Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Relation of Promoter Methylation of the Oxytocin Gene to Stressful Life Events and Depression Severity


Oxytocin (OT) is a neuropeptide associated with trauma, sociality, and depression. Despite the widely accepted assumption of OT playing a role in the etiology of mood and anxiety disorders, associations between stressful life events, depression, and epigenetic regulation of the gene coding for OT (OXT) have not yet been investigated. We therefore aimed to examine the interrelations of stressful life events, depression severity, and methylation of the promoter region of OXT in a sample of N = 146 inpatients suffering from major depression. We found significant negative associations of stressful life events with mean methylation status as well as with methylation status of single CpG sites in the promoter region of OXT. There was no association between depression severity and OXT methylation. However, there were significant sex differences in methylation status of OXT with women showing higher methylation rates than men, putatively suggesting that in depression OXT is less activated in females compared to males. These results speak against an association of OXT methylation and depression severity, but support the assumption of a dysregulation of the OT system due to life stress. Our findings further emphasize the importance of including sex as an important factor in the investigation of the interrelations between OXT, stress, and depression.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2


  1. 1.

    Written in capital letters in order to refer to the Pankseppian nomenclature (Davis and Montag 2019).


  1. Abraham HD, Fava M (1999) Order of onset of substance abuse and depression in a sample of depressed outpatients. Compr Psychiatry 40(1):44–50. https://doi.org/10.1016/S0010-440X(99)90076-7

  2. Albert PR (2015) Why is depression more prevalent in women? J Psychiatry Neurosci 40(4):219–221. https://doi.org/10.1503/JPN.150205

  3. American Psychiatric Association (2003) In: Sass H, Wittchen HU, Zaudig M, Houben I (eds) Diagnostisches und statistisches Manual psychischer Störungen: Textrevision, 4th edn. Hogrefe, Göttingen

  4. Bale TL (2011) Sex differences in prenatal epigenetic programing of stress pathways. Stress 14(4):348–356. https://doi.org/10.3109/10253890.2011.586447

  5. Bale TL, Epperson CN (2015) Sex differences and stress across the lifespan. Nat Neurosci 18(10):1413–1420. https://doi.org/10.1038/nn.4112

  6. Beck A, Steer R, Brown G (2006) In: Hautzinger M, Keller F, Kühner C (eds) Beck-Depressions-Inventar–Revision (BDI-II). Deutsche Version. Harcourt Test Services, Frankfurt/Main

  7. Bell AF, Carter CS, Steer CD, Golding J, Davis JM, Steffen AD et al (2015) Interaction between oxytocin receptor DNA methylation and genotype is associated with risk of postpartum depression in women without depression in pregnancy. Front Genet:6. https://doi.org/10.3389/fgene.2015.00243

  8. Benjamini Y, Hochberg Y (2000) On the adaptive control of the false discovery rate in multiple testing with independent statistics. J Educ Behav Stat Spring 25(1):60–83

  9. Bird AP (1986) CpG-rich islands and the function of DNA methylation. Nature 321(6067):209–213. https://doi.org/10.1038/321209a0

  10. Bosch OJ, Young LJ (2017) Oxytocin and social relationships: from attachment to bond disruption. Springer, Cham, pp 97–117. https://doi.org/10.1007/7854_2017_10

  11. Buchheim A, Heinrichs M, George C, Pokorny D, Koops E, Henningsen P, O’Connor MF, Gündel H (2009) Oxytocin enhances the experience of attachment security. Psychoneuroendocrinology 34(9):1417–1422. https://doi.org/10.1016/J.PSYNEUEN.2009.04.002

  12. Byun H-M, Siegmund KD, Pan F, Weisenberger DJ, Kanel G, Laird PW, Yang AS (2009) Epigenetic profiling of somatic tissues from human autopsy specimens identifies tissue- and individual-specific DNA methylation patterns. Hum Mol Genet 18(24):4808–4817. https://doi.org/10.1093/hmg/ddp445

