Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Evidence of biologic epistasis between BDNF and SLC6A4 and implications for depression

Molecular Psychiatry volume 13, pages 709–716 (2008)Cite this article

Abstract

Complex genetic disorders such as depression likely exhibit epistasis, but neural mechanisms of such gene–gene interactions are incompletely understood. 5-HTTLPR and BDNF VAL66MET, functional polymorphisms of the serotonin (5-HT) transporter (SLC6A4) and brain-derived neurotrophic factor (BDNF) gene, impact on two distinct, but interacting signaling systems, which have been related to depression and to the modulation of neurogenesis and plasticity of circuitries of emotion processing. Recent clinical studies suggest that the BDNF MET allele, which shows abnormal intracellular trafficking and regulated secretion, has a protective effect regarding the development of depression and in mice of social defeat stress. Here we show, using anatomical neuroimaging techniques in a sample of healthy subjects (n=111), that the BDNF MET allele, which is predicted to have reduced responsivity to 5-HT signaling, protects against 5-HTTLPR S allele-induced effects on a brain circuitry encompassing the amygdala and the subgenual portion of the anterior cingulate (rAC). Our analyses revealed no effect of the 5-HTTLPR S allele on rAC volume in the presence of BDNF MET alleles, whereas a significant volume reduction (P<0.001) was seen on BDNF VAL/VAL background. Interacting genotype effects were also found in structural connectivity between amygdala and rAC (P=0.002). These data provide in vivo evidence of biologic epistasis between SLC6A4 and BDNF in the human brain by identifying a neural mechanism linking serotonergic and neurotrophic signaling on the neural systems level, and have implications for personalized treatment planning in depression.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Wong ML, Licinio J . Research and treatment approaches to depression. Nat Rev Neurosci 2001; 2: 343–351.

    Article  CAS  Google Scholar 

  2. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003; 301: 386–389.

    Article  CAS  Google Scholar 

  3. Hariri AR, Mattay VS, Tessitore A, Kolachana B, Fera F, Goldman D et al. Serotonin transporter genetic variation and the response of the human amygdala. Science 2002; 297: 400–403.

    Article  CAS  Google Scholar 

  4. Heinz A, Braus DF, Smolka MN, Wrase J, Puls I, Hermann D et al. Amygdala–prefrontal coupling depends on a genetic variation of the serotonin transporter. Nat Neurosci 2005; 8: 20–21.

    Article  CAS  Google Scholar 

  5. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996; 274: 1527–1531.

    Article  CAS  Google Scholar 

  6. Lotrich FE, Pollock BG . Meta-analysis of serotonin transporter polymorphisms and affective disorders. Psychiatr Genet 2004; 14: 121–129.

    Article  Google Scholar 

  7. Pezawas L, Meyer-Lindenberg A, Drabant EM, Verchinski BA, Munoz KE, Kolachana BS et al. 5-HTTLPR polymorphism impacts human cingulate–amygdala interactions: a genetic susceptibility mechanism for depression. Nat Neurosci 2005; 8: 828–834.

    Article  CAS  Google Scholar 

  8. Sen S, Burmeister M, Ghosh D . Meta-analysis of the association between a serotonin transporter promoter polymorphism (5-HTTLPR) and anxiety-related personality traits. Am J Med Genet 2004; 127B: 85–89.

    Article  Google Scholar 

  9. Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C et al. Deep brain stimulation for treatment-resistant depression. Neuron 2005; 45: 651–660.

    Article  CAS  Google Scholar 

  10. Lasky-Su JA, Faraone SV, Glatt SJ, Tsuang MT . Meta-analysis of the association between two polymorphisms in the serotonin transporter gene and affective disorders. Am J Med Genet B Neuropsychiatr Genet 2005; 133: 110–115.

    Article  Google Scholar 

  11. Mendlewicz J, Massat I, Souery D, Del-Favero J, Oruc L, Nothen MM et al. Serotonin transporter 5HTTLPR polymorphism and affective disorders: no evidence of association in a large European multicenter study. Eur J Hum Genet 2004; 12: 377–382.

    Article  CAS  Google Scholar 

  12. Willis-Owen SA, Turri MG, Munafo MR, Surtees PG, Wainwright NW, Brixey RD et al. The serotonin transporter length polymorphism, neuroticism, and depression: a comprehensive assessment of association. Biol Psychiatry 2005; 58: 451–456.

