Skip to main content Accessibility help

Epigenetic and inflammatory marker profiles associated with depression in a community-based epidemiologic sample

  • M. Uddin (a1), K. C. Koenen (a2), A. E. Aiello (a1), D. E. Wildman (a3), R. de los Santos (a1) and S. Galea (a4)...



Recent work suggests that epigenetic differences may be associated with psychiatric disorders. Here we investigate, in a community-based sample, whether methylation profiles distinguish between individuals with and without lifetime depression. We also investigate the physiologic consequences that may be associated with these profiles.


Using whole blood-derived genomic DNA from a subset of participants in the Detroit Neighborhood Health Study (DNHS), we applied methylation microarrays to assess genome-wide methylation profiles for over 14 000 genes in 33 persons who reported a lifetime history of depression and 67 non-depressed adults. Bioinformatic functional analyses were performed on the genes uniquely methylated and unmethylated in each group, and inflammatory biomarkers [interleukin (IL)-6 and C-reactive protein (CRP)] were measured to investigate the possible functional significance of the methylation profiles observed.


Uniquely unmethylated gene sets distinguished between those with versus without lifetime depression. In particular, some processes (e.g. brain development, tryptophan metabolism) showed patterns suggestive of increased methylation among individuals with depression whereas others (e.g. lipoprotein) showed patterns suggestive of decreased methylation among individuals with depression. IL-6 and CRP levels were elevated among those with lifetime depression and, among those with depression only, IL-6 methylation showed an inverse correlation with circulating IL-6 and CRP.


Genome-wide methylation profiles distinguish individuals with versus without lifetime depression in a community-based setting, and show coordinated signals with pathophysiological mechanisms previously implicated in the etiology of this disorder. Examining epigenetic mechanisms in concert with other dynamic markers of physiologic functioning should improve our understanding of the neurobiology of depression.


Corresponding author

*Address for correspondence: M. Uddin, Ph.D., Assistant Research Scientist, University of Michigan School of Public Health, Department of Epidemiology, 1415 Washington Heights, Ann Arbor, MI 48109-2029, USA. (Email:


