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Effects of a genome-wide supported psychosis risk variant on neural activation during a theory-of-mind task

Molecular Psychiatry volume 16, pages 462–470 (2011)Cite this article

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Abstract

Schizophrenia is associated with marked deficits in theory of mind (ToM), a higher-order form of social cognition representing the thoughts, emotions and intentions of others. Altered brain activation in the medial prefrontal cortex and temporo-parietal cortex during ToM tasks has been found in patients with schizophrenia, but the relevance of these neuroimaging findings for the heritable risk for schizophrenia is unclear. We tested the hypothesis that activation of the ToM network is altered in healthy risk allele carriers of the single-nucleotide polymorphism rs1344706 in the gene ZNF804A, a recently discovered risk variant for psychosis with genome-wide support. In all, 109 healthy volunteers of both sexes in Hardy–Weinberg equilibrium for rs1344706 were investigated with functional magnetic resonance imaging during a ToM task. As hypothesised, risk carriers exhibited a significant (P<0.05 false discovery rate, corrected for multiple comparisons) risk allele dose effect on neural activity in the medial prefrontal cortex and left temporo-parietal cortex. Moreover, the same effect was found in the left inferior parietal cortex and left inferior frontal cortex, which are part of the human analogue of the mirror neuron system. In addition, in an exploratory analysis (P<0.001 uncorrected), we found evidence for aberrant functional connectivity between the frontal and temporo-parietal regions in risk allele carriers. To conclude, we show that a dysfunction of the ToM network is associated with a genome-wide supported genetic risk variant for schizophrenia and has promise as an intermediate phenotype that can be mined for the development of biological interventions targeted to social dysfunction in psychiatry.

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References

  1. Allen AJ, Griss ME, Folley BS, Hawkins KA, Pearlson GD . Endophenotypes in schizophrenia: a selective review. Schizophr Res 2009; 109: 24–37.

    Article  PubMed  PubMed Central  Google Scholar 

  2. 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 

  3. Mier D, Kirsch P, Meyer-Lindenberg A . Neural substrates of pleiotropic action of genetic variation in COMT: a meta-analysis. Mol Psychiatry 2009; e-pub ahead of print, doi: 10.1038/mp.2009.36.

    Article  PubMed  Google Scholar 

  4. 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 

  5. Meyer-Lindenberg A, Zink CF . Imaging genetics for neuropsychiatric disorders. Child Adolesc Psychiatr Clin N Am 2007; 16: 581–597.

    Article  PubMed  Google Scholar 

  6. Weinberger DR, Egan MF, Bertolino A, Callicott JH, Mattay VS, Lipska BK et al. Prefrontal neurons and the genetics of schizophrenia. Biol Psychiatry 2001; 50: 825–844.

    Article  CAS  PubMed  Google Scholar 

  7. 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 

  8. Honea R, Verchinski BA, Pezawas L, Kolachana BS, Callicott JH, Mattay VS 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 

  9. 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 

  10. Pezawas L, Verchinski BA, Mattay VS, Callicott JH, Kolachana BS, Straub RE et al. The brain-derived neurotrophic factor val66met polymorphism and variation in human cortical morphology. J Neurosci 2004; 24: 10099–10102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Meyer-Lindenberg A, Straub RE, Lipska BK, Verchinski BA, Goldberg T, Callicott JH et al. Genetic evidence implicating DARPP-32 in human frontostriatal structure, function, and cognition. J Clin Invest 2007; 117: 672–682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. O'Donovan MC, Craddock N, Norton N, Williams H, Peirce T, Moskvina V et al. Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nat Genet 2008; 40: 1053–1055.

    Article  CAS  PubMed  Google Scholar 

  13. Purcell SM, Wray NR, Stone JL, Visscher PM, O'Donovan MC, Sullivan PF et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009; 460: 748–752.

    CAS  PubMed  Google Scholar 

  14. Esslinger C, Walter H, Kirsch P, Erk S, Schnell K, Arnold C et al. Neural mechanisms of a genome wide significant psychosis variant. Science 2009; 324: 605.

    Article  CAS  PubMed  Google Scholar 

  15. Meyer-Lindenberg AS, Olsen RK, Kohn PD, Brown T, Egan MF, Weinberger DR et al. Regionally specific disturbance of dorsolateral prefrontal-hippocampal functional connectivity in schizophrenia. Arch Gen Psychiatry 2005; 62: 379–386.

