Experimental Brain Research

, Volume 163, Issue 3, pp 352–360 | Cite as

The methionine allele of the COMT polymorphism impairs prefrontal cognition in children and adolescents with ADHD

  • Mark A. Bellgrove
  • Katharina Domschke
  • Ziarih Hawi
  • Aiveen Kirley
  • Celine Mullins
  • Ian H. Robertson
  • Michael Gill
Research Article

Abstract

ADHD is a highly heritable psychiatric disorder of childhood. A functional polymorphism (Val158Met) of the catechol-O-methyltransferase (COMT) gene has attracted interest as a candidate gene for ADHD. The high-activity valine variant of this polymorphism degrades prefrontal dopamine three to four times more quickly than the low-activity methionine variant and could therefore contribute to the proposed hypodopaminergic state in ADHD. Here we tested for association of this polymorphism with ADHD and examined its influence on prefrontal cognition in ADHD. We have previously reported no association of the Val158Met COMT gene polymorphism in 94 Irish ADHD families (Hawi et al. (2000) Am J Med Genet 96:282–284). Here we re-examined this finding with an extended sample of 179 ADHD cases using a family control design. We also examined the performance of children and adolescents with ADHD (n=61) on a standardised test of sustained attention. Analysis confirmed the absence of an association between the Val158Met COMT gene polymorphism and the clinical phenotype of ADHD. COMT genotype, however, affected prefrontal cognition in ADHD: ADHD children who were homozygous for the valine variant had significantly better sustained attention than those ADHD children possessing at least one copy of the methionine variant. Children possessing the methionine variant performed significantly below age-related norms on tests of sustained attention. Contrary to expectations, the methionine variant of the Val158Met COMT gene polymorphism impaired prefrontally-mediated cognition in ADHD. This effect may be understood by positing a hyper-functioning of prefrontal dopaminergic systems. Against this background, the slower clearance of dopamine associated with the methionine variant of the COMT gene polymorphism may be disadvantageous to cognition in ADHD.

