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Polymorphisms in the oxytocin receptor gene are associated with the development of psychopathy

Published online by Cambridge University Press:  23 September 2013

Mark R. Dadds*
Affiliation:
University of New South Wales
Caroline Moul
Affiliation:
University of New South Wales
Avril Cauchi
Affiliation:
University of New South Wales
Carol Dobson-Stone
Affiliation:
University of New South Wales Neuroscience Research Australia
David J. Hawes
Affiliation:
University of Sydney
John Brennan
Affiliation:
Sydney Children's Hospital
Ruth Urwin
Affiliation:
Children's Hospital at Westmead
Richard E. Ebstein
Affiliation:
National University of Singapore
*
Address correspondence and reprint requests to: Mark R. Dadds, School of Psychology, University of New South Wales, Sydney, NSW 2052, Australia; E-mail: m.dadds@unsw.edu.au.

Abstract

The co-occurrence of child conduct problems (CPs) and callous–unemotional (CU) traits confers risk for psychopathy. The oxytocin (OXT) system is a likely candidate for involvement in the development of psychopathy. We tested variations in the OXT receptor gene (OXTR) in CP children and adolescents with varying levels of CU traits. Two samples of Caucasian children, aged 4–16 years, who met DSM criteria for disruptive behavior problems and had no features of autism spectrum disorder, were stratified into low versus high CU traits. Measures were the frequencies of nine candidate OXTR polymorphisms (single nucleotide polymorphisms). In Sample 1, high CU traits were associated with single nucleotide polymorphism rs1042778 in the 3′ untranslated region of OXTR and the CGCT haplotype of rs2268490, rs2254298, rs237889, and rs13316193. The association of rs1042778 was replicated in the second rural sample and held across gender and child versus adolescent age groups. We conclude that polymorphic variation of the OXTR characterizes children with high levels of CU traits and CPs. The results are consistent with a hypothesized role of OXT in the developmental antecedents of psychopathy, particularly the differential amygdala activation model of psychopathic traits, and add genetic evidence that high CU traits specify a distinct subgroup within CP children.

