Dopaminergic system genes in ADHD: toward a biological hypothesis.
Converging evidence has implicated abnormalities of dopamine neurotransmission to the pathology of attention deficit hyperactivity disorder (ADHD). Several genetic association studies have been published, but so far, no DNA variants have been unequivocally demonstrated as contributing to ADHD susceptibility. Four dopamine related gene loci have been implicated, however: DAT 1, DRD 4, DBH, and DRD 5. Each of these may influence the liability of ADHD to a small degree. Notably, all are involved in signal transduction at the neuronal synapse. In this article, we investigate as candidate genes for ADHD, DNA polymorphisms at dopamine receptors, the dopamine transporter, and genes known to be involved in dopamine synthesis and metabolism. In a recent article, we confirmed the previously reported association of DAT 1 (480 bp allele) with ADHD and identified polymorphisms at two additional loci showing preferential transmission to ADHD children of alleles at DRD 5 (148 bp allele) and at DBH (allele 2, Taq I polymorphism). Increased transmission of the 4 bp deletion in the untranslated exon 1 of the DOPA decarboxylase gene was also observed but was of marginal significance. Nonsignificant trends of association were found for TH (allele 2) and DRD2 (Ser-311). No preferential transmission of alleles to ADHD children was observed for polymorphisms at DRD 1, DRD 2 (Taq I), DRD 3, DRD 4, and COMT. Analyzing the data by sex of transmitting parent showed significant preferential paternal transmission of alleles at TH (allele 2) and a nonsignificant trend for paternal transmission for DRD 2 (Ser-311). We attempt to put these findings together with what is known of the function of the particular proteins, and suggest working hypotheses.
Kirley
Aiveen
A
Department of Genetics and Psychiatry, Trinity College, Dublin, Ireland. kirleya@tcd.ie
Hawi
Ziarih
Z
Daly
Grainne
G
McCarron
Mary
M
Mullins
Celine
C
Millar
Niamh
N
Waldman
Irwin
I
Fitzgerald
Michael
M
Gill
Michael
M
D000293:Adolescent; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004298:Dopamine / Q000096:biosynthesis / Q000235:genetics*; D050483:Dopamine Plasma Membrane Transport Proteins; D005260:Female; D017353:Gene Deletion; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins; D009434:Neural Pathways / Q000378:metabolism* / Q000503:physiopathology; D011110:Polymorphism, Genetic / Q000235:genetics*; D011954:Receptors, Dopamine / Q000235:genetics; D012737:Sex Factors
D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011954:Receptors, Dopamine; C493214:SLC6A3 protein, human; D004298:Dopamine