  13. Chagnon YC, Potvin O, Hudon C, Préville M (2015) DNA methylation and single nucleotide variants in the brain-derived neurotrophic factor (BDNF) and oxytocin receptor (OXTR) genes are associated with anxiety/depression in older women. Front Genet 6. https://doi.org/10.3389/fgene.2015.00230

  14. Classen C, Field NP, Koopman C, Neville-Manning K, Spiegel D (2001) Interpersonal problems and their relationship to sexual revictimization among women sexually abused in childhood. J Interpersonal Violence 16(6):495–509. https://doi.org/10.1177/088626001016006001

  15. Culverhouse RC, Saccone NL, Horton AC, Ma Y, Anstey KJ, Banaschewski T, Burmeister M, Cohen-Woods S, Etain B, Fisher HL, Goldman N, Guillaume S, Horwood J, Juhasz G, Lester KJ, Mandelli L, Middeldorp CM, Olié E, Villafuerte S, Air TM, Araya R, Bowes L, Burns R, Byrne EM, Coffey C, Coventry WL, Gawronski KAB, Glei D, Hatzimanolis A, Hottenga JJ, Jaussent I, Jawahar C, Jennen-Steinmetz C, Kramer JR, Lajnef M, Little K, Zu Schwabedissen HM, Nauck M, Nederhof E, Petschner P, Peyrot WJ, Schwahn C, Sinnamon G, Stacey D, Tian Y, Toben C, van der Auwera S, Wainwright N, Wang JC, Willemsen G, Anderson IM, Arolt V, Åslund C, Bagdy G, Baune BT, Bellivier F, Boomsma DI, Courtet P, Dannlowski U, de Geus EJC, Deakin JFW, Easteal S, Eley T, Fergusson DM, Goate AM, Gonda X, Grabe HJ, Holzman C, Johnson EO, Kennedy M, Laucht M, Martin NG, Munafò MR, Nilsson KW, Oldehinkel AJ, Olsson CA, Ormel J, Otte C, Patton GC, Penninx BWJH, Ritchie K, Sarchiapone M, Scheid JM, Serretti A, Smit JH, Stefanis NC, Surtees PG, Völzke H, Weinstein M, Whooley M, Nurnberger JI Jr, Breslau N, Bierut LJ (2018) Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression. Mol Psychiatry 23(1):133–142. https://doi.org/10.1038/mp.2017.44

  16. Davis KL, Montag C (2019) Selected principles of Pankseppian affective neuroscience. Front Neurosci 12:1025. https://doi.org/10.3389/fnins.2018.01025

  17. de Jong TR, Menon R, Bludau A, Grund T, Biermeier V, Klampfl SM et al (2015) Salivary oxytocin concentrations in response to running, sexual self-stimulation, breastfeeding and the TSST: the Regensburg Oxytocin Challenge (ROC) study. Psychoneuroendocrinology 62:381–388. https://doi.org/10.1016/J.PSYNEUEN.2015.08.027

  18. de Wit LM, van Straten A, van Herten M, Penninx BW, Cuijpers P (2009) Depression and body mass index, a u-shaped association. BMC Public Health 9(1):14. https://doi.org/10.1186/1471-2458-9-14

  19. Decety J, Batson CD (2009) Empathy and morality: integrating social and neuroscience approaches. In: The moral brain. Springer, Dordrecht, pp 109–127. https://doi.org/10.1007/978-1-4020-6287-2_5

  20. DePrince AP, Combs MD, Shanahan M (2009) Automatic relationship—harm associations and interpersonal trauma involving close others. Psychol Women Q 33(2):163–171. https://doi.org/10.1111/j.1471-6402.2009.01486.x

