Abstract
Monoamine oxidase A (MAO A) is located on the X chromosome and metabolizes biogenic amines including dopamine, norepinephrine and serotonin. A functional promoter-region polymorphism of this gene has been described that has been studied in a number of mental illnesses but not in attention deficit hyperactivity disorder (ADHD). In the current study, we examined the MAO A promoter-region polymorphism initially in 133 triads and observed preferential transmission of the long alleles from 74 heterozygote mothers to ADHD probands (χ2 = 4.37, P = 0.036, df = 1). We also examined the role of this polymorphism in a computerized continuous performance test, the TOVA. Significant differences were observed on errors of commission (χ2 = 7.021, P = 0.008) and patients carrying the long MAO A allele made significantly more such errors. Errors of commission are a measure of impulsivity. However, following Ritalin (methylphenidate) administration the association between this polymorphism and errors of commission was markedly attenuated and no longer significant at the P < 0.05 level. We also analyzed the provisional association by the case-control design. A significant difference in allele frequency was observed between 110 male probands vs 202 male controls (Pearson χ2 = 7.94, P = 0.047). Similarly results were obtained when 19 female probands were compared to female controls (genotype χ2 = 21.28; P = 0.0032, 3 df and allele χ2 = 30.88, P= 0.0007, 2 df). All three complementary approaches employed (family-based, case-control and quantitative trait design) suggest a role for the MAO A promoter-region polymorphism in conferring risk for ADHD in our patient population.
Similar content being viewed by others
References
Gomez R, Harvey J, Quick C, Scharer I, Harris G . DSM-IV AD/HD: confirmatory factor models, prevalence, and gender and age differences based on parent and teacher ratings of Australian primary school children J Child Psychol Psychiatry 1999 40: 265–274
Anderson JC, Williams S, McGee R, Silva PA . DSM-III disorders in preadolescent children. Prevalence in a large sample from the general population Arch Gen Psychiatry 1987 44: 69–76
Chen ZY, Powell JF, Hsu YP, Breakefield XO, Craig IW . Organization of the human monoamine oxidase genes and long-range physical mapping around them Genomics 1992 14: 75–82
Shih JC, Thompson RF . Monoamine oxidase in neuropsychiatry and behavior Am J Hum Genet 1999 65: 593–598
Nolen WA, Hoencamp E, Bouvy PF, Haffmans PM . Reversible monoamine oxidase-A inhibitors in resistant major depression Clin Neuropharmacol 1993 16: S69–S76
Baldessarini RJ . Current status of antidepressants: clinical pharmacology and therapy J Clin Psychiatry 1989 50: 117–126
Brunner HG . MAOA deficiency and abnormal behaviour: perspectives on an association Ciba Found Symp 1996 194: 155–164
Cases O et al. Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA Science 1995 268: 1763–1766
Sobell JL, Lind TJ, Hebrink DD, Heston LL, Sommer SS . Screening the monoamine oxidase B gene in 100 male patients with schizophrenia: a cluster of polymorphisms in African-Americans but lack of functionally significant sequence changes Am J Med Genet 1997 74: 44–49
Mellick GD et al. The monoamine oxidase B gene GT repeat polymorphism and Parkinson's disease in a Chinese population J Neurol 2000 247: 52–55
Black GC, Chen ZY, Craig IW, Powell JF . Dinucleotide repeat polymorphism at the MAOA locus Nucleic Acids Res 1991 19: 689
Hinds HL, Hendriks RW, Craig IW, Chen ZY . Characterization of a highly polymorphic region near the first exon of the human MAOA gene containing a GT dinucleotide and a novel VNTR motif Genomics 1992 13: 896–897
Sabol SZ, Hu S, Hamer D . A functional polymorphism in the monoamine oxidase A gene promoter Hum Genet 1998 103: 273–279
Deckert J et al. Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder Hum Mol Genet 1999 8: 621–624
Denney RM, Koch H, Craig IW . Association between monoamine oxidase A activity in human male skin fibroblasts and genotype of the MAOA promoter-associated variable number tandem repeat Hum Genet 1999 105: 542–551
Syagailo YV et al. Association analysis of the functional monoamine oxidase A gene promoter polymorphism in psychiatric disorders Am J Med Genet 2001 105: 168–171
Schulze TG et al. Association between a functional polymorphism in the monoamine oxidase A gene promoter and major depressive disorder Am J Med Genet 2000 96: 801–803
