Skip to main content

Advertisement

SpringerLink
Log in

Interaction among childhood trauma and functional polymorphisms in the serotonin pathway moderate the risk of depressive disorders

  • Original Paper
  • Published:
European Archives of Psychiatry and Clinical Neuroscience Aims and scope Submit manuscript

Abstract

Depressive disorders are influenced by a complex interplay between genetic and environmental factors. Multiple studies support a role of serotonergic pathways in the pathophysiology of depressive disorders. As a rate-limiting enzyme of serotonin synthesis in the brain, tryptophan hydroxylase 2 (TPH2) represents a plausible candidate gene. This also applies to the serotonin reuptake transporter (5-HTTLPR) regulating the availability of serotonin in the synaptic gap. We hypothesize that functional polymorphisms (TPH2: rs7305115, 5-HTTLPR and rs25531) within both genes contribute to the risk of depressive disorders after childhood abuse in adult life. To confirm our results, we investigated two independent samples of Caucasian subjects from the study of health in Pomerania (SHIP–LEGEND: n = 2,029 and SHIP–TREND-0: n = 2,475). Depression severity was assessed by the Beck depression inventory (BDI-II) for LEGEND and the patient health questionnaire (PHQ-9) for TREND-0. Childhood abuse was assessed by the childhood trauma questionnaire. Rs7305115 (TPH2) revealed significant effects in SNP × abuse and SNP × SNP as well as in the three-way interaction. This three-way interaction among abuse, TPH2 and 5-HTTLPR showed a significant effect on depression score (p = 0.023). The SS genotype of 5-HTTLPR was associated with increased depression scores after childhood abuse only in carriers of the low-expression TPH2 GG genotype, whereas the TPH2 AA genotype reversed this effect. Our results support the role of interaction effects of genetic variants within serotonergic pathways. Genetic variants that may decrease the presynaptic serotonin concentration were associated with increased adult depressive symptoms in subjects with childhood abuse.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Wittchen HU, Jacobi F, Rehm J, Gustavsson A, Svensson M, Jönsson B, Olesen J, Allgulander C, Alonso J, Faravelli C, Fratiglioni L, Jennum P, Lieb R, Maercker A, vanOs J, Preisig M, Salvador-Carulla L, Simon R, Steinhausen HC (2011) The size and burden of mental disorders and other disorders of the brain in Europe 2010. Eur Neuropsychopharmacol 21(9):655–679

    Article  PubMed  CAS  Google Scholar 

  2. Sullivan PF, Neale MC, Kendler KS (2000) Genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry 157(10):1552–1562

    Article  PubMed  CAS  Google Scholar 

  3. Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium et al (2012) A mega-analysis of genome-wide association studies for major depressive disorder. Mol Psychiatry 18(4):497–511

    Google Scholar 

  4. Hek K, Demirkan A, Lahti J, Terracciano A, Teumer A et al (2013) A genome-wide association study of depressive symptoms. Biol Psychiatry 73(7):667–678

    Article  PubMed  CAS  Google Scholar 

  5. Zill P, Baghai TC, Zwanzger P, Schüle C, Eser D, Rupprecht R, Möller HJ, Bondy B, Ackenheil M (2004) SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression. Mol Psychiatry 9(11):1030–1036

    Article  PubMed  CAS  Google Scholar 

  6. Gao J, Pan Z, Jiao Z, Li F, Zhao G, Wei Q, Pan F, Evangelou E (2012) TPH2 gene polymorphisms and major depression-a meta-analysis. PLoS One. doi:10.1371/0036721

    Google Scholar 

  7. Walther DJ, Peter JU, Bashammakh S, Hörtnagl H, Voits M, Fink H, Bader M (2003) Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science 299:76

    Article  PubMed  CAS  Google Scholar 

  8. Jacobsen JPR, Medvedev IO, Caron MG (2012) The 5-HT deficiency theory of depression: perspectives from a naturalistic 5-HT deficiency model, the tryptophan hydroxylase 2Arg 439Hisknockin mouse. Phil Trans Soc B 367:2444–2459

    Article  CAS  Google Scholar 

  9. Widom CS, DuMont K, Czaja SJ (2007) A prospective investigation of major depressive disorder and comorbidity in abused and neglected children grownup. Arch Gen Psychiatry 64(1):49–56

    Article  PubMed  Google Scholar 

  10. Heim C, Binder EB (2012) Current research trends in early life stress and depression: Review of human studies on sensitive periods, gene-environment interactions, and epigenetics. Exp Neurol 233:102–111

    Article  PubMed  Google Scholar 

  11. Edwards VJ, Holden GW, Felitti VJ, Anda RF (2003) Relationship between multiple forms of childhood maltreatment and adult mental health in community respondents: results from the adverse childhood experiences study. Am J Psychiatry 160:1453–1460

