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.

  • Original Article
  • Published:

Antisocial behavior and polymorphisms in the oxytocin receptor gene: findings in two independent samples

Molecular Psychiatry volume 21, pages 983–988 (2016)Cite this article

Subjects

Abstract

The quantitative genetic contribution to antisocial behavior is well established, but few, if any, genetic variants are established as risk factors. Emerging evidence suggests that the neuropeptide oxytocin (OXT) may modulate interpersonal aggression. We here investigated whether single-nucleotide polymorphisms (SNPs) in the OXT receptor gene (OXTR) are associated with the expression of antisocial behavior. A discovery sample, including both sexes, was drawn from the Child and Adolescent Twin Study in Sweden (CATSS; n=2372), and a sample from the Twin Study of Child and Adolescent Development (TCHAD; n=1232) was used for replication. Eight SNPs in OXTR, selected on previous associations with social and antisocial behavior, were genotyped in the participants of CATSS. Significant polymorphisms were subsequently genotyped in TCHAD for replication. Participants completed self-assessment questionnaires—Life History of Aggression (LHA; available only in CATSS), and Self-Reported Delinquency (SRD; available in both samples)—designed to capture antisocial behavior as continuous traits. In the discovery sample, the rs7632287 AA genotype was associated with higher frequency of antisocial behavior in boys, and this was then replicated in the second sample. In particular, overt aggression (directly targeting another individual) was strongly associated with this genotype in boys (P=6.2 × 10−7 in the discovery sample). Meta-analysis of the results for antisocial behavior from both samples yielded P=2.5 × 10−5. Furthermore, an association between rs4564970 and LHA (P=0.00013) survived correction in the discovery sample, but there was no association with the SRD in the replication sample. We conclude that the rs7632287 and rs4564970 polymorphisms in OXTR may independently influence antisocial behavior in adolescent boys. Further replication of our results will be crucial to understanding how aberrant social behavior arises, and would support the OXT receptor as one potential target in the treatment of aggressive antisocial behavior.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Similar content being viewed by others

References

  1. Colman I, Murray J, Abbott RA, Maughan B, Kuh D, Croudace TJ et al. Outcomes of conduct problems in adolescence: 40 year follow-up of national cohort. BMJ 2009; 338: a2981.

    Article  Google Scholar 

  2. Scott S, Knapp M, Henderson J, Maughan B . Financial cost of social exclusion: follow up study of antisocial children into adulthood. BMJ 2001; 323: 191–194.

    Article  CAS  Google Scholar 

  3. Tuvblad C, Narusyte J, Grann M, Sarnecki J, Lichtenstein P . The genetic and environmental etiology of antisocial behavior from childhood to emerging adulthood. Behav Genet 2011; 41: 629–640.

    Article  Google Scholar 

  4. Neumann ID . Brain oxytocin: a key regulator of emotional and social behaviours in both females and males. J Neuroendocrinol 2008; 20: 858–865.

    Article  CAS  Google Scholar 

  5. Clark CL St, John N, Pasca AM, Hyde SA, Hornbeak K, Abramova M et al. Neonatal CSF oxytocin levels are associated with parent report of infant soothability and sociability. Psychoneuroendocrinology 2013; 38: 1208–1212.

    Article  CAS  Google Scholar 

  6. Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E . Oxytocin increases trust in humans. Nature 2005; 435: 673–676.

    Article  CAS  Google Scholar 

  7. Rimmele U, Hediger K, Heinrichs M, Klaver P . Oxytocin makes a face in memory familiar. J Neurosci 2009; 29: 38–42.

    Article  CAS  Google Scholar 

  8. Savaskan E, Ehrhardt R, Schulz A, Walter M, Schachinger H . Post-learning intranasal oxytocin modulates human memory for facial identity. Psychoneuroendocrinology 2008; 33: 368–374.

    Article  CAS  Google Scholar 

  9. Shahrestani S, Kemp AH, Guastella AJ . The impact of a single administration of intranasal oxytocin on the recognition of basic emotions in humans: a meta-analysis. Neuropsychopharmacology 2013; 38: 1929–1936.

    Article  CAS  Google Scholar 

  10. Bartz JA, Zaki J, Bolger N, Ochsner KN . Social effects of oxytocin in humans: context and person matter. Trends Cogn Sci 2011; 15: 301–309.

