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Tph2 gene variants modulate response control processes in adult ADHD patients and healthy individuals

Molecular Psychiatry volume 14, pages 1032–1039 (2009)Cite this article

Abstract

Although therapeutic interventions in attention-deficit/hyperactivity disorder (ADHD) still focus on the dopaminergic system, recent studies indicate a serotonergic dysfunction in this disease as well. In that respect, several variants of the tryptophan hydroxylase gene (TPH2), which codes for the rate-limiting enzyme in the biosynthesis of serotonin (5-HT), have been associated with ADHD. The rs4570625 G-allele polymorphisms of the TPH2 gene have already been related to altered reactivity of the brain during perception tasks with emotional stimuli in healthy adults. Here we investigated the influence of the ADHD related risk alleles for rs4570625 and for rs11178997 on prefrontal brain function during cognitive response control in large samples of adult ADHD patients (n=124) and healthy controls (n=84). Response control was elicited with a Go-NoGo task (continuous performance test; CPT) performed during recording of an ongoing EEG. From the resulting event-related potentials in the Go- and NoGo conditions of the CPT, the NoGo-anteriorization (NGA) has been calculated as a valid neurophysiological parameter for prefrontal brain function. In the current study, ADHD risk alleles of both polymorphisms were found to be associated with a reduction in the NGA in both healthy controls and ADHD patients. These findings are in line with the notion that genetic variations associated with altered serotonergic neurotransmission are also associated with the function of the prefrontal cortex during response inhibition. This mechanism might also be relevant in the pathophysiology of ADHD.

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References

  1. Brookes K, Xu X, Chen W, Zhou K, Neale B, Lowe N et al. The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes. Mol Psychiatry 2006; 11: 934–953.

    Article  CAS  PubMed  Google Scholar 

  2. Heiser P, Friedel S, Dempfle A, Konrad K, Smidt J, Grabarkiewicz J et al. Molecular genetic aspects of attention-deficit/hyperactivity disorder. Neurosci Biobehav Rev 2004; 28: 625–641.

    Article  CAS  PubMed  Google Scholar 

  3. Walther DJ, Bader M . A unique central tryptophan hydroxylase isoform. Biochem Pharmacol 2003; 66: 1673–1680.

    Article  CAS  PubMed  Google Scholar 

  4. Cote F, Thevenot E, Fligny C, Fromes Y, Darmon M, Ripoche MA et al. Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function. Proc Natl Acad Sci USA 2003; 100: 13525–13530.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sheehan K, Lowe N, Kirley A, Mullins C, Fitzgerald M, Gill M et al. Tryptophan hydroxylase 2 (TPH2) gene variants associated with ADHD. Mol Psychiatry 2005; 10: 944–949.

    Article  CAS  PubMed  Google Scholar 

  6. Walitza S, Renner TJ, Dempfle A, Konrad K, Wewetzer Ch, Halbach A et al. Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/hyperactivity disorder. Mol Psychiatry 2005; 10: 1126–1132.

    Article  CAS  PubMed  Google Scholar 

  7. Canli T, Congdon E, Gutknecht L, Constable RT, Lesch KP . Amygdala responsiveness is modulated by tryptophan hydroxylase-2 gene variation. J Neural Transm 2005; 112: 1479–1485.

    Article  CAS  PubMed  Google Scholar 

  8. Herrmann MJ, Huter T, Muller F, Muhlberger A, Pauli P, Reif A et al. Additive effects of serotonin transporter and tryptophan hydroxylase-2 gene variation on emotional processing. Cereb Cortex 2007; 17: 1160–1163.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. Lijffijt M, Kenemans JL, Verbaten MN, van Engeland H . A meta-analytic review of stopping performance in attention-deficit/hyperactivity disorder: deficient inhibitory motor control? J Abnorm Psychol 2005; 114: 216–222.

    Article  PubMed  Google Scholar 

  12. Aron AR, Poldrack RA . The cognitive neuroscience of response inhibition: relevance for genetic research in attention-deficit/hyperactivity disorder. Biol Psychiatry 2005; 57: 1285–1292.

