Skip to main content
SpringerLink
Log in

Association Between Polymorphisms of the Dopamine Receptor D2 and Catechol-o-Methyl Transferase Genes and Cognitive Function

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

Abstract

The dopaminergic neurotransmitter system of the brain is involved in working memory and other cognitive functions. Studies suggest an important role for dopamine synthesis and uptake in modulation of human cognitive processes. We studied the association between polymorphisms in the catechol-o-methyl transferase (COMT) and dopamine receptor D2 (DRD2) genes and general cognitive ability in a secondary analysis of 2091 men and women, aged 55–80 years living in Scotland. General cognitive ability ‘g’ was derived from five cognitive tests of different domains. COMT was not associated with cognitive ability in this population. The DRD2 C:C genotype of rs6277 was associated with decreased general cognitive ability ‘g’ (p = 0.003), and DRD2 rs1800497 heterozygotes had lowest mean general cognitive ability ‘g’ (p = 0.007). There was an indication of a potential interaction between the DRD2 SNPs.

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

Similar content being viewed by others

References

  • Aalto S, Bruck A, Laine M, Nagren K, Rinne JO (2005) Frontal and temporal dopamine release during working memory and attention tasks in healthy humans: a positron emission tomography study using the high-affinity dopamine d2 receptor ligand [11c]flb 457. J Neurosci 25(10):2471–2477

    Article  PubMed  Google Scholar 

  • Bäckman L, Ginovart N, Dixon RA, Wahlin T-BR, Wahlin Å, Halldin C, Farde L (2000) Age-related cognitive deficits mediated by changes in the striatal dopamine system. Am J Psychiatry 157(4):635–637

    Article  PubMed  Google Scholar 

  • Barnett JH, Jones P, Robbins T, Muller U (2007) Effects of the catechol-O-methyltransferase Val158Met polymorphism on executive function: a meta-analysis of the Wisconsin Card Sort Test in schizophrenia and healthy controls. Mol Psychiatry 12(5):502–509

    PubMed  Google Scholar 

  • Barnett JH, Scoriels L, Munafò MR (2008) Meta-analysis of the cognitive effects of the catechol-o-methyltransferase gene val158/108met polymorphism. Biol Psychiatry 64(2):137–144

    Article  PubMed  Google Scholar 

  • Bartres-Faz D, Junque C, Serra-Grabulosa JM, Lopez-Alomar A, Moya A, Bargallo N, Mercader JM, Moral P, Clemente IC (2002) Dopamine DRD2 Taq I polymorphism associates with caudate nucleus volume and cognitive performance in memory impaired subjects. Neuroreport 13(9):1121–1125

    Article  PubMed  Google Scholar 

  • Bruder GE, Keilp JG, Xu H, Shikhman M, Schori E, Gorman JM, Gilliam TC (2005) Catechol-O-Methyltransferase (COMT) genotypes and working memory: associations with differing cognitive operations. Biol Psychiatry 58(11):901–907

    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 

  • Crawford JR, Deary IJ, Starr J, Whalley LJ (2001) The NART as an index of prior intellectual functioning: a retrospective validity study covering a 66 year interval. Psychol Med 31(03):451–458

    Article  PubMed  Google Scholar 

  • Cropley VL, Fujita M, Innis RB, Nathan PJ (2006) Molecular imaging of the dopaminergic system and its association with human cognitive function. Biol Psychiatry 59(10):898–907

    Article  PubMed  Google Scholar 

  • de Frias CM, Annerbrink K, Westberg L, Eriksson E, Adolfsson R, Nilsson L-G (2004) COMT gene polymorphism is associated with declarative memory in adulthood and old age. Behav Genet 34(5):533–539

    Article  PubMed  Google Scholar 

  • de Frias CM, Annerbrink K, Westberg L, Eriksson E, Adolfsson R, Nilsson LR (2005) Catechol O-methyltransferase Val (158) Met polymorphism is associated with cognitive performance in nondemented adults. J Cogn Neurosci 17(7):1018–1025

    Article  PubMed  Google Scholar 

  • Deary IJ, Batty GD (2007) Cognitive epidemiology. J Epidemiol Community Health 61(5):378–384

    Article  PubMed  Google Scholar 

  • Deary IJ, Whalley LJ, Crawford JR (2004a) An ‘instantaneous’ estimate of a lifetime’s cognitive change. Intelligence 32(2):113–119