  21. Dick KJ, Nelson CP, Tsaprouni L, Sandling JK, Aïssi D, Wahl S, Meduri E, Morange PE, Gagnon F, Grallert H, Waldenberger M, Peters A, Erdmann J, Hengstenberg C, Cambien F, Goodall AH, Ouwehand WH, Schunkert H, Thompson JR, Spector TD, Gieger C, Trégouët DA, Deloukas P, Samani NJ (2014) DNA methylation and body-mass index: a genome-wide analysis. Lancet 383(9933):1990–1998. https://doi.org/10.1016/S0140-6736(13)62674-4

  22. Donadon MF, Martin-Santos R, de Osório FL (2018) The associations between oxytocin and trauma in humans: a systematic review. Front Pharmacol 9:154. https://doi.org/10.3389/fphar.2018.00154

  23. Engel S, Klusmann H, Ditzen B, Knaevelsrud C, Schumacher S (2019a) Menstrual cycle-related fluctuations in oxytocin concentrations: a systematic review and meta-analysis. Front Neuroendocrinol 52:144–155. https://doi.org/10.1016/J.YFRNE.2018.11.002

  24. Engel S, Laufer S, Knaevelsrud C, Schumacher S (2019b) The endogenous oxytocin system in depressive disorders: a systematic review and meta-analysis. Psychoneuroendocrinology 101:138–149. https://doi.org/10.1016/J.PSYNEUEN.2018.11.011

  25. Ernst C, Angst J (1995) Depression in old age. Eur Arch Psychiatry Clin Neurosci 245(6):272–287. https://doi.org/10.1007/BF02191869

  26. Feil R, Fraga MF (2012) Epigenetics and the environment: emerging patterns and implications. Nat Rev Genet 13(2):97–109. https://doi.org/10.1038/nrg3142

  27. Feinberg AP, Irizarry RA, Fradin D, Aryee MJ, Murakami P, Aspelund T et al (2010) Personalized epigenomic signatures that are stable over time and covary with body mass index. Sci Transl Med 2(49):49ra67. https://doi.org/10.1126/scitranslmed.3001262

  28. Feldman R, Bakermans-Kranenburg MJ (2017) Oxytocin: a parenting hormone. Curr Opin Psychol 15:13–18. https://doi.org/10.1016/J.COPSYC.2017.02.011

  29. Galbally M, Ryan J, van IJzendoorn M, Watson SJ, Spigset O, Lappas M et al (2018) Maternal depression, antidepressant use and placental oxytocin receptor DNA methylation: findings from the MPEWS study. Psychoneuroendocrinology 90:1–8. https://doi.org/10.1016/J.PSYNEUEN.2018.01.004

  30. Gilbert P (2000) The relationship of shame, social anxiety and depression: the role of the evaluation of social rank. Clin Psychol Psychother 7(3):174–189. https://doi.org/10.1002/1099-0879(200007)7:3<174::AID-CPP236>3.0.CO;2-U

  31. Goldberg AD, Allis CD, Bernstein E (2007) Epigenetics: a landscape takes shape. Cell 128(4):635–638. https://doi.org/10.1016/j.cell.2007.02.006

  32. Gouin JP, Zhou QQ, Booij L, Boivin M, Côté SM, Hébert M, Ouellet-Morin I, Szyf M, Tremblay RE, Turecki G, Vitaro F (2017) Associations among oxytocin receptor gene (OXTR) DNA methylation in adulthood, exposure to early life adversity, and childhood trajectories of anxiousness. Sci Rep 7(1):7446–7414. https://doi.org/10.1038/s41598-017-07950-x

  33. Haas BW, Filkowski MM, Cochran RN, Denison L, Ishak A, Nishitani S, Smith AK (2016) Epigenetic modification of OXT and human sociability. Proc Natl Acad Sci U S A 113(27):E3816–E3823. https://doi.org/10.1073/pnas.1602809113

  34. Hankin BL (2005) Childhood maltreatment and psychopathology: prospective tests of attachment, cognitive vulnerability, and stress as mediating processes. Cogn Ther Res 29(6):645–671. https://doi.org/10.1007/s10608-005-9631-z

