Skip to main content Accessibility help

Variation in DNA methylation of the oxytocin receptor gene predicts children's resilience to prenatal stress

  • Izabela Milaniak (a1), Charlotte A. M. Cecil (a2), Edward D. Barker (a2), Caroline L. Relton (a3), Tom R. Gaunt (a3), Wendy McArdle (a3) and Sara R. Jaffee (a1)...


Emerging research in epigenetics has shown that there is variability in how environmental exposures “get under the skin” through mechanisms like DNA methylation to influence gene expression that may lead to differential adaptations to stress. This is the first study to examine prospectively the relationship between DNA methylation at birth and resilience to prenatal environmental stressors in several domains (conduct, hyperactivity, emotional problems, and global symptomatology) in middle childhood. We focused on DNA methylation in the vicinity of the oxytocin receptor (OXTR) gene as it has been previously associated with impairments in social–cognitive processes that may underlie a wide range of childhood psychopathology. Participants were 91 youth exposed to pre- and postnatal adversity with established conduct problem trajectories drawn from the Avon Longitudinal Study of Parents and Children. Consistent with our hypothesis, OXTR DNA methylation was predictive of resilience in the conduct problems domain in middle childhood. DNA methylation profiles did not predict resilience in domains of emotional, hyperactivity, and global symptomatology, suggesting a potential role for OXTR in the development of conduct problems in particular. However, individuals who were resilient to conduct problems were also broadly resilient across multiple domains. Therefore, future research should elucidate the biological pathways between OXTR DNA methylation and gene expression and its relation to impairments in social behavior.


Corresponding author

Address correspondence and reprint requests to: Sara Jaffee, Department of Psychology, University of Pennsylvania, 425 South University Avenue, Philadelphia, PA 19104; E-mail:


Hide All

We are extremely grateful to all the families who took part in this study, the midwives for their help in recruiting them, and the whole Avon Longitudinal Study of Parents and Children (ALSPAC) team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. With regard to the ALSPAC DNA methylation, we thank all involved, particularly the laboratory scientists and bioinformaticians who contributed considerable time and expertise to the data in this paper. The UK Medical Research Council and the Wellcome Trust (Grant 102215/2/13/2) and the University of Bristol provide core support for the ALSPAC. This publication is the work of the authors, who will serve as guarantors for the contents of this paper. This research was specifically supported by National Institute of Child and Human Development Grant R01HD068437 (to E.D.B.). ARIES was funded by the BBSRC (Grants BBI025751/1 and BB/I025263/1). Funding was provided by the Medical Research Council Integrative Epidemiology Unit at the University of Bristol Grants MC_UU_12013/2 and MC_UU_12013/8 (to C.L.R. and T.R.G). Finally, support was provided by the Economic and Social Research Council Grant ES/N001273/1 (to C.A.M.C.).



