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:

Polymorphisms in inflammation-related genes are associated with susceptibility to major depression and antidepressant response

Abstract

There are clinical parallels between the nature and course of depressive symptoms in major depressive disorder (MDD) and those of inflammatory disorders. However, the characterization of a possible immune system dysregulation in MDD has been challenging. Emerging data support the role of T-cell dysfunction. Here we report the association of MDD and antidepressant response to genes important in the modulation of the hypothalamic–pituitary–adrenal axis and immune functions in Mexican Americans with major depression. Specifically, single nucleotide polymorphisms (SNPs) in two genes critical for T-cell function are associated with susceptibility to MDD: PSMB4 (proteasome β4 subunit), important for antigen processing, and TBX21 (T bet), critical for differentiation. Our analyses revealed a significant combined allele dose–effect: individuals who had one, two and three risk alleles were 2.3, 3.2 and 9.8 times more likely to have the diagnosis of MDD, respectively. We found associations of several SNPs and antidepressant response; those genes support the role of T cell (CD3E, PRKCH, PSMD9 and STAT3) and hypothalamic–pituitary–adrenal axis (UCN3) functions in treatment response. We also describe in MDD increased levels of CXCL10/IP-10, which decreased in response to antidepressants. This further suggests predominance of type 1 T-cell activity in MDD. T-cell function variations that we describe here may account for 47.8% of the attributable risk in Mexican Americans with moderate MDD. Immune function genes are highly variable; therefore, different genes might be implicated in distinct population groups.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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. Wong ML, Licinio J . From monoamines to genomic targets: a paradigm shift for drug discovery in depression. Nat Rev Drug Discov 2004; 3: 136–151.

    Article  CAS  Google Scholar 

  3. Raju TN . The Nobel chronicles. 1927: Julius Wagner-Jauregg (1857–1940). Lancet 1998; 352: 1714.

    Article  CAS  Google Scholar 

  4. Marques-Deak AH, Neto FL, Dominguez WV, Solis AC, Kurcgant D, Sato F et al. Cytokine profiles in women with different subtypes of major depressive disorder. J Psychiatr Res 2007; 41: 152–159.

    Article  CAS  Google Scholar 

  5. Gold PW, Goodwin FK, Chrousos GP . Clinical and biochemical manifestations of depression. Relation to the neurobiology of stress (2). N Engl J Med 1988; 319: 413–420.

    Article  CAS  Google Scholar 

  6. Gold PW, Chrousos GP . The endocrinology of melancholic and atypical depression: relation to neurocircuitry and somatic consequences. Proc Assoc Am Phys 1999; 111: 22–34.

    Article  CAS  Google Scholar 

  7. Sachar EJ, Hellman L, Fukushima DK, Gallagher TF . Cortisol production in depressive illness. A clinical and biochemical clarification. Arch Gen Psychiatry 1970; 23: 289–298.

    Article  CAS  Google Scholar 

  8. Gold PW, Loriaux DL, Roy A, Kling MA, Calabrese JR, Kellner CH et al. Responses to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing's disease. Pathophysiologic and diagnostic implications. N Engl J Med 1986; 314: 1329–1335.

    Article  CAS  Google Scholar 

  9. Nemeroff CB, Widerlov E, Bissette G, Walleus H, Karlsson I, Eklund K et al. Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science (New York, NY) 1984; 226: 1342–1344.

    Article  CAS  Google Scholar 

  10. Holsboer F, Von Bardeleben U, Gerken A, Stalla GK, Muller OA . Blunted corticotropin and normal cortisol response to human corticotropin-releasing factor in depression. N Engl J Med 1984; 311: 1127.

    CAS  Google Scholar 

  11. Wong ML, Kling MA, Munson PJ, Listwak S, Licinio J, Prolo P et al. Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: relation to hypercortisolism and corticotropin-releasing hormone. Proc Natl Acad Sci USA 2000; 97: 325–330.

    Article  CAS  Google Scholar 

  12. Veith RC, Lewis N, Linares OA, Barnes RF, Raskind MA, Villacres EC et al. Sympathetic nervous system activity in major depression. Basal and desipramine-induced alterations in plasma norepinephrine kinetics. Arch Gen Psychiatry 1994; 51: 411–422.

    Article  CAS  Google Scholar 

  13. Musselman DL, Lawson DH, Gumnick JF, Manatunga AK, Penna S, Goodkin RS et al. Paroxetine for the prevention of depression induced by high-dose interferon alfa. N Engl J Med 2001; 344: 961–966.

