Skip to main content

Advertisement

SpringerLink
Log in

Gene–Gene Interaction Between COMT and MAOA Potentially Predicts the Intelligence of Attention-Deficit Hyperactivity Disorder Boys in China

  • Original Research
  • Published:
Behavior Genetics Aims and scope Submit manuscript

Abstract

The catechol-O-methyltransferase (COMT) gene contains a functional polymorphism (Val158Met) affecting the activity of the enzyme, and the monoamine oxidase A (MAOA) gene contains a VNTR polymorphism (MAOA-uVNTR) that affects the transcription of the gene. COMT and MAOA each contribute to the enzymatic degradation of dopamine and noradrenaline. Prefrontal cortical (PFC) function, which plays an important role in individual cognitive abilities, including intelligence, is modulated by dopamine. Since our previous association studies between attention deficit hyperactivity disorder (ADHD) and these two functional polymorphisms consistently showed the low activity alleles were preferentially transmitted to inattentive ADHD boys, the goal of the present study was to test the hypothesis that the interaction between COMT Val158Met and MAOA-uVNTR may affect the intelligence in a clinical sample of Chinese male ADHD subjects (n = 264). We found that the COMT × MAOA interaction significantly predicted full scale (FSIQ) and performance (PIQ) IQ scores (P = 0.039, 0.011); the MAOA-uVNTR significantly predicted FSIQ, PIQ and verbal IQ (VIQ) (P = 0.009, 0.019, 0.038); COMT Val158Met independently had no effect on any of the IQ scores. Only the COMT × MAOA interaction for PIQ remained significant after a Bonferroni correction. Among all combined genotypes, the valval-3R genotype predicted higher intelligence, (average 106.7 ± 1.6, 95% C.I. 103.7–109.8 for FSIQ), and the valval-4R predicted lower intelligence (average 98.0 ± 2.3, 95% C.I. 93.5–102.6 for FSIQ). These results suggest that there is an inverted U-shaped relationship between intelligence and dopaminergic activity in our sample. Our finding that gene–gene interaction between COMT and MAOA predicts the intelligence of ADHD boys in China is intriguing but requires replication in other samples.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Abi-Dargham A, Mawlawi O, Lombardo I, Gil R, Martinez D, Huang Y, Hwang DR, Keilp J, Kochan L, Van Heertum R, Gorman JM, Laruelle M (2002) Prefrontal dopamine D1 receptors and working memory in schizophrenia. J Neurosci 22(9):3708–3719

    PubMed  Google Scholar 

  • American Psychiatric Association (1994) Diagnostic and statistical manual of mental disorders (DSM-IV), 4th edn. American Psychiatric Association, Washington, DC

    Google Scholar 

  • Antshel KM, Phillips MH, Gordon M, Barkley R, Faraone SV (2006) Is ADHD a valid disorder in children with intellectual delays? Clin Psychol Rev 26(5):555–572

    Article  PubMed  Google Scholar 

  • Arnsten AF, Li BM (2005) Neurobiology of executive functions: catecholamine influences on prefrontal cortical functions. Biol Psychiatry 57(11):1377–1384

    Article  PubMed  Google Scholar 

  • Aron AR, Poldrack RA (2005) The cognitive neuroscience of response inhibition: relevance for genetic research in attention-deficit/hyperactivity disorder. Biol Psychiatry 57(11):1285–1292

    Article  PubMed  Google Scholar 

  • Barkley RA (1998) Attention-deficit hyperactivity disorder: a clinical workbook, 2nd edn. Guilford, New York, pp 39–55

    Google Scholar 

  • Barnett JH, Heron J, Ring SM, Golding J, Goldman D, Xu K, Jones PB (2007) Gender-specific effects of the catechol-O-methyltransferase Val108/158Met polymorphism on cognitive function in children. Am J Psychiatry 164(1):142–149

    Article  PubMed  Google Scholar 

  • Bellgrove MA, Domschke K, Hawi Z, Kirley A, Mullins C, Robertson IH, Gill M (2005a) The methionine allele of the COMT polymorphism impairs prefrontal cognition in children and adolescents with ADHD. Exp Brain Res 163(3):352–360

    Article  PubMed  Google Scholar 

  • Bellgrove MA, Hawi Z, Kirley A, Fitzgerald M, Gill M, Robertson IH (2005b) Association between dopamine transporter (DAT1) genotype, left-sided inattention, and an enhanced response to methylphenidate in attention-deficit hyperactivity disorder. Neuropsychopharmacology 30(12):2290–2297