    Article  PubMed  Google Scholar 

  16. Couture SM, Penn DL, Roberts DL . The functional significance of social cognition in schizophrenia: a review. Schizophr Bull 2006; 32 (Suppl 1): S44–S63.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Penn DL, Sanna LJ, Roberts DL . Social cognition in schizophrenia: an overview. Schizophr Bull 2008; 34: 408–411.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Chung YS, Kang DH, Shin NY, Yoo SY, Kwon JS . Deficit of theory of mind in individuals at ultra-high-risk for schizophrenia. Schizophr Res 2008; 99: 111–118.

    Article  PubMed  Google Scholar 

  19. Marjoram D, Miller P, McIntosh AM, Cunningham Owens DG, Johnstone EC, Lawrie S . A neuropsychological investigation into ‘Theory of Mind’ and enhanced risk of schizophrenia. Psychiatry Res 2006; 144: 29–37.

    Article  PubMed  Google Scholar 

  20. Mazza M, Di Michele V, Pollice R, Casacchia M, Roncone R . Pragmatic language and theory of mind deficits in people with schizophrenia and their relatives. Psychopathology 2008; 41: 254–263.

    Article  PubMed  Google Scholar 

  21. Brune M . ‘Theory of mind’ in schizophrenia: a review of the literature. Schizophr Bull 2005; 31: 21–42.

    Article  PubMed  Google Scholar 

  22. Harrington L, Langdon R, Siegert RJ, McClure J . Schizophrenia, theory of mind, and persecutory delusions. Cognit Neuropsychiatry 2005; 10: 87–104.

    Article  Google Scholar 

  23. Sprong M, Schothorst P, Vos E, Hox J, van Engeland H . Theory of mind in schizophrenia: meta-analysis. Br J Psychiatry 2007; 191: 5–13.

    Article  PubMed  Google Scholar 

  24. Brune M, Brune-Cohrs U . Theory of mind—evolution, ontogeny, brain mechanisms and psychopathology. Neurosci Biobehav Rev 2006; 30: 437–455.

    Article  PubMed  Google Scholar 

  25. Burns J . The social brain hypothesis of schizophrenia. World Psychiatry 2006; 5: 77–81.

    PubMed  PubMed Central  Google Scholar 

  26. Donaldson ZR, Young LJ . Oxytocin, vasopressin, and the neurogenetics of sociality. Science 2008; 322: 900–904.

    Article  CAS  PubMed  Google Scholar 

  27. Robinson GE, Fernald RD, Clayton DF . Genes and social behavior. Science 2008; 322: 896–900.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Frith CD, Frith U . Interacting minds—a biological basis. Science 1999; 286: 1692–1695.

    Article  CAS  PubMed  Google Scholar 

  29. Frith CD, Frith U . The neural basis of mentalizing. Neuron 2006; 50: 531–534.

    Article  CAS  PubMed  Google Scholar 

  30. Gallagher HL, Frith CD . Functional imaging of ‘theory of mind’. Trends Cogn Sci 2003; 7: 77–83.

    Article  PubMed  Google Scholar 

  31. Bora E, Murat Y, Pantelis C . Theory of mind impairment in schizophrenia: meta-analysis. Schizophrenia Research 2009; 109: 1–9.

    Article  PubMed  Google Scholar 

  32. Langdon R, Ward PB, Coltheart M . Reasoning anomalies associated with delusions in schizophrenia. Schizophr Bull 2008; e-pub ahead of print: doi: 10.1093/schbul/sbn069.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Blakemore SJ, Smith J, Steel R, Johnstone CE, Frith CD . The perception of self-produced sensory stimuli in patients with auditory hallucinations and passivity experiences: evidence for a breakdown in self-monitoring. Psychol Med 2000; 30: 1131–1139.

    Article  CAS  PubMed  Google Scholar 

  34. Schnell K, Heekeren K, Daumann J, Schnell T, Schnitker R, Möller-Hartmann W et al. Correlation of passivity symptoms and dysfunctional visuomotor action monitoring in psychosis. Brain 2008; 131 (Part 10): 2783–2797.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Spence SA, Brooks DJ, Hirsch SR, Liddle PF, Meehan J, Grasby PM . A PET study of voluntary movement in schizophrenic patients experiencing passivity phenomena (delusions of alien control). Brain 1997; 120 (Part 11): 1997–2011.

    Article  PubMed  Google Scholar 

  36. Abu-Akel A, Bailey AL . The possibility of different forms of theory of mind impairment in psychiatric and developmental disorders. Psychol Med 2000; 30: 735–738.

