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Neural substrates of pleiotropic action of genetic variation in COMT: a meta-analysis

Abstract

Genetic variation in catechol-O-methyltransferase (COMT), encoding an enzyme critical for prefrontal dopamine flux, has been studied extensively using both behavioral and neuroimaging methods. In behavior, pleiotropic action of a functional Val158Met (rs4680) polymorphism on executive cognition and emotional stability has been described and proposed to be of evolutionary significance (the ‘warrior/worrier’ hypothesis). We conducted a meta-analysis of all available neuroimaging studies of rs4680 to investigate the evidence for a neural substrate of this behavioral pleiotropy. We show significant association between the COMT genotype and prefrontal activation, with large (d=0.73) effect size without evidence for publication bias. Strong and opposing effects were found for executive cognition paradigms (favoring Met allele carriers) and emotional paradigms (favoring Val), providing meta-analytical evidence for a neural substrate for the pleiotropic behavioral effects of COMT genetic variation and validating the use of intermediate phenotypes as a method to bridge between genes and behavior.

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References

  1. Gottesman II, Gould TD . The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 2003; 160: 636–645.

    Article  PubMed  Google Scholar 

  2. Gottesman II, Shields J . A polygenic theory of schizophrenia. Proc Natl Acad Sci USA 1967; 58: 199–205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Meyer-Lindenberg A, Weinberger DR . Intermediate phenotypes and genetic mechanisms of psychiatric disorders. Nat Rev Neurosci 2006; 7: 818–827.

    Article  CAS  PubMed  Google Scholar 

  4. Hariri AR, Weinberger DR . Imaging genomics. Br Med Bull 2003; 65: 259–270.

    Article  CAS  PubMed  Google Scholar 

  5. Flint J, Munafo MR . The endophenotype concept in psychiatric genetics. Psychol Med 2007; 37: 163–180.

    Article  PubMed  Google Scholar 

  6. Lewis DA, Melchitzky DS, Sesack SR, Whitehead RE, Auh S, Sampson A . Dopamine transporter immunoreactivity in monkey cerebral cortex: regional, laminar, and ultrastructural localization. J Comp Neurol 2001; 432: 119–136.

    Article  CAS  PubMed  Google Scholar 

  7. Tunbridge EM, Bannerman DM, Sharp T, Harrison PJ . Catechol-o-methyltransferase inhibition improves set-shifting performance and elevates stimulated dopamine release in the rat prefrontal cortex. J Neurosci 2004; 24: 5331–5335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Tunbridge EM, Harrison PJ, Weinberger DR . Catechol-o-methyltransferase, cognition, and psychosis: Val(158)Met and beyond. Biol Psychiatry 2006; 60: 141–151.

    Article  CAS  PubMed  Google Scholar 

  9. Owen MJ, Williams NM, O'Donovan MC . The molecular genetics of schizophrenia: new findings promise new insights. Mol Psychiatry 2004; 9: 14–27.

    Article  CAS  PubMed  Google Scholar 

  10. Stefansson H, Rujescu D, Cichon S, Pietilainen OP, Ingason A, Steinberg S et al. Large recurrent microdeletions associated with schizophrenia. Nature 2008; 455: 232–236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Murphy KC . Schizophrenia and velo-cardio-facial syndrome. Lancet 2002; 359: 426–430.

    Article  PubMed  Google Scholar 

  12. Chen J, Lipska BK, Halim N, Ma QD, Matsumoto M, Melhem S et al. 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 2004; 75: 807–821.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bertolino A, Blasi G, Latorre V, Rubino V, Rampino A, Sinibaldi L et al. Additive effects of genetic variation in dopamine regulating genes on working memory cortical activity in human brain. J Neurosci 2006a; 26: 3918–3922.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bertolino A, Caforio G, Petruzzella V, Latorre V, Rubino V, Dimalta S et al. Prefrontal dysfunction in schizophrenia controlling for COMT Val158Met genotype and working memory performance. Psychiatry Res 2006b; 147: 221–226.

    Article  CAS  PubMed  Google Scholar 

  15. Caldu X, Vendrell P, Bartres-Faz D, Clemente I, Bargallo N, Jurado MA et al. Impact of the COMT Val108/158 Met and DAT genotypes on prefrontal function in healthy subjects. Neuroimage 2007; 37: 1437–1444.

    Article  PubMed  Google Scholar 

  16. Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mattay VS, Goldberg TE, Fera F, Hariri AR, Tessitore A, Egan MF et al. Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci USA 2003; 100: 6186–6191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Meyer-Lindenberg A, Nichols T, Callicott JH, Ding J, Kolachana B, Buckholtz J et al. Impact of complex genetic variation in COMT on human brain function. Mol Psychiatry 2006; 11: 867–877, 797.