    Article  PubMed  Google Scholar 

  • Biederman J (2005) Attention-deficit/hyperactivity disorder: a selective overview. Biol Psychiatry 57(11):1215–1220

    Article  PubMed  Google Scholar 

  • Biederman J, Kim JW, Doyle AE, Mick E, Fagerness J, Smoller JW, Faraone SV (2008) Sexually dimorphic effects of four genes (COMT, SLC6A2, MAOA, SLC6A4) in genetic associations of ADHD: a preliminary study. Am J Med Genet B Neuropsychiatr Genet 147B(8):1511–1518

    Article  PubMed  Google Scholar 

  • Blackburn LB, Lee GP, Westerveld M, Hempel A, Park YD, Loring DW (2007) The verbal IQ/performance IQ discrepancy as a sign of seizure focus laterality in pediatric patients with epilepsy. Epilepsy Behav 10(1):84–88

    Article  PubMed  Google Scholar 

  • Brennan AR, Arnsten AF (2008) Neuronal mechanisms underlying attention deficit hyperactivity disorder the influence of arousal on prefrontal cortical function. Ann NY Acad Sci 1129:236–245

    Article  PubMed  Google Scholar 

  • Cases O, Seif I, Grimsby J, Gaspar P, Chen K, Pournin S, Müller U, Aguet M, Babinet C, Shih JC et al (1995) Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA. Science 268(5218):1763–1766

    Article  PubMed  Google Scholar 

  • Caspi A, McClay J, Moffitt TE, Mill J, Martin J, Craig IW, Taylor A, Poulton R (2002) Role of genotype in the cycle of violence in maltreated children. Science 297(5582):851–854

    Article  PubMed  Google Scholar 

  • Chen J, Lipska BK, Halim N, Ma QD, Matsumoto M, Melhem S, Kolachana BS, Hyde TM, Herman MM, Apud J, Egan MF, Kleinman JE, Weinberger DR (2004) Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet 75(5):807–821

    Article  PubMed  Google Scholar 

  • Cheuk DK, Wong V (2006) Meta-analysis of association between a catechol-O-methyltransferase gene polymorphism and attention deficit hyperactivity disorder. Behav Genet 36(5):651–659

    Article  PubMed  Google Scholar 

  • Cools R, Robbins TW (2004) Chemistry of the adaptive mind. Philos Transact A Math Phys Eng Sci 362(1825):2871–2888

    Article  PubMed  Google Scholar 

  • Deckert J, Catalano M, Syagailo YV, Bosi M, Okladnova O, Di Bella D, Nöthen MM, Maffei P, Franke P, Fritze J, Maier W, Propping P, Beckmann H, Bellodi L, Lesch KP (1999) Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder. Hum Mol Genet 8(4):621–624

    Article  PubMed  Google Scholar 

  • Diamond A, Briand L, Fossella J, Gehlbach L (2004) Genetic and neurochemical modulation of prefrontal cognitive functions in children. Am J Psychiatry 161(1):125–132

    Article  PubMed  Google Scholar 

  • Ducci F, Newman TK, Funt S, Brown GL, Virkkunen M, Goldman D (2006) A functional polymorphism in the MAOA gene promoter (MAOA-LPR) predicts central dopamine function and body mass index. Mol Psychiatry 11(9):858–866

    Article  PubMed  Google Scholar 

  • Duncan J, Seitz RJ, Kolodny J, Bor D, Herzog H, Ahmed A, Newell FN, Emslie H (2000) A neural basis for general intelligence. Science 289(5478):457–460

    Article  PubMed  Google Scholar 

  • Eisenberg J, Mei-Tal G, Steinberg A, Tartakovsky E, Zohar A, Gritsenko I, Nemanov L, Ebstein RP (1999) Haplotype relative risk study of catechol-O-methyltransferase and attention deficit hyperactivity disorder (ADHD): association of the high-enzyme activity allele with ADHD impulsive-hyerpactive people. Am J Med Genet 88(5):497–502

    Article  PubMed  Google Scholar 

  • Eisenhofer G, Finberg JP (1994) Different metabolism of norepinephrine and epinephrine by catechol-O-methyltransferase and monoamine oxidase in rats. J Pharmacol Exp Ther 268(3):1242–1251

