Advertisement

Impact of TCF4 on the genetics of schizophrenia

  • Leonhard Lennertz
  • Boris B. Quednow
  • Jens Benninghoff
  • Michael Wagner
  • Wolfgang Maier
  • Rainald MössnerEmail author
Review

Abstract

Mutations of the transcription factor 4 (TCF4) gene cause mental retardation with or without associated facial dysmorphisms and intermittent hyperventilation. Subsequently, a polymorphism of TCF4 was shown in a genome-wide association study to slightly increase the risk of schizophrenia. We have further analysed the impact of this TCF4 variant rs9960767 on early information processing and cognitive functions in schizophrenia patients. We have shown in a sample of 401 schizophrenia patients that TCF4 influences verbal memory in the Rey Auditory Verbal Learning Test. Contrary to expectations, carriers of the schizophrenia-associated allele showed better recognition, thus indicating that while TCF4 influences verbal memory, the TCF4-mediated schizophrenia risk is not determined by the influence of TCF4 on verbal memory. TCF4 does not impact on various other cognitive functions belonging to the domains of attention and executive functions. Moreover, in a pharmacogenetic approach, TCF4 does not modulate the improvement of positive or negative schizophrenia symptoms during treatment with antipsychotics. Finally, we have assessed a key electrophysiological endophenotype of schizophrenia, sensorimotor gating. As measured by prepulse inhibition, the schizophrenia risk allele C of TCF4 rs9960767 reduces sensorimotor gating. This indicates that TCF4 influences key mechanisms of information processing, which may contribute to the pathogenesis of schizophrenia.

Keywords

Schizophrenia TCF4 PPI Verbal memory Sensorimotor Gating Pharmacogenetics 

Notes

Acknowledgments

This work was supported by the European Union (Grant FP7-Health-F4-2009-242257-ADAMS), by the German Federal Ministry for Education and Research (BMBF) (Grants POSITIVE 01GV0907, NGFN MooDs PNM-01GS08146-3), and by the DFG (Grant WA 737/7). Dr. Quednow is supported by the Swiss National Science Foundation (Grant No. PP00P1 123516). We thank V. Guttenthaler and A. Petruschke for excellent technical assistance.

Conflict of interest

The authors declare that they have no conflict of interest.

This supplement was not sponsored by outside commercial interests. It was funded by the German Association for Psychiatry and Psychotherapy (DGPPN).