    CAS  Google Scholar 

  11. Ferris CF, Foote KB, Meltser HM, Plenby MG, Smith KL, Insel TR . Oxytocin in the amygdala facilitates maternal aggression. Ann NY Acad Sci 1992; 652: 456–457.

    Article  CAS  Google Scholar 

  12. Lubin DA, Elliott JC, Black MC, Johns JM . An oxytocin antagonist infused into the central nucleus of the amygdala increases maternal aggressive behavior. Behav Neurosci 2003; 117: 195–201.

    Article  CAS  Google Scholar 

  13. Harmon AC, Huhman KL, Moore TO, Albers HE . Oxytocin inhibits aggression in female Syrian hamsters. J Neuroendocrinol 2002; 14: 963–969.

    Article  CAS  Google Scholar 

  14. DeVries AC, Young WS 3rd, Nelson RJ . Reduced aggressive behaviour in mice with targeted disruption of the oxytocin gene. J Neuroendocrinol 1997; 9: 363–368.

    Article  CAS  Google Scholar 

  15. Winslow JT, Hearn EF, Ferguson J, Young LJ, Matzuk MM, Insel TR . Infant vocalization, adult aggression, and fear behavior of an oxytocin null mutant mouse. Horm Behav 2000; 37: 145–155.

    Article  CAS  Google Scholar 

  16. Ragnauth AK, Devidze N, Moy V, Finley K, Goodwillie A, Kow LM et al. Female oxytocin gene-knockout mice, in a semi-natural environment, display exaggerated aggressive behavior. Genes Brain Behav 2005; 4: 229–239.

    Article  CAS  Google Scholar 

  17. Fetissov SO, Hallman J, Nilsson I, Lefvert AK, Oreland L, Hokfelt T . Aggressive behavior linked to corticotropin-reactive autoantibodies. Biol Psychiatry 2006; 60: 799–802.

    Article  CAS  Google Scholar 

  18. Lee R, Ferris C, Van de Kar LD, Coccaro EF . Cerebrospinal fluid oxytocin, life history of aggression, and personality disorder. Psychoneuroendocrinology 2009; 34: 1567–1573.

    Article  CAS  Google Scholar 

  19. Johansson A, Bergman H, Corander J, Waldman ID, Karrani N, Salo B et al. Alcohol and aggressive behavior in men—moderating effects of oxytocin receptor gene (OXTR) polymorphisms. Genes Brain Behav 2012; 11: 214–221.

    Article  CAS  Google Scholar 

  20. 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 

  21. Beitchman JH, Zai CC, Muir K, Berall L, Nowrouzi B, Choi E et al. Childhood aggression, callous-unemotional traits and oxytocin genes. Eur Child Adolesc Psychiatry 2012; 21: 125–132.

    Article  Google Scholar 

  22. Dadds MR, Moul C, Cauchi A, Dobson-Stone C, Hawes DJ, Brennan J et al. Polymorphisms in the oxytocin receptor gene are associated with the development of psychopathy. Dev Psychopathol 2014; 26: 21–31.

    Article  Google Scholar 

  23. Malik AI, Zai CC, Abu Z, Nowrouzi B, Beitchman JH . The role of oxytocin and oxytocin receptor gene variants in childhood-onset aggression. Genes Brain Behav 2012; 11: 545–551.

    Article  CAS  Google Scholar 

  24. Malik AI, Zai CC, Berall L, Abu Z, Din F, Nowrouzi B et al. The role of genetic variants in genes regulating the oxytocin-vasopressin neurohumoral system in childhood-onset aggression. Psychiatr Genet 2014; 24: 201–210.

    CAS  PubMed  Google Scholar 

  25. 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 

  26. Cecil CA, Lysenko LJ, Jaffee SR, Pingault JB, Smith RG, Relton CL et al. Environmental risk, oxytocin receptor gene (OXTR) methylation and youth callous-unemotional traits: a 13-year longitudinal study. Mol Psychiatry 2014; 19: 1071–1077.