    Article  Google Scholar 

  • Deary IJ, Wright AF, Harris SE, Whalley LJ, Starr JM (2004b) Searching for genetic influences on normal cognitive ageing. Trends Cogn Sci 8(4):178–184

    Article  PubMed  Google Scholar 

  • Deary IJ, Spinath FM, Bates TC (2006) Genetics of intelligence. Eur J Hum Genet 14(6):690–700

    Article  PubMed  Google Scholar 

  • Delcomyn F (1998) Foundations of neurobiology. WH Freeman, New York

    Google Scholar 

  • Dreher J-C, Meyer-Lindenberg A, Kohn P, Berman KF (2008) Age-related changes in midbrain dopaminergic regulation of the human reward system. Proc Natl Acad Sci USA 105(39):15106–15111

    Article  PubMed  Google Scholar 

  • Duan J, Wainwright MS, Comeron JM, Saitou N, Sanders AR, Gelernter J, Gejman PV (2003) Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. Hum Mol Genet 12(3):205–216

    Article  PubMed  Google Scholar 

  • Fetsko LA, Xu R, Wang Y (2005) Effects of age and dopamine D2L receptor-deficiency on motor and learning functions. Neurobiol Aging 26(4):521–530

    Article  PubMed  Google Scholar 

  • Finkel D, Reynolds CA, McArdle JJ, Pedersen NL (2005) The longitudinal relationship between processing speed and cognitive ability: genetic and environmental influences. Behav Genet 35(5):535–549

    Article  PubMed  Google Scholar 

  • Folstein MF, Folstein SE, McHugh PR (1975) “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12(3):189–198

    Article  PubMed  Google Scholar 

  • Foltynie T, Lewis SGJ, Goldberg TE, Blackwell AD, Kolachana BS, Weinberger DR, Robbins TW, Barker RA (2005) The BDNF Val66Met polymorphism has a gender specific influence on planning ability in Parkinson’s disease. J Neurol 252(7):833–838

    Article  PubMed  Google Scholar 

  • Fowkes FGR, Price JF, Stewart MCW, Butcher I, Leng GC, Pell ACH, Sandercock PAG, Fox KAA, Lowe GDO, Murray GD, & for the aspirin for asymptomatic Atherosclerosis T (2010) Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial. JAMA 303(9):841–848

    Article  PubMed  Google Scholar 

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

    Article  Google Scholar 

  • Goldman D, Weinberger DR, Malhotra AK, Goldberg TE (2009) The role of COMT Val158Met in cognition. Biol Psychiatry 65(1):e1–e2

    Article  PubMed  Google Scholar 

  • Gosso MF, de Geus EJC, Polderman TJC, Boomsma DI, Heutink P, Posthuma D (2008) Catechol O-methyl transferase and dopamine D2 receptor gene polymorphisms: evidence of positive heterosis and gene-gene interaction on working memory functioning. Eur J Hum Genet 16(9):1075–1082

    Article  PubMed  Google Scholar 

  • Green AE, Munafo MR, DeYoung CG, Fossella JA, Fan J, Gray JR (2008) Using genetic data in cognitive neuroscience: from growing pains to genuine insights. Nat Rev Neurosci 9(9):710–720

    Article  PubMed  Google Scholar 

  • Hariri AR, Goldberg TE, Mattay VS, Kolachana BS, Callicott JH, Egan MF, Weinberger DR (2003) Brain-Derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J Neurosci 23:6690–6694

    PubMed  Google Scholar 

  • Harris SE, Wright AF, Hayward C, Starr JM, Whalley LJ, Deary IJ (2005) The functional COMT polymorphism, Val158Met, is associated with logical memory and the personality trait intellect/imagination in a cohort of healthy 79 year olds. Neurosci Lett 385(1):1–6

    Article  PubMed  Google Scholar 

  • Ho BC, Wassink TH, O’Leary DS, Sheffield VC, Andreasen NC (2005) Catechol-O-methyl transferase Val158Met gene polymorphism in schizophrenia: working memory, frontal lobe MRI morphology and frontal cerebral blood flow. Mol Psychiatry 10(3):287–298

    Article  Google Scholar 

  • Hooi JD, Kester ADM, Stoffers HEJH, Rinkens PELM, Knottnerus JA, van Ree JW (2004) Asymptomatic peripheral arterial occlusive disease predicted cardiovascular morbidity and mortality in a 7 year follow-up study. J Clin Epidemiol 57(3):294–300