    Article  PubMed  Google Scholar 

  13. Crean J, Richards JB, de Wit H . Effect of tryptophan depletion on impulsive behavior in men with or without a family history of alcoholism. Behav Brain Res 2002; 136: 349–357.

    Article  CAS  PubMed  Google Scholar 

  14. Walderhaug E, Lunde H, Nordvik JE, Landro NI, Refsum H, Magnusson A . Lowering of serotonin by rapid tryptophan depletion increases impulsiveness in normal individuals. Psychopharmacology (Berl) 2002; 164: 385–391.

    Article  CAS  Google Scholar 

  15. Bjork JM, Moeller FG, Dougherty DM, Swann AC, Machado MA, Hanis CL . Serotonin 2a receptor T102C polymorphism and impaired impulse control. Am J Med Genet 2002; 114: 336–339.

    Article  PubMed  Google Scholar 

  16. Stoltenberg SF, Glass JM, Chermack ST, Flynn HA, Li S, Weston ME et al. Possible association between response inhibition and a variant in the brain-expressed tryptophan hydroxylase-2 gene. Psychiatr Genet 2006; 16: 35–38.

    Article  PubMed  Google Scholar 

  17. LeMarquand DG, Pihl RO, Young SN, Tremblay RE, Seguin JR, Palmour RM et al. Tryptophan depletion, executive functions, and disinhibition in aggressive, adolescent males. Neuropsychopharmacology 1998; 19: 333–341.

    Article  CAS  PubMed  Google Scholar 

  18. LeMarquand DG, Benkelfat C, Pihl RO, Palmour RM, Young SN . Behavioral disinhibition induced by tryptophan depletion in nonalcoholic young men with multigenerational family histories of paternal alcoholism. Am J Psychiatry 1999; 156: 1771–1779.

    CAS  PubMed  Google Scholar 

  19. Fallgatter AJ, Jatzke S, Bartsch AJ, Hamelbeck B, Lesch KP . Serotonin transporter promoter polymorphism influences topography of inhibitory motor control. Int J Neuropsychopharmacol 1999; 2: 115–120.

    Article  CAS  PubMed  Google Scholar 

  20. Kaiser S, Unger J, Kiefer M, Markela J, Mundt C, Weisbrod M . Executive control deficit in depression: event-related potentials in a Go/Nogo task. Psychiatry Res 2003; 122: 169–184.

    Article  PubMed  Google Scholar 

  21. Rubia K, Lee F, Cleare AJ, Tunstall N, Fu CH, Brammer M et al. Tryptophan depletion reduces right inferior prefrontal activation during response inhibition in fast, event-related fMRI. Psychopharmacology (Berl) 2005; 179: 791–803.

    Article  CAS  Google Scholar 

  22. Fallgatter AJ, Herrmann MJ, Roemmler J, Ehlis AC, Wagener A, Heidrich A et al. Allelic variation of serotonin transporter function modulates the brain electrical response for error processing. Neuropsychopharmacology 2004; 29: 1506–1511.

    Article  CAS  PubMed  Google Scholar 

  23. 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 

  24. Fallgatter AJ, Brandeis D, Strik WK . A robust assessment of the NoGo-anteriorisation of P300 microstates in a cued Continuous Performance Test. Brain Topogr 1997; 9: 295–302.

    Article  CAS  PubMed  Google Scholar 

  25. Pascual Marqui RD, Michel CM, Lehmann D . Low resolution electromagnetic tomography: a new method for localizing electrical activity in the brain. Int J Psychophysiol 1994; 18: 49–65.

    Article  CAS  PubMed  Google Scholar 

  26. Strik WK, Fallgatter AJ, Brandeis D, Pascual Marqui RD . Three-dimensional tomography of event-related potentials during response inhibition: evidence for phasic frontal lobe activation. Electroencephalogr Clin Neurophysiol 1998; 108: 406–413.