    Article  CAS  Google Scholar 

  14. Licinio J, Wong ML . The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection. Mol Psychiatry 1999; 4: 317–327.

    Article  CAS  Google Scholar 

  15. Kronfol Z, Remick DG . Cytokines and the brain: implications for clinical psychiatry. Am J Psychiatry 2000; 157: 683–694.

    Article  CAS  Google Scholar 

  16. Pavon L, Sandoval-Lopez G, Eugenia Hernandez M, Loria F, Estrada I, Perez M et al. Th2 cytokine response in major depressive disorder patients before treatment. J Neuroimmunol 2006; 172: 156–165.

    Article  CAS  Google Scholar 

  17. Sluzewska A, Rybakowski J, Bosmans E, Sobieska M, Berghmans R, Maes M et al. Indicators of immune activation in major depression. Psychiatry Res 1996; 64: 161–167.

    Article  CAS  Google Scholar 

  18. Moser M, Murphy KM . Dendritic cell regulation of TH1-TH2 development. Nat Immunol 2000; 1: 199–205.

    Article  CAS  Google Scholar 

  19. Akahoshi M, Obara K, Hirota T, Matsuda A, Hasegawa K, Takahashi N et al. Functional promoter polymorphism in the TBX21 gene associated with aspirin-induced asthma. Hum Genet 2005; 117: 16–26.

    Article  CAS  Google Scholar 

  20. Szabo SJ, Sullivan BM, Stemmann C, Satoskar AR, Sleckman BP, Glimcher LH . Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8T cells. Science (New York, NY) 2002; 295: 338–342.

    Article  CAS  Google Scholar 

  21. Hwang ES, Szabo SJ, Schwartzberg PL, Glimcher LH . T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3. Science (New York, NY) 2005; 307: 430–433.

    Article  CAS  Google Scholar 

  22. Monaco JJ, Nandi D . The genetics of proteasomes and antigen processing. Annu Rev Genet 1995; 29: 729–754.

    Article  CAS  Google Scholar 

  23. Schneebaum AB, Singleton JD, West SG, Blodgett JK, Allen LG, Cheronis JC et al. Association of psychiatric manifestations with antibodies to ribosomal P proteins in systemic lupus erythematosus. Am J Med 1991; 90: 54–62.

    Article  CAS  Google Scholar 

  24. Wong ML, O′Kirwan F, Hannestad JP, Irizarry KJ, Elashoff D, Licinio J . St John's wort and imipramine-induced gene expression profiles identify cellular functions relevant to antidepressant action and novel pharmacogenetic candidates for the phenotype of antidepressant treatment response. Mol Psychiatry 2004; 9: 237–251.

    Article  CAS  Google Scholar 

  25. Weiss ST, Lake SL, Silverman ES, Silverman EK, Richter B, Drazen JM et al. Asthma steroid pharmacogenetics: a study strategy to identify replicated treatment responses. Proc Am Thorac Soc 2004; 1: 364–367.

    Article  CAS  Google Scholar 

  26. Wong ML, Whelan F, Deloukas P, Whittaker P, Delgado M, Cantor RM et al. Phosphodiesterase genes are associated with susceptibility to major depression and antidepressant treatment response. Proc Natl Acad Sci USA 2006; 103: 15124–15129.

    Article  CAS  Google Scholar 

  27. Licinio J, O′Kirwan F, Irizarry K, Merriman B, Thakur S, Jepson R et al. Association of a corticotropin-releasing hormone receptor 1 haplotype and antidepressant treatment response in Mexican Americans. Mol Psychiatry 2004; 9: 1075–1082.

    Article  CAS  Google Scholar 

  28. Rabe-Jablonska J, Bienkiewicz W . [Anxiety disorders in the fourth edition of the classification of mental disorders prepared by the American Psychiatric Association: diagnostic and statistical manual of mental disorders (DMS-IV—options book]. Psychiatr Pol 1994; 28: 255–268.

    CAS  PubMed  Google Scholar 

  29. Hamilton M . A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23: 56–62.

    Article  CAS  Google Scholar 

  30. Giardina E, Capon F, De Rosa MC, Mango R, Zambruno G, Orecchia A et al. Characterization of the loricrin (LOR) gene as a positional candidate for the PSORS4 psoriasis susceptibility locus. Ann Hum Genet 2004; 68 (Part 6): 639–645.