    Article  CAS  PubMed  Google Scholar 

  37. Frith C . The Cognitive Neuropsycholgy of Schizophrenia. Psychology Press: Hove, 1992.

    Google Scholar 

  38. Bora E, Gokcen S, Kayahan B, Veznedaroglu B . Deficits of social-cognitive and social-perceptual aspects of theory of mind in remitted patients with schizophrenia: effect of residual symptoms. J Nerv Ment Dis 2008; 196: 95–99.

    Article  PubMed  Google Scholar 

  39. Herold R, Tenyi T, Lenard K, Trixler M . Theory of mind deficit in people with schizophrenia during remission. Psychol Med 2002; 32: 1125–1129.

    Article  CAS  PubMed  Google Scholar 

  40. Brunet-Gouet E, Decety J . Social brain dysfunctions in schizophrenia: a review of neuroimaging studies. Psychiatry Res 2006; 148: 75–92.

    Article  PubMed  Google Scholar 

  41. Andreasen NC, Calage CA, O'Leary DS . Theory of mind and schizophrenia: a positron emission tomography study of medication-free patients. Schizophr Bull 2008; 34: 708–719.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Brunet E, Sarfati Y, Hardy-Bayle MC, Decety J . Abnormalities of brain function during a nonverbal theory of mind task in schizophrenia. Neuropsychologia 2003; 41: 1574–1582.

    Article  PubMed  Google Scholar 

  43. Russell TA, Rubia K, Bullmore ET, Soni W, Suckling J, Brammer MJ et al. Exploring the social brain in schizophrenia: left prefrontal underactivation during mental state attribution. Am J Psychiatry 2000; 157: 2040–2042.

    Article  CAS  PubMed  Google Scholar 

  44. Marjoram D, Job DE, Whalley HC, Gountouna VE, McIntosh AM, Simonotto E et al. A visual joke fMRI investigation into Theory of Mind and enhanced risk of schizophrenia. Neuroimage 2006; 31: 1850–1858.

    Article  PubMed  Google Scholar 

  45. Walter H, Ciaramidaro A, Adenzato M, Vasic N, Ardito RB, Erk S et al. Dysfunction of the social brain is modulated by intention type: an FMRI study. Soc Cogn Affect Neurosci 2009; 4: 166–176.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Ciaramidaro A, Adenzato M, Enrici I, Erk S, Pia L, Bara BG et al. The intentional network: how the brain reads varieties of intentions. Neuropsychologia 2007; 45: 3105–3113.

    Article  CAS  PubMed  Google Scholar 

  47. Walter H, Adenzato M, Ciaramidaro A, Enrici I, Pia L, Bara BG . Understanding intentions in social interaction: the role of the anterior paracingulate cortex. J Cogn Neurosci 2004; 16: 1854–1863.

    Article  PubMed  Google Scholar 

  48. 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 

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

    Article  CAS  PubMed  Google Scholar 

  50. Amodio DM, Frith CD . Meeting of minds: the medial frontal cortex and social cognition. Nat Rev Neurosci 2006; 7: 268–277.

    Article  CAS  PubMed  Google Scholar 

  51. Saxe R, Powell LJ . It's the thought that counts: specific brain regions for one component of theory of mind. Psychol Sci 2006; 17: 692–699.

    Article  PubMed  Google Scholar 

  52. Rasetti R, Mattay VS, Wiedholz LM, Kolachana BS, Hariri AR, Callicott JH et al. Evidence that altered amygdala activity in schizophrenia is related to clinical state and not genetic risk. Am J Psychiatry 2009; 166: 216–225.

    Article  PubMed  Google Scholar 

  53. Hynes CA, Baird AA, Grafton ST . Differential role of the orbital frontal lobe in emotional versus cognitive perspective-taking. Neuropsychologia 2006; 44: 374–383.

    Article  PubMed  Google Scholar 

  54. Vogeley K, Bussfeld P, Newen A, Herrmann S, Happe F, Falkai P et al. Mind reading: neural mechanisms of theory of mind and self-perspective. Neuroimage 2001; 14 (1 Part 1): 170–181.

    Article  CAS  PubMed  Google Scholar 

  55. Desmurget M, Reilly KT, Richard N, Szathmari A, Mottolese C, Sirigu A . Movement intention after parietal cortex stimulation in humans. Science 2009; 324: 811–813.

    Article  CAS  PubMed  Google Scholar 

  56. Frith CD, Blakemore SJ, Wolpert DM . Abnormalities in the awareness and control of action. Philos Trans R Soc Lond B Biol Sci 2000; 355: 1771–1788.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Iacoboni M, Molnar-Szakacs I, Gallese V, Buccino G, Mazziotta JC, Rizzolatti G . Grasping the intentions of others with one's own mirror neuron system. PLoS Biol 2005; 3: e79.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Rizzolatti G, Fabbri-Destro M . The mirror system and its role in social cognition. Curr Opin Neurobiol 2008; 18: 179–184.

