There is an increasing body of knowledge on the influence of differential DNA methylation of specific genomic regions in psychiatric disorders. However, fewer studies have addressed global DNA methylation (GMe) levels. GMe is an estimative of biological functioning that is regulated by pervasive mechanisms able to capture the big picture of metabolic and environmental influences upon gene expression. In the present perspective article, we highlighted evidence for the relationships between cortisol and sex hormones and GMe in psychiatric disorders. We argue that the far-reaching effects of cortisol and sexual hormones on GMe may lie on the pathways linking stress and mental health. Further research on these endocrine–epigenetic links may help to explain the role of environmental stress as well as sex differences in the prevalence of psychiatric disorders.
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Assary E, Vincent JP, Keers R, Pluess M. Gene-environment interaction and psychiatric disorders: review and future directions. Semin Cell Dev Biol. 2018;77:133–43.
Bakusik J, Schaufeli W, Claes S, Lode G. Stress, burnout and depression: a systematic review on DNA methylation mechanisms. J Psychosom Res. 2017;92:34–44.
Li M, Arcy CD, Li X, Zhang T. What do DNA methylation studies tell us about depression? A systematic review. Transl Psychiatry. 2019;9:981. https://doi.org/10.1038/s41398-019-0412-y.
Crider KS, Yang TP, Berry RJ, Bailey LB. Folate and DNA methylation: a review of molecular mechanisms and the evidence for folate’s role. Adv Nutr. 2012;3:21–38.
Wu H, Zhang Y. Reversing DNA methylation: mechanisms, genomics, and biological functions. Cell.2014;156:45–68.
Lyko F. The DNA methyltransferase family: a versatile toolkit for epigenetic regulation. Nat Rev Genet. 2018;19:81–92.
Pérez RF, Tejedor JR, Bayón GF, Fernández AF, Fraga MF. Distinct chromatin signatures of DNA hypomethylation in aging and cancer. Aging Cell. 2018;27:1–16.
Pfeifer GP. Defining driver DNA methylation changes in human cancer. Int J Mol Sci. 2018;19:1–13.
Shimabukuro M, Sasaki T, Imamura A, Tsujita T, Fuke C, Umekage T, et al. Global hypomethylation of peripheral leukocyte DNA in male patients with schizophrenia: a potential link between epigenetics and schizophrenia. J Psychiatr Res. 2007;41:1042–6.
Bromberg A, Bersudsky Y, Levine J, Agam G. Global leukocyte DNA methylation is not altered in euthymic bipolar patients. J Affect Disord. 2009;118:234–9.
Jiang T, Zong L, Zhou L, Hou Y, Zhang L, Zheng X, et al. Variation in global DNA hydroxymethylation with age associated with schizophrenia. Psychiatry Res. 2017;257:497–500.
Melas PA, Rogdaki M, Ösby U, Schalling M, Lavebratt C, Ekström TJ. Epigenetic aberrations in leukocytes of patients with schizophrenia: association of global DNA methylation with antipsychotic drug treatment and disease onset. FASEB J. 2012;26:2712–8.
Huzayyin AA, Andreazza AC, Turecki G, Cruceanu C, Rouleau GA, Alda M, et al. Decreased global methylation in patients with bipolar disorder who respond to lithium. Int J Neuropsychopharmacol. 2014;17:561–9.
Li S, Yang Q, Hou Y, Jiang T, Zong L, Wang Z, et al. Hypomethylation of LINE-1 elements in schizophrenia and bipolar disorder. J Psychiatr Res. 2018;107:68–72.
Semmler A, Heese P, Stoffel-Wagner B, Muschler M, Heberlein A, Bigler L, et al. Alcohol abuse and cigarette smoking are associated with global DNA hypermethylation: results from the German Investigation on Neurobiology in Alcoholism (GINA). Alcohol. 2015;49:97–101.
Glad CAM, Andersson-assarsson JC, Berglund P, Bergthorsdottir R, Ragnarsson O, Johannsson G. Reduced DNA methylation and psychopathology following endogenous hypercortisolism—a genome-wide study. Sci Rep. 2017;7:1–11.
