Abstract
Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable childhood-onset psychiatric disorder with significant genetic contribution. Considerable evidence has implicated involvement of dopaminergic system and the prefrontal cortex (PFC) in the pathomechanism of ADHD. The catechol-O-methyltransferase (COMT) gene is of particular interest for ADHD as its crucial role in the degradation of dopamine in the PFC. We summarized the reported findings investigating associations between COMT gene and ADHD and performed a meta-analysis of previous studies to assess the overall magnitude and significance of the association.
Similar content being viewed by others
References
Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA (2007) The worldwide prevalence of ADHD: a systematic review and metaregression analysis. Am J Psychiatry 164(6):942–948
APA (1994) Diagnostic and statistical manual of mental disorders, 4th edn. DSM-IV, Washington DC
Kronenberger WK, Meyer RG (2001) The Child Clinician’s Handbook, 2nd edn. Allyn& Bacon, Needham Heights, MA
Barkley RA (2005) Attention-deficit hyperactivity disorder: a handbook for diagnosis and treatment. Guilford, New York
Swanson J, Sergeant J, Taylor E, Sonuga-Barke E, Jensen P, Cantwell D (1998) Attention-deficit hyperactivity disorder and hyperkinetic disorder. Lancet 351:429–433
Kessler R, Adler L, Barkley R, Biederman J, Conners C, Faraone S (2005) Patterns and predictors of attentiondeficit/hyperactivity disorder persistence into adulthood: results from the national comorbidity survey replication. Biol Psychiatry 56(11):1442–1451
Faraone S, Biederman J, Spencer T, Wilens T, Seidman L, Mick E (2000) Attention-deficit/hyperactivity disorder in adults: an overview. Biol Psychiatry 48(1):9–20
Biederman J, Faraone SV, Keenan K (1992) Further evidence for family–genetic risk factors in attention deficit hyperactivity disorder. Arch Gen Psychiatry 49:728–738
Souza I, Pinheiro MA, Denardin D, Mattos P, Rohde LA (2004) Attention-deficit/hyperactivity disorder and comorbidity in Brazil: comparisons between two referred samples. Eur Child Adolesc Psychiatry 13(4):243–248
Biederman J (2005) Attention-deficit/hyperactivity disorder: a selective overview. Biol Psychiatry 57(11):1215–1220
Thapar A, van den Bree M, Fowler T, Langley K, Whittinger N (2006) Predictors of antisocial behavior in children with attention deficit hyperactivity disorder. Eur Child Adolesc Psychiatry 15:118–125
Faraone S, Biederman J (1998) Neurobiology of attentiondeficit hyperactivity disorder. Biol Psychiatry 44:951–958
Comings DE (2001) Clinical and molecular genetics of ADHD and Tourette's syndrome. Two related polygenic disorders. Ann N Y Acad Sci 931:50–83
Faraone S, Biederman J, Milberger S (1994) An exploratory study of ADHD among second-degree relatives of ADHD children. Biol Psychiatry 35:398–402
Morrison J, Stewart M (1973) The psychiatric status of the legal families of adopted hyperactive children. Arch Gen Psychiatry 28:888–891
Hechtman L (1996) Families of children with attention deficit hyperactivity disorder: a review. Can J Psychiatry 41:350–360
Cantwell D (1975) Genetics of hyperactivity. J Child Psychol Psychiatry 16:261–264
Faraone S, Perlis R, Doyle A, Smoller J, Goralnick J, Holmgren M, Sklar P (2005) Molecular genetics of attention-deficit hyperactivity disorder. Biol Psychiatry 51:1313–1323