    Article  CAS  Google Scholar 

  13. Barr CS, Newman TK, Becker ML, Champoux M, Lesch KP, Suomi SJ et al. Serotonin transporter gene variation is associated with alcohol sensitivity in rhesus macaques exposed to early-life stress. Alcohol Clin Exp Res 2003; 27: 812–817.

    Article  CAS  Google Scholar 

  14. Gaspar P, Cases O, Maroteaux L . The developmental role of serotonin: news from mouse molecular genetics. Nat Rev Neurosci 2003; 4: 1002–1012.

    Article  CAS  Google Scholar 

  15. Gross C, Hen R . The developmental origins of anxiety. Nat Rev Neurosci 2004; 5: 545–552.

    Article  CAS  Google Scholar 

  16. Castren E . Is mood chemistry? Nat Rev Neurosci 2005; 6: 241–246.

    Article  CAS  Google Scholar 

  17. Martinowich K, Lu B . Interaction between BDNF and serotonin: role in mood disorders. Neuropsychopharmacology 2008; 33: 73–83.

    Article  CAS  Google Scholar 

  18. McEwen BS, Olie JP . Neurobiology of mood, anxiety, and emotions as revealed by studies of a unique antidepressant: tianeptine. Mol Psychiatry 2005; 10: 525–537.

    Article  CAS  Google Scholar 

  19. Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM . Neurobiology of depression. Neuron 2002; 34: 13–25.

    Article  CAS  Google Scholar 

  20. De Foubert G, Carney SL, Robinson CS, Destexhe EJ, Tomlinson R, Hicks CA et al. Fluoxetine-induced change in rat brain expression of brain-derived neurotrophic factor varies depending on length of treatment. Neuroscience 2004; 128: 597–604.

    Article  CAS  Google Scholar 

  21. Murphy DL, Uhl GR, Holmes A, Ren-Patterson R, Hall FS, Sora I et al. Experimental gene interaction studies with SERT mutant mice as models for human polygenic and epistatic traits and disorders. Genes Brain Behav 2003; 2: 350–364.

    Article  CAS  Google Scholar 

  22. Ren-Patterson RF, Cochran LW, Holmes A, Sherrill S, Huang SJ, Tolliver T et al. Loss of brain-derived neurotrophic factor gene allele exacerbates brain monoamine deficiencies and increases stress abnormalities of serotonin transporter knockout mice. J Neurosci Res 2005; 79: 756–771.

    Article  CAS  Google Scholar 

  23. Tan HY, Chen Q, Sust S, Buckholtz JW, Meyers JD, Egan MF et al. Epistasis between catechol-O-methyltransferase and type II metabotropic glutamate receptor 3 genes on working memory brain function. Proc Natl Acad Sci USA 2007; 104: 12536–12541.

    Article  CAS  Google Scholar 

  24. Martinowich K, Manji H, Lu B . New insights into BDNF function in depression and anxiety. Nat Neurosci 2007; 10: 1089–1093.

    Article  CAS  Google Scholar 

  25. Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 2003; 112: 257–269.

    Article  CAS  Google Scholar 

  26. Lee JL, Everitt BJ, Thomas KL . Independent cellular processes for hippocampal memory consolidation and reconsolidation. Science 2004; 304: 839–843.

    Article  CAS  Google Scholar 

  27. Krishnan V, Han M-H, Graham DL, Berton O, Renthal W, Russo SJ et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 2007; 131: 391–404.

    Article  CAS  Google Scholar 

  28. Rybakowski JK, Suwalska A, Skibinska M, Dmitrzak-Weglarz M, Leszczynska-Rodziewicz A, Hauser J . Response to lithium prophylaxis: interaction between serotonin transporter and BDNF genes. Am J Med Genet B Neuropsychiatr Genet 2007; 144: 820–823.

    Article  Google Scholar 

  29. Ren-Patterson RF, Cochran LW, Holmes A, Lesch KP, Lu B, Murphy DL . Gender-dependent modulation of brain monoamines and anxiety-like behaviors in mice with genetic serotonin transporter and BDNF deficiencies. Cell Mol Neurobiol 2006; 26: 753–778.

    Article  Google Scholar 

  30. Kaufman J, Yang BZ, Douglas-Palumberi H, Grasso D, Lipschitz D, Houshyar S et al. Brain-derived neurotrophic factor-5-HTTLPR gene interactions and environmental modifiers of depression in children. Biol Psychiatry 2006; 59: 673–680.