    Article  CAS  PubMed  Google Scholar 

  59. Gallese V, Fadiga L, Fogassi L, Rizzolatti G . Action recognition in the premotor cortex. Brain 1996; 119 (Part 2): 593–609.

    Article  PubMed  Google Scholar 

  60. Dinstein I, Gardner JL, Jazayeri M, Heeger DJ . Executed and observed movements have different distributed representations in human aIPS. J Neurosci 2008; 28: 11231–11239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Lingnau A, Gesierich B, Caramazza A . Asymmetric fMRI adaptation reveals no evidence for mirror neurons in humans. Proc Natl Acad Sci USA 2009; 106: 9925–9930.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Kerr N, Dunbar RI, Bentall RP . Theory of mind deficits in bipolar affective disorder. J Affect Disord 2003; 73: 253–259.

    Article  PubMed  Google Scholar 

  63. Olley AL, Malhi GS, Bachelor J, Cahill CM, Mitchell PB, Berk M . Executive functioning and theory of mind in euthymic bipolar disorder. Bipolar Disord 2005; 7 (Suppl 5): 43–52.

    Article  PubMed  Google Scholar 

  64. Shamay-Tsoory S, Harari H, Szepsenwol O, Levkovitz Y . Neuropsychological evidence of impaired cognitive empathy in euthymic bipolar disorder. J Neuropsychiatry Clin Neurosci 2009; 21: 59–67.

    Article  PubMed  Google Scholar 

  65. Tost H, Ruf M, Schmal C, Schulze TG, Knorr C, Vollmert C et al. Prefrontal-temporal gray matter deficits in bipolar disorder patients with persecutory delusions. J Affect Disord 2010; 120: 54–61.

    Article  PubMed  Google Scholar 

  66. Abu-Akel A . The neurochemical hypothesis of ‘theory of mind’. Med Hypotheses 2003; 60: 382–386.

    Article  CAS  PubMed  Google Scholar 

  67. Knafo A, Israel S, Darvasi A, Bachner-Melman R, Uzefovsky F, Cohen L et al. Individual differences in allocation of funds in the dictator game associated with length of the arginine vasopressin 1a receptor RS3 promoter region and correlation between RS3 length and hippocampal mRNA. Genes Brain Behav 2008; 7: 266–275.

    Article  CAS  PubMed  Google Scholar 

  68. Silk JB . Social components of fitness in primate groups. Science 2007; 317: 1347–1351.

    Article  CAS  PubMed  Google Scholar 

  69. Domes G, Heinrichs M, Michel A, Berger C, Herpertz SC . Oxytocin improves ‘mind-reading’ in humans. Biol Psychiatry 2007; 61: 731–733.

    Article  CAS  PubMed  Google Scholar 

  70. Guastella AJ, Mitchell PB, Dadds MR . Oxytocin increases gaze to the eye region of human faces. Biol Psychiatry 2008; 63: 3–5.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Funding for this study was provided by BMBF (NGFNplus MooDS) and DFG (SFB 636-B7). We thank Beate Newport, Carola Opitz von Boberfeld, Dagmar Gass, Oliver Grimm, Carina Sauer and Torsten Paul for help with data acquisition, Traute Demirakca, Matthias Ruf and Peter Trautner for technical support, Sarah Bluschke, Brigitte Konradt and Sabrina Franz for help in stimulus design, and Gerhard C Bukow for proofreading. HW, KS, SE and AM-L had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

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  1. H Walter, K Schnell and S Erk: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy, Division of Mind and Brain Research, Charité—Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany

    H Walter & S Erk

  2. Division of Medical Psychology, University of Bonn, Bonn, Germany

    H Walter, S Erk, C Arnold & M M Schmitgen

  3. Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany

    H Walter & K Schnell

  4. Department of General Psychiatry, Heidelberg University Hospital, University of Heidelberg, Heidelberg, Germany

    K Schnell

  5. Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany

    P Kirsch, C Esslinger, D Mier & A Meyer-Lindenberg

  6. Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany

    M Rietschel & S H Witt

  7. Department of Genomics, Life and Brain Center and Institute of Human Genetics, University of Bonn, Bonn, Germany

    M M Nöthen & S Cichon

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Walter, H., Schnell, K., Erk, S. et al. Effects of a genome-wide supported psychosis risk variant on neural activation during a theory-of-mind task. Mol Psychiatry 16, 462–470 (2011). https://doi.org/10.1038/mp.2010.18

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