References

  1. 1.
    Amiel J, Rio M, de Pontual L, Redon R, Malan V, Boddaert N, Plouin P, Carter NP, Lyonnet S, Munnich A, Colleaux L (2007) Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction. Am J Hum Genet 80:988–993PubMedCrossRefGoogle Scholar
  2. 2.
    Anokhin AP, Heath AC, Myers E, Ralano A, Wood S (2003) Genetic influences on prepulse inhibition of startle reflex in humans. Neurosci Lett 353:45–48PubMedCrossRefGoogle Scholar
  3. 3.
    Braff DL, Grillon C, Geyer MA (1992) Gating and habituation of the startle reflex in schizophrenic patients. Arch Gen Psychiatr 49:206–215PubMedGoogle Scholar
  4. 4.
    Brockschmidt A et al (2007) Severe mental retardation with breathing abnormalities (Pitt-Hopkins syndrome) is caused by haploinsufficiency of the neuronal bHLH transcription factor TCF4. Hum Mol Genet 16:1488–1494PubMedCrossRefGoogle Scholar
  5. 5.
    Brzozka MM, Radyushkin K, Wichert SP, Ehrenreich H, Rossner MJ (2010) Cognitive and sensorimotor gating impairments in transgenic mice overexpressing the schizophrenia susceptibility gene Tcf4 in the brain. Biol Psychiatr 68:33–40CrossRefGoogle Scholar
  6. 6.
    Cadenhead KS, Geyer MA, Braff DL (1993) Impaired startle prepulse inhibition and habituation in patients with schizotypal personality disorder. Am J Psychiatr 150:1862–1867PubMedGoogle Scholar
  7. 7.
    Cadenhead KS, Light GA, Geyer MA, Braff DL (2000) Sensory gating deficits assessed by the P50 event-related potential in subjects with schizotypal personality disorder. Am J Psychiatr 157:55–59PubMedCrossRefGoogle Scholar
  8. 8.
    Cannon TD, Huttunen MO, Lonnqvist J, Tuulio-Henriksson A, Pirkola T, Glahn D, Finkelstein J, Hietanen M, Kaprio J, Koskenvuo M (2000) The inheritance of neuropsychological dysfunction in twins discordant for schizophrenia. Am J Hum Genet 67:369–382PubMedCrossRefGoogle Scholar
  9. 9.
    de Pontual L et al (2009) Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome. Hum Mutat 30:669–676PubMedCrossRefGoogle Scholar
  10. 10.
    Dickinson D, Ramsey ME, Gold JM (2007) Overlooking the obvious: a meta-analytic comparison of digit symbol coding tasks and other cognitive measures in schizophrenia. Arch Gen Psychiatr 64:532–542PubMedCrossRefGoogle Scholar
  11. 11.
    Faraone SV, Seidman LJ, Kremen WS, Toomey R, Pepple JR, Tsuang MT (2000) Neuropsychologic functioning among the nonpsychotic relatives of schizophrenic patients: the effect of genetic loading. Biol Psychiatr 48:120–126CrossRefGoogle Scholar
  12. 12.
    Fendt M, Li L, Yeomans JS (2001) Brain stem circuits mediating prepulse inhibition of the startle reflex. Psychopharmacology (Berl) 156:216–224CrossRefGoogle Scholar
  13. 13.
    Flora A, Garcia JJ, Thaller C, Zoghbi HY (2007) The E-protein Tcf4 interacts with Math1 to regulate differentiation of a specific subset of neuronal progenitors. Proc Natl Acad Sci USA 104:15382–15387PubMedCrossRefGoogle Scholar
  14. 14.
    Gottesman II, Gould TD (2003) The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatr 160:636–645PubMedCrossRefGoogle Scholar
  15. 15.
    Graham FK (1975) Presidential Address, 1974. The more or less startling effects of weak prestimulation. Psychophysiology 12:238–248PubMedCrossRefGoogle Scholar
  16. 16.
    Greenwood TA et al (2007) Initial heritability analyses of endophenotypic measures for schizophrenia: the consortium on the genetics of schizophrenia. Arch Gen Psychiatr 64:1242–1250PubMedCrossRefGoogle Scholar
  17. 17.
    Helmstaedter C, Lendt M, Lux S (2001) VLMT—Verbaler Lern- und Merkfähigkeitstest Manual. Beltz, GöttingenGoogle Scholar
  18. 18.
    Kalscheuer VM, Feenstra I, Van Ravenswaaij-Arts CM, Smeets DF, Menzel C, Ullmann R, Musante L, Ropers HH (2008) Disruption of the TCF4 gene in a girl with mental retardation but without the classical Pitt-Hopkins syndrome. Am J Med Genet A 146A:2053–2059PubMedCrossRefGoogle Scholar
  19. 19.
    Kumari V, Das M, Zachariah E, Ettinger U, Sharma T (2005) Reduced prepulse inhibition in unaffected siblings of schizophrenia patients. Psychophysiology 42:588–594PubMedCrossRefGoogle Scholar
  20. 20.
    Kumari V, Soni W, Mathew VM, Sharma T (2000) Prepulse inhibition of the startle response in men with schizophrenia: effects of age of onset of illness, symptoms, and medication. Arch Gen Psychiatr 57:609–614PubMedCrossRefGoogle Scholar
  21. 21.
    Lennertz L, Rujescu D, Wagner M, Frommann I, Schulze-Rauschenbach S, Schuhmacher A, Landsberg MW, Franke P, Moller HJ, Wolwer W, Gaebel W, Hafner H, Maier W, Mössner R (2011) Novel schizophrenia risk gene TCF4 influences verbal learning and memory functioning in schizophrenia patients. Neuropsychobiology 63:131–136PubMedCrossRefGoogle Scholar
  22. 22.
    Ludewig K, Geyer MA, Vollenweider FX (2003) Deficits in prepulse inhibition and habituation in never-medicated, first-episode schizophrenia. Biol Psychiatr 54:121–128CrossRefGoogle Scholar