    PubMed  Google Scholar 

  • Faraone SV, Sergeant J, Gillberg C, Biederman J (2003) The worldwide prevalence of ADHD: is it an American condition? World Psychiatry 2(2):104–113

    PubMed  Google Scholar 

  • Gevins A, Smith ME (2000) Neurophysiological measures of working memory and individual differences in cognitive ability and cognitive style. Cereb Cortex 10(9):829–839

    Article  PubMed  Google Scholar 

  • 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 USA 95(17):9991–9996

    Article  PubMed  Google Scholar 

  • Goldberg TE, Weinberger DR (2004) Genes and the parsing of cognitive processes. Trends Cogn Sci 8(7):325–335

    Article  PubMed  Google Scholar 

  • Goldman-Rakic PS, Muly EC 3rd, Williams GV (2000) D(1) receptors in prefrontal cells and circuits. Brain Res Rev 31(2–3):295–301

    Article  PubMed  Google Scholar 

  • Gong YX, Cai TS (1993) Manual of wechsler intelligence scale for children, Chinese revision (C-WISC). Hunan Map Press, Changsha, China

    Google Scholar 

  • Gray JR, Thompson PM (2004) Neurobiology of intelligence: science and ethics. Nat Neurosci 5(6):471–482

    Google Scholar 

  • Hechtman L (1994) Genetic and neurobiological aspects of attention deficit hyperactivity disorder: a review. J Psychiatr Neurosci 19(3):193–201

    Google Scholar 

  • Huang YY, Cate SP, Battistuzzi C, Oquendo MA, Brent D, Mann JJ (2004) An association between a functional polymorphism in the monoamine oxidase a gene promoter, impulsive traits and early abuse experiences. Neuropsychopharmacology 29(8):1498–1505

    Article  PubMed  Google Scholar 

  • Illi A, Sundberg S, Ojala-Karlsson P, Scheinin M, Gordin A (1996) Simultaneous inhibition of catechol-O-methyltransferase and monoamine oxidase A: effects on hemodynamics and catecholamine metabolism in healthy volunteers. Clin Pharmacol Ther 59(4):450–457

    Article  PubMed  Google Scholar 

  • Ishii T, Takahashi O, Kawamura Y, Ohta T (2003) Comorbidity in attention deficit-hyperactivity disorder. Psychiatry Clin Neurosci 57(5):457–463

    Article  PubMed  Google Scholar 

  • Jepsen JR, Fagerlund B, Mortensen EL (2009) Do attention deficits influence IQ assessment in children and adolescents with ADHD? J Atten Disord 12(6):551–562

    Article  PubMed  Google Scholar 

  • Jönsson EG, Nortonb N, Gustavssonc JP, Oreland L, Owen MJ, Sedvall GC (2000) A promoter polymorphism in the monoamine oxidase A gene and its relationships to monoamine metabolite concentrations in CSF of healthy volunteers. J Psychiatr Res 34(3):239–244

    Article  PubMed  Google Scholar 

  • Karoum F, Chrapusta SJ, Egan MF (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(3):972–979

    Article  PubMed  Google Scholar 

  • Kellendonk C, Simpson EH, Polan HJ, Malleret G, Vronskaya S, Winiger V, Moore H, Kandel ER (2006) Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning. Neuron 49(4):603–615

    Article  PubMed  Google Scholar 

  • Konrad K, Neufang S, Hanisch C, Fink GR, Herpetz-Dahlmann B (2006) Dysfunctional attentional networks in children with ADHD: evidence from an event-related fMRI study. Biol Psychiatry 59(7):643–651

    Article  PubMed  Google Scholar 

  • Kuntsi J, Eley TC, Taylor A, Hughes C, Asherson P, Caspi A, Moffitt TE (2004) Co-occurrence of ADHD and low IQ has genetic origins. Am J Med Genet 124B(1):41–47

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Levy F (2009) Dopamine vs noradrenaline: inverted-U effects and ADHD theories. Aust NZ J Psychiatry 43(2):101–108

    Article  Google Scholar 

  • Malone MA, Kershner JR, Swanson JM (1994) Hemispheric processing and methylphenidate effects in attention-deficit hyperactivity disorder. J Child Neurol 9(2):181–189