    Article  PubMed  Google Scholar 

  12. Chapman DP, Whitfield CL, Felitti VJ, Dube SR, Edwards VJ, Anda RF (2004) Adverse childhood experiences and the risk of depressive disorders in adulthood. J Affect Disord 82:217–225

    Article  PubMed  Google Scholar 

  13. Kendler KS, Eaves LJ (1986) Models for the joint effect of genotype and environment on liability to psychiatric illness. Am J Psychiatry 143(3):279–289

    PubMed  CAS  Google Scholar 

  14. Cadoret RJ, Yates WR, Troughton E, Woodworth G, Stewart MA (1995) Genetic-environmental interaction in the genesis of aggressivity and conduct disorders. Arch Gen Psychiatry 52(11):916–924

    Article  PubMed  CAS  Google Scholar 

  15. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R (2004) Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 301(5631):386–389

    Article  Google Scholar 

  16. Grabe HJ, Schwahn C, Mahler J, Schulz A, Spitzer C, Fenske K, Appel K, Barnov S, Nauck M, Schomerus G, Rosskopf D, Biffar R, John U, Völzke H, Freyberger HJ (2012) Moderation of adult depression by the serotonin transporter promoter variant (5-HTTLPR), childhood abuse and adult traumatic events in a general population sample. Am J Med Genet B Neuropsychiatr Genet 159B(3):298–309

    Article  PubMed  Google Scholar 

  17. Fergusson DM, Horwood LJ, Miller AL, Kennedy MA (2011) Life stress, 5-HTTLPR and mental disorder: findings from a 30-year longitudinal study. Br J Psychiatry 198(2):129–135

    Article  PubMed  PubMed Central  Google Scholar 

  18. Lim JE, Pinsonneault J, Sadee W, Saffen D (2007) Tryptophan hydroxylase 2 (TPH2) haplotypes predict levels of TPH2 mRNA expression in human pons. Mol Psychiatry 12:491–501

    PubMed  CAS  Google Scholar 

  19. Grohmann M, Hammer P, Walther M, Paulmann N, Büttner A, Eisenmenger W, Baghai TC, Schüle C, Rupprecht R, Bader M, Bondy B, Zill P, Priller J, Walther DJ (2010) Alternative splicing and extensive RNA editing of human TPH2 transcripts. PLoS One. doi:10.1371/0008956

    PubMed  PubMed Central  Google Scholar 

  20. Zhang Y, Zhang C, Yuan G, Yao J, Cheng Z, Liu C, Liu Q, Wan G, Shi G, Cheng Y, Ling Y, Li K (2010) Effect of tryptophan hydroxylase 2 rs7305115 SNP on suicide attempt risk in major depression. Behav Brain Funct 25:6–49

    CAS  Google Scholar 

  21. Xu Z, Zhang Z, Shi Y, Pu M, Yuan Y, Zhang X, Li L, Reynolds GP (2012) Influence and interaction of genetic polymorphisms in the serotonin system and life stress on antidepressant drug response. J Psychopharmacol 26:349–359

    Article  PubMed  CAS  Google Scholar 

  22. Herrmann MJ, Huter T, Müller F, Mühlberger A, Pauli P, Reif A, Renner T, Canli T, Fallgatter AJ, Lesch KP (2007) Additive effects of serotonin transporter and tryptophan hydroxylase-2 gene variation on emotional processing. Cereb Cortex 17(5):1160–1163

    Article  PubMed  Google Scholar 

  23. ZhengS YuM, Lu X, Huo T, Ge L, Yang J, Wu C, Li F (2010) Urinary metabolomics study on biochemical changes in chronic unpredictable mild stress model of depression. Clin Chim Acta 411(3–4):204–209

    Article  Google Scholar 

  24. Zhang F, Jia Z, Gao P, Kong H, Li X, Lu X, Wu Y, Xu G (2010) Metabolomics study of urine and plasma in depression and excess fatigue rats by ultra fast liquid chromatography coupled with ion trap-time of flight mass spectrometry. Mol Biosyst 6(5):852–861

    Article  PubMed  CAS  Google Scholar 

  25. Oreland L, Nordquist N, Hallman J, Harro J, Nilsson KW (2010) Environment and the serotonergic system. Eur Psychiatry 25:304–306

    Article  PubMed  CAS  Google Scholar 

  26. John U, Greiner B, Hensel E, Ludemann J, Piek M, Sauer S, Adam C, Born G, Alte D, Greiser E, Haertel U, Hense HW, Haerting J, Willich S, Kessler C (2001) Study of health in pomerania (SHIP): a health examination survey in an east German region: objectives and design. Soz Praventivmed 46:186–194