    Article  CAS  PubMed  Google Scholar 

  19. Meyer-Lindenberg A, Poline JB, Kohn PD, Holt JL, Egan MF, Weinberger DR et al. Evidence for abnormal cortical functional connectivity during working memory in schizophrenia. Am J Psychiatry 2001; 158: 1809–1817.

    Article  CAS  PubMed  Google Scholar 

  20. Bertolino A, Di Giorgio A, Blasi G, Sambataro F, Caforio G, Sinibaldi L et al. Epistasis between dopamine regulating genes identifies a nonlinear response of the human hippocampus during memory tasks. Biol Psychiatry 2008; 64: 226–234.

    Article  CAS  PubMed  Google Scholar 

  21. Bertolino A, Rubino V, Sambataro F, Blasi G, Latorre V, Fazio L et al. Prefrontal-hippocampal coupling during memory processing is modulated by COMT val158met genotype. Biol Psychiatry 2006; 60: 1250–1258.

    Article  CAS  PubMed  Google Scholar 

  22. Barnett JH, Jones PB, Robbins TW, Muller U . 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 2007; 12: 502–509.

    Article  CAS  PubMed  Google Scholar 

  23. Barnett JH, Scoriels L, Munafo MR . Meta-analysis of the cognitive effects of the catechol-O-methyltransferase gene Val158/108Met polymorphism. Biol Psychiatry 2008; 64: 137–144.

    Article  CAS  PubMed  Google Scholar 

  24. Munafo MR, Bowes L, Clark TG, Flint J . Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case–control studies. Mol Psychiatry 2005; 10: 765–770.

    Article  CAS  PubMed  Google Scholar 

  25. Mattay VS, Goldberg TE, Fera F, Hariri AR, Tessitore A, Egan MF et al. Catechol O-methyltransferase val158met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci USA 2003; 100: 6186–6191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Fan JB, Zhang CS, Gu NF, Li XW, Sun WW, Wang HY et al. Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: a large-scale association study plus meta-analysis. Biol Psychiatry 2005; 57: 139–144.

    Article  CAS  PubMed  Google Scholar 

  27. Domschke K, Freitag CM, Kuhlenbaumer G, Schirmacher A, Sand P, Nyhuis P et al. Association of the functional V158M catechol-O-methyl-transferase polymorphism with panic disorder in women. Int J Neuropsychopharmacol 2004; 7: 183–188.

    Article  CAS  PubMed  Google Scholar 

  28. Enoch MA, Xu K, Ferro E, Harris CR, Goldman D . Genetic origins of anxiety in women: a role for a functional catechol-O-methyltransferase polymorphism. Psychiatr Genet 2003; 13: 33–41.

    Article  PubMed  Google Scholar 

  29. Olsson CA, Anney RJ, Lotfi-Miri M, Byrnes GB, Williamson R, Patton GC . Association between the COMT Val158Met polymorphism and propensity to anxiety in an Australian population-based longitudinal study of adolescent health. Psychiatr Genet 2005; 15: 109–115.

    Article  PubMed  Google Scholar 

  30. Olsson CA, Byrnes GB, Anney RJ, Collins V, Hemphill SA, Williamson R et al. COMT Val(158)Met and 5HTTLPR functional loci interact to predict persistence of anxiety across adolescence: results from the Victorian Adolescent Health Cohort Study. Genes Brain Behav 2007; 6: 647–652.

    Article  CAS  PubMed  Google Scholar 

  31. Pooley EC, Fineberg N, Harrison PJ . 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 2007; 12: 556–561.

    Article  CAS  PubMed  Google Scholar 

  32. Woo JM, Yoon KS, Choi YH, Oh KS, Lee YS, Yu BH . The association between panic disorder and the L/L genotype of catechol-O-methyltransferase. J Psychiatr Res 2004; 38: 365–370.

    Article  PubMed  Google Scholar 

  33. Diatchenko L, Slade GD, Nackley AG, Bhalang K, Sigurdsson A, Belfer I et al. Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet 2005; 14: 135–143.

    Article  CAS  PubMed  Google Scholar 

  34. Lang UE, Bajbouj M, Sander T, Gallinat J . Gender-dependent association of the functional catechol-O-methyltransferase Val158Met genotype with sensation seeking personality trait. Neuropsychopharmacology 2007; 32: 1950–1955.

    Article  CAS  PubMed  Google Scholar 

  35. Reuter M, Peters K, Schroeter K, Koebke W, Lenardon D, Bloch B et al. The influence of the dopaminergic system on cognitive functioning: a molecular genetic approach. Behav Brain Res 2005; 164: 93–99.