  35. Hayasaka Y, Purgato M, Magni LR, Ogawa Y, Takeshima N, Cipriani A, Barbui C, Leucht S, Furukawa TA (2015) Dose equivalents of antidepressants: evidence-based recommendations from randomized controlled trials. J Affect Disord 180:179–184. https://doi.org/10.1016/J.JAD.2015.03.021

  36. Heim C, Binder EB (2012) Current research trends in early life stress and depression: review of human studies on sensitive periods, gene–environment interactions, and epigenetics. Exp Neurol 233(1):102–111. https://doi.org/10.1016/J.EXPNEUROL.2011.10.032

  37. Heim C, Nemeroff CB (2001) The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biol Psychiatry 49(12):1023–1039. https://doi.org/10.1016/S0006-3223(01)01157-X

  38. Heim C, Newport DJ, Heit S, Graham YP, Wilcox M, Bonsall R, Miller AH, Nemeroff CB (2000) Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood. JAMA 284(5):592–597. https://doi.org/10.1001/jama.284.5.592

  39. Hrdy S (2009) Mothers and others: the evolutionary origins of mutual understanding. Harvard University Press, Cambridge Retrieved from https://scholar.google.com/scholar?hl=en&q=Hrdy+SB.+2009.+Mothers+and+Others%3A+The+Evolutionary+Origins+of+Mutual+Understanding.+Cambridge%2C+MA%3A+Belknap+Press%2C+Harvard+Univ.+Press. Accessed 13 May 2019

  40. Jack A, Connelly JJ, Morris JP (2012) DNA methylation of the oxytocin receptor gene predicts neural response to ambiguous social stimuli. Front Hum Neurosci 6:280. https://doi.org/10.3389/fnhum.2012.00280

  41. Jobst A, Krause D, Maiwald C, Härtl K, Myint A-M, Kästner R, Obermeier M, Padberg F, Brücklmeier B, Weidinger E, Kieper S, Schwarz M, Zill P, Müller N (2016) Oxytocin course over pregnancy and postpartum period and the association with postpartum depressive symptoms. Arch Womens Ment Health 19(4):571–579. https://doi.org/10.1007/s00737-016-0644-2

  42. Jones PA, Takai D (2001) The role of DNA methylation in mammalian epigenetics. Science (New York, N.Y.) 293(5532):1068–1070. https://doi.org/10.1126/science.1063852

  43. Jurek B, Neumann ID (2018) The oxytocin receptor: from intracellular signaling to behavior. Physiol Rev 98(3):1805–1908. https://doi.org/10.1152/physrev.00031.2017

  44. Jurek B, Slattery DA, Hiraoka Y, Liu Y, Nishimori K, Aguilera G, Neumann ID, van den Burg EH (2015) Oxytocin regulates stress-induced Crf gene transcription through CREB-regulated transcription coactivator 3. J Neurosci 35(35):12248–12260. https://doi.org/10.1523/JNEUROSCI.1345-14.2015

  45. Kimmel M, Clive M, Gispen F, Guintivano J, Brown T, Cox O, Beckmann MW, Kornhuber J, Fasching PA, Osborne LM, Binder E, Payne JL, Kaminsky Z (2016) Oxytocin receptor DNA methylation in postpartum depression. Psychoneuroendocrinology 69:150–160. https://doi.org/10.1016/J.PSYNEUEN.2016.04.008

  46. King L, Robins S, Chen G, Yerko V, Zhou Y, Nagy C et al (2017) Perinatal depression and DNA methylation of oxytocin-related genes: a study of mothers and their children. Horm Behav 96:84–94. https://doi.org/10.1016/J.YHBEH.2017.09.006

  47. Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E (2005) Oxytocin increases trust in humans. Nature 435(7042):673–676. https://doi.org/10.1038/nature03701

  48. Lara-Cinisomo S, McKenney K, Di Florio A, Meltzer-Brody S (2017) Associations between postpartum depression, breastfeeding, and oxytocin levels in Latina mothers. Breastfeed Med 12(7):436–442. https://doi.org/10.1089/bfm.2016.0213

  49. Lee KWK, Pausova Z (2013) Cigarette smoking and DNA methylation. Front Genet 4:132. https://doi.org/10.3389/fgene.2013.00132

  50. Lim DHK, Maher ER (2010) DNA methylation: a form of epigenetic control of gene expression. Obstet Gynaecol 12(1):37–42. https://doi.org/10.1576/toag.