    Article  PubMed  Google Scholar 

  • Mannuzza S, Klein RG, Moulton JL III (2008) Lifetime criminality among boys with attention deficit hyperactivity disorder: a prospective follow-up study into adulthood using official arrest records. Psychiatry Res 160(3):237–246

    Article  PubMed  Google Scholar 

  • Manor I, Tyano S, Mel E, Eisenberg J, Bachner-Melman R, Kotler M, Ebstein RP (2002) 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(6):626–632

    Article  PubMed  Google Scholar 

  • Matsuda Y, Hirano H, Watanabe Y (2002) Effects of estrogen on acetylcholine release in frontal cortex of female rats: involvement of serotonergic neuronal systems. Brain Res 937(1–2):58–65

    Article  PubMed  Google Scholar 

  • Mattay VS, Callicott JH, Bertolino A, Heaton I, Frank JA, Coppola R, Berman KF, Goldberg TE, Weinberger DR (2000) Effects of dextroamphetamine on cognitive performance and cortical activation. Neuroimage 12(3):268–275

    Article  PubMed  Google Scholar 

  • Mick E, Faraone SV (2008) Genetics of attention deficit hyperactivity disorder. Child Adolesc Psychiatr Clin N Am 17(2):261–284 vii-viii

    Article  PubMed  Google Scholar 

  • Muller U, von Cramon DY, Pollmann S (1998) D1- versus D2-receptor modulation of visuospatial working memory in humans. J Neurosci 18(7):2720–2728

    PubMed  Google Scholar 

  • Nigg JT, Willcutt EG, Doyle AE, Sonuga-Barke EJ (2005) Causal heterogeneity in attention-deficit/hyperactivity disorder: do we need neuropsychologically impaired subtypes? Biol Psychiatry 57(11):1224–1230

    Article  PubMed  Google Scholar 

  • Pliszka SR, Glahn DC, Semrud-Clikeman M, Franklin C, Perez R 3rd, Xiong J, Liotti M (2006) Neuroimaging of inhibitory control areas in children with attention deficit hyperactivity disorder who were treatment naive or in long-term treatment. Am J Psychiatry 163(6):1052–1060

    Article  PubMed  Google Scholar 

  • Prince J (2008) Catecholamine dysfunction in attention-deficit/hyperactivity disorder: an update. J Clin Psychopharmacol 28(3 Suppl 2):S39–45

    Article  PubMed  Google Scholar 

  • 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 118B(1):103–109

    Article  PubMed  Google Scholar 

  • Rapport MD, Alderson RM, Kofler MJ, Sarver DE, Bolden J, Sims V (2008) Working memory deficits in boys with attention-deficit/hyperactivity disorder (ADHD): the contribution of central executive and subsystem processes. J Abnorm Child Psychol 36(6):825–837

    Article  PubMed  Google Scholar 

  • Roessner V, Banaschewski T, Fillmer-Otte A, Becker A, Albrecht B, Uebel H, Sergeant J, Tannock R, Rothenberger A (2008) Color perception deficits in co-existing attention-deficit/hyperactivity disorder and chronic tic disorders. J Neural Transm 115(2):235–239

    Article  PubMed  Google Scholar 

  • Russell VA (2002) Hypodopaminergic and hypernoradrenergic activity in prefrontal cortex slices of an animal model for attention-deficit hyperactivity disorder—the spontaneously hypertensive rat. Behav Brain Res 130(1–2):191–196

    Article  PubMed  Google Scholar 

  • Sabol SZ, Hu S, Hamer D (1998) A functional polymorphism in the monoamine oxidase A gene promoter. Hum Genet 103(3):273–279

    Article  PubMed  Google Scholar 

  • Saito T, Lachman HM, Diaz L, Hallikainen T, Kauhanen J, Salonen JT, Ryynänen OP, Karvonen MK, Syvälahti E, Pohjalainen T, Hietala J, Tiihonen J (2002) Analysis of monoamine oxidase A (MAOA) promoter polymorphism in Finnish male alcoholics. Psychiatry Res 109(2):113–119

    Article  PubMed  Google Scholar 

  • Savitz J, Solms M, Ramesar R (2006) The molecular genetics of cognition: dopamine, COMT and BDNF. Genes Brain Behav 5(4):311–328

    Article  PubMed  Google Scholar 

  • Schulz KP, Newcorn JH, Fan J, Tang C, Halperin JM (2005) Brain activation gradients in ventrolateral prefrontal cortex related to persistence of ADHD in adolescent boys. J Am Acad Child Adolesc Psychiatry 44(1):47–54

