: A
authors.lastname: Kirley
authors.forename: Celine
authors.initials: C
authors.lastname: Mullins
authors.forename: Michael
authors.initials: M
authors.lastname: Fitzgerald
authors.forename: Michael
authors.initials: M
authors.lastname: Gill
authors.forename: Ziarih
authors.initials: Z
authors.lastname: Hawi
mesh_terms: D000328:Adult; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics*; D002648:Child; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D018598:Minisatellite Repeats / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D017448:Receptors, Dopamine D2 / Q000235:genetics*; D050638:Receptors, Dopamine D4
chemical_list: C493599:DRD4 protein, human; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4; D004247:DNA