Sprich S, Biederman J, Crawford M, Mundy E, Faraone S (2000) Adoptive and biological families of children and adolescents with ADHD. J Am cad Child Adolesc Psychiatry 39:1432–1437
Palmason H, Moser D, Sigmund J, Vogler C, Hanig S, Schneider A, Seitz C, Marcus A, Meyer J, Freitag CM (2010) Attention-deficit/hyperactivity disorder phenotype is influenced by a functional catechol-O-methyltransferase variant. J Neural Transm 117(2):259–267
Faraone S, Doyle A (2001) The nature and heritability of attention deficit hyperactivity disorder. Child Adolesc Psychiatr Clinics North Am 10:299–316
Gizer IR, Ficks C, Waldman ID (2009) Candidate gene studies of ADHD: a meta-analytic review. Hum Genet 126(1):51–90
McGough J (2005) Attention-deficit hyperactivity disorder pharmacogenomics. Biol Psychiatry 57:1367–1373
Giros B, Jaber M, Jones S, Wightman R, Caron M (1996) Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379:606–612
Gainetdinov RR, Wetsel WC, Jones SR, Levin ED, Jaber M, Caron MG (1999) Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity. Science 283(5400):397–401
Jaber M, Dumartin B, Sagne C, Haycock JW, Roubert C, Giros B, Bloch B, Caron MG (1999) Differential regulation of tyrosine hydroxylase in the basal ganglia of mice lacking the dopamine transporter. Eur J Neurosci 11(10):3499–3511
Russell VA (2000) The nucleus accumbens motor-limbic interface of the spontaneously hypertensive rat as studied in vitro by the superfusion slice technique. Neurosci Biobehav Rev 24(1):133–136
Dougherty DD, Bonab AA, Spencer TJ, Rauch SL, Madras BK, Fischman AJ (1999) Dopamine transporter density in patients with attention deficit hyperactivity disorder. Lancet 354(9196):2132–2133
Krause KH, Dresel SH, Krause J, Kung HF, Tatsch K (2000) 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 285(2):107–110
Lasky-Su J et al (2008) Genome-wide association scan of quantitative traits for attention deficit hyperactivity disorder identifies novel associations and confirms candidate gene associations. Am J Med Genet B Neuropsychiatr Genet 147B(8):1345–1354
Lesch KP, Timmesfeld N, Renner TJ, Halperin R, Roser C, Nguyen TT, Craig DW, Romanos J, Heine M, Meyer J, Freitag C, Warnke A, Romanos M, Schafer H, Walitza S, Reif A, Stephan DA, Jacob C (2008) Molecular genetics of adult ADHD: converging evidence from genome-wide association and extended pedigree linkage studies. J Neural Transm 115(11):1573–1585
Goldman-Rakic P (1990) Cellular and circuit basis of working memory in prefrontal cortex of nonhuman primates. Prog Brain Res 85:325–335
Levy F (2007) What do dopamine transporter and catechol-o-methyltransferase tell us about attention deficit-hyperactivity disorder? Pharmacogenomic implications. Aust N Z J Psychiatry 41(1):10–16
Dalley JW, Cardinal RN, Robbins TW (2004) Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates. Neurosci Biobehav Rev 28(7):771–784
Tekin S, Cummings JL (2002) Frontal–subcortical neuronal circuits and clinical neuropsychiatry: an update. J Psychosom Res 53(2):647–654
Choudhry Z, Sengupta S, Thakur G, Page V, Schmitz N, Grizenko N, Joober R (2012) Catechol-O-Methyltransferase Gene and Executive Function in Children With ADHD. J Atten Disord
Barkley RA (2010) Differential diagnosis of adults with ADHD: the role of executive function and self-regulation. J Clin Psychiatry 71(7):e17
Welsh MC, Pennington BF (1988) Assessing frontal lobe functioning in children: views from developmental psychology. Dev Neuropsychol 4:199–230