    Article  CAS  Google Scholar 

  27. Smearman EL, Winiarski DA, Brennan PA, Najman J, Johnson KC . Social stress and the oxytocin receptor gene interact to predict antisocial behavior in an at-risk cohort. Dev Psychopathol 2015; 27: 309–318.

    Article  Google Scholar 

  28. 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 

  29. Plomin R, Haworth CM, Davis OS . Common disorders are quantitative traits. Nat Rev Genet 2009; 10: 872–878.

    Article  CAS  Google Scholar 

  30. Anckarsater H, Lundstrom S, Kollberg L, Kerekes N, Palm C, Carlstrom E et al. The Child and Adolescent Twin Study in Sweden (CATSS). Twin Res Hum Genet 2011; 14: 495–508.

    Article  Google Scholar 

  31. Hannelius U, Gherman L, Makela VV, Lindstedt A, Zucchelli M, Lagerberg C et al. Large-scale zygosity testing using single nucleotide polymorphisms. Twin Res Hum Genet 2007; 10: 604–625.

    Article  Google Scholar 

  32. Lichtenstein P, Tuvblad C, Larsson H, Carlstrom E . The Swedish Twin study of CHild and Adolescent Development: the TCHAD-study. Twin Res Hum Genet 2007; 10: 67–73.

    Article  Google Scholar 

  33. Coccaro EF, Berman ME, Kavoussi RJ . Assessment of life history of aggression: development and psychometric characteristics. Psychiatry Res 1997; 73: 147–157.

    Article  CAS  Google Scholar 

  34. Coccaro EF, Kavoussi RJ, Berman ME, Lish JD . Intermittent explosive disorder-revised: development, reliability, and validity of research criteria. Compr Psychiatry 1998; 39: 368–376.

    Article  CAS  Google Scholar 

  35. Hofvander B, Stahlberg O, Nyden A, Wentz E, degl'Innocenti A, Billstedt E et al. Life History of Aggression scores are predicted by childhood hyperactivity, conduct disorder, adult substance abuse, and low cooperativeness in adult psychiatric patients. Psychiatry Res 2011; 185: 280–285.

    Article  Google Scholar 

  36. Junger-Tas J, Terlouw G, Klein M . Delinquent Behaviour Among Young People in the Western World. Kluwer: Amsterdam, The Netherlands, 1994.

    Google Scholar 

  37. Ring J . Hem och skola, kamrater och brott. University of Stockholm: Stockholm, 1999.

    Google Scholar 

  38. Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.

    Article  CAS  Google Scholar 

  39. Ge D 2009 MetaP [Software]. Available from: http://people.genome.duke.edu/~dg48/metap.php.

  40. Ward LD, Kellis M . HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res 2012; 40: D930–D934.

    Article  CAS  Google Scholar 

  41. Vassos E, Collier DA, Fazel S . Systematic meta-analyses and field synopsis of genetic association studies of violence and aggression. Mol Psychiatry 2014; 19: 471–477.

    Article  CAS  Google Scholar 

  42. Tiihonen J, Rautiainen MR, Ollila HM, Repo-Tiihonen E, Virkkunen M, Palotie A et al. Genetic background of extreme violent behavior. Mol Psychiatry 2014; 20: 786–792.

    Article  Google Scholar 

  43. Dorfman HM, Meyer-Lindenberg A, Buckholtz JW . Neurobiological mechanisms for impulsive-aggression: the role of MAOA. Curr Top Behav Neurosci 2014; 17: 297–313.

    Article  Google Scholar 

  44. LoParo D, Waldman ID . The oxytocin receptor gene (OXTR) is associated with autism spectrum disorder: a meta-analysis. Mol Psychiatry 2014; 20: 640–646.

    Article  Google Scholar 

  45. Walum H, Lichtenstein P, Neiderhiser JM, Reiss D, Ganiban JM, Spotts EL et al. Variation in the oxytocin receptor gene is associated with pair-bonding and social behavior. Biol Psychiatry 2012; 71: 419–426.

    Article  CAS  Google Scholar 

  46. Genomes Project C, Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM et al. An integrated map of genetic variation from 1,092 human genomes. Nature 2012; 491: 56–65.

    Article  Google Scholar 

  47. Tansey KE, Brookes KJ, Hill MJ, Cochrane LE, Gill M, Skuse D et al. Oxytocin receptor (OXTR) does not play a major role in the aetiology of autism: genetic and molecular studies. Neurosci Lett 2010; 474: 163–167.