    Article  CAS  PubMed  Google Scholar 

  36. Reuter M, Schmitz A, Corr P, Hennig J . Molecular genetics support Gray's personality theory: the interaction of COMT and DRD2 polymorphisms predicts the behavioural approach system. Int J Neuropsychopharmacol 2006; 9: 155–166.

    CAS  PubMed  Google Scholar 

  37. Stein MB, Fallin MD, Schork NJ, Gelernter J . COMT polymorphisms and anxiety-related personality traits. Neuropsychopharmacology 2005; 30: 2092–2102.

    Article  CAS  PubMed  Google Scholar 

  38. Goldman D, Oroszi G, Ducci F . The genetics of addictions: uncovering the genes. Nat Rev Genet 2005; 6: 521–532.

    Article  CAS  PubMed  Google Scholar 

  39. Papaleo F, Crawley JN, Song J, Lipska BK, Pickel J, Weinberger DR et al. Genetic dissection of the role of catechol-O-methyltransferase in cognition and stress reactivity in mice. J Neurosci 2008; 28: 8709–8723.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Domschke K, Ohrmann P, Braun M, Suslow T, Bauer J, Hohoff C et al. Influence of the catechol-O-methyltransferase val158met genotype on amygdala and prefrontal cortex emotional processing in panic disorder. Psychiatry Res 2008; 163: 13–20.

    Article  CAS  PubMed  Google Scholar 

  41. Drabant EM, Hariri AR, Meyer-Lindenberg A, Munoz KE, Mattay VS, Kolachana BS et al. Catechol O-methyltransferase val158met genotype and neural mechanisms related to affective arousal and regulation. Arch Gen Psychiatry 2006; 63: 1396–1406.

    Article  CAS  PubMed  Google Scholar 

  42. Smolka MN, Schumann G, Wrase J, Grusser SM, Flor H, Mann K et al. Catechol-O-methyltransferase Val158Met genotype affects processing of emotional stimuli in the amygdala and prefrontal cortex. J Neurosci 2005; 25: 836–842.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Yacubian J, Sommer T, Schroeder K, Glascher J, Kalisch R, Leuenberger B et al. Gene–gene interaction associated with neural reward sensitivity. Proc Natl Acad Sci USA 2007; 104: 8125–8130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Munafo MR, Flint J . Meta-analysis of genetic association studies. Trends Genet 2004; 20: 439–444.

    Article  CAS  PubMed  Google Scholar 

  45. Cohn LD, Becker BJ . How meta-analysis increases statistical power. Psychol Methods 2003; 8: 243–253.

    Article  PubMed  Google Scholar 

  46. Tan HY, Chen Q, Sust S, Buckholtz JW, Meyers JD, Egan MF et al. Epistasis between catechol-O-methyltransferase and type II metabotropic glutamate receptor 3 genes on working memory brain function. Proc Natl Acad Sci USA 2007a; 104: 12536–12541.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Egger M, Davey Smith G, Schneider M, Minder C . Bias in meta-analysis detected by a simple, graphical test. Br Med J 1997; 315: 629–634.

    Article  CAS  Google Scholar 

  48. Sterne JA, Gavaghan D, Egger M . Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol 2000; 53: 1119–1129.

    Article  CAS  PubMed  Google Scholar 

  49. Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L . Comparison of two methods to detect publication bias in meta-analysis. JAMA 2006; 295: 676–680.

    Article  CAS  PubMed  Google Scholar 

  50. Rosenthal R, DiMatteo MR . Meta-analysis: recent developments in quantitative methods for literature reviews. Annu Rev Psychol 2001; 52: 59–82.

    Article  CAS  PubMed  Google Scholar 

  51. Bishop SJ, Cohen JD, Fossella J, Casey BJ, Farah MJ . COMT genotype influences prefrontal response to emotional distraction. Cogn Affect Behav Neurosci 2006; 6: 62–70.

    Article  PubMed  Google Scholar 

  52. Higgins JP, Thompson SG . Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21: 1539–1558.

    Article  PubMed  Google Scholar 

  53. Bertolino A, Rubino V, Sambataro F, Blasi G, Latorre V, Fazio L et al. Prefrontal-hippocampal coupling during memory processing is modulated by COMT val158met genotype. Biol Psychiatry 2006c; 60: 1250–1258.

    Article  CAS  PubMed  Google Scholar 

  54. Ettinger U, Kumari V, Collier DA, Powell J, Luzi S, Michel TM et al. Catechol-O-methyltransferase (COMT) Val(158)Met genotype is associated with BOLD response as a function of task characteristic. Neuropsychopharmacology 2008; 33: 3046–3057.