Hide All
Bakulski, K. M., Halladay, A., Hu, V. W., Mill, J., & Fallin, M. D. (2016). Epigenetic research in neuropsychiatric disorders: The “Tissue Issue.” Current Behavioral Neuroscience Reports, 3, 264274. doi:10.1007/s40473-016-0083-4
Barker, E. D., Jaffee, S. R., Uher, R., & Maughan, B. (2011). The contribution of prenatal and postnatal maternal anxiety and depression to child maladjustment. Depression and Anxiety, 28, 696702. doi:10.1002/da.20856
Barker, E. D., & Maughan, B. (2009). Differentiating early-onset persistent versus childhood-limited conduct problem youth. American Journal of Psychiatry, 166, 900908. doi:10.1176/appi.ajp.2009.08121770
Barker, E. D., Oliver, B. R., & Maughan, B. (2010). Co-occurring problems of early onset persistent, childhood limited, and adolescent onset conduct problem youth. Journal of Child Psychology and Psychiatry, 51, 12171226.
Bergman, K., Sarkar, P., Glover, V., & O'Connor, T. G. (2008). Quality of child–parent attachment moderates the impact of antenatal stress on child fearfulness. Journal of Child Psychology and Psychiatry, 49, 10891098. doi:10.1111/j.1469-7610.2008.01987.x
Bergman, K., Sarkar, P., Glover, V., & O'Connor, T. G. (2010). Maternal prenatal cortisol and infant cognitive development: Moderation by infant–mother attachment. Biological Psychiatry, 67, 10261032. doi:10.1016/j.biopsych.2010.01.002
Bick, J., Naumova, O., Hunter, S., Barbot, B., Lee, M., Luthar, S. S., … Grigorenko, E. L. (2012). Childhood adversity and DNA methylation of genes involved in the hypothalamus–pituitary–adrenal axis and immune system: Whole-genome and candidate-gene associations. Development and Psychopathology, 24, 14171425. doi:10.1017/S0954579412000806.
Billack, B., Serio, R., Silva, I., & Kinsley, C. H. (2012). Epigenetic changes brought about by perinatal stressors: A brief review of the literature. Journal of Pharmacological and Toxicological Methods, 66, 221231. doi:10.1016/j.vascn.2012.08.169
Boyd, A., Golding, J., Macleod, J., Lawlor, D. A., Fraser, A., Henderson, J., … Davey Smith, G. (2013). Cohort profile: The ‘children of the 90s’—The index offspring of the Avon Longitudinal Study of Parents and Children. International Journal of Epidemiology, 42, 111127. doi:10.1093/ije/dys064
Braithwaite, E. C., Murphy, S. E., & Ramchandani, P. G. (2014). Prenatal risk factors for depression: A critical review of the evidence and potential mechanisms. Journal of Developmental Origins of Health and Disease, 5, 339350. doi:10.1017/S2040174414000324
Byun, H. M., Siegmund, K. D., Pan, F., Weisenberger, D. J., Kanel, G., Laird, P. W., & Yang, A. S. (2009). Epigenetic profiling of somatic tissues from human autopsy specimens identifies tissue- and individual-specific DNA methylation patterns. Human Molecular Genetics, 18, 48084817. doi:10.1093/hmg/ddp445
Cecil, C. A., Lysenko, L. J., Jaffee, S. R., Pingault, J. B., Smith, R. G., Relton, C. L., … Barker, E. D. (2014). Environmental risk, oxytocin receptor gene (OXTR) methylation and youth callous-unemotional traits: A 13-year longitudinal study. Molecular Psychiatry, 19, 10711077. doi:10.1038/mp.2014.95
Chen, Y., Lemire, M., Choufani, S., Butcher, D. T., Grafodatskaya, D., Zanke, B. W., … Weksberg, R. (2013). Discovery of cross-reactive probes and polymorphic CpGs in the Illumina Infinium HumanMethylation450 microarray. Epigenetics, 8, 203209. doi:10.4161/epi.23470
Conradt, E., Lester, B. M., Appleton, A. A., Armstrong, D. A., & Marsit, C. J. (2013). The roles of DNA methylation of NR3C1 and 11β-HSD2 and exposure to maternal mood disorder in utero on newborn neurobehavior. Epigenetics, 8, 13211329. doi:10.4161/epi.26634
Dadds, M. R., Moul, C., Cauchi, A., Dobson-Stone, C., Hawes, D. J., Brennan, J., & Ebstein, R. E. (2014). Methylation of the oxytocin receptor gene and oxytocin blood levels in the development of psychopathy. Development and Psychopathology, 26, 3340. doi:10.1017/S0954579413000497
Davies, M. N., Volta, M., Pidsley, R., Lunnon, K., Dixit, A., Lovestone, S., … Mill, J. (2012). Functional annotation of the human brain methylome identifies tissue-specific epigenetic variation across brain and blood. Genome Biology, 13, R43. doi:10.1186/gb-2012-13-6-r43
Eckhardt, F., Lewin, J., Cortese, R., Rakyan, V. K., Attwood, J., Burger, M., … Beck, S. (2006). DNA methylation profiling of human chromosomes 6, 20 and 22. Nature Genetics, 38, 13781385. doi:10.1038/ng1909
Fraser, A., Macdonald-Wallis, C., Tilling, K., Boyd, A., Golding, J., Smith, G. D., … Lawlor, D. A. (2013). Cohort profile: The Avon Longitudinal Study of Parents and Children: ALSPAC mothers cohort. International Journal of Epidemiology, 42, 97110. doi:10.1093/ije/dys066
Gaunt, T. R., Shihab, H. A., Hemani, G., Min, J. L., Woodward, G., Lyttleton, O., … Relton, C. L. (2016). Systematic identification of genetic influences on methylation across the human life course. Genome Biology, 17, 61. doi:10.1186/s13059-016-0926-z
Gluckman, P. D., Hanson, M. A., Cooper, C., & Thornburg, K. L. (2008). Effect of in utero and early-life conditions on adult health and disease. New England Journal of Medicine, 359, 6173. doi:10.1056/NEJMra0708473
Goodman, R. (1997). The Strengths and Difficulties Questionnaire: A research note. Journal of Child Psychology and Psychiatry, 38, 581586. doi:10.1111/j.1469-7610.1997.tb01545.x
Goodman, R. (2001). Psychometric properties of the Strengths and Difficulties Questionnaire. Journal of the American Academy of Child & Adolescent Psychiatry, 40, 13371345. doi:10.1097/00004583-200111000-00015
Gregory, S. G., Connelly, J. J., Towers, A. J., Johnson, J., Biscocho, D., Markunas, C. A., … Pericak-Vance, M. A. (2009). Genomic and epigenetic evidence for oxytocin receptor deficiency in autism. BMC Medicine, 7, 62. doi:10.1186/1741-7015-7-62
Heinrichs, M., von Dawans, B., & Domes, G. (2009). Oxytocin, vasopressin, and human social behavior. Frontiers in Neuroendocrinology, 30, 548557. doi:10.1016/j.yfrne.2009.05.005
Hompes, T., Izzi, B., Gellens, E., Morreels, M., Fieuws, S., Pexsters, A., … Claes, S. (2013). Investigating the influence of maternal cortisol and emotional state during pregnancy on the DNA methylation status of the glucocorticoid receptor gene (NR3C1) promoter region in cord blood. Journal of Psychiatric Research, 47, 880891. doi:10.1016/j.jpsychires.2013.03.009
Houseman, E. A., Accomando, W. P., Koestler, D. C., Christensen, B. C., Marsit, C. J., Nelson, H. H., … Kelsey, K. T. (2012). DNA methylation arrays as surrogate measures of cell mixture distribution. BMC Bioinformatics, 13, 86. doi:10.1186/1471-2105-13-86
Jack, A., Connelly, J. J., & Morris, J. P. (2012). DNA methylation of the oxytocin receptor gene predicts neural response to ambiguous social stimuli. Frontiers in Human Neuroscience, 6, 17. doi:10.3389/fnhum.2012.00280
Jaffee, S. R., Caspi, A., Moffitt, T. E., Polo-Tomás, M., & Taylor, A. (2007). Individual, family, and neighborhood factors distinguish resilient from non-resilient maltreated children: A cumulative stressors model. Child Abuse and Neglect, 31, 231253. doi:10.1016/j.chiabu.2006.03.011
Jaffee, S. R., & Gallop, R. (2007). Social, emotional, and academic competence among children who have had contact with Child Protective Services: Prevalence and stability estimates. Journal of the American Academy of Child & Adolescent Psychiatry, 46, 757765. doi:10.1097/chi.0b013e318040b247
Johnson, W. E., Li, C., & Rabinovic, A. (2007). Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics, 8, 118127. doi:10.1093/biostatistics/kxj037
Jones, M. J., Fejes, A. P., & Kobor, M. S. (2013). DNA methylation, genotype and gene expression: Who is driving and who is along for the ride? Genome Biology, 14, 126. doi:10.1186/gb-2013-14-7-126
Jones, P. A. (2012). Functions of DNA methylation: Islands, start sites, gene bodies and beyond. Nature Reviews Genetics, 13, 484492. doi:10.1038/nrg3230
Kim-Cohen, J., Moffitt, T. E., Caspi, A., & Taylor, A. (2004). Genetic and environmental processes in young children's resilience and vulnerability to socioeconomic deprivation. Child Development, 75, 651668. doi:10.1111/j.1467-8624.2004.00699.x
Klengel, T., Mehta, D., Anacker, C., Rex-Haffner, M., Pruessner, J. C., Pariante, C. M., … Binder, E. B. (2013). Allele-specific FKBP5 DNA demethylation mediates gene–childhood trauma interactions. Nature Neuroscience, 16, 3341. doi:10.1038/nn.3275
Kumsta, R., Hummel, E., Chen, F. S., & Heinrichs, M. (2013). Epigenetic regulation of the oxytocin receptor gene: Implications for behavioral neuroscience. Frontiers in Neuroscience, 7, 16. doi:10.3389/fnins.2013.00083
Kusui, C., Kimura, T., Ogita, K., Nakamura, H., Matsumura, Y., Koyama, M., … Murata, Y. (2001). DNA methylation of the human oxytocin receptor gene promoter regulates tissue-specific gene suppression. Biochemical and Biophysical Research Communications, 289, 681686. doi:10.1006/bbrc.2001.6024
Lam, L. L., Emberly, E., Fraser, H. B., Neumann, S. M., Chen, E., Miller, G. E., & Kobor, M. S. (2012). Factors underlying variable DNA methylation in a human community cohort. Proceedings of the National Academy of Sciences, 109, 1725317260. doi:10.1073/pnas.1121249109
Laucht, M., Esser, G., Baving, L., Gerhold, M., Hoesch, I., Ihle, W., … Schmidt, M. H. (2000). Behavioral sequelae of perinatal insults and early family adversity at 8 years of age. Journal of the American Academy of Child & Adolescent Psychiatry, 39, 12291237. doi:10.1097/00004583-200010000-00009
Luthar, S. S., Cicchetti, D., & Becker, B. (2000). The construct of resilience: A critical evaluation and guidelines for future work. Child Development, 71, 543562.
Luthar, S. S., Crossman, E. J., & Small, P. J. (2015). Resilience and adversity. In Lerner, R. M. & Lamb, M. E. (Eds.), Handbook of child psychology and developmental science (7th ed., Vol. 3, pp. 247286). Hoboken, NJ: Wiley.
Mamrut, S., Harony, H., Sood, R., Shahar-Gold, H., Gainer, H., Shi, Y. J., … Wagner, S. (2013). DNA methylation of specific CpG sites in the promoter region regulates the transcription of the mouse oxytocin receptor. PLOS ONE, 8, e56869. doi:10.1371/journal.pone.0056869
Martinez-Torteya, C., Anne Bogat, G., Von Eye, A., & Levendosky, A. A. (2009). Resilience among children exposed to domestic violence: The role of risk and protective factors. Child Development, 80, 562577. doi:10.1111/j.1467-8624.2009.01279.x
Masliah, E., Dumaop, W., Galasko, D., & Desplats, P. (2013). Distinctive patterns of DNA methylation associated with Parkinson disease. Epigenetics, 8, 10301038. doi:10.4161/epi.25865
Masten, A. (2013). Risk and resilience in development. In Zelazo, P. D. (Ed.), The Oxford handbook of developmental psychology: Vol. 2. Self and other (p. 579). Oxford: Oxford University Press. doi:10.1093/oxfordhb/9780199958474.013.0023
McGowan, P. O., & Roth, T. L. (2015). Epigenetic pathways through which experiences become linked with biology. Development and Psychopathology, 27, 637648. doi:10.1017/S0954579415000206
Moran, P., Ford, T., Butler, G., & Goodman, R. (2008). Callous and unemotional traits in children and adolescents living in Great Britain. British Journal of Psychiatry, 192, 6566. doi:10.1192/bjp.bp.106.034876
Mulligan, C., D'Errico, N., Stees, J., & Hughes, D. (2012). Methylation changes at NR3C1 in newborns associate with maternal prenatal stress exposure and newborn birth weight. Epigenetics, 7, 853857. doi:10.4161/epi.21180
Oberlander, T. F., Papsdorf, M., Brain, U. M., Misri, S., Ross, C., & Grunau, R. E. (2010). Prenatal effects of selective serotonin reuptake inhibitor antidepressants, serotonin transporter promoter genotype (SLC6A4), and maternal mood on child behavior at 3 years of age. Archives of Pediatrics and Adolescent Medicine, 164, 444451. doi:10.1001/archpediatrics.2010.51
O'Connor, T. G., Heron, J., Golding, J., Beveridge, M., & Glover, V. (2002). Maternal antenatal anxiety and children's behavioural/emotional problems at 4 years. British Journal of Psychiatry, 180, 502508. doi:10.1192/bjp.180.6.502
O'Donnell, K. J., Glover, V., Barker, E. D., & O'Connor, T. G. (2014). The persisting effect of maternal mood in pregnancy on childhood psychopathology. Development and Psychopathology, 26, 393403. doi:10.1017/S0954579414000029
Oland, A. A., & Shaw, D. S. (2005). Pure versus co-occurring externalizing and internalizing symptoms in children: The potential role of socio-developmental milestones. Clinical Child and Family Psychology Review, 8, 247270. doi:10.1007/s10567-005-8808-z
Patterson, G. R., DeBaryshe, B. D., & Ramsey, E. (1989). A developmental perspective on antisocial behavior. American Psychologist, 44, 329335.
Pawlby, S., Hay, D. F., Sharp, D., Waters, C. S., & O'Keane, V. (2009). Antenatal depression predicts depression in adolescent offspring: Prospective longitudinal community-based study. Journal of Affective Disorders, 113, 236243. doi:10.1016/j.jad.2008.05.018
Perroud, N., Rutembesa, E., Paoloni-Giacobino, A., Mutabaruka, J., Mutesa, L., Stenz, L., … Karege, F. (2014). The Tutsi genocide and transgenerational transmission of maternal stress: Epigenetics and biology of the HPA axis. World Journal of Biological Psychiatry, 15, 334345. doi:10.3109/15622975.2013.866693
Pluess, M., Velders, F. P., Belsky, J., van IJzendoorn, M. H., Bakermans-Kranenburg, M. J., Jaddoe, V. W. V., … Tiemeier, H. (2011). Serotonin transporter polymorphism moderates effects of prenatal maternal anxiety on infant negative emotionality. Biological Psychiatry, 69, 520525. doi:10.1016/j.biopsych.2010.10.006
Radtke, K. M., Ruf, M., Gunter, H. M., Dohrmann, K., Schauer, M., Meyer, A., & Elbert, T. (2011). Transgenerational impact of intimate partner violence on methylation in the promoter of the glucocorticoid receptor. Translational Psychiatry, 1, e21. doi:10.1038/tp.2011.21
Reiner, I., van IJzendoorn, M. H., Bakermans-Kranenburg, M. J., 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. Journal of Psychiatric Research, 65, 915. doi:10.1016/j.jpsychires.2015.03.012
Relton, C. L., Gaunt, T., McArdle, W., Ho, K., Duggirala, A., Shihab, H., … Smith, G. D. (2015). Data resource profile: Accessible Resource for Integrated Epigenomic Studies (ARIES). International Journal of Epidemiology. Advance online publication. doi:10.1093/ije/dyv072
Rice, F., Jones, I., & Thapar, A. (2007). The impact of gestational stress and prenatal growth on emotional problems in offspring: A review. Acta Psychiatrica Scandinavica, 115, 171183. doi:10.1111/j.1600-0447.2006.00895.x
Robinson, M., Mattes, E., Oddy, W. H., Pennell, C. E., van Eekelen, A., McLean, N. J., … Newnham, J. P. (2011). Prenatal stress and risk of behavioral morbidity from age 2 to 14 years: The influence of the number, type, and timing of stressful life events. Development and Psychopathology, 23, 507520. doi:10.1017/S0954579411000241
Ronald, A., Pennell, C. E., & Whitehouse, A. J. O. (2011). Prenatal maternal stress associated with ADHD and autistic traits in early childhood. Developmental Psychology, 1, 223. doi:10.3389/fpsyg.2010.00223
Rutter, M. (2006). Implications of resilience concepts for scientific understanding. Annals of the New York Academy of Sciences, 1094, 112. doi:10.1196/annals.1376.002
Rutter, M. (2012). Resilience as a dynamic concept. Development and Psychopathology, 24, 335344. doi:10.1017/S0954579412000028
Skuse, D. H., Mandy, W. P. L., & Scourfield, J. (2005). Measuring autistic traits: Heritability, reliability and validity of the Social and Communication Disorders Checklist. British Journal of Psychiatry, 187, 568572. doi:10.1192/bjp.187.6.568
Unternaehrer, E., Meyer, A. H., Burkhardt, S. C. A., Dempster, E., Staehli, S., Theill, N., … Meinlschmidt, G. (2015). 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, 18, 451461. doi:10.3109/10253890.2015.1038992
Van den Bergh, B. R. H., & Marcoen, A. (2004). High antenatal maternal anxiety is related to ADHD symptoms, externalizing problems, and anxiety in 8- and 9-year-olds. Child Development, 75, 10851097. doi:10.1111/j.1467-8624.2004.00727.x
Van der Knaap, L. J., Riese, H., Hudziak, J. J., Verbiest, M. M. P. J., Verhulst, F. C., Oldehinkel, A. J., & van Oort, F. V. A. (2015). Adverse life events and allele-specific methylation of the serotonin transporter gene (SLC6A4) in adolescents: The TRAILS study. Psychosomatic Medicine, 77, 246255. doi:10.1097/psy.0000000000000159
Velders, F. P., Dieleman, G., Cents, R. A., Bakermans-Kranenburg, M. J., Jaddoe, V. W., Hofman, A., … Tiemeier, H. (2012). Variation in the glucocorticoid receptor gene at rs41423247 moderates the effect of prenatal maternal psychological symptoms on child cortisol reactivity and behavior. Neuropsychopharmacology, 37, 25412549. doi:10.1038/npp.2012.118
Walton, E., Hass, J., Liu, J., Roffman, J. L., Bernardoni, F., Roessner, V., … Ehrlich, S. (2016). Correspondence of DNA methylation between blood and brain tissue and its application to schizophrenia research. Schizophrenia Bulletin, 42, 406414. doi:10.1093/schbul/sbv074
Ziegler, C., Dannlowski, U., Bräuer, D., Stevens, S., Laeger, I., Wittmann, H., … Domschke, K. (2015). Oxytocin receptor gene methylation: Converging multilevel evidence for a role in social anxiety. Neuropsychopharmacology, 40, 15281538. doi:10.1038/npp.2015.2


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