    Article  CAS  Google Scholar 

  31. Wigginton JE, Cutler DJ, Abecasis GR . A note on exact tests of Hardy–Weinberg equilibrium. Am J Hum Genet 2005; 76: 887–893.

    Article  CAS  Google Scholar 

  32. Benjamini Y, Drai D, Elmer G, Kafkafi N, Golani I . Controlling the false discovery rate in behavior genetics research. Behav Brain Res 2001; 125: 279–284.

    Article  CAS  Google Scholar 

  33. Rockhill B, Newman B, Weinberg C . Use and misuse of population attributable fractions. Am J Public Health 1998; 88: 15–19.

    Article  CAS  Google Scholar 

  34. Wang N, Akey JM, Zhang K, Chakraborty R, Jin L . Distribution of recombination crossovers and the origin of haplotype blocks: the interplay of population history, recombination, and mutation. Am J Hum Genet 2002; 71: 1227–1234.

    Article  CAS  Google Scholar 

  35. Rothman KJ . Modern Epidemiology. 2nd edn. Lippincott-Raven Publishers: Philadelphia, PA, 1998.

    Google Scholar 

  36. Luster AD, Ravetch JV . Biochemical characterization of a gamma interferon-inducible cytokine (IP-10). J Exp Med 1987; 166: 1084–1097.

    Article  CAS  Google Scholar 

  37. Kimball AB, Jacobson C, Weiss S, Vreeland MG, Wu Y . The psychosocial burden of psoriasis. Am J Clin Dermatol 2005; 6: 383–392.

    Article  Google Scholar 

  38. Scott KM, Von Korff M, Ormel J, Zhang MY, Bruffaerts R, Alonso J et al. Mental disorders among adults with asthma: results from the World Mental Health Survey. Gen Hosp Psychiatry 2007; 29: 123–133.

    Article  Google Scholar 

  39. Conne B, Stutz A, Vassalli JD . The 3′ untranslated region of messenger RNA: a molecular ′hotspot′ for pathology? Nat Med 2000; 6: 637–641.

    Article  CAS  Google Scholar 

  40. Le Moine C, Fauchey V, Jaber M . Opioid receptor gene expression in dopamine transporter knock-out mice in adult and during development. Neuroscience 2002; 112: 131–139.

    Article  CAS  Google Scholar 

  41. Seidel A, Arolt V, Hunstiger M, Rink L, Behnisch A, Kirchner H . Major depressive disorder is associated with elevated monocyte counts. Acta Psychiatr Scand 1996; 94: 198–204.

    Article  CAS  Google Scholar 

  42. Glassman AH, Shapiro PA . Depression and the course of coronary artery disease. Am J Psychiatry 1998; 155: 4–11.

    Article  CAS  Google Scholar 

  43. Maes M . The immunoregulatory effects of antidepressants. Hum Psychopharmacol 2001; 16: 95–103.

    Article  CAS  Google Scholar 

  44. DeJarnette JB, Sommers CL, Huang K, Woodside KJ, Emmons R, Katz K et al. Specific requirement for CD3epsilon in T cell development. Proc Natl Acad Sci USA 1998; 95: 14909–14914.

    Article  CAS  Google Scholar 

  45. Watanabe TK, Saito A, Suzuki M, Fujiwara T, Takahashi E, Slaughter CA et al. cDNA cloning and characterization of a human proteasomal modulator subunit, p27 (PSMD9). Genomics 1998; 50: 241–250.

    Article  CAS  Google Scholar 

  46. Levy DE, Lee CK . What does Stat3 do? J Clin Invest 2002; 109: 1143–1148.

    Article  CAS  Google Scholar 

  47. Hsu SY, Hsueh AJ . Human stresscopin and stresscopin-related peptide are selective ligands for the type 2 corticotropin-releasing hormone receptor. Nat Med 2001; 7: 605–611.

    Article  CAS  Google Scholar 

  48. Le Deist F, Thoenes G, Corado J, Lisowska-Grospierre B, Fischer A . Immunodeficiency with low expression of the T cell receptor/CD3 complex. Effect on T lymphocyte activation. Eur J Immunol 1991; 21: 1641–1647.

    Article  CAS  Google Scholar 

  49. Soudais C, de Villartay JP, Le Deist F, Fischer A, Lisowska-Grospierre B . Independent mutations of the human CD3-epsilon gene resulting in a T cell receptor/CD3 complex immunodeficiency. Nat Genet 1993; 3: 77–81.

