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Epistatic interaction between COMT and DTNBP1 modulates prefrontal function in mice and in humans

Molecular Psychiatry volume 19, pages 311–316 (2014)Cite this article

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Abstract

Cognitive functions are highly heritable and the impact of complex genetic interactions, though undoubtedly important, has received little investigation. Here we show in an animal model and in a human neuroimaging experiment a consistent non-linear interaction between two genes—catechol-O-methyl transferase (COMT) and dysbindin (dys; dystrobrevin-binding protein 1 (DTNBP1))—implicated through different mechanisms in cortical dopamine signaling and prefrontal cognitive function. In mice, we found that a single genetic mutation reducing expression of either COMT or DTNBP1 alone produced working memory advantages, while, in dramatic contrast, genetic reduction of both in the same mouse produced working memory deficits. We found evidence of the same non-linear genetic interaction in prefrontal cortical function in humans. In healthy volunteers (N=176) studied with functional magnetic resonance imaging during a working memory paradigm, individuals homozygous for the COMT rs4680 Met allele that reduces COMT enzyme activity showed a relatively more efficient prefrontal engagement. In contrast, we found that the same genotype was less efficient on the background of a dys haplotype associated with decreased DTNBP1 expression. These results illustrate that epistasis can be functionally multi-directional and non-linear and that a putatively beneficial allele in one epistastic context is a relatively deleterious one in another. These data also have important implications for single-locus association analyses of complex traits.

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References

  1. Davies G, Tenesa A, Payton A, Yang J, Harris SE, Liewald D et al. Genome-wide association studies establish that human intelligence is highly heritable and polygenic. Mol Psychiatry 2011; 16: 996–1005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Papaleo F, Lipska BK, Weinberger DR . Mouse models of genetic effects on cognition: relevance to schizophrenia. Neuropharmacology 2012; 62: 1204–1220.

    Article  CAS  PubMed  Google Scholar 

  3. Robbins TW, Kousta S . Uncovering the genetic underpinnings of cognition. Trends Cogn Sci 2011; 15: 375–377.

    Article  PubMed  Google Scholar 

  4. Cools R, D'Esposito M . Inverted-U-shaped dopamine actions on human working memory and cognitive control. Biol Psychiatry 2011; 69: e113–e125.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Goldman-Rakic PS . The cortical dopamine system: role in memory and cognition. Adv Pharmacol 1998; 42: 707–711.

    Article  CAS  PubMed  Google Scholar 

  6. Verma A, Moghaddam B . NMDA receptor antagonists impair prefrontal cortex function as assessed via spatial delayed alternation performance in rats: modulation by dopamine. J Neurosci 1996; 16: 373–379.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Seamans JK, Gorelova N, Durstewitz D, Yang CR . Bidirectional dopamine modulation of GABAergic inhibition in prefrontal cortical pyramidal neurons. J Neurosci 2001; 21: 3628–3638.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Williams GV, Goldman-Rakic PS . Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 1995; 376: 572–575.

    Article  CAS  PubMed  Google Scholar 

  9. Arnsten AF, Cai JX, Murphy BL, Goldman-Rakic PS . Dopamine D1 receptor mechanisms in the cognitive performance of young adult and aged monkeys. Psychopharmacology 1994; 116: 143–151.

    Article  CAS  PubMed  Google Scholar 

  10. Vijayraghavan S, Wang M, Birnbaum SG, Williams GV, Arnsten AF . Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nat Neurosci 2007; 10: 376–384.

    Article  CAS  PubMed  Google Scholar 

  11. 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 

  12. Kaenmaki M, Tammimaki A, Myohanen T, Pakarinen K, Amberg C, Karayiorgou M et al. Quantitative role of COMT in dopamine clearance in the prefrontal cortex of freely moving mice. J Neurochem 2010; 114: 1745–1755.

    Article  CAS  PubMed  Google Scholar 

  13. 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 

  14. 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 

  15. Sambataro F, Reed JD, Murty VP, Das S, Tan HY, Callicott JH et al. Catechol-O-methyltransferase valine(158)methionine polymorphism modulates brain networks underlying working memory across adulthood. Biol Psychiatry 2009; 66: 540–548.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Scheggia D, Sannino S, Scattoni ML, Papaleo F . COMT as a drug target for cognitive functions and dysfunctions. CNS Neurol Disord Drug Targets 2012; 11: 209–221.