    Article  PubMed  Google Scholar 

  • Kaasinen V, Rinne JO (2002) Functional imaging studies of dopamine system and cognition in normal aging and Parkinson’s disease. Neurosci Biobehav Rev 26(7):785–793

    Article  PubMed  Google Scholar 

  • Kemppainen N, Laine M, Laakso MP, Kaasinen V, Nagren K, Vahlberg T, Kurki T, Rinne JO (2003) Hippocampal dopamine D2 receptors correlate with memory functions in Alzheimer’s disease. Eur J Neurosci 18(1):149–154

    Article  PubMed  Google Scholar 

  • Lezak MD (1995) Neuropsychological assessment. Oxford University Press, New York

    Google Scholar 

  • 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 thermolabile variant of the enzyme. Biochemistry 34(13):4202–4210

    Article  PubMed  Google Scholar 

  • 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 Psychiatry 159(4):652–654

    Article  PubMed  Google Scholar 

  • McAllister TW, Flashman LA, Harker Rhodes C, Tyler AL, Moore JH, Saykin AJ, McDonald BC, Tosteson TD, Tsongalis GJ (2008) Single nucleotide polymorphisms in ANKK1 and the dopamine D2 receptor gene affect cognitive outcome shortly after traumatic brain injury: a replication and extension study. Brain Inj 22(9):705–714

    Article  PubMed  Google Scholar 

  • McClearn GE, Johansson B, Berg S, Pedersen NL, Ahern F, Petrill SA, Plomin R (1997) Substantial genetic influence on cognitive abilities in twins 80 or more years old. Science 276(5318):1560–1563

    Article  PubMed  Google Scholar 

  • McGurn B, Starr JM, Topfer JA, Pattie A, Whiteman MC, Lemmon HA, Whalley LJ, Deary IJ (2004) Pronunciation of irregular words is preserved in dementia, validating premorbid IQ estimation. Neurology 62(7):1184–1186

    PubMed  Google Scholar 

  • Moises HW, Frieboes RM, Spelzhaus P, Yang L, Köhnke M, Herden-Kirchhoff O, Vetter P, Neppert J, Gottesman II (2001) No association between dopamine D2 receptor gene (DRD2) and human intelligence. J Neural Transm 108(1):115–121

    Article  PubMed  Google Scholar 

  • National_Statistics (ed.) (2005) Office for National Statistics—age structure. http://www.statistics.gov.uk/cci/nugget.asp?Id=1308

  • Nelson HE, Willison J (1991) National adult reading test (NART) test manual, 2nd edn. NFER-Nelson, Windsor

    Google Scholar 

  • O’Hara R, Miller E, Liao C-P, Way N, Lin X, Hallmayer J (2006) COMT genotype, gender and cognition in community-dwelling, older adults. Neurosci Lett 409(3):205–209

    Article  PubMed  Google Scholar 

  • Petrill SA, Lipton PA, Hewitt JK, Plomin R, Cherny SS, Corley R, DeFries JC (2004) Genetic and environmental contributions to general cognitive ability through the first 16 years of Life. Dev Psychol 40(5):805–812

    Article  PubMed  Google Scholar 

  • Prata DP, Mechelli A, Fu CHY, Picchioni M, Kane F, Kalidindi S, McDonald C, Howes O, Kravariti E, Demjaha A, Toulopoulou T, Diforti M, Murray RM, Collier DA, McGuire PK (2009) Opposite effects of catechol-o-methyltransferase val158met on cortical function in healthy subjects and patients with schizophrenia. Biol Psychiatry 65(6):473–480

    Article  PubMed  Google Scholar 

  • Price JF, McDowell S, Whiteman MC, Deary IJ, Stewart MC, Fowkes FGR (2006) Ankle brachial index as a predictor of cognitive impairment in the general population: ten-year follow-up of the Edinburgh artery study. J Am Geriatr Soc 54(5):763

    Article  PubMed  Google Scholar 

  • Price JF, Stewart MC, Deary IJ, Murray GD, Sandercock P, Butcher I, Fowkes FGR, & on behalf of the AAAT (2008) Low dose aspirin and cognitive function in middle aged to elderly adults: randomised controlled trial. BMJ 337:a1198

