Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Environmental risk, Oxytocin Receptor Gene (OXTR) methylation and youth callous-unemotional traits: a 13-year longitudinal study

Abstract

Youth with high callous-unemotional traits (CU) are at risk for early-onset and persistent conduct problems. Research suggests that there may be different developmental pathways to CU (genetic/constitutional vs environmental), and that the absence or presence of co-occurring internalizing problems is a key marker. However, it is unclear whether such a distinction is valid. Intermediate phenotypes such as DNA methylation, an epigenetic modification regulating gene expression, may help to clarify etiological pathways. This is the first study to examine prospective inter-relationships between environmental risk (prenatal/postnatal) and DNA methylation (birth, age 7 and 9) in the prediction of CU (age 13), for youth low vs high in internalizing problems. We focused on DNA methylation in the vicinity of the oxytocin receptor (OXTR) gene as it has been previously implicated in CU. Participants were 84 youth with early-onset and persistent conduct problems drawn from the Avon Longitudinal Study of Parents and Children. For youth with low internalizing problems (46%), we found that (i) OXTR methylation at birth associated with higher CU (age 13) as well as decreased experience of victimization during childhood (evocative epigenetic-environment correlation; birth–age 7), (ii) higher prenatal parental risks (maternal psychopathology, criminal behaviors, substance use) associated with higher OXTR methylation at birth and (iii) OXTR methylation levels were more stable across time (birth–age 9). In contrast, for youth with high internalizing problems, CU were associated with prenatal risks of an interpersonal nature (that is, intimate partner violence, family conflict) but not OXTR methylation. Findings support the existence of distinct developmental pathways to CU.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

References

  1. Dandreaux DM, Frick PJ . Developmental pathways to conduct problems: a further test of the childhood and adolescent-onset distinction. J Abnorm Child Psychol 2009; 37: 375–385.

    Article  Google Scholar 

  2. Rowe R, Maughan B, Moran P, Ford T, Briskman J, Goodman R . The role of callous and unemotional traits in the diagnosis of conduct disorder. J Child Psychol Psychiatry 2010; 51: 688–695.

    Article  Google Scholar 

  3. Frick PJ, Viding E . Antisocial behavior from a developmental psychopathology perspective. Dev Psychopathol 2009; 21(Special issue 04): 1111–1131.

    Article  Google Scholar 

  4. Kahn RE, Frick PJ, Youngstrom EA, Kogos Youngstrom J, Feeny NC, Findling RL . Distinguishing primary and secondary variants of callous-unemotional traits among adolescents in a clinic-referred sample. Psychol Assess 2013; 25: 966–978.

    Article  Google Scholar 

  5. Kimonis ER, Frick PJ, Cauffman E, Goldweber A, Skeem J . Primary and secondary variants of juvenile psychopathy differ in emotional processing. Dev Psychopathol. 2012; 24: 1091–1103.

    Article  Google Scholar 

  6. Tatar JR, Cauffman E, Kimonis ER, Skeem JL . Victimization History and Posttraumatic Stress: An Analysis of Psychopathy Variants in Male Juvenile Offenders. J Child Adolesc Trauma 2012; 5: 102–113.

    Article  Google Scholar 

  7. Vaughn MG, Edens JF, Howard MO, Smith ST . An investigation of primary and secondary psychopathy in a statewide sample of incarcerated youth. Youth Violence and Juvenile Justice 2009; 7: 172–188.

    Article  Google Scholar 

  8. Jaenisch R, Bird A . Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 2003; 33: 245–254.

    Article  CAS  Google Scholar 

  9. Champagne FA . Epigenetic influence of social experiences across the lifespan. Dev Psychobiol 2010; 52: 299–311.

    Article  CAS  Google Scholar 

  10. Dadds MR, Moul C, Cauchi A, Dobson-Stone C, Hawes DJ, Brennan J et al. Methylation of the oxytocin receptor gene and oxytocin blood levels in the development of psychopathy. Dev Psychopathol 2014; 26: 33–40.

    Article  Google Scholar 

  11. Frick PJ, Ray JV, Thornton LC, Kahn RE . Annual research review: A developmental psychopathology approach to understanding callous-unemotional traits in children and adolescents with serious conduct problems. J Child Psychol Psychiatry 2013; 55: 532–548.

    Article  Google Scholar 

  12. Insel TR . The challenge of translation in social neuroscience: a review of oxytocin, vasopressin, and affiliative behavior. Neuron 2010; 65: 768–779.

    Article  CAS  Google Scholar 

  13. Kumsta R, Hummel E, Chen FS, Heinrichs M . Epigenetic regulation of the oxytocin receptor gene: implications for behavioral neuroscience. Front Neurosci 2013; 7: 83.

    Article  Google Scholar 

  14. Barker ED, Oliver BR, Maughan B . Co-occurring problems of early onset persistent, childhood limited, and adolescent onset conduct problem youth. J Child Psychol Psychiatry 2010; 51: 1217–1226.