    Article  PubMed  Google Scholar 

  • Tsai SJ, Yu YW, Chen TJ, Chen JY, Liou YJ, Chen MC, Hong CJ (2003) Association study of a functional catechol-O-methyltransferase gene polymorphism and cognitive function in healthy females. Neurosci Lett 338(2):123–126

    Article  PubMed  Google Scholar 

  • Tunbridge EM, Harrison PJ, Weinberger DR (2006) Catechol-o-methyltransferase, cognition, and psychosis: Val158Met and beyond. Biol Psychiatry 60(2):141–151

    Article  PubMed  Google Scholar 

  • Vaidya CJ, Stollstorff M (2008) Cognitive neuroscience of attention deficit hyperactivity disorder: current status and working hypotheses. Dev Disabil Res Rev 14(4):261–267

    Article  PubMed  Google Scholar 

  • Vaidya CJ, Bunge SA, Dudukovic NM, Zalecki CA, Elliott GR, Gabrieli JD (2005) Altered neural substrates of cognitive control in childhood ADHD: evidence from functional magnetic resonance imaging. Am J Psychiatry 162(9):1605–1613

    Article  PubMed  Google Scholar 

  • Vance A, Silk TJ, Casey M, Rinehart NJ, Bradshaw JL, Bellgrove MA, Cunnington R (2007) Right parietal dysfunction in children with attention deficit hyperactivity disorder, combined type: a functional MRI study. Mol Psychiatry 12(9):826–832 793

    Article  PubMed  Google Scholar 

  • Yang L, Wang YF, Qian QJ, Gu BM (2001) Primary exploration of the clinical subtupes of attention deficit hyperactivity disorder in Chinese children. Chin J Psychiatry 34(4):204–207 Chinese

    Google Scholar 

  • Yang L, Wang YF, Qian QJ, Biederman J, Faraone SV (2004) DSM-IV subtypes of ADHD in a Chinese outpatient sample. J Am Acad Child Adolesc Psychiatry 43(3):248–250

    Article  PubMed  Google Scholar 

  • Yu YW, Tsai SJ, Hong CJ, Chen MC, Yang CW, Chen TJ (2005) Association study of a functional MAOA-uVNTR gene polymorphism and cognitive function in healthy females. Neuropsychobiology 52(2):77–82

    Article  PubMed  Google Scholar 

  • Zhang H, Wang Y, Li J, Yang L, Wang B, Cubells J, Tang Y, Sham P (2005) Association study between three polymorphisms of MAOA gene and attention deficit hyperactivity disorder among the Chinese Han ethnicity. Am J Med Genet B Neuropsychiatr Genet 138B(1):63–64

    Google Scholar 

Download references

Acknowledgments

The authors are grateful to Prof. Stacey Cherny and two anonymous reviewers for the constructive comments which significantly improved the manuscript. This study was partly funded by the National Natural Sciences Foundation of China (Grant number: 30770774), the Commonweal Sciences Foundation, Ministry of Health, China (Grant number: 200802073), and the National Foundation, Ministry of Science and Technology, China (Grant number: 2007BAI17B03)

Author information

Authors and Affiliations

  1. Institute of Mental Health, Key Laboratory of Mental Health, Ministry of Health, Peking University, 100191, Beijing, China

    Qiu-Jin Qian, Li Yang, Yu-Feng Wang, Hao-Bo Zhang, Li-Li Guan, Yun Chen, Ning Ji & Lu Liu

  2. Departments of Psychiatry and Neuroscience & Physiology, SUNY Upstate Medical University, Syracuse, NY, USA

    S. V. Faraone

Authors
  1. Qiu-Jin Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Li Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yu-Feng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hao-Bo Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Li-Li Guan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yun Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ning Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lu Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. S. V. Faraone
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yu-Feng Wang.

Additional information

Edited by Stacey Cherny.

Qiu-Jin Qian and Li Yang contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Qian, QJ., Yang, L., Wang, YF. et al. Gene–Gene Interaction Between COMT and MAOA Potentially Predicts the Intelligence of Attention-Deficit Hyperactivity Disorder Boys in China. Behav Genet 40, 357–365 (2010). https://doi.org/10.1007/s10519-009-9314-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10519-009-9314-8

Keywords

Search

Navigation