    Article  PubMed  Google Scholar 

  • Raven J, Raven JC, Court JH (1998) Manual for Raven’s progressive matrices and vocabulary scales. Oxford Psychologists Press, Oxford

    Google Scholar 

  • Reuter M, Peters K, Schroeter K, Koebke W, Lenardon D, Bloch B, Hennig J (2005) The influence of the dopaminergic system on cognitive functioning: a molecular genetic approach. Behav Brain Res 164(1):93–99

    Article  PubMed  Google Scholar 

  • Reynolds CA, Finkel D, McArdle JJ, Gatz M, Berg S, Pedersen NL (2005) Quantitative genetic analysis of latent growth curve models of cognitive abilities in adulthood. Dev Psychol 41(1):3–16

    Article  PubMed  Google Scholar 

  • Rodriguez-Jimenez R, Hoenicka J, Jimenez-Arriero M, Ponce G, Bagney A, Aragues M, Palomo T (2006) Performance in the Wisconsin card sorting test and the C957T polymorphism of the DRD2 gene in healthy volunteers. Neuropsychobiology 54:166–170

    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 

  • Spreen O, Strauss E (1991) A compendium of neuropsychological tests: administration, norms, and commentary. Oxford University Press, New York

    Google Scholar 

  • Stewart MCW, Deary IJ, Fowkes FGR, Price JF (2006) Relationship between lifetime smoking, smoking status at older age and human cognitive function. Neuroepidemiology 26:83–92

    Article  PubMed  Google Scholar 

  • Tsai S-J, Yu YW-Y, Lin C-H, Chen T-J, Chen S-P, Hong C-J (2002) Dopamine D2 receptor and N-Methyl-D-aspartate receptor 2B subunit genetic variants and intelligence. Neuropsychobiology 45:128–130

    Article  PubMed  Google Scholar 

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

    Article  Google Scholar 

  • Ulmanen I, Peranen J, Tenhunen J, Tilgmann C, Karhunen T, Panula P, Bernasconi L, Aubry J-P, Lundstrom K (1997) Expression and intracellular localization of catechol o-methyltransferase in transfected mammalian cells. Eur J Biochem 243(1–2):452–459

    Article  PubMed  Google Scholar 

  • Volkow ND, Ding Y-S, Fowler JS, Wang G-J, Logan J, Gatley SJ, Hitzemann R, Smith G, Fields SD, Gur R (1996) Dopamine transporters decrease with age. J Nucl Med 37(4):554–559

    PubMed  Google Scholar 

  • Welton NJ, Johnstone EC, David SP, Munafò MR (2008) A cost-effectiveness analysis of genetic testing of the DRD2 Taq1A polymorphism to aid treatment choice for smoking cessation. Nicotine Tob Res 10(1):231–240

    Article  PubMed  Google Scholar 

  • Weschler D (1998) Weschler adult intelligence scale, 3rd edn. Psychological Corporation, London

    Google Scholar 

  • Xu H, Kellendonk CB, Simpson EH, Keilp JG, Bruder GE, Polan HJ, Kandel ER, Gilliam TC (2007) DRD2 C957T polymorphism interacts with the COMT Val158Met polymorphism in human working memory ability. Schizophr Res 90(1–3):104–107

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Public Health Sciences, University of Edinburgh, Medical School, Teviot Place, Edinburgh, EH9 1NN, UK

    Jennifer L. Bolton, Riccardo E. Marioni, Marlene C. Stewart, Gordon D. Murray, F. Gerry R. Fowkes & Jackie F. Price

  2. Department of Psychology, University of Edinburgh, Edinburgh, UK

    Ian J. Deary & Sarah E. Harris

Authors
  1. Jennifer L. Bolton
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Riccardo E. Marioni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ian J. Deary
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sarah E. Harris
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marlene C. Stewart
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gordon D. Murray
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. F. Gerry R. Fowkes
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jackie F. Price
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jennifer L. Bolton.

Additional information

Edited by Danielle Posthuma.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bolton, J.L., Marioni, R.E., Deary, I.J. et al. Association Between Polymorphisms of the Dopamine Receptor D2 and Catechol-o-Methyl Transferase Genes and Cognitive Function. Behav Genet 40, 630–638 (2010). https://doi.org/10.1007/s10519-010-9372-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10519-010-9372-y

Keywords

Search

Navigation