Santos A, Resmini E, Antonia M, Momblán M, Valassi E, Martel L, et al. Quality of life in patients with Cushing’s disease. Front Endocrinol. 2019;10:1–10.
Dorn LD, Kolkob DJ, Susman EJ, Huang B, Howard S, Music E, et al. Salivary gonadal and adrenal hormone differences in boys and girls with and without disruptive behavior disorders: contextual variants. Biol Psychol. 2010;81:31–9.
Pivonello R, Simeoli C, De Martino MC, Cozzolino A, De Leo M, Iacuaniello D, et al. Neuropsychiatric disorders in Cushing’ s syndrome. Front Neurosci. 2015;9:1–6.
Dick A, Provencal N. Central neuroepigenetic regulation of the hypothalamic–pituitary–adrenal axis. In: Bart P. F. Rutten editor. Neuroepigenetics and mental illness. 1st ed. Vol. 158. Cambridge, MA: Elsevier Inc.; 2018. pp. 105–127.
Khoury JE, Enlow MB, Plamondon A, Lyons-Ruth K. The association between adversity and hair cortisol levels in humans: a meta-analysis. Psychoneuroendocrinology. 2019;103:104–17.
Kuehl LK, Schultebraucks K, Deuter CE, May A, Spitzer C, Otte C, et al. Stress effects on cognitive function in patients with major depressive disorder: does childhood trauma play a role? Dev Psychopathol. 2020;32:1007–16.
Jaworska-andryszewska P, Rybakowski JK. Childhood trauma in mood disorders: neurobiological mechanisms and implications for treatment. Pharmacol Rep. 2019;71:112–20.
Johnson SA, Fournier NM, Kalynchuk LE. Effect of different doses of corticosterone on depression-like behavior and HPA axis responses to a novel stressor. Behav Brain Res. 2006;168:280–8.
Zhao Y, Ma R, Shen J, Su H, Xing D, Du L. A mouse model of depression induced by repeated corticosterone injections. Eur J Pharmacol. 2008;581:113–20.
Starnawska A, Tan Q, Soerensen M, McGue M, Mors O, Børglum AD, et al. Epigenome-wide association study of depression symptomatology in elderly monozygotic twins. Transl Psychiatry. 2019;9:321–38.
Talarowska M. Epigenetic mechanisms in the neurodevelopmental theory of depression. Depression Res Treat. 2020;2020:6357873.
Kennis M, Gerritsen L, Van Dalen M, Williams A, Cuijpers P, Bockting C. Prospective biomarkers of major depressive disorder: a systematic review and meta-analysis. Mol Psychiatry. 2019;25:321–38.
Byrne EM, Henders AK, Bowdler L, Mcrae AF, Heath AC, Martin NG, et al. Monozygotic twins affected with major depressive disorder have greater variance in methylation than their unaffected co-twin. Transl Psychiatry. 2013;3:e269–6.
Tseng P, Lin P, Lee Y, Lung F, Chen C-S, Chong M-Y. Age-associated decrease in global DNA methylation in patients with major depression. Neuropsychiatr Dis Treat. 2014;10:2105–14.
McCoy CR, Jackson NL, Day J, Clinton SM. Genetic predisposition to high anxiety- and depression-like behavior coincides with diminished DNA methylation in the adult rat amygdala. Behav Brain Res. 2017;320:165–78.
Shen X, Yuan H, Wang G, Xue H, Liu Y, Zhang C-X. Role of DNA hypomethylation in lateral habenular nucleus in the development of depressive-like behavior in rats. J Affect Disord. 2019;252:373–81.
Rowson SA, Bekhbat M, Kelly SD, Binder EB, Hyer MM, Shaw G, et al. Chronic adolescent stress sex-specifically alters the hippocampal transcriptome in adulthood. Neuropsychopharmacology. 2019;44:1207–15.
