Genetics of attention-deficit hyperactivity disorder (ADHD) (original) (raw)
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The dopamine transporter (DAT) is the major site of methylphenidate action, which is one of the main drugs used to treat attention-deficit/hyperactivity disorder (ADHD). Most association studies with ADHD focused in a VNTR at the 3 0 -untranslated region of the gene (3 0 UTR) presenting conflicting results. However, the most common explanation to inconsistent results is variable linkage disequilibrium with an adjacent functional variant, just a few number of DAT1 studies have reported LD structure across the gene. In this study, we screened 16 polymorphisms across the DAT1 gene to understand LD structure in a Brazilian sample of families with ADHD probands and to verify if there were evidence for a biased transmission of alleles and haplotypes from parents to their 243 children with ADHD. In the DSM-IV combined subtype, we observed a preferential transmission of the haplotype A/C/C/ C/A derived from five SNPs (rs2550948, rs11564750, rs261759, rs2652511, rs2975223) in 5 0 region (P corrected ¼ 0.018) and no association with any allele/haplotype at the 3 0 region of the gene, including the 3 0 VNTR and the VNTR of intron 8. These results suggest a role for the promoter region in ADHD susceptibility and that allele heterogeneity should be highly considered in DAT1 gene association studies highlighting the importance of this gene in the genetics of the disorder.
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.
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
The genetics of ADHD: A literature review of 2005
Current Psychiatry Reports, 2006
Investigations into the genetic basis of attention-deficit/ hyperactivity disorder (ADHD) continue to yield compelling results as candidate gene studies reveal more information about this elusive disorder. Family, twin, and adoption studies further the notion that ADHD is a highly heritable disorder with direct genetic and environmental influence. The year 2005 saw many ADHD candidate gene studies, with most focused on the catecholaminergic candidates. Although many genes were studied in 2005, a large portion of findings has been supportive of the roles of dopaminergic genes’ relationship to clinical phenotypes and drug response. These studies often require replication. Clinical implications continue to be speculative, as larger sample sizes are needed to validate findings to the general population. Further understanding of endophenotypes and the impact of comorbidities also is necessary for proper clinical intervention. Forthwith, we provide a summary of ADHD genetic studies published in 2005.
Molecular Psychiatry, 2003
Phone: 310-794-7981 FAX: 310-794-5446 Abstract Attention-deficit hyperactivity disorder (ADHD) is one of the most common childhood behavioral disorders. Genetic factors contribute to the underlying liability to develop ADHD. Reports implicate variants of genes important for the synthesis, uptake, transport and receptor binding of dopamine in the etiology of ADHD, including DRD4, DAT1, DRD2, and DRD5. In the present study, we genotyped a large multiplex sample of ADHD affected children and their parents for polymorphisms in genes previously reported to be associated with ADHD. Associations were tested by the transmission disequilibrium test (TDT). 1 The sample is sufficient to detect genotype relative risks for putative risk alleles. The DRD4 gene 120-bp insertion/deletion promoter polymorphism displayed significant bias in transmission of the insertion (χ2 = 7.58, p = 0.006) as suggested by an analysis of a subset of these families. 2 The 7 repeat allele of the DRD4 48-bp repeat polymorphism (DRD4.7) was not significantly associated with ADHD in the large sample in contrast to our earlier findings in a smaller subset. 3 We replicate an association of a microsatellite polymorphism near the DRD5 gene with ADHD by showing biased non-transmission of the 146-bp allele (p=0.02) and a trend toward excess transmission of the 148-bp allele (p=0.053). No evidence for an association was found for polymorphisms in DRD2 or DAT1 in this sample. The DRD5 146-bp (DRD5.146) allele and the DRD4 240-bp (DRD4.240) allele of the promoter polymorphism emerge as the two DNA variants showing significant association in this large sample of predominantly multiplex families with ADHD, with estimated genotype relative risks of Washington, D.C.: American Psychiatric Association; 1994. 7. Biederman J, Newcorn J, Sprich S. Comorbidity of attention deficit hyperactivity disorder with conduct, depressive, anxiety, and other disorders. Am J Psychiatry 1991;148(5):564-77. 8. Bird HR, Gould MS, Staghezza BM. Patterns of diagnostic comorbidity in a community sample of children aged 9 through 16 years. J Am Acad Child Adolesc Psychiatry 1993;32(2):361-8. a sample of Turkish children. Mol Psychiatry 2000;5(4):396-404. 22. Meador-Woodruff JH, Damask SP, Wang J, Haroutunian V, Davis KL, Watson SJ. Dopamine receptor mRNA expression in human striatum and neocortex.
American Journal of Medical Genetics, 2001
Attention-deficit hyperactivity disorder (ADHD) is one of the most common psychiatric disorders of childhood. The role of genetic factors in its etiology is strongly supported by family, adoption, and twin studies. Several investigations have reported associations between ADHD and both the 7-repeat allele of the 48 bp VNTR at the DRD4 gene and the 10-repeat allele of the 40 bp VNTR at the DAT1 gene, but the results have been inconsistent. A sample of 81 Brazilian ADHD children and adolescents and their parents were screened for these DRD4 and DAT1 VNTRs. An excess of the DRD4 7-repeat allele was observed when both ADHD probands and their parents were compared with an ethnically matched control sample (chi-square ¼ 11.55, P ¼ 0.03; chi-square ¼ 12.17, P ¼ 0.03, respectively). However, haplotype relative risk (HRR) analysis showed no preferential transmission of the DRD4 7-repeat allele. No evidence of association with the DAT1 polymorphism was detected by both approaches. Nevertheless, an interaction effect of both genes on ADHD hyperactive/ impulsive dimension was observed (F ¼ 4.68; P ¼ 0.03). These results add to the group of studies that together suggest a small effect of these genes in the susceptibility to ADHD. ß
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2008
Multiple studies have reported an association between attention deficit hyperactivity disorder (ADHD) and the 10-repeat allele of a variable number tandem repeat (VNTR) polymorphism in the 30-untranslated region (30UTR) of the dopamine transporter gene (DAT1). Yet, recent meta-analyses of available data find little or no evidence for this association; although there is strong evidence for heterogeneity between datasets. This pattern of findings could arise for several reasons including the presence of relatively rare risk alleles on common haplotype backgrounds or the functional interaction of two or more loci within the gene. We previously described the importance of a specific haplotype at the 30 end of DAT1, as well as the identification of associated single nucleotide polymorphisms (SNPs) within or close to 50 regulatory sequences. In this study we replicate the association of SNPs at the 50 end of the gene and identify a specific risk haplotype spanning the 50 and 30 markers. These findings indicate the presence of at least two loci associated with ADHD within the DAT1 gene and suggest that either additive or interaction effects of these two loci on the risk for ADHD. Overall these data provide further evidence that genetic variants of the dopamine transporter gene confer an increased risk for ADHD.