title: Linkage disequilibrium mapping at DAT1, DRD5 and DBH narrows the search for ADHD susceptibility alleles at these loci.
abstract: Abnormalities in dopaminergic neurotransmission are now accepted as factors in predisposing to ADHD. Evidence of associations between dopamine transporter gene polymorphism and ADHD was first reported by Cook et al. We confirmed the DAT1 association and also identified two additional susceptibility loci at the DRD5 and DBH. Notably, none of the associated variants at these three genes are known to be expressed. Other variants within or closely mapped to the associated alleles are likely to be relevant. In this investigation, we analyse additional markers creating a high-density map across and flanking these genes, and measure intermarker linkage disequilibrium (LD). None of the newly examined markers were more strongly associated with ADHD. At DAT1, the pattern of intermarker LD and haplotype association with the phenotype between exon 9 and the 3' of the gene suggests that the functional variant at DAT1 may be located to this region. For DRD5, three markers, covering a region of approximately 68 kb including the single DRD5 exon are all associated with disease, and thus do not provide localizing information. However, the data for DBH point to a region close to the centre of the gene. Correlation between D' and physical distance was observed between markers at DAT1 and DRD5 for distances less than 50 kb. This was not the case for DBH, where LD breakdown was observed between the intron 5 and intron 9 polymorphisms although they are only 9 kb apart. Further genetic analysis is unlikely to refine the location of susceptibility variants and functional assessment of variants within associated regions is required.
authors.affiliation: Department of Genetics and Psychiatry, Trinity College, Dublin, Ireland. zhhawi@tcd.ie
authors.forename: Z
authors.initials: Z
authors.lastname: Hawi
authors.forename: N
authors.initials: N
authors.lastname: Lowe
authors.forename: A
authors.initials: A
authors.lastname: Kirley
authors.forename: F
authors.initials: F
authors.lastname: Gruenhage
authors.forename: M
authors.initials: M
authors.lastname: Nöthen
authors.forename: T
authors.initials: T
authors.lastname: Greenwood
authors.forename: J
authors.initials: J
authors.lastname: Kelsoe
authors.forename: M
authors.initials: M
authors.lastname: Fitzgerald
authors.forename: M
authors.initials: M
authors.lastname: Gill
mesh_terms: D000293:Adolescent; D000483:Alleles; D001289:Attention Deficit Disorder with Hyperactivity / Q000453:epidemiology / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D050483:Dopamine Plasma Membrane Transport Proteins; D004299:Dopamine beta-Hydroxylase / Q000235:genetics*; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000235:genetics*; D009419:Nerve Tissue Proteins; D017447:Receptors, Dopamine D1 / Q000235:genetics*; D050641:Receptors, Dopamine D5; D012307:Risk Factors
chemical_list: C493605:DRD5 protein, human; D050483:Dopamine Plasma Membrane Transport Proteins; D005819:Genetic Markers; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D017447:Receptors, Dopamine D1; C493214:SLC6A3 protein, human; D050641:Receptors, Dopamine D5; D004299:Dopamine beta-Hydroxylase