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

Published online by Cambridge University Press:  14 September 2010

M. Uddin ,
K. C. Koenen ,
A. E. Aiello ,
D. E. Wildman ,
R. de los Santos  and
S. Galea
M. Uddin*
Affiliation:
Center for Social Epidemiology and Population Health and Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA
K. C. Koenen
Affiliation:
Departments of Society, Human Development, and Health and Epidemiology, Harvard School of Public Health, Boston, MA, USA
A. E. Aiello
Affiliation:
Center for Social Epidemiology and Population Health and Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA
D. E. Wildman
Affiliation:
Center for Molecular Medicine and Genetics and Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
R. de los Santos
Affiliation:
Center for Social Epidemiology and Population Health and Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA
S. Galea
Affiliation:
Department of Epidemiology, Columbia University Mailman School of Public Health, New York, NY, USA
*
*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: uddinm@umich.edu)
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Abstract

Background

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.

Method

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.

Results

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.

Conclusions

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.

Keywords

Epidemiologyinflammationmethylationpsychiatry
Type
Original Articles
Information
Psychological Medicine , Volume 41 , Issue 5 , May 2011 , pp. 997 - 1007
Copyright
Copyright © Cambridge University Press 2010

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References

aan het Rot, M, Mathew, SJ, Charney, DS (2009). Neurobiological mechanisms in major depressive disorder. Canadian Medical Association Journal 180, 305–313.CrossRefGoogle ScholarPubMed
ACS (2009). 2005–2007 American Community Survey 3-Year Estimates. U.S. Census Bureau: Washington, DC.Google Scholar
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, 185–191.CrossRefGoogle ScholarPubMed
Andrews, G, Peters, L (1998). The psychometric properties of the Composite International Diagnostic Interview. Social Psychiatry and Psychiatric Epidemiology 33, 80–88.CrossRefGoogle ScholarPubMed
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, 588–594.CrossRefGoogle ScholarPubMed
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, 176–184.CrossRefGoogle ScholarPubMed
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, 2877–2883.CrossRefGoogle ScholarPubMed
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, 1044–1056.CrossRefGoogle ScholarPubMed
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, 46–56.CrossRefGoogle ScholarPubMed
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, 1378–1385.CrossRefGoogle Scholar
Egger, G, Liang, G, Aparicio, A, Jones, PA (2004). Epigenetics in human disease and prospects for epigenetic therapy. Nature 429, 457–463.CrossRefGoogle ScholarPubMed
Elenkov, IJ (2008). Neurohormonal-cytokine interactions: implications for inflammation, common human diseases and well-being. Neurochemistry International 52, 40–51.CrossRefGoogle ScholarPubMed
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, 615–624.Google ScholarPubMed
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, 413–423.CrossRefGoogle ScholarPubMed
Gladkevich, A, Kauffman, HF, Korf, J (2004). Lymphocytes as a neural probe: potential for studying psychiatric disorders. Progress in Neuropsychopharmacology and Biological Psychiatry 28, 559–576.CrossRefGoogle ScholarPubMed
Gold, SM, Irwin, MR (2009). Depression and immunity: inflammation and depressive symptoms in multiple sclerosis. Immunology and Allergy Clinics of North America 29, 309–320.CrossRefGoogle ScholarPubMed
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, 171–186.CrossRefGoogle ScholarPubMed
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, 617–624.CrossRefGoogle ScholarPubMed
Huang, DW, Sherman, BT, Lempicki, RA (2009). Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature Protocols 4, 44–57.CrossRefGoogle ScholarPubMed
Irwin, MR, Miller, AH (2007). Depressive disorders and immunity: 20 years of progress and discovery. Brain Behavior and Immunity 21, 374–383.CrossRefGoogle ScholarPubMed
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, 1429–1438.CrossRefGoogle ScholarPubMed
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, 13329–13340.CrossRefGoogle ScholarPubMed