    Article  CAS  PubMed  Google Scholar 

  17. Straub RE, Jiang Y, MacLean CJ, Ma Y, Webb BT, Myakishev MV et al. Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia. Am J Hum Genet 2002; 71: 337–348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Burdick KE, Lencz T, Funke B, Finn CT, Szeszko PR, Kane JM et al. Genetic variation in DTNBP1 influences general cognitive ability. Hum Mol Genet 2006; 15: 1563–1568.

    Article  CAS  PubMed  Google Scholar 

  19. Fallgatter AJ, Herrmann MJ, Hohoff C, Ehlis AC, Jarczok TA, Freitag CM et al. DTNBP1 (dysbindin) gene variants modulate prefrontal brain function in healthy individuals. Neuropsychopharmacology 2006; 31: 2002–2010.

    Article  CAS  PubMed  Google Scholar 

  20. Papaleo F, Weinberger DR . Dysbindin and schizophrenia: it's dopamine and glutamate all over again. Biol Psychiatry 2011; 69: 2–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Papaleo F, Yang F, Garcia S, Chen J, Lu B, Crawley JN et al. Dysbindin-1 modulates prefrontal cortical activity and schizophrenia-like behaviors via dopamine/D2 pathways. Mol Psychiatry 2012; 17: 85–98.

    Article  CAS  PubMed  Google Scholar 

  22. Jentsch JD, Trantham-Davidson H, Jairl C, Tinsley M, Cannon TD, Lavin A . Dysbindin modulates prefrontal cortical glutamatergic circuits and working memory function in mice. Neuropsychopharmacology 2009; 34: 2601–2608.

    Article  CAS  PubMed  Google Scholar 

  23. Dickman DK, Davis GW . The schizophrenia susceptibility gene dysbindin controls synaptic homeostasis. Science 2009; 326: 1127–1130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Iizuka Y, Sei Y, Weinberger DR, Straub RE . Evidence that the BLOC-1 protein dysbindin modulates dopamine D2 receptor internalization and signaling but not D1 internalization. J Neurosci 2007; 27: 12390–12395.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ji Y, Yang F, Papaleo F, Wang HX, Gao WJ, Weinberger DR et al. Role of dysbindin in dopamine receptor trafficking and cortical GABA function. Proc Natl Acad Sci USA 2009; 106: 19593–19598.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gogos JA, Morgan M, Luine V, Santha M, Ogawa S, Pfaff D et al. Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proc Natl Acad Sci USA 1998; 95: 9991–9996.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Callicott JH, Mattay VS, Verchinski BA, Marenco S, Egan MF, Weinberger DR . Complexity of prefrontal cortical dysfunction in schizophrenia: more than up or down. Am J Psychiatry 2003; 160: 2209–2215.

    Article  PubMed  Google Scholar 

  28. 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 

  29. Rasetti R, Sambataro F, Chen Q, Callicott JH, Mattay VS, Weinberger DR . Altered cortical network dynamics: a potential intermediate phenotype for schizophrenia and association with ZNF804A. Arch Gen Psychiatry 2011; 68: 1207–1217.

    Article  PubMed  Google Scholar 

  30. Cox MM, Tucker AM, Tang J, Talbot K, Richer DC, Yeh L et al. Neurobehavioral abnormalities in the dysbindin-1 mutant, sandy, on a C57BL/6J genetic background. Genes Brain Behav 2009; 8: 390–397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Talbot K, Ong WY, Blake DJ, Tang J, Louneva N, Carlson GC et al. Dysbindin-1 and its protein family. In: Javitt DC, Kantrowitz J (eds). Handbook of Neurochemistry and Molecular Neurobiology vol. 27 3rd edn Springer Science: New York, NY, USA, 2009 pp 107–241.

    Chapter  Google Scholar 

  32. Elvevag B, Goldberg TE . Cognitive impairment in schizophrenia is the core of the disorder. Crit Rev Neurobiol 2000; 14: 1–21.

    Article  CAS  PubMed  Google Scholar 

  33. Kellendonk C, Simpson EH, Polan HJ, Malleret G, Vronskaya S, Winiger V et al. Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning. Neuron 2006; 49: 603–615.

