Genes and attention-deficit hyperactivity disorder (original) (raw)
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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 (Ser-311). 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 (Ser-311). We attempt to put these findings together with what is known of the function of the particular proteins, and suggest working hypotheses. ?? 2002 American College of Neuropsychopharmacology. Published by Elsevier Science Inc.
Molecular Psychiatry, 2000
Attention deficit hyperactivity disorder (ADHD) is a common childhood-onset neurodevelopmental disorder. Evidence from twin, adoption, and family studies provide support for a genetic contribution to the etiology of ADHD. Several candidate gene studies have identified an association between a 7-repeat variant in exon 3 of the dopamine 4 receptor gene (DRD4) and ADHD. However, in spite of the positive reports finding association of the exon 3 VNTR with ADHD, several other polymorphisms within DRD4 have been identified that conceivably could contribute to risk for ADHD. Recently, another common polymorphism of the DRD4 gene has been described involving a 120-bp repeat element upstream of the 5Ј transcription initiation site. In this report, we describe results of analysis of the DRD4 120-bp repeat promoter polymorphism in a sample of 371 children with ADHD and their parents, using the transmission disequilibrium test (TDT). Results showed a significant preferential transmission of the 240bp (long) allele with ADHD. Exploratory analyses of the Inattentive phenotypic subtype of ADHD strengthened the evidence for linkage. These data add further support for the role of DRD4 variants conferring increased risk for ADHD, and imply that additional studies of DRD4 and other related genes are needed. Molecular Psychiatry (2000) 5, 531-536.
Dopaminergic system genes in ADHD: Toward a biological hypothesis
2002
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
Linkage of the dopamine receptor D1 gene to attention-deficit/hyperactivity disorder
Molecular Psychiatry, 2004
Attention-deficit/hyperactivity disorder (ADHD) has a strong genetic basis, and evidence from human and animal studies suggests the dopamine receptor D1 gene, DRD1, to be a good candidate for involvement. Here, we tested for linkage of DRD1 to ADHD by examining the inheritance of four biallelic DRD1 polymorphisms [D1P.5 (-1251HaeIII), D1P.6 (À800HaeIII), D1.1 (À48DdeI) and D1.7 ( þ 1403Bsp1286I)] in a sample of 156 ADHD families. Owing to linkage disequilibrium between alleles at the four markers, only three haplotypes are common in our sample. Using the transmission/disequilibrium test (TDT), we observed a strong bias for transmission of Haplotype 3 (1.1.1.2) from heterozygous parents to their affected children (P¼0.008). Furthermore, using quantitative trait TDT analyses, we found significant and positive relationships between Haplotype 3 transmission and the inattentive symptoms, but not the hyperactive/impulsive symptoms, of ADHD. These findings support the proposed involvement of DRD1 in ADHD, and implicate Haplotype 3, in particular, as containing a potential risk factor for the inattentive symptom dimension of the disorder. Since none of the four marker alleles comprising Haplotype 3 is predicted to alter DRD1 function, we hypothesize that a functional DRD1 variant, conferring susceptibility to ADHD, is on this haplotype. To search for such a variant we screened the DRD1 coding region, by sequencing, focusing on the children who showed preferential transmission of Haplotype 3. DNA from 41 children was analysed, and no sequence variations were identified, indicating that the putative DRD1 risk variant for ADHD resides outside of the coding region of the gene.
Proceedings of the National Academy of Sciences, 2000
An association of the dopamine receptor D4 (DRD4) gene located on chromosome 11p15.5 and attention deficit͞hyperactivity disorder (ADHD) has been demonstrated and replicated by multiple investigators. A specific allele [the 7-repeat of a 48-bp variable number of tandem repeats (VNTR) in exon 3] has been proposed as an etiological factor in attentional deficits manifested in some children diagnosed with this disorder. In the current study, we evaluated ADHD subgroups defined by the presence or absence of the 7-repeat allele of the DRD4 gene, using neuropsychological tests with reaction time measures designed to probe attentional networks with neuroanatomical foci in D4-rich brain regions. Despite the same severity of symptoms on parent and teacher ratings for the ADHD subgroups, the average reaction times of the 7-present subgroup showed normal speed and variability of response whereas the average reaction times of the 7-absent subgroup showed the expected abnormalities (slow and variable responses). This was opposite the primary prediction of the study. The 7-present subgroup seemed to be free of some of the neuropsychological abnormalities thought to characterize ADHD.
Genetics of attention-deficit hyperactivity disorder (ADHD)
Attention-deficit hyperactivity disorder (ADHD) is a clinically and genetically heterogeneous syndrome which is comorbid with childhood conduct disorder, alcoholism, substance abuse, dis-social personality disorder, and affective disorders. A small but consistent overlap with autistic symptoms has also been established. Twin and family studies of ADHD show a substantial genetic heritability with little or no family environmental effect. Linkage and association studies have conclusively implicated the dopamine transporter gene (DAT1). DAT1 has also been confirmed as being associated with bipolar disorder. Remarkably, and for the first time in psychiatry, genetic markers at the DAT1 locus appear to be able to predict clinical heterogeneity because the non-conduct disordered subgroup of ADHD is associated with DAT1 whereas other subgroups do not appear to be associated. The second most well replicated susceptibility gene encodes the DRD4 dopamine receptor and many other dopamine related genes appear to be implicated. It is becoming increasingly clear that genes causing bipolar mania overlap with genes for a subtype of ADHD. The key to understanding the genetics of ADHD is to accept very considerable heterogeneity with different genes having effects in different families and in different individuals. It is too early to interpret the new wave of genome-wide association and copy number variant studies but preliminary data support the overlap with affective disorder genes and also with CNS connectivity genes likely to be involved in autism and affective disorders.
Molecular Psychiatry, 1998
mic loop of the protein due to a 16-amino acid (48-bp) IMMEDIATE COMMUNICATION region that can be repeated two to eleven times. 3 Third, in vitro studies suggest that the D4 receptor variants Association of the display functionally different pharmacological properties. 4 Fourth, the DRD4 gene 5,6 has been associated dopamine receptor D4 with the personality trait of novelty seeking as defined by Cloninger, 7 which may be related to the manifes-(DRD4) gene with a refined tation of symptoms of ADHD. Fifth, the localization of DRD4 mRNA in frontal and prefrontal cortical regions phenotype of attention of the brain, 8 suggest that this gene may be involved in the executive control and regulation of attention. 9 deficit hyperactivity In our initial evaluation of the DRD4 gene and disorder (ADHD): a family-ADHD, 1 we observed a higher percentage of the 7repeat DRD4 allele in an ADHD group (29%) compared based approach to the ethnically-matched control group (12%). In addition, we observed a higher percentage of cases