Willcutt EG, Doyle AE, Nigg JT, Faraone SV, Pennington BF (2005) Validity of the executive function theory of attention-deficit/hyperactivity disorder: a meta-analytic review. Biol Psychiatry 57(11):1336–1346
Arnsten AF (1998) Catecholamine modulation of prefrontal cortical cognitive function. Trends Cogn Sci 2(11):436–447
Karoum F, Chrapusta S, Egan M (1994) 3-Methoxytyramine is the major metabolite of released dopamine in the rat frontal cortex: reassessment of the effects of antipsychotics on the dynamics of dopamine release and metabolism in the frontal cortex, nucleus accumbens, and striatum by a simple two pool model. J Neurochem 63:972–979
Diaz-Asper CM, Weinberger DR, Goldberg TE (2006) Catechol-O-methyltransferase polymorphisms and some implications for cognitive therapeutics. NeuroRx 3(1):97–105
Biederman J, Monuteaux M, Seidman L (2004) Impact of executive function deficits and ADHD on academic outcomes in children. J Consult Clin Psychol 72:757–766
Salatino-Oliveira A, Genro JP, Zeni C, Polanczyk GV, Chazan R, Guimaraes AP, Callegari-Jacques SM, Rohde LA, Hutz MH (2011) Catechol-O-methyltransferase valine158methionine polymorphism moderates methylphenidate effects on oppositional symptoms in boys with attention-deficit/hyperactivity disorder. Biol Psychiatry 70(3):216–221
Zhang L, Chang S, Li Z, Zhang K, Du Y, Ott J, Wang J (2012) ADHD gene: a genetic database for attention deficit hyperactivity disorder. Nucleic Acids Res 40(Database issue): D1003-D1009
Bonifacio MJ, Archer M, Rodrigues ML, Matias PM, Learmonth DA, Carrondo MA, Soares-Da-Silva P (2002) Kinetics and crystal structure of catechol-o-methyltransferase complex with co-substrate and a novel inhibitor with potential therapeutic application. Mol Pharmacol 62(4):795–805
Vidgren J, Svensson LA, Liljas A (1994) Crystal structure of catechol O-methyltransferase. Nature 368(6469):354–358
Mannisto PT, Kaakkola S (1999) Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. Pharmacol Rev 51(4):593–628
Vidgren J, Tilgmann C, Lundstrom K, Liljas A (1991) Crystallization and preliminary X-ray investigation of a recombinant form of rat catechol O-methyltransferase. Proteins 11(3):233–236
Lundstrom K, Salminen M, Jalanko A, Savolainen R, Ulmanen I (1991) Cloning and characterization of human placental catechol-O-methyltransferase cDNA. DNA Cell Biol 10(3):181–189
Bertocci B, Miggiano V, Da PM, Dembic Z, Lahm HW, Malherbe P (1991) Human catechol-O-methyltransferase: cloning and expression of the membrane-associated form. Proc Natl Acad Sci U S A 88(4):1416–1420
Salminen M, Lundstrom K, Tilgmann C, Savolainen R, Kalkkinen N, Ulmanen I (1990) Molecular cloning and characterization of rat liver catechol-O-methyltransferase. Gene 93(2):241–247
Tenhunen J, Salminen M, Jalanko A, Ukkonen S, Ulmanen I (1993) Structure of the rat catechol-O-methyltransferase gene: separate promoters are used to produce mRNAs for soluble and membrane-bound forms of the enzyme. DNA Cell Biol 12(3):253–263
Tenhunen J, Salminen M, Lundstrom K, Kiviluoto T, Savolainen R, Ulmanen I (1994) Genomic organization of the human catechol O-methyltransferase gene and its expression from two distinct promoters. Eur J Biochem 223(3):1049–1059
Napolitano A, Cesura AM, Da PM (1995) The role of monoamine oxidase and catechol O-methyltransferase in dopaminergic neurotransmission. J Neural Transm Suppl 45:35–45