Hide All
aan het Rot, M, Mathew, SJ, Charney, DS (2009). Neurobiological mechanisms in major depressive disorder. Canadian Medical Association Journal 180, 305313.
ACS (2009). 2005–2007 American Community Survey 3-Year Estimates. U.S. Census Bureau: Washington, DC.
Anderson, IM, Parry-Billings, M, Newsholme, EA, Poortmans, JR, Cowen, PJ (1990). Decreased plasma tryptophan concentration in major depression: relationship to melancholia and weight loss. Journal of Affective Disorders 20, 185191.
Andrews, G, Peters, L (1998). The psychometric properties of the Composite International Diagnostic Interview. Social Psychiatry and Psychiatric Epidemiology 33, 8088.
Babcock, TA, Carlin, JM (2000). Transcriptional activation of indoleamine dioxygenase by interleukin 1 and tumor necrosis factor alpha in interferon-treated epithelial cells. Cytokine 12, 588594.
Backdahl, L, Bushell, A, Beck, S (2009). Inflammatory signalling as mediator of epigenetic modulation in tissue-specific chronic inflammation. International Journal of Biochemistry and Cell Biology 41, 176184.
Bjornsson, HT, Sigurdsson, MI, Fallin, MD, Irizarry, RA, Aspelund, T, Cui, H, Yu, W, Rongione, MA, Ekstrom, TJ, Harris, TB, Launer, LJ, Eiriksdottir, G, Leppert, MF, Sapienza, C, Gudnason, V, Feinberg, AP (2008). Intra-individual change over time in DNA methylation with familial clustering. Journal of the American Medical Association 299, 28772883.
Brunner, AL, Johnson, DS, Kim, SW, Valouev, A, Reddy, TE, Neff, NF, Anton, E, Medina, C, Nguyen, L, Chiao, E, Oyolu, CB, Schroth, GP, Absher, DM, Baker, JC, Myers, RM (2009). Distinct DNA methylation patterns characterize differentiated human embryonic stem cells and developing human fetal liver. Genome Research 19, 10441056.
Dantzer, R, O'Connor, JC, Freund, GG, Johnson, RW, Kelley, KW (2008). From inflammation to sickness and depression: when the immune system subjugates the brain. Nature Reviews Neuroscience 9, 4656.
Eckhardt, F, Lewin, J, Cortese, R, Rakyan, VK, Attwood, J, Burger, M, Burton, J, Cox, TV, Davies, R, Down, TA, Haefliger, C, Horton, R, Howe, K, Jackson, DK, Kunde, J, Koenig, C, Liddle, J, Niblett, D, Otto, T, Pettett, R, Seemann, S, Thompson, C, West, T, Rogers, J, Olek, A, Berlin, K, Beck, S (2006). DNA methylation profiling of human chromosomes 6, 20 and 22. Nature Genetics 38, 13781385.
Egger, G, Liang, G, Aparicio, A, Jones, PA (2004). Epigenetics in human disease and prospects for epigenetic therapy. Nature 429, 457463.
Elenkov, IJ (2008). Neurohormonal-cytokine interactions: implications for inflammation, common human diseases and well-being. Neurochemistry International 52, 4051.
Galecki, P, Kedziora, J, Florkowski, A, Galecka, E (2007). Lipid peroxidation and copper-zinc superoxide dismutase activity in patients treated with fluoxetine during the first episode of depression [in Polish]. Psychiatria Polska 41, 615624.
Gimeno, D, Kivimaki, M, Brunner, EJ, Elovainio, M, De Vogli, R, Steptoe, A, Kumari, M, Lowe, GD, Rumley, A, Marmot, MG, Ferrie, JE (2009). Associations of C-reactive protein and interleukin-6 with cognitive symptoms of depression: 12-year follow-up of the Whitehall II study. Psychological Medicine 39, 413423.
Gladkevich, A, Kauffman, HF, Korf, J (2004). Lymphocytes as a neural probe: potential for studying psychiatric disorders. Progress in Neuropsychopharmacology and Biological Psychiatry 28, 559576.
Gold, SM, Irwin, MR (2009). Depression and immunity: inflammation and depressive symptoms in multiple sclerosis. Immunology and Allergy Clinics of North America 29, 309320.
Howren, MB, Lamkin, DM, Suls, J (2009). Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosomatic Medicine 71, 171186.
Hu, B, Hissong, BD, Carlin, JM (1995). Interleukin-1 enhances indoleamine 2,3-dioxygenase activity by increasing specific mRNA expression in human mononuclear phagocytes. Journal of Interferon and Cytokine Research 15, 617624.
Huang, DW, Sherman, BT, Lempicki, RA (2009). Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature Protocols 4, 4457.
Irwin, MR, Miller, AH (2007). Depressive disorders and immunity: 20 years of progress and discovery. Brain Behavior and Immunity 21, 374383.
Kalman, J, Palotas, A, Juhasz, A, Rimanoczy, A, Hugyecz, M, Kovacs, Z, Galsi, G, Szabo, Z, Pakaski, M, Feher, LZ, Janka, Z, Puskas, LG (2005). Impact of venlafaxine on gene expression profile in lymphocytes of the elderly with major depression – evolution of antidepressants and the role of the ‘neuro-immune’ system. Neurochemical Research 30, 14291438.