    Article  CAS  PubMed  Google Scholar 

  55. Gothelf D, Hoeft F, Hinard C, Hallmayer JF, Stoecker JV, Antonarakis SE et al. Abnormal cortical activation during response inhibition in 22q11.2 deletion syndrome. Hum Brain Mapp 2007; 28: 533–542.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Schott BH, Seidenbecher CI, Fenker DB, Lauer CJ, Bunzeck N, Bernstein HG et al. The dopaminergic midbrain participates in human episodic memory formation: evidence from genetic imaging. J Neurosci 2006; 26: 1407–1417.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Tan HY, Chen Q, Goldberg TE, Mattay VS, Meyer-Lindenberg A, Weinberger DR et al. Catechol-O-methyltransferase Val158Met modulation of prefrontal-parietal-striatal brain systems during arithmetic and temporal transformations in working memory. J Neurosci 2007b; 27: 13393–13401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Williams-Gray CH, Hampshire A, Robbins TW, Owen AM, Barker RA . Catechol O-methyltransferase Val158Met genotype influences frontoparietal activity during planning in patients with Parkinson's disease. J Neurosci 2007; 27: 4832–4838.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Williams-Gray CH, Hampshire A, Barker RA, Owen AM . Attentional control in Parkinson's disease is dependent on COMT Val158met genotype. Brain 2008; 131 (Part 2): 397–408.

    Article  PubMed  Google Scholar 

  60. Munafo MR, Brown SM, Hariri AR . Serotonin transporter (5-HTTLPR) genotype and amygdala activation: a meta-analysis. Biol Psychiatry 2008; 63: 852–857.

    Article  CAS  PubMed  Google Scholar 

  61. Meyer-Lindenberg A, Kohn PD, Kolachana B, Kippenhan S, McInerney-Leo A, Nussbaum R et al. Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype. Nat Neurosci 2005; 8: 594–596.

    CAS  PubMed  Google Scholar 

  62. Callicott JH, Bertolino A, Mattay VS, Langheim FJ, Duyn J, Coppola R et al. Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited. Cereb Cortex 2000; 10: 1078–1092.

    Article  CAS  PubMed  Google Scholar 

  63. Durstewitz D, Seamans JK, Sejnowski TJ . Dopamine-mediated stabilization of delay-period activity in a network model of prefrontal cortex. J Neurophysiol 2000; 83: 1733–1750.

    Article  CAS  PubMed  Google Scholar 

  64. Akil M, Kolachana BS, Rothmond DA, Hyde TM, Weinberger DR, Kleinman JE . Catechol-O-methyltransferase genotype and dopamine regulation in the human brain. J Neurosci 2003; 23: 2008–2013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Callicott JH, Straub RE, Pezawas L, Egan MF, Mattay VS, Hariri AR et al. Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. Proc Natl Acad Sci USA 2005; 102: 8627–8632.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Apud JA, Mattay V, Chen J, Kolachana BS, Callicott JH, Rasetti R et al. Tolcapone improves cognition and cortical information processing in normal human subjects. Neuropsychopharmacology 2007; 32: 1011–1020.

    Article  CAS  PubMed  Google Scholar 

  67. Bilder RM, Volavka J, Lachman HM, Grace AA . The catechol-O-methyltransferase polymorphism: relations to the tonic-phasic dopamine hypothesis and neuropsychiatric phenotypes. Neuropsychopharmacology 2004; 29: 1943–1961.

    Article  CAS  PubMed  Google Scholar 

  68. Honea R, Verchinski B, Pezawas L, Kolachana B, Callicott JH, Mattay V et al. Impact of interacting functional variants in COMT on regional gray matter volume in human brain. Neuroimage 2009; 45: 44–51.

    Article  PubMed  Google Scholar 

  69. Meyer-Lindenberg A, Nicodemus KK, Egan MF, Callicott JH, Mattay V, Weinberger DR . False positives in imaging genetics. Neuroimage 2008; 40: 655–661.

    Article  PubMed  Google Scholar 

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The funding for this study was provided by BMBF (NGFNplus MooDS) and DFG (SFB 636-B7).

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Mier, D., Kirsch, P. & Meyer-Lindenberg, A. Neural substrates of pleiotropic action of genetic variation in COMT: a meta-analysis. Mol Psychiatry 15, 918–927 (2010). https://doi.org/10.1038/mp.2009.36

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  • DOI: https://doi.org/10.1038/mp.2009.36

Keywords

  • meta-analysis
  • catechol-O-methyltransferase
  • magnetic resonance imaging
  • prefrontal cortex
  • cognition
  • emotions

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