Dirven BCJ, Homberg JR, Kozicz T, Henckens MJAG. Epigenetic programming of the neuroendocrine stress response by adult life stress. J Mol Endocrinol. 2017;59:R11–31.
van Der Voorn B, Hollanders JJ, Ket JCF, Rotteveel J, Finken MJJ. Gender-specific differences in hypothalamus–pituitary–adrenal axis activity during childhood: a systematic review and meta-analysis. Biol Sex Differ. 2017;8:1–9.
Fuke C, Shimabukuro M, Petronis A, Sugimoto J, Oda T, Miura K, et al. Age related changes in 5-methylcytosine content in human peripheral leukocytes and placentas: an HPLC-based study. Ann Hum Genet. 2004;68:196–204.
Suderman M, Simpkin A, Sharp G, Gaunt T, Lyttleton O, Mcardle W, et al. Sex-associated autosomal DNA methylation differences are wide-spread and stable throughout childhood. bioRvix. 2017;1–63. https://www.biorxiv.org/content/10.1101/118265v1.full.
Sahakyan A, Plath K, Rougeulle C. Regulation of X-chromosome dosage compensation in human: mechanisms and model systems. Philos Trans R Soc B Biol Sci. 2017;372:1–9.
McCarthy NS, Melton PE, Cadby G, Yazar S, Franchina M, Moses EK, et al. Meta-analysis of human methylation data for evidence of sex-specific autosomal patterns. BMC Genom. 2014;15:981. https://doi.org/10.1186/1471-2164-15-981.
Dipietro JA, Costigan KA, Kivlighan KT, Chen P, Laudenslager ML. Maternal salivary cortisol differs by fetal sex during the second halfhalf of pregnancy. Psychoneuroendocrinology. 2011;36:588–91.
Forger NG. Past, present and future of epigenetics in brain sexual differentiation. J Neuroendocrinol. 2018;30:e12492.
Ghahramani NM, Ngun TC, Chen PY, Tian Y, Krishnan S, Muir S, et al. The effects of perinatal testosterone exposure on the DNA methylome of the mouse brain are late-emerging. Biol Sex Differ. 2014;5:1–18.
Gabory A, Attig L, Junien C. Sexual dimorphism in environmental epigenetic programming. Mol Cell Endocrinol. 2009;304:8–18.
Fairchild G, Baker E, Eaton S. Hypothalamic–pituitary–adrenal axis function in children and adults with severe antisocial behavior and the impact of early adversity. Curr Psychiatry Rep. 2018;20:84. https://doi.org/10.1007/s11920-018-0952-5.
Hawes DJ, Brennan J, Dadds MR. Cortisol, callous-unemotional traits, and pathways to antisocial behavior. Curr Opin Psychiatry. 2009;22:357–62.
Alink LRA, van IJzendoorn MH, Bakermans-Kranenburg MJ, Mesman J, Juffer F, Koot HM. Cortisol and externalizing behavior in children and adolescents: mixed meta-analytic evidence for the inverse relation of basal cortisol and cortisol reactivity with externalizing behavior. Dev Psychobiol. 2008;50:427–50.
Teicher MH, Samson JA, Anderson CM, Ohashi K. The effects of childhood maltreatment on brain structure, function and connectivity. Nat Rev Neurosci. 2016;17:652–66.
Romanowska J, Joshi A. From genotype to phenotype: through chromatin. Genes. 2019;10:76. https://doi.org/10.3390/genes10020076.
This work received financial support from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (Grants 466722/2014-1, 424041/2016-2, 426905/2016-2, 431472/2018-1, 140853/2019-7). Also, this study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES)—Finance Code 001 and FIPE-HCPA 160600, GPPG-HCPA 01-321.
Conflict of interest
EHG was on the speaker’s bureau for Novartis and Shire for the last 3 years. He also received travel awards (air tickets and hotel accommodations) for participating in three psychiatric meetings from Shire and Novartis. The remaining authors declare no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Müller, D., Grevet, E.H., da Silva, B.S. et al. The neuroendocrine modulation of global DNA methylation in neuropsychiatric disorders. Mol Psychiatry 26, 66–69 (2021). https://doi.org/10.1038/s41380-020-00924-y
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