  51. Liu D, Diorio J, Tannenbaum B, Caldji C, Francis D, Freedman A et al (1997) Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science (New York, N.Y.) 277(5332):1659–1662. https://doi.org/10.1126/SCIENCE.277.5332.1659

  52. McGowan PO, Sasaki A, D’Alessio AC, Dymov S, Labonté B, Szyf M et al (2009) Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci 12(3):342–348. https://doi.org/10.1038/nn.2270

  53. Meaney MJ, Szyf M (2005) Environmental programming of stress responses through DNA methylation: life at the interface between a dynamic environment and a fixed genome. Dialogues Clin Neurosci 7(2):103–123 Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/16262207. Accessed 23 October 2017

  54. Meynen G, Unmehopa UA, Hofman MA, Swaab DF, Hoogendijk WJG (2007) Hypothalamic oxytocin mRNA expression and melancholic depression. Mol Psychiatry 12(2):118–119. https://doi.org/10.1038/sj.mp.4001911

  55. Montag C, Davis KL (2018) Affective neuroscience theory and personality: an update. Pers Neurosci 1:e12. https://doi.org/10.1017/pen.2018.10

  56. Montgomery SA, Asberg M (1979) A new depression scale designed to be sensitive to change. Br J Psychiatry 134(4):382–389. https://doi.org/10.1192/bjp.134.4.382

  57. Munro ML, Brown SL, Pournajafi-Nazarloo H, Carter CS, Lopez WD, Seng JS (2013) In search of an adult attachment stress provocation to measure effect on the oxytocin system. J Am Psychiatr Nurses Assoc 19(4):180–191. https://doi.org/10.1177/1078390313492173

  58. Murgatroyd C, Patchev AV, Wu Y, Micale V, Bockmühl Y, Fischer D et al (2009) Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nat Neurosci 12(12):1559–1566. https://doi.org/10.1038/nn.2436

  59. Nave G, Camerer C, McCullough M (2015) Does oxytocin increase trust in humans? A critical review of research. Perspect Psychol Sci 10(6):772–789. https://doi.org/10.1177/1745691615600138

  60. Olff M, Frijling JL, Kubzansky LD, Bradley B, Ellenbogen MA, Cardoso C, Bartz JA, Yee JR, van Zuiden M (2013) The role of oxytocin in social bonding, stress regulation and mental health: an update on the moderating effects of context and interindividual differences. Psychoneuroendocrinology 38(9):1883–1894. https://doi.org/10.1016/J.PSYNEUEN.2013.06.019

  61. Ozer EJ, Best SR, Lipsey TL, Weiss DS (2003) Predictors of posttraumatic stress disorder and symptoms in adults: a meta-analysis. Psychol Bull 129(1):52–73. https://doi.org/10.1037/0033-2909.129.1.52

  62. Panksepp J (2004) Affective neuroscience: the foundations of human and animal emotions. Oxford University Press, New York

  63. Panksepp J, Watt DF (2011) Why does depression hurt? Ancestral primary-process separation-distress (PANIC/GRIEF) and diminished brain reward (SEEKING) processes in the genesis of depressive affect. Psychiatry 74(1):5–13. https://doi.org/10.1521/psyc.2011.74.1.5

  64. Philibert RA, Plume JM, Gibbons FX, Brody GH, Beach SRH (2012) The impact of recent alcohol use on genome wide DNA methylation signatures. Front Genet 3:54. https://doi.org/10.3389/fgene.2012.00054

  65. Pierrehumbert B, Torrisi R, Laufer D, Halfon O, Ansermet F, Beck Popovic M (2010) Oxytocin response to an experimental psychosocial challenge in adults exposed to traumatic experiences during childhood or adolescence. Neuroscience 166(1):168–177. https://doi.org/10.1016/J.NEUROSCIENCE.2009.12.016

  66. Plieger T, Melchers M, Montag C, Meermann R, Reuter M (2015) Life stress as potential risk factor for depression and burnout. Burn Res 2(1):19–24. https://doi.org/10.1016/J.BURN.2015.03.001

  67. Purba JS, Hoogendijk WJG, Hofman MA, Swaab DF (1996) Increased number of vasopressin- and oxytocin-expressing neurons in the paraventricular nucleus of the hypothalamus in depression. Arch Gen Psychiatry 53(2):137–143. https://doi.org/10.1001/archpsyc.1996.01830020055007

  68. R Development Core Team (2008) R: a language and environment for statistical computing. Austria, Vienna Retrieved from http://www.gnu.org/copyleft/gpl.html. Accessed 22 November 2019

  69. Rao G, Löffler C, Battey J, Hansmann I (1992) The human gene for oxytocin-neurophysin I (OXT) is physically mapped to chromosome 20p13 by in situ hybridization. Cytogenet Genome Res 61(4):271–273. https://doi.org/10.1159/000133420

  70. Reiner I, Van IJzendoorn MH, Bakermans-Kranenburg MJ, Bleich S, Beutel M, Frieling H (2015) Methylation of the oxytocin receptor gene in clinically depressed patients compared to controls: the role of OXTR rs53576 genotype. J Psychiatr Res 65:9–15. https://doi.org/10.1016/J.JPSYCHIRES.2015.03.012

  71. Richard P, Moos F, Freund-Mercier MJ (1991) Central effects of oxytocin. Physiol Rev 71(2):331–370. https://doi.org/10.1152/physrev.1991.71.2.331

  72. Rijlaarsdam J, van IJzendoorn MH, Verhulst FC, Jaddoe VWV, Felix JF, Tiemeier H, Bakermans-Kranenburg MJ (2017) Prenatal stress exposure, oxytocin receptor gene (OXTR) methylation, and child autistic traits: the moderating role of OXTR rs53576 genotype. Autism Res 10(3):430–438. https://doi.org/10.1002/aur.1681

  73. Roth TL, Lubin FD, Funk AJ, Sweatt JD (2009) Lasting epigenetic influence of early-life adversity on the BDNF gene. Biol Psychiatry 65(9):760–769 Retrieved from https://www.sciencedirect.com/science/article/pii/S0006322308015308. Accessed 22 March 2018

  74. Russell JA, Leng G, Douglas AJ (2003) The magnocellular oxytocin system, the fount of maternity: adaptations in pregnancy. Front Neuroendocrinol 24(1):27–61. https://doi.org/10.1016/S0091-3022(02)00104-8

  75. Scantamburlo G, Hansenne M, Fuchs S, Pitchot W, Maréchal P, Pequeux C, Ansseau M, Legros JJ (2007) Plasma oxytocin levels and anxiety in patients with major depression. Psychoneuroendocrinology 32(4):407–410. https://doi.org/10.1016/J.PSYNEUEN.2007.01.009

  76. Shamay-Tsoory SG, Abu-Akel A (2016) The social salience hypothesis of oxytocin. Biol Psychiatry 79(3):194–202. https://doi.org/10.1016/J.BIOPSYCH.2015.07.020

  77. Simons RL, Beach RH, Cutrona CE, Philibert RA (2017) Methylation of the oxytocin receptor gene mediates the effect of adversity on negative schemas and depression. Dev Psychopathol 29(3):725–736. https://doi.org/10.1017/S0954579416000420