Kang, HJ, Adams, DH, Simen, A, Simen, BB, Rajkowska, G, Stockmeier, CA, Overholser, JC, Meltzer, HY, Jurjus, GJ, Konick, LC, Newton, SS, Duman, RS (2007). Gene expression profiling in postmortem prefrontal cortex of major depressive disorder. Journal of Neuroscience 27, 1332913340.
Kiecolt-Glaser, JK, Glaser, R (2002). Depression and immune function: central pathways to morbidity and mortality. Journal of Psychosomatic Research 53, 873876.
Kim, JK, Samaranayake, M, Pradhan, S (2009). Epigenetic mechanisms in mammals. Cellular and Molecular Life Sciences 66, 596612.
Kinnally, EL, Capitanio, JP, Leibel, R, Deng, L, Leduc, C, Haghighi, F, Mann, JJ (2010). Epigenetic regulation of serotonin transporter expression and behavior in infant rhesus macaques. Genes, Brain and Behavior 6, 575582.
Kroenke, K, Spitzer, RL, Williams, JB (2001). The PHQ-9: validity of a brief depression severity measure. Journal of General Internal Medicine 16, 606613.
Kronfol, Z, Remick, DG (2000). Cytokines and the brain: implications for clinical psychiatry. American Journal of Psychiatry 157, 683694.
Lee, JS, Lo, PK, Fackler, MJ, Argani, P, Zhang, Z, Garrett-Meyer, E, Sukumar, S (2007). A comparative study of Korean with Caucasian breast cancer reveals frequency of methylation in multiple genes correlates with breast cancer in young, ER, PR-negative breast cancer in Korean women. Cancer Biology and Therapy 6, 11141120.
Le-Niculescu, H, Kurian, SM, Yehyawi, N, Dike, C, Patel, SD, Edenberg, HJ, Tsuang, MT, Salomon, DR, Nurnberger, JI Jr., Niculescu, AB (2009). Identifying blood biomarkers for mood disorders using convergent functional genomics. Molecular Psychiatry 14, 156174.
Leonard, BE, Myint, A (2009). The psychoneuroimmunology of depression. Human Psychopharmacology 24, 165175.
Maes, M (1999). Major depression and activation of the inflammatory response system. Advances in Experimental Medicine and Biology 461, 2546.
Maes, M (2008). The cytokine hypothesis of depression: inflammation, oxidative & nitrosative stress (IO&NS) and leaky gut as new targets for adjunctive treatments in depression. Neuroendocrinology Letters 29, 287291.
Maes, M, Bosmans, E, Meltzer, HY, Scharpe, S, Suy, E (1993 a). Interleukin-1 beta: a putative mediator of HPA axis hyperactivity in major depression? American Journal of Psychiatry 150, 11891193.
Maes, M, Meltzer, HY, Bosmans, E, Bergmans, R, Vandoolaeghe, E, Ranjan, R, Desnyder, R (1995). Increased plasma concentrations of interleukin-6, soluble interleukin-6, soluble interleukin-2 and transferrin receptor in major depression. Journal of Affective Disorders 34, 301309.
Maes, M, Meltzer, HY, Scharpe, S, Bosmans, E, Suy, E, De Meester, I, Calabrese, J, Cosyns, P (1993 b). Relationships between lower plasma L-tryptophan levels and immune-inflammatory variables in depression. Psychiatry Research 49, 151165.
Maes, M, Scharpe, S, Meltzer, HY, Bosmans, E, Suy, E, Calabrese, J, Cosyns, P (1993 c). Relationships between interleukin-6 activity, acute phase proteins, and function of the hypothalamic-pituitary-adrenal axis in severe depression. Psychiatry Research 49, 1127.
Maes, M, Verkerk, R, Vandoolaeghe, E, Van Hunsel, F, Neels, H, Wauters, A, Demedts, P, Scharpe, S (1997). Serotonin-immune interactions in major depression: lower serum tryptophan as a marker of an immune-inflammatory response. European Archives of Psychiatry and Clinical Neuroscience 247, 154161.
Maes, M, Yirmyia, R, Noraberg, J, Brene, S, Hibbeln, J, Perini, G, Kubera, M, Bob, P, Lerer, B, Maj, M (2009). The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression. Metabolic Brain Disease 24, 2753.
Manji, HK, Moore, GJ, Chen, G (2000 a). Clinical and preclinical evidence for the neurotrophic effects of mood stabilizers: implications for the pathophysiology and treatment of manic-depressive illness. Biological Psychiatry 48, 740754.
Manji, HK, Moore, GJ, Rajkowska, G, Chen, G (2000 b). Neuroplasticity and cellular resilience in mood disorders. Molecular Psychiatry 5, 578593.
Mill, J, Tang, T, Kaminsky, Z, Khare, T, Yazdanpanah, S, Bouchard, L, Jia, P, Assadzadeh, A, Flanagan, J, Schumacher, A, Wang, SC, Petronis, A (2008). Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. American Journal of Human Genetics 82, 696711.
Miller, AH, Maletic, V, Raison, CL (2009). Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biological Psychiatry 65, 732741.