    Article  Google Scholar 

  15. Barker ED, Oliver BR, Viding E, Salekin RT, Maughan B . The impact of prenatal maternal risk, fearless temperament and early parenting on adolescent callous-unemotional traits: a 14-year longitudinal investigation. J Child Psychol Psychiatry 2011; 52: 878–888.

    Article  Google Scholar 

  16. Fraser A, Macdonald-Wallis C, Tilling K, Boyd A, Golding J, Davey Smith G et al. Cohort Profile: the Avon Longitudinal Study of Parents and Children: ALSPAC mothers cohort. Int J Epidemiol 2013; 42: 97–110.

    Article  Google Scholar 

  17. Boyd A, Golding J, Macleod J, Lawlor DA, Fraser A, Henderson J et al. Cohort Profile: the 'children of the 90s'—the index offspring of the Avon Longitudinal Study of Parents and Children. Int J Epidemiol 2013; 42: 111–127.

    Article  Google Scholar 

  18. Barker ED, Maughan B . Differentiating early-onset persistent versus childhood-limited conduct problem youth. Am J Psychiatry 2009; 166: 900–908.

    Article  Google Scholar 

  19. Pidsley R, YW CC, Volta M, Lunnon K, Mill J, Schalkwyk LC . A data-driven approach to preprocessing Illumina 450K methylation array data. BMC Genomics 2013; 14: 293.

    Article  CAS  Google Scholar 

  20. Johnson WE, Li C, Rabinovic A . Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics 2007; 8: 118–127.

    Article  Google Scholar 

  21. 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.

    Article  Google Scholar 

  22. Jack A, Connelly JJ, Morris JP . DNA methylation of the oxytocin receptor gene predicts neural response to ambiguous social stimuli. Front Hum Neurosci 2012; 6: 280.

    Article  CAS  Google Scholar 

  23. 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: 681–686.

    Article  CAS  Google Scholar 

  24. Thompson B . Exploratory and Confirmatory Factor Analysis: Understanding Concepts and Applications. American Psychological Association: Washington, DC, USA, 2004.

    Book  Google Scholar 

  25. Goodman A, Heiervang E, Collishaw S, Goodman R . The 'DAWBA bands' as an ordered-categorical measure of child mental health: description and validation in British and Norwegian samples. Soci Psychiatry Psychiatri Epidemiol 2011; 46: 521–532.

    Article  Google Scholar 

  26. Moran P, Ford T, Butler G, Goodman R . Callous and unemotional traits in children and adolescents living in Great Britain. Brit J Psychiatry 2008; 192: 65–66.

    Article  Google Scholar 

  27. Moran P, Rowe R, Flach C, Briskman J, Ford T, Maughan B et al. Predictive value of callous-unemotional traits in a large community sample. J Am Acad Child Adolesc Psychiatry 2009; 48: 1079–1084.

    Article  Google Scholar 

  28. Muthen LK, Muthen BO . MPLUS User’s Guide, 1998-2010, 6th edn. Muthen & Muthen: Los Angeles, CA, USA, 2011.

  29. Kline RB . Principles and Practice of Structural Equation Modeling, 3rd edn. The Guildford Press: New York, NY, USA, 2010.

    Google Scholar 

  30. Hu Lt, Bentler PM . Cutoff criteria for fit indexes in covariance structure analysis: Conventional criteria versus new alternatives. Struct Equation Model 1999; 6: 1–55.

    Article  Google Scholar 

  31. Satorra A . Scaled and adjusted restricted tests in multi-sample analysis of moment structures. In: Heijmans DDH, Pollock DSG, Satorra A (eds). Innovations in Multivariate Statistical Analysis. A festschrift for Heinz Neudecker. Kluwer Academic Publishers: Dordrecht, Netherlands, 2000, pp 233–247.

    Chapter  Google Scholar 

  32. Sheskin D . The Handbook Of Parametric And Nonparametric Statistical Procedures. CRC Press: Boca Raton, FL, 2003.

    Book  Google Scholar 

  33. Meaburn EL, Schalkwyk LC, Mill J . Allele-specific methylation in the human genome: implications for genetic studies of complex disease. Epigenetics 2010; 5: 578–582.

    Article  CAS  Google Scholar 

  34. Schalkwyk LC, Meaburn EL, Smith R, Dempster EL, Jeffries AR, Davies MN et al. Allelic skewing of DNA methylation is widespread across the genome. Am J Hum Genet 2010; 86: 196–212.

    Article  CAS  Google Scholar 

  35. Eicher JD, Powers NR, Miller LL, Akshoomoff N, Amaral DG, Bloss CS et al. Genome-wide association study of shared components of reading disability and language impairment. Genes Brain Behav 2013; 12: 792–801.

    Article  CAS  Google Scholar 

  36. Johansson A, Westberg L, Sandnabba K, Jern P, Salo B, Santtila P . Associations between oxytocin receptor gene (OXTR) polymorphisms and self-reported aggressive behavior and anger: Interactions with alcohol consumption. Psychoneuroendocrinology 2012; 37: 1546–1556.