  78. Smith AK, Kilaru V, Klengel T, Mercer KB, Bradley B, Conneely KN, Ressler KJ, Binder EB (2015) DNA extracted from saliva for methylation studies of psychiatric traits: evidence tissue specificity and relatedness to brain. Am J Med Genet B Neuropsychiatr Genet 168(1):36–44. https://doi.org/10.1002/ajmg.b.32278

  79. Szyf M, Bick J (2013) DNA methylation: a mechanism for embedding early life experiences in the genome. Child Dev 84(1):49–57. https://doi.org/10.1111/j.1467-8624.2012.01793.x

  80. Toepfer P, O’Donnell KJ, Entringer S, Garg E, Heim CM, Lin DTS et al (2019) Dynamic DNA methylation changes in the maternal oxytocin gene locus (OXT) during pregnancy predict postpartum maternal intrusiveness. Psychoneuroendocrinology 103:156–162. https://doi.org/10.1016/J.PSYNEUEN.2019.01.013

  81. Tylee DS, Kawaguchi DM, Glatt SJ (2013) On the outside, looking in: a review and evaluation of the comparability of blood and brain “-omes.”. Am J Med Genet B Neuropsychiatr Genet 162(7):595–603. https://doi.org/10.1002/ajmg.b.32150

  82. Unternaehrer E, Bolten M, Nast I, Staehli S, Meyer AH, Dempster E, Hellhammer DH, Lieb R, Meinlschmidt G (2016) Maternal adversities during pregnancy and cord blood oxytocin receptor (OXTR) DNA methylation. Soc Cogn Affect Neurosci 11(9):1460–1470. https://doi.org/10.1093/scan/nsw051

  83. Waller C, Wittfoth M, Fritzsche K, Timm L, Wittfoth-Schardt D, Rottler E, Heinrichs M, Buchheim A, Kiefer M, Gündel H (2015) Attachment representation modulates oxytocin effects on the processing of own-child faces in fathers. Psychoneuroendocrinology 62:27–35. https://doi.org/10.1016/J.PSYNEUEN.2015.07.003

  84. Watt F, Molloy PL (1988) Cytosine methylation prevents binding to DNA of a HeLa cell transcription factor required for optimal expression of the adenovirus major late promoter. Gene Dev 2(9):1136–1143 Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/3192075. Accessed 22 March 2018

  85. Watt DF, Panksepp J (2009) Depression: an evolutionarily conserved mechanism to terminate separation distress? A review of aminergic, peptidergic, and neural network perspectives. Neuropsychoanalysis 11(1):7–51. https://doi.org/10.1080/15294145.2009.10773593

  86. Weaver ICG, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR et al (2004) Epigenetic programming by maternal behavior. Nat Neurosci 7(8):847–854. https://doi.org/10.1038/nn1276

  87. Winter J, Jurek B (2019) The interplay between oxytocin and the CRF system: regulation of the stress response. Cell Tissue Res 375(1):85–91. https://doi.org/10.1007/s00441-018-2866-2

Download references


The position of CM is funded by a Heisenberg-grant awarded to him by the German Research Foundation (MO 2363/3-2).

Author information

S.S., C.M., and M.K. designed the present study. S.S. analyzed the data and wrote the first draft of the manuscript. All authors commented on previous versions of the manuscript. All authors read and approved the manuscript.

Correspondence to Simon Sanwald.

Ethics declarations

Conflict of Interest

There authors declare that they have no competing interests.

Ethical Approval

All procedures performed in this study were in accordance with the ethical standards of the ethics committee of Ulm University, Ulm, Germany (reference number: 25/18), and with the 1964 Helsinki Declaration and its later amendments.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sanwald, S., Gahr, M., Widenhorn-Müller, K. et al. Relation of Promoter Methylation of the Oxytocin Gene to Stressful Life Events and Depression Severity. J Mol Neurosci 70, 201–211 (2020). https://doi.org/10.1007/s12031-019-01446-1

Download citation


  • Major depression
  • Oxytocin
  • Epigenetics
  • DNA methylation
  • Sex