    Article  PubMed  CAS  Google Scholar 

  27. Völzke H, Alte D, Schmidt CO, Radke D, Lorbeer R, Friedrich N, Aumann N, Lau K, Piontek M, Born G, Havemann C, Ittermann T, Schipf S, Haring R, Baumeister SE, Wallaschofski H, Nauck M, Frick S, Arnold A, Junger M, Mayerle J, Kraft M, Lerch MM, Dorr M, Reffelmann T, Empen K, Felix SB, Obst A, Koch B, Glaser S, Ewert R, Fietze I, Penzel T, Doren M, Rathmann W, Haerting J, Hannemann M, Ropcke J, Schminke U, Jurgens C, Tost F, Rettig R, Kors JA, Ungerer S, Hegenscheid K, Kuhn JP, Kuhn J, Hosten N, Puls R, Henke J, Gloger O, Teumer A, Homuth G, Volker U, Schwahn C, Holtfreter B, Polzer I, Kohlmann T, Grabe HJ, Rosskopf D, Kroemer HK, Kocher T, Biffar R, John U, Hoffmann W (2011) Cohort profile: the study of health in Pomerania. Int J Epidemiol 40:294–307

    Article  Google Scholar 

  28. Beck AT, Steer RA (1987) Beck Depression Inventory-Manual. The Physiological Corporation, San Antonio

    Google Scholar 

  29. Kroenke K, Spitzer RL, Williams JB (2001) The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 16(9):606–613

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Wahl I, Löwe B, Bjorner JB, Fischer F, Langs G, Voderholzer U, Aita SA, Bergemann N, Brähler E, Rose M (2014) Standardization of depression measurement: a common metric was developed for 11 self-report depression measures. J Clin Epidemiol 67:73–86

    Article  PubMed  Google Scholar 

  31. Bernstein DP, Stein JA, Newcomb MD, Walker E, Pogge D, Ahluvalia T, Strokes J, Handelsman L, Medrano M, Desmond D et al (2003) Development and validation of a brief screening version of the childhood trauma questionnaire. Child Abuse Negl 27(2):169–190

    Article  PubMed  Google Scholar 

  32. Wingenfeld K, Spitzer C, Mensebach C, Grabe HJ, Hill A, Gast U, Schlosser N, Höpp H, Beblo T, Driessen M (2010) The german version of the childhood trauma questionnaire (CTQ):Preliminary Psychometric Properties. Psychother Psychosom Med Psychol 60(11):442–450

    Article  PubMed  Google Scholar 

  33. Schulz, A., Becker, M., Barnow, S., Appel, K., Mahler, J., Schmidt, C.O., John, U., Freyberger, H.J., Grabe, H.J. (2014). The impact of childhood trauma on depression: does resilience matter?. J Psychosom Res, accepted for puplication

  34. Heils A, Teufel A, Petri S, Seemann M, Bengel D, Balling U et al (1995) Functional promoter and polyadenylation site mapping of the human serotonin (5-HT) transporter gene. J Neural Transm Gen Sect 102:247–254

    Article  PubMed  CAS  Google Scholar 

  35. Hu XZ, Lipsky RH, Zhu G, Akhtar LA, Taubman J, Greenberg BD, Xu K, Arnold PD, Richter MA, Kennedy JL, Murphy DL, Goldman D (2006) Serotonin transporter promoter gain-of-function genotypes are linked to obsessive-compulsive disorder. Am J Hum Genet 78:815–826

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  36. Perroud N, Salzmann A, Saiz PA, Baca-Garcia E, Sarchiapone M, Garcia-Portilla MP et al (2010) Rare genotype combination of the serotonin transporter gene associated with treatment response in severe personality disorder. Am J Med Genet B Neuropsychiatr Genet 153B:1494–1497

    Article  PubMed  CAS  Google Scholar 

  37. Harrell FE Jr (200) Regression Modeling Strategies.With Applications to Linear Models, Logistic Regression, and Survival Analysis. Springer, New York, p 596

    Google Scholar 

  38. Hosmer DW, Lemeshow S (2000) Applied Logistic Regression, 2nd edn. Wiley, New York, p 392

    Book  Google Scholar 

  39. Greenland S (2008) Introduction to regression models. In: Rothman KJ, Greenland S, Lash TL (eds) Modern Epidemiology, 3rd edn. Lippincott Williams & Wilkins, Philadelphia, pp 381–417

    Google Scholar 

  40. Persons JB, Perloff JM (1989) The relationship between attributions and depression varies across attributional dimensions and across samples. J Psychophathol Behav Assess 11:47–60

    Article  Google Scholar 

  41. Keller MC (2014) Gene-environment interaction studies have not properly controlled for potential confounders: the problem and the (simple) solution. Biol Psychiatry 75:18–24