Guldberg HC, Marsden CA (1975) Catechol-O-methyl transferase: pharmacological aspects and physiological role. Pharmacol Rev 27(2):135–206
Grossman MH, Emanuel BS, Budarf ML (1992) Chromosomal mapping of the human catechol-O-methyltransferase gene to 22q11. 1–q11. 2. Genomics 12(4):822–825
Nemoda Z, Szekely A, Sasvari-Szekely M (2011) Psychopathological aspects of dopaminergic gene polymorphisms in adolescence and young adulthood. Neurosci Biobehav Rev 35(8):1665–1686
Lotta T, Vidgren J, Tilgmann C, Ulmanen I, Melen K, Julkunen I, Taskinen J (1995) Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermo labile variant of the enzyme. Biochemistry 34(13):4202–4210
Hong J, Shu-Leong H, Tao X, Lap-Ping Y (1998) Distribution of catechol-O-methyltransferase expression in human central nervous system. Neuroreport 9(12):2861–2864
Lundstrom K, Tenhunen J, Tilgmann C, Karhunen T, Panula P, Ulmanen I (1995) Cloning, expression, and structure of catechol-O-methyltransferase. Biochim Biophys Acta 1251(1):1–10
Soares-da-Silva P, Vieira-Coelho MA, Parada A (2003) Catechol-O-methyltransferase inhibition in erythrocytes and liver by BIA 3–202 (1-[3,4-dibydroxy-5-nitrophenyl]-2-phenyl-ethanone). Pharmacol Toxicol 92(6):272–278
Nunes T, Machado R, Rocha JF, Fernandes-Lopes C, Costa R, Torrao L, Loureiro AI, Falcao A, Vaz-da-Silva M, Wright L, Almeida L, Soares-da-Silva P (2009) Pharmacokinetic-pharmacodynamic interaction between nebicapone and controlled-release levodopa/benserazide: a single-center, Phase I, double-blind, randomized, placebo-controlled, four-way crossover study in healthy subjects. Clin Ther 31(10):2258–2271
Matsumoto M, Weickert CS, Akil M, Lipska BK, Hyde TM, Herman MM, Kleinman JE, Weinberger DR (2003) Catechol O-methyltransferase mRNA expression in human and rat brain: evidence for a role in cortical neuronal function. Neuroscience 116(1):127–137
Papaleo F, Crawley JN, Song J, Lipska BK, Pickel J, Weinberger DR, Chen J (2008) Genetic dissection of the role of catechol-O-methyltransferase in cognition and stress reactivity in mice. J Neurosci 28(35):8709–8723
Kaenmaki M, Tammimaki A, Myohanen T, Pakarinen K, Amberg C, Karayiorgou M, Gogos JA, Mannisto PT (2010) Quantitative role of COMT in dopamine clearance in the prefrontal cortex of freely moving mice. J Neurochem 114(6):1745–1755
Meyer-Lindenberg A, Kohn PD, Kolachana B, Kippenhan S, McInerney-Leo A, Nussbaum R, Weinberger DR, Berman KF (2005) Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype. Nat Neurosci 8(5):594–596
Tunbridge EM, Weickert CS, Kleinman JE, Herman MM, Chen J, Kolachana BS, Harrison PJ, Weinberger DR (2007) Catechol-o-methyltransferase enzyme activity and protein expression in human prefrontal cortex across the postnatal lifespan. Cereb Cortex 17(5):1206–1212
Karhunen T, Tilgmann C, Ulmanen I, Panula P (1995) Neuronal and non-neuronal catechol-O-methyltransferase in primary cultures of rat brain cells. Int J Dev Neurosci 13(8):825–834
Chen J, Song J, Yuan P, Tian Q, Ji Y, Ren-Patterson R, Liu G, Sei Y, Weinberger DR (2011) Orientation and cellular distribution of membrane-bound catechol-O-methyltransferase in cortical neurons: implications for drug development. J Biol Chem 286(40):34752–34760
Ulmanen I, Peranen J, Tenhunen J, Tilgmann C, Karhunen T, Panula P, Bernasconi L, Aubry JP, Lundstrom K (1997) Expression and intracellular localization of catechol O-methyltransferase in transfected mammalian cells. Eur J Biochem 243(1–2):452–459