Myint, AM, Kim, YK (2003). Cytokine-serotonin interaction through IDO: a neurodegeneration hypothesis of depression. Medical Hypotheses 61, 519525.
Oberlander, TF, Weinberg, J, Papsdorf, M, Grunau, R, Misri, S, Devlin, AM (2008). Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics 3, 97–106.
Olsson, CA, Foley, DL, Parkinson-Bates, M, Byrnes, G, McKenzie, M, Patton, GC, Morley, R, Anney, RJ, Craig, JM, Saffery, R (2010). Prospects for epigenetic research within cohort studies of psychological disorder: a pilot investigation of a peripheral cell marker of epigenetic risk for depression. Biological Psychology 83, 159165.
Pepys, MB, Hirschfield, GM (2003). C-reactive protein: a critical update. Journal of Clinical Investigation 111, 18051812.
Petronis, A (2010). Epigenetics as a unifying principle in the aetiology of complex traits and diseases. Nature 465, 721727.
Philibert, RA, Sandhu, H, Hollenbeck, N, Gunter, T, Adams, W, Madan, A (2008). The relationship of 5HTT (SLC6A4) methylation and genotype on mRNA expression and liability to major depression and alcohol dependence in subjects from the Iowa Adoption Studies. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 147B, 543549.
Pike, BL, Greiner, TC, Wang, X, Weisenburger, DD, Hsu, YH, Renaud, G, Wolfsberg, TG, Kim, M, Weisenberger, DJ, Siegmund, KD, Ye, W, Groshen, S, Mehrian-Shai, R, Delabie, J, Chan, WC, Laird, PW, Hacia, JG (2008). DNA methylation profiles in diffuse large B-cell lymphoma and their relationship to gene expression status. Leukemia 22, 10351043.
Ptak, C, Petronis, A (2010). Epigenetic approaches to psychiatric disorders. Dialogues in Clinical Neuroscience 12, 2535.
Ranjit, N, Diez-Roux, AV, Shea, S, Cushman, M, Seeman, T, Jackson, SA, Ni, H (2007). Psychosocial factors and inflammation in the multi-ethnic study of atherosclerosis. Archives of Internal Medicine 167, 174181.
Schiepers, OJ, Wichers, MC, Maes, M (2005). Cytokines and major depression. Progress in Neuropsychopharmacology and Biological Psychiatry 29, 201217.
Sluzewska, A, Rybakowski, J, Bosmans, E, Sobieska, M, Berghmans, R, Maes, M, Wiktorowicz, K (1996). Indicators of immune activation in major depression. Psychiatry Research 64, 161167.
Stenvinkel, P, Karimi, M, Johansson, S, Axelsson, J, Suliman, M, Lindholm, B, Heimburger, O, Barany, P, Alvestrand, A, Nordfors, L, Qureshi, AR, Ekstrom, TJ, Schalling, M (2007). Impact of inflammation on epigenetic DNA methylation – a novel risk factor for cardiovascular disease? Journal of Internal Medicine 261, 488499.
Trzonkowski, P, Mysliwska, J, Godlewska, B, Szmit, E, Lukaszuk, K, Wieckiewicz, J, Brydak, L, Machala, M, Landowski, J, Mysliwski, A (2004). Immune consequences of the spontaneous pro-inflammatory status in depressed elderly patients. Brain, Behavior, and Immunity 18, 135148.
Uddin, M, Aiello, AE, Wildman, DE, Koenen, KC, Pawelec, G, de Los Santos, R, Goldmann, E, Galea, S (2010). Epigenetic and immune function profiles associated with posttraumatic stress disorder. Proceedings of the National Academy of Sciences USA 107, 94709475.
Valinluck, V, Sowers, LC (2007). Endogenous cytosine damage products alter the site selectivity of human DNA maintenance methyltransferase DNMT1. Cancer Research 67, 946950.
Weaver, IC, Cervoni, N, Champagne, FA, D'Alessio, AC, Sharma, S, Seckl, JR, Dymov, S, Szyf, M, Meaney, MJ (2004). Epigenetic programming by maternal behavior. Nature Neuroscience 7, 847854.
Weaver, IC, Champagne, FA, Brown, SE, Dymov, S, Sharma, S, Meaney, MJ, Szyf, M (2005). Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: altering epigenetic marking later in life. Journal of Neuroscience 25, 1104511054.
Wrona, D (2006). Neural-immune interactions: an integrative view of the bidirectional relationship between the brain and immune systems. Journal of Neuroimmunology 172, 3858.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *


Type Description Title
Supplementary materials

Uddin supplementary material
Table 1.xls

 Excel (147 KB)
147 KB
Supplementary materials

Uddin supplementary material
Table 2.xls

 Excel (40 KB)
40 KB
Supplementary materials

Uddin supplementary material
Table 3.xls

 Excel (205 KB)
205 KB
Supplementary materials

Uddin supplementary material
Table 4.xls

 Excel (330 KB)
330 KB
Supplementary materials

Uddin supplementary material
Figure S1.doc

 Word (52 KB)
52 KB


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed