Although oxytocin (OXT) plays an important role in secure attachment formation with a primary caregiver, which is impaired in many children with childhood maltreatment (CM), epigenetic regulation in response to CM is a key factor in brain development during childhood. To address this issue, we first investigated differences in salivary DNA methylation of the oxytocin receptor (OXTR) between CM and Non-CM groups of Japanese children (CM: n = 44; Non-CM: n = 41) and its impact on brain structures in subgroup analysis using brain imaging and full clinical data (CM: n = 24; Non-CM: n = 31). As a result, we observed that the CM group showed higher CpG 5,6 methylation than did the Non-CM group and confirmed negative correlations of gray matter volume (GMV) in the left orbitofrontal cortex (OFC) with CpG 5,6 methylation. In addition, the CM group showed significantly lower GMV in the left OFC than did the Non-CM group. Furthermore, as a result of examining the relationship between GMV in the left OFC and psychiatric symptoms in CM, we observed a negative association with insecure attachment style and also confirmed the mediation effect of left-OFC GMV reduction on the relationship between OXTR methylation and insecure attachment style. These results suggest that any modulation of the oxytocin signaling pathway induced by OXTR hypermethylation at CpG 5,6 leads to atypical development of the left OFC, resulting in distorted attachment formation in children with CM.
Subscribe to Journal
Get full journal access for 1 year
only $43.69 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
World Health Organization. Global status report on violence prevention 2014. Geneva: World Health Organization; 2014.
Edwards VJ, Holden GW, Felitti VJ, Anda RF. Relationship between multiple forms of childhood maltreatment and adult mental health in community respondents: results from the adverse childhood experiences study. Am J Psychiatry. 2013;160:1453–60.
Crittenden PM, Ainsworth MDS. Child maltreatment and attachment theory. In: Cicchetti D, Carlson V, editors. Child maltreatment: Theory and research on the causes and consequences of child abuse and neglect. New York: Cambridge University Press; 1989. p 432–63. .
Messman-Moore TL, Coates AA. The impact of childhood psychological abuse on adult interpersonal conflict: the role of early maladaptive schemas and patterns of interpersonal behavior. J Emot Abus. 2007;7:75–92.
Fergusson DM, McLeod GF, John Horwood L. Parental separation/divorce in childhood and partnership outcomes at age 30. J Child Psychol Psychiatry. 2014;55:352–60.
Lamoureux BE, Palmieri PA, Jackson AP, Hobfoll SE. Child sexual abuse and adulthood-interpersonal outcomes: examining pathways for intervention. Psychol. Trauma . 2012;4:605–13.
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.
Dannlowski U, Stuhrmann A, Beutelmann V, Zwanzger P, Lenzen T, Grotegerd D, et al. Limbic scars: long-term consequences of childhood maltreatment revealed by functional and structural magnetic resonance imaging. Biol Psychiatry. 2012;71:286–93.
Kitayama N, Vaccarino V, Kutner M, Weiss P, Bremner JD. Magnetic resonance imaging (MRI) measurement of hippocampal volume in posttraumatic stress disorder: a meta-analysis. J Affect Disord. 2005;88:79–86.
Choi J, Jeong B, Rohan ML, Polcari AM, Teicher MH. Preliminary evidence for white matter tract abnormalities in young adults exposed to parental verbal abuse. Biol Psychiatry. 2009;65:227–34.
Raine A, Park S, Lencz T, Bihrle S, LaCasse L, Widom CS, et al. Reduced right hemisphere activation in severely abused violent offenders during a working memory task: an fMRI study. Aggress Behav. 2001;27:111–29.
Dillon DG, Holmes AJ, Birk JL, Brooks N, Lyons-Ruth K, Pizzagalli DA. Childhood adversity is associated with left basal ganglia dysfunction during reward anticipation in adulthood. Biol Psychiatry. 2009;66:206–13.
Bolhuis JJ, Honey RC. Imprinting, learning and development: from behavior to brain and back. Trends Neurosci. 1998;21:306–11.
Weaver IC, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR, et al. Epigenetic programming by maternal behavior. Nat Neurosci. 2004;7:847–54.
Fortuin J, van Geel M, Vedder P. Peer influences on internalizing and externalizing problems among adolescents: a longitudinal social network analysis. J Youth Adolesc. 2015;44:887–97.
Hart H, Rubia K. Neuroimaging of child abuse: a critical review. Front Hum Neurosci. 2012;6:52.
Bick J, Nelson CA. Early adverse experiences and the developing brain. Neuropsychopharmacology . 2016;41:177–96.
McCrory E, De Brito SA, Viding E. The impact of childhood maltreatment: a review of neurobiological and genetic factors. Front Psychiatry. 2011;2:1–14.
Carrion VG, Weems CF, Watson C, Eliez S, Menon V, Reiss AL. Converging evidence for abnormalities of the prefrontal cortex and evaluation of midsagittal structures in pediatric posttraumatic stress disorder: An MRI study. Psychiatry Res. 2009;172:226–34.
De Brito SA, Viding E, Sebastian CL, Kelly PA, Mechelli A, Maris H, et al. Reduced orbitofrontal and temporal grey matter in a community sample of maltreated children. J Child Psychol Psychiatry. 2013;54:105–12.
McGowan PO, Sasaki A, D’Alessio AC, Dymov S, Labonté B, Szyf M, et al. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci. 2009;12:342–8.
Zannas AS, Provençal N, Binder EB. Epigenetics of posttraumatic stress disorder: current evidence, challenges, and future directions. Biol Psychiatry. 2015;78:327–35.
Simons RL, Lei MK, Beach SRH, Cutrona CE, Philibert RA. Methylation of the oxytocin receptor gene mediates the effect of adversity on negative schemas and depression. Dev Psychopathol. 2017;29:725–36.
Gouin JP, Zhou QQ, Booij L, Boivin M, Côté SM, Hébert M, et al. Associations among oxytocin receptor gene (OXTR) DNA methylation in adulthood, exposure to early life adversity, and childhood trajectories of anxiousness. Sci Rep. 2017;7:7446.
Smearman EL, Almli LM, Conneely KN, Brody GH, Sales JM, Bradley B, et al. Oxytocin receptor genetic and epigenetic variations: association with child abuse and adult psychiatric symptoms. Child Dev. 2016;87:122–34.
Donaldson ZR, Young LJ. Oxytocin, vasopressin, and the neurogenetics of sociality. Science . 2008;322:900–4.
Feldman R, Gordon I, Zagoory-Sharon O. Maternal and paternal plasma, salivary, and urinary oxytocin and parent-infant synchrony: considering stress and affiliation components of human bonding. Dev Sci. 2011;14:752–61.
Wismer Fries AB, Ziegler TE, Kurian JR, Jacoris S, Pollak SD. Early experience in humans is associated with changes in neuropeptides critical for regulating social behavior. Proc Natl Acad Sci USA. 2005;102:17237–40.
Pierrehumbert B, Torrisi R, Laufer D, Halfon O, Ansermet F, Beck Popovic M. Oxytocin response to an experimental psychosocial challenge in adults exposed to traumatic experiences during childhood or adolescence. Neuroscience. 2010;166:168–77.
Sheehan DV, Sheehan KH, Shytle RD, Janavs J, Bannon Y, Rogers JE, et al. Reliability and validity of the Mini International neuropsychiatric interview for children and adolescents (MINI-KID). J Clin Psychiatry. 2010;71:313–26.
Wechsler D. Wechsler Intelligence Scale for Children. 4th ed. San Antonio, TX: Psychological Corporation; 2003.
Wechsler D. Wechsler Adult Intelligence Scale, 3rd ed. San Antonio, TX: Psychological Corporation; 1997.
Sanders B, Becker-Lausen E. The measurement of psychological maltreatment: early data on the Child Abuse and Trauma Scale. Child Abus Negl. 1995;19:315–23.
Birleson P. The validity of depressive disorder in childhood and the development of a self-rating scale: a research report. J Child Psychol Psychiatry. 1981;22:73–88.
Achenbach TM. Manual for the child behavior checklist/4–18 and 1991 profile. Burlington, VT: Department of Psychiatry, University of Vermont; 1991.
Hazan C, Shaver P. Romantic love conceptualized as an attachment process. J Pers Soc Psychol. 1987;52:511–24.
Collins NL, Read SJ. Adult attachment, working models, and relationship quality in dating couples. J Pers Soc Psychol. 1990;58:644–63.
Takuma T, Toda K. Interpersonal attitude in adolescence from the viewpoint of attachment theory. J Soc Sci Humanit (Jimbun gakuho). 1988;196:1–16.
Kasuya K, Kawamura S. Development of an internal working model for junior high school students: examination of reliability and validity. Jpn J Couns Sci. 2005;38:141–8.
Kusui C, Kimura T, Ogita K, Nakamura H, Matsumura Y, Koyama M, et al. DNA methylation of the human oxytocin receptor gene promoter regulates tissue-specific gene suppression. Biochem Biophys Res Commun. 2001;289:681–86.
Nishitani S, Parets SE, Haas BW, Smith AK. DNA methylation analysis from saliva samples for epidemiological studies. Epigenetics . 2018;13:352–62.
BLUEPRINT consortium. Quantitative comparison of DNA methylation assays for biomarker development and clinical applications. Nat Biotechnol. 2016;34:726–37.
Coolen MW, Statham AL, Gardiner-Garden M, Clark SJ. Genomic profiling of CpG methylation and allelic specificity using quantitative high-throughput mass spectrometry: critical evaluation and improvements. Nucleic Acids Res. 2007;35:e119.
Koolschijn PC, van Haren NE, Lensvelt-Mulders GJ, Hulshoff Pol HE, Kahn RS. Brain volume abnormalities in major depressive disorder: a meta-analysis of magnetic resonance imaging studies. Hum Brain Mapp. 2009;30:3719–35.
Takiguchi S, Fujisawa TX, Mizushima S, Saito DN, Shimada K, Okamoto Y, et al. The neural effects of intranasal oxytocin administration in reactive attachment disorder. No To Hattatsu. 2016;48:S234.
Boccia ML, Petrusz P, Suzuki K, Marson L, Pedersen CA. Immunohistochemical localization of oxytocin receptors in human brain. Neuroscience. 2013;253:155–64.
Maldjian JA, Laurienti PJ, Kraft RA, Burdette JH. An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. Neuroimage . 2003;19:1233–9.
Rubin LH, Connelly JJ, Reilly JL, Carter CS, Drogos LL, Pournajafi-Nazarloo H, et al. Sex and diagnosis specific associations between DNA methylation of the oxytocin receptor gene with emotion processing and temporal-limbic and prefrontal brain volumes in psychotic disorders. Biol Psychiatry Cogn Neurosci Neuroimaging. 2016;1:141–51.
Haas BW, Filkowski MM, Cochran RN, Denison L, Ishak A, Nishitani S, et al. Epigenetic modification of OXT and human sociability. Proc Natl Acad Sci USA. 2016;113:E3816–23.
Unternaehrer E, Meyer AH, Burkhardt SC, Dempster E, Staehli S, Theill N, et al. Childhood maternal care is associated with DNA methylation of the genes for brain-derived neurotrophic factor (BDNF) and oxytocin receptor (OXTR) in peripheral blood cells in adult men and women. Stress . 2015;18:451–61.
Needham BL, Smith JA, Zhao W, Wang X, Mukherjee B, Kardia SL, et al. Life course socioeconomic status and DNA methylation in genes related to stress reactivity and inflammation: the multi-ethnic study of atherosclerosis. Epigenetics. 2015;10:958–69.
Puglia MH, Lillard TS, Morris JP, Connelly JJ. Epigenetic modification of the oxytocin receptor gene influences the perception of anger and fear in the human brain. Proc Natl Acad Sci USA. 2015;112:3308–13.
Perkeybile AM, Carter CS, Wroblewski KL, Puglia MH, Kenkel WM, Lillard TS, et al. Early nurture epigenetically tunes the oxytocin receptor. Psychoneuroendocrinology. 2019;99:128–36.
Gregory SG, Connelly JJ, Towers AJ, Johnson J, Biscocho D, Markunas CA, et al. Genomic and epigenetic evidence for oxytocin receptor deficiency in autism. BMC Med. 2009;7:62.
Yoshida M, Takayanagi Y, Inoue K, Kimura T, Young LJ, Onaka T, et al. Evidence that oxytocin exerts anxiolytic effects via oxytocin receptor expressed in serotonergic neurons in mice. J Neurosci. 2009;29:2259–71.
Bethlehem RAI, Lombardo MV, Lai MC, Auyeung B, Crockford SK, Deakin J, et al. Intranasal oxytocin enhances intrinsic corticostriatal functional connectivity in women. Transl Psychiatry. 2017;7:e1099.
Vrtička P, Vuilleumier P. Neuroscience of human social interactions and adult attachment style. Front Hum Neurosci. 2012;6:212.
Rilling JK, Young LJ. The biology of mammalian parenting and its effect on offspring social development. Science . 2014;345:771–6.
Skuse DH, Gallagher L. Dopaminergic-neuropeptide interactions in the social brain. Trends Cogn Sci. 2009;13:27–35.
Quintana DS, Rokicki J, van der Meer D, Alnæs D, Kaufmann T, Córdova-Palomera A. Oxytocin pathway gene networks in the human brain. Nat Commun. 2019;10:668.
Xiao L, Priest MF, Nasenbeny J, Lu T, Kozorovitskiy Y. Biased oxytocinergic modulation of midbrain dopamine systems. Neuron. 2017;95:368–84.
Feldman R. The Neurobiology of Human Attachments. Trends Cogn Sci. 2017;21:80–99.
Gillath O, Bunge SA, Shaver PR, Wendelken C, Mikulincer M. Attachment style differences in the ability to suppress negative thoughts: exploring the neural correlates. Neuroimage . 2005;28:835–47.
Vrtička P, Sander D, Anderson B, Badoud D, Eliez S, Debbané M. Social feedback processing from early to late adolescence: influence of sex, age, and attachment style. Brain Behav. 2014;4:703–20.
Friston KJ, Rotshtein P, Geng JJ, Sterzer P, Henson RN. A critique of functional localisers. Neuroimage. 2006;30:1077–87.
Smith AK, Kilaru V, Klengel T, Mercer KB, Bradley B, Conneely KN, et al. DNA extracted from saliva for methylation studies of psychiatric traits: evidence tissue specificity and relatedness to brain. Am J Med Genet B Neuropsychiatr Genet. 2015;168B:36–44.
Braun PR, Han S, Hing B, Nagahama Y, Gaul LN, Heinzman JT, et al. Genome-wide DNA methylation comparison between live human brain and peripheral tissues within individuals. Transl Psychiatry. 2019;9:47.
Theda C, Hwang SH, Czajko A, Loke YJ, Leong P, Craig JM. Quantitation of the cellular content of saliva and buccal swab samples. Sci Rep. 2018;8:6944.
Smyke AT, et al. A randomized controlled trial comparing foster care and institutional care for children with signs of reactive attachment disorder. Am J Psychiatry. 2012;169:508–14.
De Bellis MD, Woolley DP, Hooper SR. Neuropsychological findings in pediatric maltreatment: relationship of PTSD, dissociative symptoms, and abuse/neglect indices to neurocognitive outcomes. Child Maltreat. 2013;18:171–83.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Fujisawa, T.X., Nishitani, S., Takiguchi, S. et al. Oxytocin receptor DNA methylation and alterations of brain volumes in maltreated children. Neuropsychopharmacol. 44, 2045–2053 (2019). https://doi.org/10.1038/s41386-019-0414-8
Epigenetic modification of the oxytocin receptor gene: implications for autism symptom severity and brain functional connectivity
Frontiers in Psychiatry (2019)