Sesack SR, Hawrylak VA, Matus C, Guido MA, Levey AI (1998) Dopamine axon varicosities in the prelimbic division of the rat prefrontal cortex exhibit sparse immunoreactivity for the dopamine transporter. J Neurosci 18(7):2697–2708
Wayment HK, Schenk JO, Sorg BA (2001) Characterization of extracellular dopamine clearance in the medial prefrontal cortex: role of monoamine uptake and monoamine oxidase inhibition. J Neurosci 21(1):35–44
Garris PA, Collins LB, Jones SR, Wightman RM (1993) Evoked extracellular dopamine in vivo in the medial prefrontal cortex. J Neurochem 61(2):637–647
Mazei MS, Pluto CP, Kirkbride B, Pehek EA (2002) Effects of catecholamine uptake blockers in the caudate-putamen and subregions of the medial prefrontal cortex of the rat. Brain Res 936(1–2):58–67
Zhou K et al (2008) Meta-analysis of genome-wide linkage scans of attention deficit hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet 147B(8):1392–1398
Roth JA (1992) Membrane-bound catechol-O-methyltransferase: a reevaluation of its role in the O-methylation of the catecholamine neurotransmitters. Rev Physiol Biochem Pharmacol 120:1–29
Karoum F, Chrapusta SJ, Egan MF, Wyatt RJ (1993) Absence of 6-hydroxydopamine in the rat brain after treatment with stimulants and other dopaminergic agents: a mass fragmentographic study. J Neurochem 61(4):1369–1375
Busch AE, Karbach U, Miska D, Gorboulev V, Akhoundova A, Volk C, Arndt P, Ulzheimer JC, Sonders MS, Baumann C, Waldegger S, Lang F, Koepsell H (1998) Human neurons express the polyspecific cation transporter hOCT2, which translocates monoamine neurotransmitters, amantadine, and memantine. Mol Pharmacol 54(2):342–352
Wu X, Kekuda R, Huang W, Fei YJ, Leibach FH, Chen J, Conway SJ, Ganapathy V (1998) Identity of the organic cation transporter OCT3 as the extraneuronal monoamine transporter (uptake2) and evidence for the expression of the transporter in the brain. J Biol Chem 273(49):32776–32786
Woodard RW, Tsai MD, Floss HG, Crooks PA, Coward JK (1980) Stereochemical course of the transmethylation catalyzed by catechol O-methyltransferase. J Biol Chem 255(19):9124–9127
Tunnicliff G, Ngo TT (1983) Kinetics of rat brain soluble catechol-O-methyltransferase and its inhibition by substrate analogues. Int J Biochem 15(5):733–738
Rivett AJ, Roth JA (1982) Kinetic studies on the O-methylation of dopamine by human brain membrane-bound catechol O-methyltransferase. Biochemistry 21(8):1740–1742
Ovaska M, Yliniemela A (1998) A semiempirical study on inhibition of catechol O-methyltransferase by substituted catechols. J Comput Aided Mol Des 12(3):301–307
Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshilboum RM (1996) Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 6(3):243–250
Zubieta C, He XZ, Dixon RA, Noel JP (2001) Structures of two natural product methyltransferases reveal the basis for substrate specificity in plant O-methyltransferases. Nat Struct Biol 8(3):271–279
Weinshilboum RM, Raymond FA (1977) Inheritance of low erythrocyte catechol-o-methyltransferase activity in man. Am J Hum Genet 29(2):125–135
Tunbridge EM, Harrison PJ, Weinberger DR (2006) Catechol-o-methyltransferase, cognition, and psychosis: Val158Met and beyond. Biol Psychiatry 60(2):141–151
Bilder RM, Volavka J, Lachman HM, Grace AA (2004) The catechol-O-methyltransferase polymorphism: relations to the tonic-phasic dopamine hypothesis and neuropsychiatric phenotypes. Neuropsychopharmacology 29(11):1943–1961
Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE, Goldman D, Weinberger DR (2001) Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci U S A 98(12):6917–6922
Mattay VS et al (2003) Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. ProcNatlAcadSci U S A 100(10):6186–6191
Gogos JA, Morgan M, Luine V, Santha M, Ogawa S, Pfaff D, Karayiorgou M (1998) Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proc Natl Acad Sci U S A 95(17):9991–9996
Huotari M, Gogos JA, Karayiorgou M, Koponen O, Forsberg M, Raasmaja A, Hyttinen J, Mannisto PT (2002) Brain catecholamine metabolism in catechol-O-methyltransferase (COMT)-deficient mice. Eur J Neurosci 15(2):246–256
Babovic D, O’Tuathaigh CM, O’Connor AM, O’Sullivan GJ, Tighe O, Croke DT, Karayiorgou M, Gogos JA, Cotter D, Waddington JL (2008) Phenotypic characterization of cognition and social behavior in mice with heterozygous versus homozygous deletion of catechol-O-methyltransferase. Neuroscience 155(4):1021–1029
Desbonnet L, Tighe O, Karayiorgou M, Gogos JA, Waddington JL, O’Tuathaigh CM (2012) Physiological and behavioral responsivity to stress and anxiogenic stimuli in COMT-deficient mice. Behav Brain Res 228(2):351–358
Schendzielorz N, Mannisto PT, Karayiorgou M, Gogos JA, Raasmaja A (2012) A transient inhibition and permanent lack of catechol-O-methyltransferase have minor effects on feeding pattern of female rodents. Basic Clin Pharmacol Toxicol 110(4):307–313
Winterer G, Egan MF, Kolachana BS, Goldberg TE, Coppola R, Weinberger DR (2006) Prefrontal electrophysiologic “noise” and catechol-O-methyltransferase genotype in schizophrenia. Biol Psychiatry 60(6):578–584
Karayiorgou M, Gogos JA, Galke BL, Wolyniec PS, Nestadt G, Antonarakis SE, Kazazian HH, Housman DE, Pulver AE (1998) Identification of sequence variants and analysis of the role of the catechol-O-methyl-transferase gene in schizophrenia susceptibility. Biol Psychiatry 43(6):425–431
Kotler M, Barak P, Cohen H, Averbuch IE, Grinshpoon A, Gritsenko I, Nemanov L, Ebstein RP (1999) Homicidal behavior in schizophrenia associated with a genetic polymorphism determining low catechol O-methyltransferase (COMT) activity. Am J Med Genet 88(6):628–633
Li T, Vallada H, Curtis D, Arranz M, Xu K, Cai G, Deng H, Liu J, Murray R, Liu X, Collier DA (1997) Catechol-O-methyltransferase Val158Met polymorphism: frequency analysis in Han Chinese subjects and allelic association of the low activity allele with bipolar affective disorder. Pharmacogenetics 7(5):349–353
Kirov G, Murphy KC, Arranz MJ, Jones I, McCandles F, Kunugi H, Murray RM, McGuffin P, Collier DA, Owen MJ, Craddock N (1998) Low-activity allele of catechol-O-methyltransferase gene associated with rapid cycling bipolar disorder. Mol Psychiatry 3(4):342–345
Ohara K, Nagai M, Suzuki Y, Ohara K (1998) Low-activity allele of catechol-o-methyltransferase gene and Japanese unipolar depression. Neuroreport 9(7):1305–1308
Pooley EC, Fineberg N, Harrison PJ (2007) The met(158) allele of catechol-O-methyltransferase (COMT) is associated with obsessive-compulsive disorder in men: case–control study and meta-analysis. Mol Psychiatry 12(6):556–561
Karayiorgou M, Altemus M, Galke BL, Goldman D, Murphy DL, Ott J, Gogos JA (1997) Genotype determining low catechol-O-methyltransferase activity as a risk factor for obsessive-compulsive disorder. Proc Natl Acad Sci U S A 94(9):4572–4575