    Article  CAS  Google Scholar 

  50. Drenth JP, te Morsche RH, Smink R, Bonifacino JS, Jansen JB . Germline mutations in PRKCSH are associated with autosomal dominant polycystic liver disease. Nat Genet 2003; 33: 345–347.

    Article  CAS  Google Scholar 

  51. Reynolds AJ, Bartlett SE, Hendry IA . Molecular mechanisms regulating the retrograde axonal transport of neurotrophins. Brain Res 2000; 33: 169–178.

    Article  CAS  Google Scholar 

  52. Li XS, Reddy MS, Baev D, Edgerton M . Candida albicans Ssa1/2p is the cell envelope binding protein for human salivary histatin 5. J Biol Chem 2003; 278: 28553–28561.

    Article  CAS  Google Scholar 

  53. Gragnoli C, Cronsell J . PSMD9 gene variants within NIDDM2 may rarely contribute to type 2 diabetes. J Cell Physiol 2007; 212: 568–571.

    Article  CAS  Google Scholar 

  54. Minegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature 2007; 448: 1058–1062.

    Article  CAS  Google Scholar 

  55. Holland SM, DeLeo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N et al. STAT3 mutations in the hyper-IgE syndrome. N Engl J Med 2007; 357: 1608–1619.

    Article  CAS  Google Scholar 

  56. Renner ED, Torgerson TR, Rylaarsdam S, Anover-Sombke S, Golob K, LaFlam T et al. STAT3 mutation in the original patient with Job's syndrome. N Engl J Med 2007; 357: 1667–1668.

    Article  CAS  Google Scholar 

  57. Selgrade M, Boykin EH, Haykal-Coates N, Woolhiser MR, Wiescinski C, Andrews DL et al. Inconsistencies between cytokine profiles, antibody responses, and respiratory hyperresponsiveness following dermal exposure to isocyanates. Toxicol Sci 2006; 94: 108–117.

    Article  CAS  Google Scholar 

  58. Adler MW, Geller EB, Chen X, Rogers TJ . Viewing chemokines as a third major system of communication in the brain. AAPS J 2005; 7: E865–E870.

    Article  CAS  Google Scholar 

  59. Scarpini E, Galimberti D, Baron P, Clerici R, Ronzoni M, Conti G et al. IP-10 and MCP-1 levels in CSF and serum from multiple sclerosis patients with different clinical subtypes of the disease. J Neurol Sci 2002; 195: 41–46.

    Article  CAS  Google Scholar 

  60. Gerard C, Rollins BJ . Chemokines and disease. Nat Immunol 2001; 2: 108–115.

    Article  CAS  Google Scholar 

  61. Chanock S, Taylor JG . Using genetic variation to study immunomodulation. Curr Opin Pharmacol 2002; 2: 463–469.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by NIH grants GM61394, RR017365, MH062777, RR000865, RR16996, HG002500 and DK063240, and institutional funds from the University of Miami, Department of Psychiatry & Behavioral Sciences. We thank the Mexican American individuals who have participated in this study. We are grateful for the contributions to the care of our patients from Dr Israel Alvarado, Dr Deborah Flores and Dr Anil Sharma; our nursing staff Rita Jepson and Lorraine Garcia-Teague; our social workers Patricia Reyes and Gabriela Marquez at the Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles (UCLA) and staff of the UCLA GCRC. We thank Dr Kristopher Irizarry (UCLA), Dr Luciana Ribeiro (University of Miami) and Dr Joao Busnello (University of Miami) who have helped us with bioinformatics and database aspects of the work. We are also grateful for the contributions of Fiona O’Kirwan and Sarika Thakur (Semel Institute), and Dr Rita Cantor, Department of Genetics, UCLA, in preliminary statistics analyses. We also thank Dr Scott Weiss for facilitating our interactions with the Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, and Dr Panos Deloukas for facilitating genotyping work at the Wellcome Trust Sanger Institute, UK.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M-L Wong.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wong, ML., Dong, C., Maestre-Mesa, J. et al. Polymorphisms in inflammation-related genes are associated with susceptibility to major depression and antidepressant response. Mol Psychiatry 13, 800–812 (2008). https://doi.org/10.1038/mp.2008.59

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2008.59

Keywords

This article is cited by

Search

Quick links