Keywords

ADHD COMT Dopamine Attention Genetics 

References

  1. Akil M, Kolachana BS, Rothmond DA, Hyde TM, Weinberger DR, Kleinman JE (2003) Catechol-O-methyltransferase genotype and dopamine regulation in the human brain. J Neurosci 23:2008–2013Google Scholar
  2. American Psychiatric Association (1995) Diagnostic and statistical manual of mental disorders. American Psychiatric Association, Washington, DCGoogle Scholar
  3. Angold A, Predergast M, Cox A, Harrington R, Simonoff E, Rutter M (1995) The child and adolescent psychiatric assessment (CAPA). Psychol Med 25:739–753PubMedGoogle Scholar
  4. Arnsten AFT (1998) Catecholamine modulation of prefrontal cortical cognitive function. Trends Cogn Sci 2: 436-447CrossRefGoogle Scholar
  5. 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 88:710–713CrossRefGoogle Scholar
  6. Bilder RM, Volavka J, Czobor Pa, Malhotra AK, Kennedy JL, Ni X, Goldman RS, Hoptman MJ, Sheitman B, Lindenmayer J-P (2002) Neurocognitive correlates of the COMT Val158Met polymorphism in chronic schizophrenia. Biol Psychiat 52:701–707CrossRefPubMedGoogle Scholar
  7. Castellanos FX, Tannock R (2002) Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes. Nat Rev Neurosci 3:617–628PubMedGoogle Scholar
  8. Conners CK (1998) Rating scales in attention deficit hyperactivity disorder: use in assessment and treatment monitoring. J Clin Psychiat 59:24–30Google Scholar
  9. Diamond A, Briand L, Fossella J, Gehlbach L (2004) Genetic and neurochemical modulation of prefrontal cognitive functions in children. Am J Psychiat 161:125–132CrossRefGoogle Scholar
  10. Domschke K, Freitag CM, Kuhlenbumer G, Schirmacher A, Sand P, Nyhuis P, Jacob C, Fritze J, Franke P, Rietschel M, Garritsen HS, Fimmers R, Nthen MM, Lesch KP, Stgbauer F, Deckert J (2004) Association of the functional V158M catechol-O-methyl-transferase polymorphism with panic disorder in women. Int J Neuropsychoph 7:183–188Google Scholar
  11. Duncan J, Emslie H, Williams P, Johnson R, Freer C (1996) Intelligence and the frontal lobe: the organization of goal-directed behavior. Cognitive Psychol 30:257–303CrossRefGoogle Scholar
  12. Durston S, Tottenham NT, Thomas KM, Davidson MC, Eigsti IM, Yang Y, Ulug AM, Casey BJ (2003) Differential patterns of striatal activation in young children with and without ADHD. Biol Psychiat 53:871–878CrossRefGoogle Scholar
  13. 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. P Natl Acad Sci USA 98:6917–6922CrossRefGoogle Scholar
  14. 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 (COMT) and attention deficit hyperactivity disorder (ADHD): Association of the high-enzyme activity val allele with ADHD impulsive-hyperactive phenotype. Am J Med Genet 88:497–502Google Scholar
  15. Garavan H, Ross TJ, Stein EA (1999) Right hemisphere dominance for inhibitory control: An event-related functional MRI study. P Natl Acad Sci USA 96:8301–8306CrossRefGoogle Scholar
  16. Goldberg TE, Egan MF, Gscheidle, Cappola R, Weickert T, Kolachana BS, Goldman D, Weinberger DR (2003) Executive subprocesses in working memory: Relationship to catechol-O-methyltransferase Val158Met genotype and schizophrenia. Arch Gen Psychiat 60:889–896CrossRefPubMedGoogle Scholar
  17. Hawi Z, Millar N, Daly G, Fitzgerald M, Gill M (2000) No association between catechol-O-methyltransferase (COMT) gene polymorphism and attention deficit hyperactivity disorder (ADHD) in an Irish sample. Am J Med Genet 96:282–284CrossRefGoogle Scholar
  18. Holmes J, Lawson D, Langley K, Fitzpatrick H, Trumper A, Pay H, Harrington R, Thapar A (2004) The child attention-deficit hyperactivity disorder teacher telephone interview (CHATTI): reliability and validity. Br J Psychiat 184:74–78CrossRefGoogle Scholar
  19. 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 63:972–979Google Scholar
  20. Kimko HC, Cross JT, Abernathy DR (1999) Pharmacokinetics and clinical effectiveness of methylphenidate. Clin Pharmacokinet 37:457–470Google Scholar
  21. Kirley A, Hawi Z, Daly G, McCarron M, Mullins C, Millar N, Waldman I, Fitzgerald M, Gill M (2002) Dopaminergic system genes in ADHD: toward a biological hypothesis. Neuropsychopharmacol 27:607–619Google Scholar
  22. 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 6:243–250PubMedGoogle Scholar
  23. Malhotra AK, Kestler LJ, Mazzanti C, Bates JA, Goldberg T, Goldman D (2002) A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition. Am J Psychiat 159:652–654CrossRefPubMedGoogle Scholar
  24. Manly T, Anderson V, Nimmo-Smith I, Turner A, Watson P, Robertson IH (2001) The differential assessment of children’s attention: the test of everyday attention for children (TEA-Ch), normative sample and ADHD performance. J Child Psychol Psyc 42:1065–1081CrossRefGoogle Scholar
  25. Manly T, Owen AM, McAvenue L, Datta A, Lewis GH, Scott SK, Rorden C, Pickard J, Robertson IH (2003) Enhancing the sensitivity of a sustained attention task to frontal damage: convergent clinical and functional imaging evidence. Neurocase 9:340–349CrossRefGoogle Scholar
  26. Manor I, Kotler M, Sever Y, Eisenberg J, Cohen H, Ebstein RP, Tyano S (2000) Failure to replicate an association between the catechol-O-methyltransferase polymorphism and attention deficit hyperactivity disorder in a second, independently recruited Israeli cohort. Am J Med Genet 96:858–860CrossRefGoogle Scholar