Azzam A, Mathews CA (2003) Meta-analysis of the association between the catecholamine-O-methyl-transferase gene and obsessive-compulsive disorder. Am J Med Genet B Neuropsychiatr Genet 123B(1):64–69
Vandenbergh DJ, Rodriguez LA, Miller IT, Uhl GR, Lachman HM (1997) High-activity catechol-O-methyltransferase allele is more prevalent in polysubstance abusers. Am J Med Genet 74(4):439–442
Horowitz R, Kotler M, Shufman E, Aharoni S, Kremer I, Cohen H, Ebstein RP (2000) Confirmation of an excess of the high enzyme activity COMT Val allele in heroin addicts in a family-based haplotype relative risk study. Am J Med Genet 96(5):599–603
Carlson C, Sirotkin H, Pandita R, Goldberg R, McKie J, Wadey R, Patanjali SR, Weissman SM, Anyane-Yeboa K, Warburton D, Scambler P, Shprintzen R, Kucherlapati R, Morrow BE (1997) Molecular definition of 22q11 deletions in 151 velocardiofacial syndrome patients. Am J Hum Genet 61(3):620–629
Gothelf D, Michaelovsky E, Frisch A, Zohar AH, Presburger G, Burg M, Aviram-Goldring A, Frydman M, Yeshaya J, Shohat M, Korostishevsky M, Apter A, Weizman A (2007) Association of the low-activity COMT 158Met allele with ADHD and OCD in subjects with velocardiofacial syndrome. Int J Neuropsychopharmacol 10(3):301–308
Faraone S, Biederman J (2002) Pathophysiology of Attention Deficit Hyperactivity Disorder. Neuropsychopharmacology: The Fifth Generation of Progress: 577–596
Barr CL, Xu C, Kroft J, Feng Y, Wigg K, Zai G, Tannock R, Schachar R, Malone M, Roberts W, Nothen MM, Grunhage F, Vandenbergh DJ, Uhl G, Sunohara G, King N, Kennedy JL (2001) Haplotype study of three polymorphisms at the dopamine transporter locus confirm linkage to attention-deficit/hyperactivity disorder. Biol Psychiatry 49(4):333–339
LaHoste GJ, Swanson JM, Wigal SB, Glabe C, Wigal T, King N, Kennedy JL (1996) Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. Mol Psychiatry 1(2):121–124
Cook EJ, Stein MA, Krasowski MD, Cox NJ, Olkon DM, Kieffer JE, Leventhal BL (1995) Association of attention-deficit disorder and the dopamine transporter gene. Am J Hum Genet 56(4):993–998
Faraone SV, Biederman J, Chen WJ, Milberger S, Warburton R, Tsuang MT (1995) Genetic heterogeneity in attention-deficit hyperactivity disorder (ADHD): gender, psychiatric comorbidity, and maternal ADHD. J Abnorm Psychol 104(2):334–345
Allen NC, Bagade S, McQueen MB, Ioannidis JP, Kavvoura FK, Khoury MJ, Tanzi RE, Bertram L (2008) Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nat Genet 40(7):827–834
Palmatier MA, Kang AM, Kidd KK (1999) Global variation in the frequencies of functionally different catechol-O-methyltransferase alleles. Biol Psychiatry 46(4):557–567
Cahill L (2006) Why sex matters for neuroscience. Nat Rev Neurosci 7(6):477–484
Cosgrove KP, Mazure CM, Staley JK (2007) Evolving knowledge of sex differences in brain structure, function, and chemistry. Biol Psychiatry 62(8):847–855
Qian Q, Wang Y, Zhou R, Li J, Wang B, Glatt S, Faraone SV (2003) Family-based and case–control association studies of catechol-O-methyltransferase in attention deficit hyperactivity disorder suggest genetic sexual dimorphism. Am J Med Genet B Neuropsychiatr Genet 118B:103–109
Ernst M, Liebenauer LL, King AC, Fitzgerald GA, Cohen RM, Zametkin AJ (1994) Reduced brain metabolism in hyperactive girls. J Am Acad Child Adolesc Psychiatry 33(6):858–868
Nolan KA, Volavka J, Czobor P, Cseh A, Lachman H, Saito T, Tiihonen J, Putkonen A, Hallikainen T, Kotilainen I, Rasanen P, Isohanni M, Jarvelin MR, Karvonen MK (2000) Suicidal behavior in patients with schizophrenia is related to COMT polymorphism. Psychiatr Genet 10(3):117–124