Kiecolt-Glaser, JK, Glaser, R (2002). Depression and immune function: central pathways to morbidity and mortality. Journal of Psychosomatic Research 53, 873–876.CrossRefGoogle ScholarPubMed
Kim, JK, Samaranayake, M, Pradhan, S (2009). Epigenetic mechanisms in mammals. Cellular and Molecular Life Sciences 66, 596–612.CrossRefGoogle ScholarPubMed
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, 575–582.CrossRefGoogle Scholar
Kroenke, K, Spitzer, RL, Williams, JB (2001). The PHQ-9: validity of a brief depression severity measure. Journal of General Internal Medicine 16, 606–613.CrossRefGoogle ScholarPubMed
Kronfol, Z, Remick, DG (2000). Cytokines and the brain: implications for clinical psychiatry. American Journal of Psychiatry 157, 683–694.CrossRefGoogle ScholarPubMed
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, 1114–1120.CrossRefGoogle Scholar
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, 156–174.CrossRefGoogle ScholarPubMed
Leonard, BE, Myint, A (2009). The psychoneuroimmunology of depression. Human Psychopharmacology 24, 165–175.CrossRefGoogle ScholarPubMed
Maes, M (1999). Major depression and activation of the inflammatory response system. Advances in Experimental Medicine and Biology 461, 25–46.CrossRefGoogle ScholarPubMed
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, 287–291.Google Scholar
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, 1189–1193.Google ScholarPubMed
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, 301–309.CrossRefGoogle ScholarPubMed
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, 151–165.CrossRefGoogle ScholarPubMed
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, 11–27.CrossRefGoogle ScholarPubMed
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, 154–161.CrossRefGoogle ScholarPubMed
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, 27–53.CrossRefGoogle Scholar
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, 740–754.CrossRefGoogle ScholarPubMed
Manji, HK, Moore, GJ, Rajkowska, G, Chen, G (2000 b). Neuroplasticity and cellular resilience in mood disorders. Molecular Psychiatry 5, 578–593.CrossRefGoogle ScholarPubMed
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, 696–711.CrossRefGoogle ScholarPubMed
Miller, AH, Maletic, V, Raison, CL (2009). Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biological Psychiatry 65, 732–741.CrossRefGoogle ScholarPubMed
Myint, AM, Kim, YK (2003). Cytokine-serotonin interaction through IDO: a neurodegeneration hypothesis of depression. Medical Hypotheses 61, 519–525.CrossRefGoogle Scholar
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.CrossRefGoogle ScholarPubMed
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, 159–165.CrossRefGoogle ScholarPubMed
Pepys, MB, Hirschfield, GM (2003). C-reactive protein: a critical update. Journal of Clinical Investigation 111, 1805–1812.CrossRefGoogle ScholarPubMed
Petronis, A (2010). Epigenetics as a unifying principle in the aetiology of complex traits and diseases. Nature 465, 721–727.CrossRefGoogle ScholarPubMed
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, 543–549.CrossRefGoogle ScholarPubMed
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, 1035–1043.CrossRefGoogle ScholarPubMed
Ptak, C, Petronis, A (2010). Epigenetic approaches to psychiatric disorders. Dialogues in Clinical Neuroscience 12, 25–35.CrossRefGoogle ScholarPubMed
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, 174–181.CrossRefGoogle ScholarPubMed
Schiepers, OJ, Wichers, MC, Maes, M (2005). Cytokines and major depression. Progress in Neuropsychopharmacology and Biological Psychiatry 29, 201–217.CrossRefGoogle ScholarPubMed
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, 161–167.CrossRefGoogle ScholarPubMed
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, 488–499.CrossRefGoogle Scholar
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, 135–148.CrossRefGoogle ScholarPubMed
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, 9470–9475.CrossRefGoogle ScholarPubMed
Valinluck, V, Sowers, LC (2007). Endogenous cytosine damage products alter the site selectivity of human DNA maintenance methyltransferase DNMT1. Cancer Research 67, 946–950.CrossRefGoogle ScholarPubMed
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, 847–854.CrossRefGoogle ScholarPubMed
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, 11045–11054.CrossRefGoogle ScholarPubMed
Wrona, D (2006). Neural-immune interactions: an integrative view of the bidirectional relationship between the brain and immune systems. Journal of Neuroimmunology 172, 38–58.CrossRefGoogle ScholarPubMed
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