    Article  CAS  Google Scholar 

  37. Nyffeler J, Walitza S, Bobrowski E, Gundelfinger R, Grunblatt E . Association study in siblings and case-controls of serotonin- and oxytocin-related genes with high functioning autism. J Mol Psychiatry 2014; 2: 1.

    Article  Google Scholar 

  38. Loth E, Poline JB, Thyreau B, Jia T, Tao C, Lourdusamy A et al. Oxytocin receptor genotype modulates ventral striatal activity to social cues and response to stressful life events. Biol Psychiatry 2014; 76: 367–376.

    Article  CAS  Google Scholar 

  39. Wu N, Li Z, Su Y . The association between oxytocin receptor gene polymorphism (OXTR) and trait empathy. J Affect Disord 2012; 138: 468–472.

    Article  CAS  Google Scholar 

  40. Button TM, Corley RP, Rhee SH, Hewitt JK, Young SE, Stallings MC . Delinquent peer affiliation and conduct problems: a twin study. J Abnorm Psychol 2007; 116: 554–564.

    Article  Google Scholar 

  41. Jaffee SR, Price TS . Gene-environment correlations: a review of the evidence and implications for prevention of mental illness. Mol Psychiatry 2007; 12: 432–442.

    Article  CAS  Google Scholar 

  42. Kendler KS, Jacobson KC, Gardner CO, Gillespie N, Aggen SA, Prescott CA . Creating a social world: a developmental twin study of peer-group deviance. Arch Gen Psychiatry 2007; 64: 958–965.

    Article  Google Scholar 

  43. McAdams TA, Gregory AM, Eley TC . Genes of experience: explaining the heritability of putative environmental variables through their association with behavioural and emotional traits. Behav Genet 2013; 43: 314–328.

    Article  Google Scholar 

  44. Barker ED, Arseneault L, Brendgen M, Fontaine N, Maughan B . Joint development of bullying and victimization in adolescence: relations to delinquency and self-harm. J Am Acad Child Adolesc Psychiatry 2008; 47: 1030–1038.

    PubMed  Google Scholar 

  45. Barker ED, Salekin RT . Irritable oppositional defiance and callous unemotional traits: is the association partially explained by peer victimization? J Child Psychol Psychiatry 2012; 53: 1167–1175.

    Article  Google Scholar 

  46. Reijntjes A, Kamphuis JH, Prinzie P, Telch MJ . Peer victimization and internalizing problems in children: a meta-analysis of longitudinal studies. Child Abuse Neglect 2010; 34: 244–252.

    Article  Google Scholar 

  47. Meaney MJ, Szyf M, Seckl JR . Epigenetic mechanisms of perinatal programming of hypothalamic-pituitary-adrenal function and health. Trends Mol Med 2007; 13: 269–277.

    Article  CAS  Google Scholar 

  48. Johannes F, Porcher E, Teixeira FK, Saliba-Colombani V, Simon M, Agier N et al. Assessing the Impact of Transgenerational Epigenetic Variation on Complex Traits. PLoS Genet 2009; 5: e1000530.

    Article  Google Scholar 

  49. Richards EJ . Inherited epigenetic variation—revisiting soft inheritance. Nat Rev Genet 2006; 7: 395–401.

    Article  CAS  Google Scholar 

  50. Skeem JL, Poythress N, Edens JF, Lilienfeld SO, Cale EM . Psychopathic personality or personalities? Exploring potential variants of psychopathy and their implications for risk assessment. Aggress Violent Behav 2003; 8: 513–546.

    Article  Google Scholar 

  51. O'Connor TG, Heron J, Golding J, Beveridge M, Glover V . Maternal antenatal anxiety and children's behavioural/emotional problems at 4 years. Report from the Avon Longitudinal Study of Parents and Children. Brit J Psychiatry 2002; 180: 502–508.

    Article  Google Scholar 

  52. Sadeh N, Javdani S, Jackson JJ, Reynolds EK, Potenza MN, Gelernter J et al. Serotonin transporter gene associations with psychopathic traits in youth vary as a function of socioeconomic resources. J Abnorm Psychol 2010; 119: 604–609.

    Article  Google Scholar 

  53. Craig IW, Halton KE . Genetics of human aggressive behaviour. Hum Genet 2009; 126: 101–113.

    Article  Google Scholar 

Download references

Acknowledgements

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 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. We also thank Prof Dieter Wolke for his helpful comments on a previous version of this manuscript. The UK Medical Research Council and the Wellcome Trust (Grant ref: 092731) and the University of Bristol provided core support for ALSPAC. This work was funded by the National Institute of Child and Human Development grant (R01HD068437). JBP was supported by a Marie Curie Intra-European Fellowship (No. 330699).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to E D Barker.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cecil, C., Lysenko, L., Jaffee, S. et al. Environmental risk, Oxytocin Receptor Gene (OXTR) methylation and youth callous-unemotional traits: a 13-year longitudinal study. Mol Psychiatry 19, 1071–1077 (2014). https://doi.org/10.1038/mp.2014.95

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2014.95

This article is cited by

Search

Quick links