    Article  CAS  Google Scholar 

  31. Kim JM, Stewart R, Kim SW, Yang SJ, Shin IS, Kim YH et al. Interactions between life stressors and susceptibility genes (5-HTTLPR and BDNF) on depression in Korean elders. Biol Psychiatry 2007; 62: 423–428.

    Article  CAS  Google Scholar 

  32. Hunnerkopf R, Strobel A, Gutknecht L, Brocke B, Lesch KP . Interaction between BDNF Val66Met and dopamine transporter gene variation influences anxiety-related traits. Neuropsychopharmacology 2007; 32: 2552–2560.

    Article  Google Scholar 

  33. Lang UE, Hellweg R, Kalus P, Bajbouj M, Lenzen KP, Sander T et al. Association of a functional BDNF polymorphism and anxiety-related personality traits. Psychopharmacology (Berl) 2005; 180: 95–99.

    Article  CAS  Google Scholar 

  34. Frodl T, Schule C, Schmitt G, Born C, Baghai T, Zill P et al. Association of the brain-derived neurotrophic factor Val66Met polymorphism with reduced hippocampal volumes in major depression. Arch Gen Psychiatry 2007; 64: 410–416.

    Article  CAS  Google Scholar 

  35. Jiang X, Xu K, Hoberman J, Tian F, Marko AJ, Waheed JF et al. BDNF variation and mood disorders: a novel functional promoter polymorphism and Val66Met are associated with anxiety but have opposing effects. Neuropsychopharmacology 2005; 30: 1353–1361.

    Article  CAS  Google Scholar 

  36. Schumacher J, Jamra RA, Becker T, Ohlraun S, Klopp N, Binder EB et al. Evidence for a relationship between genetic variants at the brain-derived neurotrophic factor (BDNF) locus and major depression. Biol Psychiatry 2005; 58: 307–314.

    Article  CAS  Google Scholar 

  37. Strauss J, Barr CL, George CJ, Devlin B, Vetro A, Kiss E et al. Brain-derived neurotrophic factor variants are associated with childhood-onset mood disorder: confirmation in a Hungarian sample. Mol Psychiatry 2005; 10: 861–867.

    Article  CAS  Google Scholar 

  38. Neves-Pereira M, Mundo E, Muglia P, King N, Macciardi F, Kennedy JL . The brain-derived neurotrophic factor gene confers susceptibility to bipolar disorder: evidence from a family-based association study. Am J Hum Genet 2002; 71: 651–655.

    Article  CAS  Google Scholar 

  39. Sklar P, Gabriel SB, McInnis MG, Bennett P, Lim YM, Tsan G et al. Family-based association study of 76 candidate genes in bipolar disorder: BDNF is a potential risk locus. Brain-derived neurotrophic factor. Mol Psychiatry 2002; 7: 579–593.

    Article  CAS  Google Scholar 

  40. Meyer-Lindenberg A, Weinberger DR . Intermediate phenotypes and genetic mechanisms of psychiatric disorders. Nat Rev Neurosci 2006; 7: 818–827.

    Article  CAS  Google Scholar 

  41. Buckholtz JW, Sust S, Tan HY, Mattay VS, Straub RE, Meyer-Lindenberg A et al. fMRI evidence for functional epistasis between COMT and RGS4. Mol Psychiatry 2007; 12: 893–895, 885.

    Article  CAS  Google Scholar 

  42. Buckholtz JW, Prust M, Sust S, Tan HY, Mattay VS, Straub RE et al. Imaging epistasis in vivo: COMT and RGS4. Mol Psychiatry 2007; 12: 885.

    Article  Google Scholar 

  43. Straub RE, Lipska BK, Egan MF, Goldberg TE, Callicott JH, Mayhew MB et al. Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression. Mol Psychiatry 2007; 12: 854–869.

    Article  CAS  Google Scholar 

  44. 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  Google Scholar 

  45. 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  Google Scholar 

  46. 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  Google Scholar 

  47. Drabant EM, Hariri AR, Meyer-Lindenberg A, Munoz KE, Mattay VS, Kolachana BS et al. Catechol O-methyltransferase val158met genotype and neural mechanisms related to affective arousal and regulation. Arch Gen Psychiatry 2006; 63: 1396–1406.