Karayiorgou M, Sobin C, Blundell ML, Galke BL, Malinova L, Goldberg P, Ott J, Gogos JA (1999) Family-based association studies support a sexually dimorphic effect of COMT and MAOA on genetic susceptibility to obsessive-compulsive disorder. Biol Psychiatry 45(9):1178–1189
Galva MD, Bondiolotti GP, Olasmaa M, Picotti GB (1995) Effect of aging on lazabemide binding, monoamine oxidase activity, and monoamine metabolites in human frontal cortex. J Neural Transm Gen Sect 101(1–3):83–94
Venero JL, Machado A, Cano J (1991) Turnover of dopamine and serotonin and their metabolites in the striatum of aged rats. J Neurochem 56(6):1940–1948
Stramentinoli G, Gualano M, Algeri S, de Gaetano G, Rossi EC (1978) Catechol-o-methyl transferase (COMT) in human and rat platelets. Thromb Haemost 39(1):238–239
Meng SZ, Ozawa Y, Itoh M, Takashima S (1999) Developmental and age-related changes of dopamine transporter and dopamine D1 and D2 receptors in human basal ganglia. Brain Res 843(1–2):136–144
Lee JJ, Chang CK, Liu IM, Chi TC, Yu HJ, Cheng JT (2001) Changes in endogenous monoamines in aged rats. Clin Exp Pharmacol Physiol 28(4):285–289
Demarest KT, Riegle GD, Moore KE (1980) Characteristics of dopaminergic neurons in the aged male rat. Neuroendocrinology 31(3):222–227
Estes KS, Simpkins JW (1980) Age-related alterations in catecholamine concentrations in discrete preoptic area and hypothalamic regions in the male rat. Brain Res 194(2):556–560
Carlsson A, Winblad B (1976) Influence of age and time interval between death and autopsy on dopamine and 3-methoxytyramine levels in human basal ganglia. J Neural Transm 38(3–4):271–276
Riederer P, Wuketich S (1976) Time course of nigrostriatal degeneration in Parkinson's disease. A detailed study of influential factors in human brain amine analysis. J Neural Transm 38(3–4):277–301
Shifman S et al (2002) A highly significant association between a COMT haplotype and schizophrenia. Am J Hum Genet 71(6):1296–1302
Bray NJ, Buckland PR, Williams NM, Williams HJ, Norton N, Owen MJ, O’Donovan MC (2003) A haplotype implicated in schizophrenia susceptibility is associated with reduced COMT expression in human brain. Am J Hum Genet 73(1):152–161
Nackley AG, Shabalina SA, Tchivileva IE, Satterfield K, Korchynskyi O, Makarov SS, Maixner W, Diatchenko L (2006) Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure. Science 314(5807):1930–1933
Wu J, Xiao H, Sun H, Zou L, Zhu LQ (2012) Role of dopamine receptors in ADHD: a systematic meta-analysis. Mol Neurobiol 45(3):605–620
Zhong R, Tian Y, Liu L, Qiu Q, Wang Y, Rui R, Yang BF, Duan SY, Shi JX, Miao XP, Wang L, Li H (2012) HBV-related hepatocellular carcinoma susceptibility gene KIF1B is not associated with development of chronic hepatitis B. PLoS One 7:e28839
Acknowledgments
This work is supported by the National Nature Science Foundation of China (NSFC) (81101016).
Conflicts of interest
The authors have declared no conflicts of interest.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
ESM 1
(DOCX 330 kb)
Rights and permissions
About this article
Cite this article
Sun, H., Yuan, F., Shen, X. et al. Role of COMT in ADHD: a Systematic Meta-Analysis. Mol Neurobiol 49, 251–261 (2014). https://doi.org/10.1007/s12035-013-8516-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12035-013-8516-5