    Article  CAS  Google Scholar 

  48. Lerer E, Levi S, Salomon S, Darvasi A, Yirmiya N, Ebstein RP . Association between the oxytocin receptor (OXTR) gene and autism: relationship to Vineland Adaptive Behavior Scales and cognition. Mol Psychiatry 2008; 13: 980–988.

    Article  CAS  Google Scholar 

  49. Blanks AM, Shmygol A, Thornton S . Regulation of oxytocin receptors and oxytocin receptor signaling. Semin Reprod Med 2007; 25: 52–59.

    Article  CAS  Google Scholar 

  50. Kuersten S, Goodwin EB . The power of the 3' UTR: translational control and development. Nat Rev Genet 2003; 4: 626–637.

    Article  CAS  Google Scholar 

  51. Campbell DB, Datta D, Jones ST, Batey Lee E, Sutcliffe JS, Hammock EA et al. Association of oxytocin receptor (OXTR) gene variants with multiple phenotype domains of autism spectrum disorder. J Neurodev Dis 2011; 3: 101–112.

    Article  Google Scholar 

  52. Westberg L, Walum H . Oxytocin and Vasopressin Gene Variation and the Neural Basis of Social Behaviors. In: Canli T (ed). The Oxford Handbook of Molecular Psychology. Oxford University Press: Oxford, UK, 2015, pp 145–166.

    Google Scholar 

  53. Carter CS . Oxytocin pathways and the evolution of human behavior. Annu Rev Psychol 2014; 65: 17–39.

    Article  Google Scholar 

  54. Young LJ, Wang Z . The neurobiology of pair bonding. Nat Neurosci 2004; 7: 1048–1054.

    Article  CAS  Google Scholar 

  55. Feng C, Hackett PD, DeMarco AC, Chen X, Stair S, Haroon E et al. Oxytocin and vasopressin effects on the neural response to social cooperation are modulated by sex in humans. Brain Imaging Behav 2014 (e-pub ahead of print).

  56. Sala M, Braida D, Lentini D, Busnelli M, Bulgheroni E, Capurro V et al. Pharmacologic rescue of impaired cognitive flexibility, social deficits, increased aggression, and seizure susceptibility in oxytocin receptor null mice: a neurobehavioral model of autism. Biol Psychiatry 2011; 69: 875–882.

    Article  CAS  Google Scholar 

  57. Calcagnoli F, de Boer SF, Althaus M, den Boer JA, Koolhaas JM . Antiaggressive activity of central oxytocin in male rats. Psychopharmacology 2013; 229: 639–651.

    Article  CAS  Google Scholar 

  58. Calcagnoli F, Kreutzmann JC, de Boer SF, Althaus M, Koolhaas JM . Acute and repeated intranasal oxytocin administration exerts anti-aggressive and pro-affiliative effects in male rats. Psychoneuroendocrinology 2015; 51: 112–121.

    Article  CAS  Google Scholar 

  59. Calcagnoli F, Meyer N, de Boer SF, Althaus M, Koolhaas JM . Chronic enhancement of brain oxytocin levels causes enduring anti-aggressive and pro-social explorative behavioral effects in male rats. Horm Behav 2014; 65: 427–433.

    Article  CAS  Google Scholar 

  60. Calcagnoli F, Stubbendorff C, Meyer N, de Boer SF, Althaus M, Koolhaas JM . Oxytocin microinjected into the central amygdaloid nuclei exerts anti-aggressive effects in male rats. Neuropharmacology 2015; 90: 74–81.

    Article  CAS  Google Scholar 

  61. Calcagnoli F, de Boer SF, Beiderbeck DI, Althaus M, Koolhaas JM, Neumann ID . Local oxytocin expression and oxytocin receptor binding in the male rat brain is associated with aggressiveness. Behav Brain Res 2014; 261: 315–322.

    Article  CAS  Google Scholar 

  62. Pagani JH, Williams Avram SK, Cui Z, Song J, Mezey E, Senerth JM et al. Raphe serotonin neuron-specific oxytocin receptor knockout reduces aggression without affecting anxiety-like behavior in male mice only. Genes Brain Behav 2015; 14: 167–176.