    Article  CAS  Google Scholar 

  48. Mechelli A, Friston KJ, Frackowiak RS, Price CJ . Structural covariance in the human cortex. J Neurosci 2005; 25: 8303–8310.

    Article  CAS  Google Scholar 

  49. Drevets WC, Price JL, Simpson Jr JR, Todd RD, Reich T, Vannier M et al. Subgenual prefrontal cortex abnormalities in mood disorders. Nature 1997; 386: 824–827.

    Article  CAS  Google Scholar 

  50. Paus T . Primate anterior cingulate cortex: where motor control, drive and cognition interface. Nat Rev Neurosci 2001; 2: 417–424.

    Article  CAS  Google Scholar 

  51. Raz N, Gunning FM, Head D, Dupuis JH, McQuain J, Briggs SD et al. Selective aging of the human cerebral cortex observed in vivo: differential vulnerability of the prefrontal gray matter. Cereb Cortex 1997; 7: 268–282.

    Article  CAS  Google Scholar 

  52. Raz N, Gunning-Dixon F, Head D, Rodrigue KM, Williamson A, Acker JD . Aging, sexual dimorphism, and hemispheric asymmetry of the cerebral cortex: replicability of regional differences in volume. Neurobiol Aging 2004; 25: 377–396.

    Article  Google Scholar 

  53. Raz N, Lindenberger U, Rodrigue KM, Kennedy KM, Head D, Williamson A et al. Regional brain changes in aging healthy adults: general trends, individual differences and modifiers. Cereb Cortex 2005; 15: 1676–1689.

    Article  Google Scholar 

  54. Woodruff PW, Wright IC, Shuriquie N, Russouw H, Rushe T, Howard RJ et al. Structural brain abnormalities in male schizophrenics reflect fronto-temporal dissociation. Psychol Med 1997; 27: 1257–1266.

    Article  CAS  Google Scholar 

  55. Goldman D, Oroszi G, Ducci F . The genetics of addictions: uncovering the genes. Nat Rev Genet 2005; 6: 521–532.

    Article  CAS  Google Scholar 

  56. Berton O, McClung CA, Dileone RJ, Krishnan V, Renthal W, Russo SJ et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 2006; 311: 864–868.

    Article  CAS  Google Scholar 

  57. Chen ZY, Jing D, Bath KG, Ieraci A, Khan T, Siao CJ et al. Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science 2006; 314: 140–143.

    Article  CAS  Google Scholar 

  58. Voight BF, Kudaravalli S, Wen X, Pritchard JK . A map of recent positive selection in the human genome. PLoS Biol 2006; 4: e72.

    Article  Google Scholar 

  59. Andrews TJ, Halpern SD, Purves D . Correlated size variations in human visual cortex, lateral geniculate nucleus, and optic tract. J Neurosci 1997; 17: 2859–2868.

    Article  CAS  Google Scholar 

  60. Gottesman II, Shields J . A polygenic theory of schizophrenia. Proc Natl Acad Sci USA 1967; 58: 199–205.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by the National Institute of Mental Health Intramural Research Program. We thank JH Callicott for support of data acquisition.

Author information

Author notes

  1. L Pezawas and A Meyer-Lindenberg: These authors contributed equally to this work.

Authors and Affiliations

  1. Genes, Cognition and Psychosis Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

    L Pezawas, A Meyer-Lindenberg, A L Goldman, B A Verchinski, B S Kolachana, M F Egan, V S Mattay & D R Weinberger

  2. Division of Biological Psychiatry, Medical University of Vienna, Vienna, Austria

    L Pezawas

  3. Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Mannheim, Germany

    A Meyer-Lindenberg

  4. Scientific and Statistical Computing Core, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

    G Chen

  5. Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    A R Hariri

Authors
  1. L Pezawas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Meyer-Lindenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A L Goldman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B A Verchinski
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. G Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. B S Kolachana
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M F Egan
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. V S Mattay
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A R Hariri
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. D R Weinberger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D R Weinberger.

Additional information

Conflict of Interest

Competing interests statement. The authors declare that they have no competing financial interests.

Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pezawas, L., Meyer-Lindenberg, A., Goldman, A. et al. Evidence of biologic epistasis between BDNF and SLC6A4 and implications for depression. Mol Psychiatry 13, 709–716 (2008). https://doi.org/10.1038/mp.2008.32

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2008.32

Keywords

This article is cited by

Search

Advanced search

Quick links