    Article  CAS  PubMed  Google Scholar 

  34. Arnsten AF, Cai JX, Steere JC, Goldman-Rakic PS . Dopamine D2 receptor mechanisms contribute to age-related cognitive decline: the effects of quinpirole on memory and motor performance in monkeys. J Neurosci 1995; 15 (5 Pt 1): 3429–3439.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Luciana M, Depue RA, Arbisi P, Leon A . Facilitation of working memory in humans by a D2 dopamine receptor agonist. J Cogn Neurosci 1992; 4: 58–68.

    Article  CAS  PubMed  Google Scholar 

  36. Mehta MA, Swainson R, Ogilvie AD, Sahakian J, Robbins TW . Improved short-term spatial memory but impaired reversal learning following the dopamine D(2) agonist bromocriptine in human volunteers. Psychopharmacology 2001; 159: 10–20.

    Article  CAS  PubMed  Google Scholar 

  37. Wang M, Vijayraghavan S, Goldman-Rakic PS . Selective D2 receptor actions on the functional circuitry of working memory. Science 2004; 303: 853–856.

    Article  CAS  PubMed  Google Scholar 

  38. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Bray NJ, Preece A, Williams NM, Moskvina V, Buckland PR, Owen MJ et al. Haplotypes at the dystrobrevin binding protein 1 (DTNBP1) gene locus mediate risk for schizophrenia through reduced DTNBP1 expression. Hum Mol Genet 2005; 14: 1947–1954.

    Article  CAS  PubMed  Google Scholar 

  40. Williams NM, Preece A, Morris DW, Spurlock G, Bray NJ, Stephens M et al. Identification in 2 independent samples of a novel schizophrenia risk haplotype of the dystrobrevin binding protein gene (DTNBP1). Arch Gen Psychiatry 2004; 61: 336–344.

    Article  CAS  PubMed  Google Scholar 

  41. Bigos KL, Weinberger DR . Imaging genetics—days of future past. Neuroimage 2010; 53: 804–809.

    Article  CAS  PubMed  Google Scholar 

  42. Mier D, Kirsch P, Meyer-Lindenberg A . Neural substrates of pleiotropic action of genetic variation in COMT: a meta-analysis. Mol Psychiatry 2010; 15: 918–927.

    Article  CAS  PubMed  Google Scholar 

  43. Callicott JH, Mattay VS, Bertolino A, Finn K, Coppola R, Frank JA et al. Physiological characteristics of capacity constraints in working memory as revealed by functional MRI. Cereb Cortex 1999; 9: 20–26.

    Article  CAS  PubMed  Google Scholar 

  44. 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 

  45. Gao WJ, Goldman-Rakic PS . Selective modulation of excitatory and inhibitory microcircuits by dopamine. Proc Natl Acad Sci USA 2003; 100: 2836–2841.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Klassen T, Davis C, Goldman A, Burgess D, Chen T, Wheeler D et al. Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy. Cell 2011; 145: 1036–1048.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank L Erickson, S. Garcia and T. Qingjun for technical assistance. We thank Dr M. Karayiorgou and Dr J A Gogos (Columbia University, New York, NY, USA) and Dr B. Lu (NIMH, Bethesda, MD, USA) for generously donating the COMT−/− and dys−/− mouse breeders, respectively. We thank Dr JN Crawley (NIMH, Bethesda, MD, USA) for important support in the mouse phenotyping and Dr J Chen for help with many aspects of mouse husbandry. This research was supported by the Intramural Program of the NIMH, the Lieber Institute for Brain Development, the Istituto Italiano di Tecnologia and the Marie Curie FP7-Reintegration-Grant No. 268247.

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Authors and Affiliations

  1. Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy

    F Papaleo

  2. Department of Scienze del Farmaco, Universita’ degli Studi di Padova, Padova, Italy

    F Papaleo

  3. Clinical Brain Disorders Branch, Genes, Cognition and Psychosis Program, National Institute of Mental Health, Bethesda, MD, USA

    F Papaleo, M C Burdick, J H Callicott & D R Weinberger

  4. Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USA

    D R Weinberger

  5. Departments of Psychiatry, Neurology, Neuroscience and the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    D R Weinberger

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Correspondence to F Papaleo or D R Weinberger.

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Papaleo, F., Burdick, M., Callicott, J. et al. Epistatic interaction between COMT and DTNBP1 modulates prefrontal function in mice and in humans. Mol Psychiatry 19, 311–316 (2014). https://doi.org/10.1038/mp.2013.133

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Keywords

  • cognition
  • fMRI
  • genes
  • translational research
  • working memory

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