    Article  PubMed  Google Scholar 

  42. Luca C, Shern L, Krainer AR (2002) Listening to silence and understanding nonsense: exonic mutations that effect splicing. Nat Rev 3:285–298

    Article  Google Scholar 

  43. Homberg JR, Lesch KP (2011) Looking on the bright side of serotonin transporter gene variation. Biol Psychiatry 69:513–519

    Article  PubMed  CAS  Google Scholar 

  44. Neumeister A, Hu X, Luckenbaugh DA, Schwarz M, Nugent AC, Bonne O, Herscovitch P, Goldman D, Drevets WC, Charney DS (2006) Differential Effects of 5-HTTLPR Genotypes on the behavioral and neural responses to tryptophan depletion in patients with major depression and controls. Arch Gen Psychiatry 63:978–986

    Article  PubMed  CAS  Google Scholar 

  45. Janssens AC, van Duijn CM (2009) Genome-based prediction of common diseases: methodological considerations for future research. Genome Med. doi:10.1186/gm20

    PubMed  PubMed Central  Google Scholar 

  46. Booij L, Wang D, Lévesque ML, Tremblay RE, Szyf M (2013) Looking beyond the DNA sequence: the relevance of DNA methylation processes for the stress – diathesis model of depression. Phil Trans R Soc B 368:20120251

    Article  PubMed  PubMed Central  Google Scholar 

  47. Vijayendran M, Beach SR, Plume JM, Brody GH, Philibert RA (2012) Effects of genotype and child abuse on DNA methylation and gene expression at the serotonin transporter. Front Psychiatry. doi:10.3389/fpsyt.2012.00055

    PubMed  PubMed Central  Google Scholar 

  48. Ghaemi SN, Vöhringer PA (2011) The heterogeneity of depression: an old debate renewed. Acta Psychiatr Scand 124(6):497

    Article  PubMed  Google Scholar 

  49. Lamers F, de Jonge P, Nolen WA, Smit JH, Zitman FG, Beekman AT, Penninx BW (2011) Identifying depressive subtypes in a large cohort study: results from the netherlands study of depression and anxiety (NESDA). J Clin Psychiatry 71(12):1582–1589

    Article  Google Scholar 

  50. Lamers F, Vogelzangs N, Merikangas KR, de Jonge P, Beekman AT, Penninx BW (2013) Evidence for a differential role of HPA-axis function, inflammation and metabolic syndrome in melancholic versus atypical depression. Mol Psychiatry 18(6):692–699

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (Grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data have been supported by the Federal Ministry of Education and Research (Grant no. 03ZIK012) and a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. This work was also funded by Federal Ministry of Education and Research (GANI_MED; Grant no. 03IS2061A) and the German Research Foundation (DFG: GR 1912/5-1).

Conflict of interest

The authors have declared that no conflicts of interest exist.

Author information

Authors and Affiliations

  1. Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany

    Sandra Van der Auwera, Deborah Janowitz, Andrea Schulz, Harald Jürgen Freyberger & Hans Jörgen Grabe

  2. Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany

    Georg Homuth

  3. Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany

    Matthias Nauck

  4. Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany

    Henry Völzke

  5. Division of Psychosomatic Medicine, Medical Department, University Medicine Berlin, Berlin, Germany

    Matthias Rose

  6. Biopharmacy, Department Pharmaceutical Sciences, University of Basel, Basel, Switzerland

    Henriette Meyer zu Schwabedissen

  7. Department of Psychiatry and Psychotherapy, HELIOS Hospital Stralsund, University Medicine Greifswald, Greifswald, Germany

    Harald Jürgen Freyberger & Hans Jörgen Grabe

  8. German Center for Neurodegenerative Diseases DZNE, Site Rostock, Greifswald, Germany

    Hans Jörgen Grabe

  9. Department of Psychiatry, University of Greifswald, Ellernholzstraße 1-2, 17475, Greifswald, Germany

    Sandra Van der Auwera

Authors
  1. Sandra Van der Auwera
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Deborah Janowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrea Schulz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Georg Homuth
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Matthias Nauck
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Henry Völzke
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Matthias Rose
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Henriette Meyer zu Schwabedissen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Harald Jürgen Freyberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hans Jörgen Grabe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sandra Van der Auwera.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 262 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Van der Auwera, S., Janowitz, D., Schulz, A. et al. Interaction among childhood trauma and functional polymorphisms in the serotonin pathway moderate the risk of depressive disorders. Eur Arch Psychiatry Clin Neurosci 264 (Suppl 1), 45–54 (2014). https://doi.org/10.1007/s00406-014-0536-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00406-014-0536-2

Keywords

Search

Navigation