Jorm AF et al. Association of a functional polymorphism of the monoamine oxidase A gene promoter with personality and psychiatric symptoms Psychiatr Genet 2000 10: 87–90
Ho LW et al. Genetic associations with clinical characteristics in bipolar affective disorder and recurrent unipolar depressive disorder Am J Med Genet 2000 96: 36–42
Preisig M et al. Association between bipolar disorder and monoamine oxidase A gene polymorphisms: results of a multicenter study Am J Psychiatry 2000 157: 948–955
Manuck SB, Flory JD, Ferrell RE, Mann JJ, Muldoon MF . Aregulatory polymorphism of the monoamine oxidase-A gene may beassociated with variability in aggression, impulsivity, and centralnervous system serotonergic responsivity Psychiatry Res 2000 95: 9–23
Schmidt LG et al. Different allele distribution of a regulatory MAOA gene promoter polymorphism in antisocial and anxious-depressive alcoholics J Neural Transm 2000 107: 681–689
Samochowiec J et al. Association of a regulatory polymorphism in the promoter region of the monoamine oxidase A gene with antisocial alcoholism Psychiatry Res 1999 86: 67–72
Hamilton SP et al. No genetic linkage or association between a functional promoter polymorphism in the monoamine oxidase-A gene and panic disorder Mol Psychiatry 2000 5: 465–466
Payton A et al. Examining for association between candidate gene polymorphisms in the dopamine pathway and attention-deficit hyperactivity disorder: a family- based study Am J Med Genet 2001 105: 464–470
Jiang S et al. Association between attention deficit hyperactivity disorder and the DXS7 locus Am J Med Genet 2000 96: 289–292
Ewens WJ, Spielman RS . The transmission/disequilibrium test : history, subdivision and admixture Am J Hum Genet 1995 57: 455–464
Spielman RS, McGinnis RE, Ewans WJ . Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM) Am J Hum Genet 1993 52: 506–516
Forbes GB . Clinical utility of the Test of Variables of Attention (TOVA) in the diagnosis of attention-deficit/hyperactivity disorder J Clin Psychol 1998 54: 461–476
Greenberg LM, Waldman ID . Developmental normative data on the test of variables of attention (T.O.V.A.) J Child Psychol Psychiatry 1993 34: 1019–1030
Gershon ES et al. Closing in on genes for manic-depressive illness and schizophrenia Neuropsychopharmacology 1998 18: 233–242
Freedman R, Adler LE, Leonard S . Alternative phenotypes for the complex genetics of schizophrenia Biol Psychiatry 1999 45: 551–558
Benjamin J, Ebstein RP, Belmaker RH . Genes for human personality traits: ‘endophenotypes’ of psychiatric disorders? World J Biol Psychiatry 2001 2: 54–57
Egan MF et al. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia Proc Natl Acad Sci USA 2001 98: 6917–6922
Ott J . Linkage analysis with biological markers Hum Hered 1995 45: 169–174
Conners CK . Rating scales in attention-deficit/hyperactivity disorder: use in assessment and treatment monitoring J Clin Psychiatry 1998 59 Suppl 7: 24–30
Achenbach TM, Edelbrock CS . Behavioral problems and competencies reported by parents of normal and disturbed children aged four through sixteen Monogr Soc Res Child Dev 1981 46: 1–82
Wechsler D . WISC-R Manual: Wechsler Intelligence Scale for Children—Revised Psychological Corporation: San Antonio 1974
Sham PC, Curtis D . An extended transmission/disequilibrium test (TDT) for multi-allele marker loci Ann Hum Genet 1995 59: 323–336
Ebstein RP, Benjamin J, Belmaker RH . Personality and polymorphisms of genes involved in aminergic neurotransmission Eur J Pharmacol 2000 410: 205–214
Ebstein RP, Benjamin J, Belmaker RH . Genetics of personality dimensions Curr Opin Psychiatry 2000 13: 617–622
Cardinal RN, Pennicott DR, Sugathapala CL, Robbins TW, Everitt BJ . Impulsive choice induced in rats by lesions of the nucleus accumbens core Science 2001 292: 2499–2501
Pliszka SR, McCracken JT, Maas JW . Catecholamines in attention-deficit hyperactivity disorder: current perspectives J Am Acad Child Adolesc Psychiatry 1996 35: 264–272
Volkow ND et al. Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain J Neurosci 2001 21: RC121
Jonsson EG et al. A promoter polymorphism in the monoamine oxidase A gene and its relationships to monoamine metabolite concentrations in CSF of healthy volunteers J Psychiatr Res 2000 34: 239–244
Faraone SV, Doyle AE, Mick E, Biederman J . Meta-analysis of the association between the 7-repeat allele of the dopamine D(4) receptor gene and attention deficit hyperactivity disorder Am J Psychiatry 2001 158: 1052–1057
