Dopaminergic system genes in ADHD: Toward a biological hypothesis (original) (raw)

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: DAT1, DRD4, DBH, and DRD5. 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 DAT1 (480bp allele) with ADHD and identified polymorphisms at two additional loci showing preferential transmission to ADHD children of alleles at DRD5 (148bp allele) and at DBH (allele 2, Taq I polymorphism). Increased transmission of the 4bp 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 . No preferential transmission of alleles to ADHD children was observed for polymorphisms at DRD1, DRD2 ( Taq I), DRD3, DRD4, 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 DRD2 . We attempt to put these findings together with what is known of the function of the particular proteins, and suggest working hypotheses. Association study of DSM IV attention -deficit hyperactivity disorder (ADHD) and monoamine pathway genes. Am J Med Genet Neuropsychiatr Genet 81:549 Ashgari V, Sanyal S, Buchwaldt S (1995): Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants. J Neurochem 65:1157-1165 Axelrod J, Weinshilboum RM (1972): Catecholamines. N Engl J Med 287:237-242 Baik JH, Picetti R, Saiardi A, Thiriet G, Dierich A, Depaulis A, Le Meur M, Borrelli E (1995): Parkinsonian-like locomotor impairment in mice lacking dopamine D2 receptors. Nature 377(6548):424-428 Barkley RA (1990): Attention Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment. New York, Guilford Barr CL, Wigg K, Malone M, Schachar R, Tannock R, Roberts W, Kennedy JL (1999): Linkage study of catechol-O-methyltransferase and attention-deficit hyperactivity disorder. Am J Med Genet 88(6):710-713 Barr CL, Wigg KG, Feng Y, Zai G, Malone M, Roberts W, Schachar R, Tannock R, Kennedy JL (2000a): Attentiondeficit hyperactivity disorder and the gene for the dopamine D5 receptor. Mol Psychiatry 5:548-551 Barr CL, Wigg KG, Wu J, Zai C, Bloom S, Tannock R, Roberts W, Malone M, Schachar R, Kennedy JL (2000b): Linkage study of two polymorphisms at the dopamine D3 receptor gene and attention-deficit hyperactivity disorder. Am J Med Genet Neuropsychiatr Genetics 96: 114-117 Barr CL, Wigg KG, Bloom S, Schachar R, Tannock R, Roberts W, Malone M, Kennedy JL (2000c): Further evidence from haplotype analysis for linkage of the dopamine D4 receptor gene and attention-deficit hyperactivity disorder. Am J Med Genet 96(3):262-267 Barr CL, Feng Y, Wigg K, Roberts W, Malone M, Schachar R, Tannock R, Kennedy JL (2000d): Identification of DNA variants in the SNAP-25 gene and linkage study of these polymorphisms and attention-deficit hyperactivity disorder. Mol Psychiatry 5:405-409