  23. 23.
    Parwani A, Duncan EJ, Bartlett E, Madonick SH, Efferen TR, Rajan R, Sanfilipo M, Chappell PB, Chakravorty S, Gonzenbach S, Ko GN, Rotrosen JP (2000) Impaired prepulse inhibition of acoustic startle in schizophrenia. Biol Psychiatr 47:662–669CrossRefGoogle Scholar
  24. 24.
    Petrovsky N, Quednow BB, Ettinger U, Schmechtig A, Mossner R, Collier DA, Kuhn KU, Maier W, Wagner M, Kumari V (2010) Sensorimotor gating is associated with CHRNA3 polymorphisms in schizophrenia and healthy volunteers. Neuropsychopharmacology 35:1429–1439PubMedCrossRefGoogle Scholar
  25. 25.
    Pitt D, Hopkins I (1978) A syndrome of mental retardation, wide mouth and intermittent overbreathing. Aust Paediatr J 14:182–184PubMedGoogle Scholar
  26. 26.
    Quednow BB (2008) Sensorimotor gating deficits in psychiatric disorders. Zeitschrift für Neuropsychologie 19:139–163CrossRefGoogle Scholar
  27. 27.
    Quednow BB, Ettinger U, Mossner R, Rujescu D, Giegling I, Collier DA, Schmechtig A, Kuhn KU, Moller HJ, Maier W, Wagner M, Kumari V (2011) The schizophrenia risk allele C of the TCF4 rs9960767 polymorphism disrupts sensorimotor gating in schizophrenia spectrum and healthy volunteers. J Neurosci 31:6684–6691PubMedCrossRefGoogle Scholar
  28. 28.
    Quednow BB, Frommann I, Berning J, Kuhn KU, Maier W, Wagner M (2008) Impaired sensorimotor gating of the acoustic startle response in the prodrome of schizophrenia. Biol Psychiatr 64:766–773CrossRefGoogle Scholar
  29. 29.
    Quednow BB, Kuhn KU, Mössner R, Schwab SG, Schuhmacher A, Maier W, Wagner M (2008) Sensorimotor gating of schizophrenia patients is influenced by 5-HT2A receptor polymorphisms. Biol Psychiatr 64:434–437CrossRefGoogle Scholar
  30. 30.
    Quednow BB, Schmechtig A, Ettinger U, Petrovsky N, Collier DA, Vollenweider FX, Wagner M, Kumari V (2009) Sensorimotor gating depends on polymorphisms of the serotonin-2A receptor and catechol-O-methyltransferase, but not on neuregulin-1 Arg38Gln genotype: a replication study. Biol Psychiatr 66:614–620CrossRefGoogle Scholar
  31. 31.
    Quednow BB, Wagner M, Mössner R, Maier W, Kuhn KU (2010) Sensorimotor gating of schizophrenia patients depends on catechol O-methyltransferase Val158Met polymorphism. Schizophr Bull 36:341–346PubMedCrossRefGoogle Scholar
  32. 32.
    Quednow BB, Wagner M, Westheide J, Beckmann K, Bliesener N, Maier W, Kuhn KU (2006) Sensorimotor gating and habituation of the startle response in schizophrenic patients randomly treated with amisulpride or olanzapine. Biol Psychiatr 59:536–545CrossRefGoogle Scholar
  33. 33.
    Rosenfeld JA et al (2009) Genotype-phenotype analysis of TCF4 mutations causing Pitt-Hopkins syndrome shows increased seizure activity with missense mutations. Genet Med 11:797–805PubMedCrossRefGoogle Scholar
  34. 34.
    Roussos P, Giakoumaki SG, Rogdaki M, Pavlakis S, Frangou S, Bitsios P (2008) Prepulse inhibition of the startle reflex depends on the catechol O-methyltransferase Val158Met gene polymorphism. Psychol Med 38:1651–1658PubMedCrossRefGoogle Scholar
  35. 35.
    Stefansson H et al (2009) Common variants conferring risk of schizophrenia. Nature 460:744–747PubMedGoogle Scholar
  36. 36.
    Swerdlow NR, Geyer MA (1998) Using an animal model of deficient sensorimotor gating to study the pathophysiology and new treatments of schizophrenia. Schizophr Bull 24:285–301PubMedGoogle Scholar
  37. 37.
    Swerdlow NR, Geyer MA, Braff DL (2001) Neural circuit regulation of prepulse inhibition of startle in the rat: current knowledge and future challenges. Psychopharmacology (Berl) 156:194–215CrossRefGoogle Scholar
  38. 38.
    van Erp TG, Therman S, Pirkola T, Tuulio-Henriksson A, Glahn DC, Bachman P, Huttunen MO, Lonnqvist J, Hietanen M, Kaprio J, Koskenvuo M, Cannon TD (2008) Verbal recall and recognition in twins discordant for schizophrenia. Psychiatry Res 159:271–280PubMedCrossRefGoogle Scholar
  39. 39.
    Ziermans T, Schothorst P, Magnee M, van Engeland H, Kemner C (2011) Reduced prepulse inhibition in adolescents at risk for psychosis: a 2-year follow-up study. J Psychiatry Neurosci 36:127–134PubMedGoogle Scholar
  40. 40.
    Zweier C et al (2007) Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome). Am J Hum Genet 80:994–1001PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Leonhard Lennertz
    • 1
  • Boris B. Quednow
    • 2
  • Jens Benninghoff
    • 3
  • Michael Wagner
    • 1
  • Wolfgang Maier
    • 1
  • Rainald Mössner
    • 1
    Email author
  1. 1.Department of Psychiatry and PsychotherapyUniversity of BonnBonnGermany
  2. 2.University Hospital of Psychiatry, Division of Experimental and Clinical PharmacopsychologyUniversity of ZurichZurichSwitzerland
  3. 3.Department of PsychiatryUniversity of Duisburg-EssenEssenGermany

Personalised recommendations