Asghari V et al. Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants J Neurochem 1995 65: 1157–1165
Krause K, Dresel SH, Krause J, Kung HF, Tatsch K . Increased striatal dopamine transporter in adult patients with attention deficit hyperactivity disorder: effects of methylphenidate as measured by single photon emission computed tomography Neurosci Lett 2001 285: 107–110
Swanson JM et al. Dopamine genes and ADHD Neurosci Biobehav Rev 2000 24: 21–25
Ernst M . et al. High midbrain [18F]DOPA accumulation in children with attention deficit hyperactivity disorder Am J Psychiatry 1999 156: 1209–1215
Swanson J, Castellanos FX, Murias M, LaHoste G, Kennedy J . Cognitive neuroscience of attention deficit hyperactivity disorder and hyperkinetic disorder Curr Opin Neurobiol 1998 8: 263–271
Florin SM, Kuczenski R, Segal DS . Regional extracellular norepinephrine responses to amphetamine and cocaine and effects of clonidine pretreatment Brain Res 1994 654: 53–62
Segal DS, Kuczenski R . Escalating dose-binge treatment with methylphenidate: role of serotonin in the emergent behavioral profile J Pharmacol Exp Ther 1999 291: 19–30
Biederman J, Spencer T . Attention-deficit/hyperactivity disorder (ADHD) as a noradrenergic disorder Biol Psychiatry 1999 46: 1234–1242
Seeger G, Schloss P, Schmidt MH . Functional polymorphism within the promotor of the serotonin transporter gene is associated with severe hyperkinetic disorders Mol Psychiatry 2001 6: 235–238
Manor I et al. Family based association study of the serotonin transporter promoter-region polymorphism (5-HTTLPR) in attention deficit hyperactivity disorder (ADHD) Am J Med Genet 2001 105: 91–95
Gainetdinov RR et al. Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity Science 1999 283: 397–401
Gainetdinov RR, Caron MG . An animal model of attention deficit hyperactivity disorder Mol Med Today 2001 6: 43–44
Gottesman II, Wolfgram DL . Schizophrenia Genesis : the Origins of Madness Freeman: New York 1991 p 296
Schuckit MA . Genetics of the risk for alcoholism Am J Addict 2000 9: 103–112
Chen WJ, Faraone SV . Sustained attention deficits as markers of genetic susceptibility to schizophrenia Am J Med Genet 2000 97: 52–57
Curran S et al. QTL association analysis of the DRD4 exon 3 VNTR polymorphism in a population sample of children screened with a parent rating scale for ADHD symptoms Am J Med Genet 2001 105: 387–393
Leboyer M et al. Psychiatric genetics: search for phenotypes Trends Neurosci 1998 21: 102–105
Cornblatt BA, Malhotra AK . Impaired attention as an endophenotype for molecular genetic studies of schizophrenia Am J Med Genet 2001 105: 11–15
Cannon TD, Gasperoni TL, van Erp TG, Rosso IM . Quantitative neural indicators of liability to schizophrenia: implications for molecular genetic studies Am J Med Genet 2001 105: 16–19
Acknowledgements
This research was supported by a grant from the Israeli Ministry of Health.
Author information
Authors and Affiliations
Corresponding author
Additional information
Beersheva Mental Health Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Israel
Rights and permissions
About this article
Cite this article
Manor, I., Tyano, S., Mel, E. et al. Family-based and association studies of monoamine oxidase A and attention deficit hyperactivity disorder (ADHD): preferential transmission of the long promoter-region repeat and its association with impaired performance on a continuous performance test (TOVA). Mol Psychiatry 7, 626–632 (2002). https://doi.org/10.1038/sj.mp.4001037
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.mp.4001037
- Springer Nature Limited
Keywords
This article is cited by
-
Evidence for anti-inflammatory effects and modulation of neurotransmitter metabolism by Salvia officinalis L.
BMC Complementary Medicine and Therapies (2022)
-
Pilot study indicate role of preferentially transmitted monoamine oxidase gene variants in behavioral problems of male ADHD probands
BMC Medical Genetics (2017)
-
Regional cortical thinning of the orbitofrontal cortex in medication-naïve female patients with major depressive disorder is not associated with MAOA-uVNTR polymorphism
Annals of General Psychiatry (2016)
-
ADHD risk alleles associated with opiate addiction: study of addicted parents and their children
Pediatric Research (2016)
-
ADHD History of the Concept: the Case of the Continuous Performance Test
Current Developmental Disorders Reports (2015)