  27. Mattay VS, Goldberg TE, Fera F, Hariri AR, Tessitore A, Egan MF, Kolachana B, Callicott JH, Weinberger DR (2003) Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. P Natl Acad Sci USA 100:6186–6191CrossRefGoogle Scholar
  28. Payton A, Holmes J, Barrett JH, Hever T, Fitzpatrick H, Trumper AL, Harrington R, McGuffin P, O’Donovan M, Owen M, Ollier W, Worthington J, Thapar A (2001) Examining for association between candidate gene polymorphisms in the dopamine pathway and attention-deficit hyperactivity disorder: a family-based study. Am J Med Genet 105:464–470CrossRefGoogle Scholar
  29. Pennington BF, Ozonoff S (1996) Executive functions and developmental psychopathology. J Child Psychol Psyc 37: 51-87PubMedGoogle Scholar
  30. Posner MI, Peterson SE (1990) The attention system of the human brain. Annu Rev Neurosci 13:35–42CrossRefGoogle Scholar
  31. 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:103–109CrossRefGoogle Scholar
  32. Robertson IH (2004) Examining attentional rehabilitation. In: Posner MI (ed) Cognitive neuroscience of attention. Guilford Press, London, pp 407–419Google Scholar
  33. Rueckert L, Grafman J (1996) Sustained attention deficits in patients with right frontal lesions. Neuropsychologia 34:953–963CrossRefGoogle Scholar
  34. Sawaguchi T, Goldman-Rakic PS (1991) D1 dopamine receptors in prefrontal cortex: involvement in working memory. Science 251:947–950PubMedGoogle Scholar
  35. Shallice T, Marzocchi GM, Coser S, Del Savio M, Meuter RF, Rumiati RI (2002) Executive function profile of children with attention deficit hyperactivity disorder. Dev Neuropsychol 21:43–71CrossRefGoogle Scholar
  36. Sowell ER, Thompson PM, Welcome SE, Henkenius AL, Toga AW, Peterson BS (2003) Cortical abnormalities in children and adolescents with attention-deficit hyperactivity disorder. Lancet 362:1699–1707CrossRefPubMedGoogle Scholar
  37. Spalletta G, Pasini A, Pau F, Guido G, Menghini L, Caltagirone C (2001) Prefrontal blood flow dysregulation in drug naive ADHD children without structural abnormalities. J Neural Transm 108:1203–1216CrossRefGoogle Scholar
  38. Spielman RS, Ewens WJ (1996) The TDT and other family-based tests for linkage disequilibrium and association. Am J Hum Genet 59:983–989PubMedGoogle Scholar
  39. Sturm W, Longoni F, Fimm B, Dietrich T, Weis S, Kemna S, Herzog H, Willmes K (2004) Network for auditory intrinsic alertness: a PET study. Neuropsychologia 42:563–568CrossRefGoogle Scholar
  40. Stuss DT, Shallice T, Alexander MP, Picton TW (1995) A multidisciplinary approach to anterior attentional functions. Ann NY Acad Sci 769:191–211Google Scholar
  41. Szameitat AJ, Schubert T, Muller K, Von Cramon DY (2002) Localization of executive functions in dual-task performance with fMRI. J Cogn Neurosci 14:1184–1199CrossRefPubMedGoogle Scholar
  42. Tahir E, Curran S, Yazgan Y, Ozbay F, Cirakoglu B, Asherson PJ (2000) No association between low- and high-activity catecholamine-methyl-transferase (COMT) and attention deficit hyperactivity disorder (ADHD) in a sample of Turkish children. Am J Med Genet 96:285–288CrossRefGoogle Scholar
  43. Tannock R, Schachar R, Logan G (1995) Methylphenidate and cognitive flexibility: dissociated dose effects in hyperactive children. J Abnorm Child Psych 23:235–266Google Scholar
  44. Tehunen 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 223:1049–1059PubMedGoogle Scholar
  45. Viggiano D, Grammatikopoulos G, Sadile AG (2002) A morphometric evidence for a hyperfunctioning mesolimbic system in an animal model of ADHD. Behav Brain Res 130:181–189CrossRefGoogle Scholar
  46. Vles JS, Feron FJ, Hendriksen JG, Jolles J, van Kroonenburgh MJ, Weber WE (2003) Methylphenidate down-regulates the dopamine receptor and transporter system in children with attention deficit hyperkinetic disorder (ADHD). Neuropediatrics 34:77–80CrossRefGoogle Scholar
  47. Waldman ID, Robinson BF, Rowe DC (1999) A logistic regression based extension of the TDT for continuous and categorical traits. Ann Hum Genet 63(4):329–340CrossRefGoogle Scholar
  48. Wilkins AJ, Shallice T, McCarthy R (1987) Frontal lesions and sustained attention. Neuropsychologia 25:359–365CrossRefGoogle Scholar
  49. Williams GV, Goldman-Rakic PS (1995) Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 376:572–575CrossRefPubMedGoogle Scholar
  50. Zhang X, Ruan L, Le Y, Zhang Y (2003) Association analysis between attention-deficit hyperactivity disorder and Val158Met polymorphism of catechol-O-methyltransferase gene. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 20:322–324Google Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Mark A. Bellgrove
    • 1
    • 2
  • Katharina Domschke
    • 2
  • Ziarih Hawi
    • 2
  • Aiveen Kirley
    • 2
  • Celine Mullins
    • 1
    • 2
  • Ian H. Robertson
    • 1
  • Michael Gill
    • 2
  1. 1.Department of Psychology and Trinity College Institute of NeuroscienceTrinity College DublinDublinIreland
  2. 2.Departments of Psychiatry and Genetics and Trinity College Institute of NeuroscienceTrinity College DublinDublinIreland

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