    Article  CAS  PubMed  Google Scholar 

  27. Fallgatter AJ, Bartsch AJ, Herrmann MJ . Electrophysiological measurements of anterior cingulate function. J Neural Transm 2002; 109: 977–988.

    Article  CAS  PubMed  Google Scholar 

  28. Fallgatter AJ, Ehlis AC, Rosler M, Strik WK, Blocher D, Herrmann MJ . Diminished prefrontal brain function in adults with psychopathology in childhood related to attention deficit hyperactivity disorder. Psychiatry Res 2005; 138: 157–169.

    Article  PubMed  Google Scholar 

  29. Fallgatter AJ, Ehlis AC, Seifert J, Strik WK, Scheuerpflug P, Zillessen KE et al. Altered response control and anterior cingulate function in attention-deficit/hyperactivity disorder boys. Clin Neurophysiol 2004; 115: 973–981.

    Article  PubMed  Google Scholar 

  30. Wittchen H-U, Wunderlich U, Gruschwitz S, Zaudig M . SKID I. Strukturiertes Klinisches Interview fur DSM-IV. Achse I: Psychische Storungen. Interviewheft und Beurteilungsheft. Eine deutschsprachige, erweiterte Bearbeitung der amerikanischen Originalversion des SCID I. Hogrefe: Göttingen, 1997.

    Google Scholar 

  31. Fydrich T, Renneberg B, Schmitz B, Wittchen H-U . SKID II. Interviewheft. Strukturiertes Klinisches Interview fur DSM-IV. Achse II (Personlichkeitsstorungen). Eine deutschsprachige, erweiterte Bearbeitung der amerikanischen Originalversion des SCID-II von: First, MB, Spitzer, RL, Gibbon, M, Williams, JBW, Benjamin, L (Version 3/96). Hogrefe: Göttingen, 1997.

    Google Scholar 

  32. Gutknecht L, Jacob C, Strobel A, Kriegebaum C, Müller J, Zeng Y et al. Tryptophan hydroxylase-2 gene variation influences personality traits and disorders related to emotional dysregulation. Int J Neuropsychopharmacol 2007; 10: 309–320.

    Article  CAS  PubMed  Google Scholar 

  33. Gratton G, Coles MG, Donchin E . A new method for off-line removal of ocular artifact. Electroencephalogr Clin Neurophysiol 1983; 55: 468–484.

    CAS  PubMed  Google Scholar 

  34. Lehmann D . Principles of spatial analysis. In: Gevins A, Remond A (eds). Handbook of Electroencephalography and Clinical Neurophysiology. Elsevier: Amsterdam, 1987, pp 309–354.

    Google Scholar 

  35. Bobb AJ, Castellanos FX, Addington AM, Rapoport JL . Molecular genetic studies of ADHD: 1991 to 2004. Am J Med Genet B Neuropsychiatr Genet 2005; 132: 109–125.

    Google Scholar 

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Acknowledgements

This study was supported by the Deutsche Forschungsgemeinschaft (KFO 125/1-1).

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Author notes

  1. C G Baehne and A-C Ehlis: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Psychiatry, University of Wuerzburg, Wuerzburg, Bavaria, Germany

    C G Baehne, A-C Ehlis, M M Plichta, C Jacob, L Gutknecht, K-P Lesch & A J Fallgatter

  2. Department of Biological and Clinical Psychology and Psychotherapy, University of Wuerzburg, Wuerzburg, Bavaria, Germany

    A Conzelmann & P Pauli

  3. Department of Psychiatry and Psychotherapy, Molecular and Clinical Psychobiology, University of Wuerzburg, Wuerzburg, Bavaria, Germany

    L Gutknecht & K-P Lesch

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  1. C G Baehne
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  9. A J Fallgatter
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Correspondence to A J Fallgatter.

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Baehne, C., Ehlis, AC., Plichta, M. et al. Tph2 gene variants modulate response control processes in adult ADHD patients and healthy individuals. Mol Psychiatry 14, 1032–1039 (2009). https://doi.org/10.1038/mp.2008.39

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