Biochemical markers and genetic research of ADHD (original) (raw)
Related papers
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.
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.
Recent genetic advances in ADHD and diagnostic and therapeutic prospects..pdf
Attention deficit hyperactivity disorder (ADHD) is a common behavioral disorder of a complex nature. Genetic and environmental factors are thought to be involved in precipitating the disorder. Pharmacological, animal model and recent molecular studies support the role of genes (of minor or medium effect) from dopamine, serotonin and norepinephrine neurotransmitter systems in ADHD. Several investigations have pointed to the dopamine transporter, the dopamine receptors D4 and D5 and the serotonin transporter as genes of minor effect for ADHD. In addition, recent molecular analysis have also implicated synaptosomal-associated protein-25 and the serotonin receptor 5-Hydroxtryptamine 1B as potential susceptibility loci for ADHD. An understanding of the genetics of ADHD will further facilitate refinement and validation of the ADHD diagnosis, and the development of reliable disease markers in the prediction of disease risk. A knowledge of genes that determine treatment response has the potential to be of predictive value and may also assist in rationalizing drug treatment in the ADHD population. However, increased understanding of inheritance brings its own challenges in the interpretation of new knowledge and in its wise and ethical use, especially in relation to future screening of at-risk individuals. This article attempts to review recent genetic advances and their possible implications for improved diagnosis and treatment.
Mini-review on the Basic Genetic Aspects for the Attention Deficit Hyperactivity Disorder (ADHD)
Bulletin of Integrative Psychiatry
Attention deficit hyperactivity disorder (ADHD) is a common and generally inherited neuropsychiatric disorder that is present in children and adults, and it is considered a multifactorial disorder. Due to the limited effects of genes on the manifestation of the disorder, we wanted to analyze the impact of the genes SNAP25, BAIAP2, ANKK1, DAT1 on attention deficit hyperactivity disorder (ADHD) and to emphasize the importance of genetic architecture in the learning experience and the development of an individual since genes can negatively affect an individual's life. Another rationale for this study was the very well-known problem of accurately diagnosing ADHD because this is usually made through questionnaires or interviews with the patient suspected of having the disorder, which can lead to errors. The idea of genetic testing to identify the different polymorphisms of genes responsible for ADHD would make the diagnosis more accurate. As a result, we searched the databases for articles in which the authors reported the impact of the genes mentioned above. We identified a total of 12 relevant articles that were discussed throughout this article. We concluded that all the genes selected for this study were implicated in the manifestation of this disorder, only when a specific circumstance was met such as a specific ethnic group was tested, or a specific polymorphism was studied.
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.
ADHD Candidate Gene Study in a Population-Based Birth Cohort: Association with DBH and DRD2
Journal of the American Academy of Child & Adolescent Psychiatry, 2007
Objective: Attention-deficit/hyperactivity disorder (ADHD) is a common childhood-onset disorder with a significant impact on public health. Although a genetic contribution to risk is evident, predisposing genetic determinants remain largely unknown despite extensive research. So far, the most promising candidate genes have been those involved in dopamine and serotonin pathways. This study tests a series of allelic variants within such candidate genes to determine their potential influence on ADHD susceptibility. Method: We used a population sample ascertained from a birth cohort of a subpopulation of Finland, characterized by founder effect and isolation, thus minimizing genetic heterogeneity. The subjects were systematically ascertained using DSM-IV diagnostic criteria for ADHD from the Northern Finland Birth Cohort 1986 of more than 9,000 individuals, resulting in the study sample of 188 ADHD cases and 166 controls. We genotyped markers in 13 candidate genes, including critical components of dopamine and serotonin pathways. Results:
Characterizing the ADHD phenotype for genetic studies
Developmental Science, 2005
The genetic study of ADHD has made considerable progress. Further developments in the field will be reliant in part on identifying the most appropriate phenotypes for genetic analysis. The use of both categorical and dimensional measures of symptoms related to ADHD has been productive. The use of multiple reporters is a valuable feature of the characterization of psychopathology in children. It is argued that the use of aggregated measures to characterize the ADHD phenotype, particularly to establish its pervasiveness, is desirable. The recognition of the multiple comorbidities of ADHD can help to isolate more specific genetic influences. In relation to both reading disability and conduct disorder there is evidence that genes may be involved in the comorbid condition that are different from pure ADHD. To date, progress with the investigation of endophenotypes for ADHD has been disappointing. It is suggested that extending such studies beyond cognitive underpinnings to include physiological and metabolic markers might facilitate progress.
Genes and attention-deficit hyperactivity disorder
Clinical Neuroscience Research, 2001
In a collaborative research program on attention-de®cit hyperactivity disorder (ADHD) initiated 20 years ago at UC Irvine, we adopted Cantwell's (1994) approach to de®ne a re®ned phenotype for use in studies of the biological bases of this disorder. We have used this re®ned phenotype (ADHD-Combined Type without internalizing comorbidities) in our molecular genetic studies of ADHD, which have paralleled the emerging literature in this new ®eld. In our research program, we used the candidate gene approach, with hypotheses derived from the dopamine theory of ADHD and Posner and Raichle's (1994) theory of attention. We proposed a candidate dopamine gene (DRD4) and discovered an association with ADHD due to an increase prevalence of the`7-repeat' allele de®ned by a 48-base-pair variable number of tandem repeats in exon III. The DRD4±ADHD association has now been con®rmed by multiple groups around the world. In the next steps of our research program, we are evaluating the impact of a putative DRD4 risk allele on cognition, initiating an investigation of DNA sequence variation in DRD4 alleles, and investigating the association of ADHD with other candidate genes. Using our collaborative research program as an example, we will review the history and current status of molecular genetic studies of ADHD. q
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.