    Article  CAS  Google Scholar 

  63. Wang K, Zhang H, Ma D, Bucan M, Glessner JT, Abrahams BS et al. Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 2009; 459: 528–533.

    Article  CAS  Google Scholar 

  64. Christ CC, Carlo G, Stoltenberg SF . Oxytocin receptor (OXTR) single nucleotide polymorphisms indirectly predict prosocial behavior through perspective taking and empathic concern. J Pers 2014 (e-pub ahead of print).

  65. Laursen HR, Siebner HR, Haren T, Madsen K, Gronlund R, Hulme O et al. Variation in the oxytocin receptor gene is associated with behavioral and neural correlates of empathic accuracy. Front Behav Neurosci 2014; 8: 423.

    Article  Google Scholar 

  66. Melchers M, Montag C, Markett S, Reuter M . Relationship between oxytocin receptor genotype and recognition of facial emotion. Behav Neurosci 2013; 127: 780–787.

    Article  CAS  Google Scholar 

  67. Rodrigues SM, Saslow LR, Garcia N, John OP, Keltner D . Oxytocin receptor genetic variation relates to empathy and stress reactivity in humans. Proc Natl Acad Sci USA 2009; 106: 21437–21441.

    Article  CAS  Google Scholar 

  68. Tost H, Kolachana B, Hakimi S, Lemaitre H, Verchinski BA, Mattay VS et al. A common allele in the oxytocin receptor gene (OXTR) impacts prosocial temperament and human hypothalamic-limbic structure and function. Proc Natl Acad Sci USA 2010; 107: 13936–13941.

    Article  CAS  Google Scholar 

  69. Bakermans-Kranenburg MJ, van Ijzendoorn MH . Oxytocin receptor (OXTR) and serotonin transporter (5-HTT) genes associated with observed parenting. Soc Cogn Affect Neurosci 2008; 3: 128–134.

    Article  Google Scholar 

  70. Israel S, Lerer E, Shalev I, Uzefovsky F, Riebold M, Laiba E et al. The oxytocin receptor (OXTR) contributes to prosocial fund allocations in the dictator game and the social value orientations task. PLoS One 2009; 4: e5535.

    Article  Google Scholar 

  71. Inoue H, Yamasue H, Tochigi M, Abe O, Liu X, Kawamura Y et al. Association between the oxytocin receptor gene and amygdalar volume in healthy adults. Biol Psychiatry 2010; 68: 1066–1072.

    Article  CAS  Google Scholar 

  72. 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 

  73. Skuse DH, Lori A, Cubells JF, Lee I, Conneely KN, Puura K et al. Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills. Proc Natl Acad Sci USA 2014; 111: 1987–1992.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by grants from the Swedish Research Council, Swedish Research Council for Working Life and Social Research, The Society of Swedish Literature in Finland and the Söderström-Königska Foundation. The research leading to these results has also received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no 602768.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    D Hovey, M Lindstedt, A Zettergren, L Jonsson, A Johansson, J Melke & L Westberg

  2. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    A Zettergren

  3. Department of Behavioral Sciences and Philosophy, University of Turku, Turku, Finland

    A Johansson

  4. Centre for Ethics, Law and Mental Health (CELAM), University of Gothenburg, Mölndal, Sweden

    N Kerekes, H Anckarsäter & S Lundström

  5. R&D Unit, Swedish Prison and Probation Service, Gothenburg, Sweden

    N Kerekes & S Lundström

  6. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    P Lichtenstein

  7. Gillberg Neuropsychiatry Centre, University of Gothenburg, Gothenburg, Sweden

    S Lundström

Authors
  1. D Hovey
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Lindstedt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Zettergren
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L Jonsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Johansson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Melke
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. N Kerekes
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. H Anckarsäter
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. P Lichtenstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S Lundström
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. L Westberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L Westberg.

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hovey, D., Lindstedt, M., Zettergren, A. et al. Antisocial behavior and polymorphisms in the oxytocin receptor gene: findings in two independent samples. Mol Psychiatry 21, 983–988 (2016). https://doi.org/10.1038/mp.2015.144

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2015.144

This article is cited by

Search

Advanced search

Quick links