Type
Regular Articles
Copyright
Copyright © Cambridge University Press 2013 

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References

Apicella, C. L., Cesarini, D., Johannesson, M., Dawes, C. T., Lichtenstein, P., Wallace, B., et al. (2010). No association between oxytocin receptor (OXTR) gene polymorphisms and experimentally elicited social preferences. PLoS ONE, 5(6).Google Scholar
Bakermans-Kranenburg, M. J., & van IJzendoorn, M. H. (2008). Oxytocin receptor (OXTR) and serotonin transporter (5-HTT) genes associated with observed parenting. Social Cognitive and Affective Neuroscience, 3, 128134.CrossRefGoogle ScholarPubMed
Bartz, J. A., & Hollander, E. (2008). Oxytocin and experimental therapeutics in autism spectrum disorders. Progress in Brain Research, 170, 451462.Google Scholar
Beitchman, J. H., Zai, C. C., Muir, K., Berall, L., Nowrouzi, B., Choi, E., et al. (2012). Childhood aggression, callous–unemotional traits and oxytocin genes. European Child and Adolescent Psychiatry, 21, 125132.CrossRefGoogle ScholarPubMed
Blair, R. J. R. (2008). Fine cuts of empathy and the amygdala: Dissociable deficits in psychopathy and autism. Quarterly Journal of Experimental Psychology, 61, 157170.CrossRefGoogle ScholarPubMed
Blair, R. J. R. (2011). Commentary: Are callous unemotional traits all in the eyes? Examining eye contact in youth with conduct problems and callous unemotional traits—Reflections on Dadds et al. (2011). Journal of Child Psychology and Psychiatry and Allied Disciplines, 52, 246247.CrossRefGoogle ScholarPubMed
Blair, R. J. R., Morris, J. S., Frith, C. D., Perrett, D. I., & Dolan, R. J. (1999). Dissociable neural responses to facial expressions of sadness and anger. Brain, 122, 883893.Google Scholar
Bora, E., Yucel, M., & Allen, N. B. (2009). Neurobiology of human affiliative behaviour: Implications for psychiatric disorders. Current Opinion in Psychiatry, 22, 320325.Google Scholar
Brüne, M. (2012). Does the oxytocin receptor polymorphism (rs2254298) confer ‘vulnerability’ for psychopathology or ‘differential susceptibility’? Insights from evolution. BMC Medicine, 10. Advance online publication. doi:10.1186/1741-7015-10-38Google Scholar
Campbell, D. B., Datta, D., Jones, S. T., Lee, E. B., Sutcliffe, J. S., Hammock, E. A. D., et al. (2011). Association of oxytocin receptor (OXTR) gene variants with multiple phenotype domains of autism spectrum disorder. Journal of Neurodevelopmental Disorders, 3, 101112.CrossRefGoogle ScholarPubMed
Chen, F. S., Barth, M., Johnson, S. L., Gotlib, I. H., & Johnson, S. C. (2011). Oxytocin receptor (intra-assay) polymorphisms and attachment in human infants. Frontiers in Psychology, 2. doi:10.3389/fpsyg.2011.00200CrossRefGoogle Scholar
Chen, F. S., & Johnson, S. C. (2012). An oxytocin receptor gene variant predicts attachment anxiety in females and autism-spectrum traits in males. Social Psychological and Personality Science, 3, 9399.CrossRefGoogle Scholar
Cohen, J. (1992). A power primer. Psychological Bulletin, 112, 155159.Google Scholar
Copeland, W., Shanahan, L., Costello, E., & Angold, A. (2009). Childhood and adolescent psychiatric disorders as predictors of young adult disorders. Archives of General Psychiatry, 66, 764772. doi:10.1001/archgenpsychiatry.2009.85Google Scholar
Costa, B., Pini, S., Gabelloni, P., Abelli, M., Lari, L., Cardini, A., et al. (2009). Oxytocin receptor polymorphisms and adult attachment style in patients with depression. Psychoneuroendocrinology, 34, 15061514.Google Scholar
Crow, T. J. (2011). The missing genes: What happened to the heritability of psychiatric disorders? Molecular Psychiatry, 16, 362364.CrossRefGoogle Scholar
Dadds, M. R., Cauchi, A. J., Wimalaweera, S., Hawes, D. J., & Brennan, J. (2012). Outcomes, moderators, and mediators of empathic-emotion recognition training for complex conduct problems in childhood. Psychiatry Research.Google Scholar
Dadds, M. R., Frost, A., Fraser, J., & Hawes, D. J. (2005). Disentangling the underlying dimensions of psychopathy and conduct problems in childhood: A community study. Journal of Consulting and Clinical Psychology, 73, 400410.Google Scholar
Dadds, M. R., & Hawes, D. J. (2006). Integrative Family Intervention for Child Conduct Disorders. Brisbane: Australian Academic Press.Google Scholar
Dadds, M. R., Perry, Y., Hawes, D. J., Merz, S., Riddell, A. C., Haines, D. J., et al. (2006). Attention to the eyes and fear-recognition deficits in child psychopathy. British Journal of Psychiatry, 189, 280281.Google Scholar
Dadds, M. R., & Rhodes, T. (2008). Aggression in young children with concurrent callous–unemotional traits: Can the neurosciences inform progress and innovation in treatment approaches? Philosophical Transactions of the Royal Society, 363B, 25672576.CrossRefGoogle Scholar
De Brito, S. A., McCrory, E. J., Mechelli, A., Wilke, M., Jones, A. P., Hodgins, S., et al. (2011). Small, but not perfectly formed: Decreased white matter concentration in boys with psychopathic tendencies. Molecular Psychiatry, 16, 476477.Google Scholar
Deeley, Q., Daly, E., Surguladze, S., Tunstall, N., Mezey, G., Beer, D., et al. (2006). Facial emotion processing in criminal psychopathy: Preliminary functional magnetic resonance imaging study. British Journal of Psychiatry, 189, 533539.Google Scholar
Ebstein, R. P., Knafo, A., Mankuta, D., Chew, S. H., & Lai, P. S. (2012). The contributions of oxytocin and vasopressin pathway genes to human behavior. Hormones and Behavior, 61, 359379.Google Scholar
Feldman, R., Zagoory-Sharon, O., Weisman, O., Schneiderman, I., Gordon, I., Maoz, R., et al. (2012). Sensitive parenting is associated with plasma oxytocin and polymorphisms in the OXTR and CD38 genes. Biological Psychiatry, 72, 175181.CrossRefGoogle ScholarPubMed
Frick, P. J., & Hare, R. D. (2001). Antisocial Process Screening Device: APSD. Toronto: Multi-Health Systems.Google Scholar
Frick, P. J., Lilienfeld, S. O., Ellis, M., Loney, B., & Silverthorn, P. (1999). The association between anxiety and psychopathy dimensions in children. Journal of Abnormal Child Psychology, 27, 383392.Google Scholar
Frick, P. J., & Moffitt, T. E. (2010). A proposal to the DSM-V childhood disorders and ADHD and disruptive behavior disorders work groups to include a specifier to the diagnosis of conduct disorder based on the presence of callous–unemotional traits. Washington, DC: American Psychiatric Association.Google Scholar
Frick, P. J., & White, S. F. (2008). The importance of callous–unemotional traits for developmental models of aggressive and antisocial behavior. Journal of Child Psychology and Psychiatry and Allied Disciplines, 49, 359375.Google Scholar
Furman, D. J., Chen, M. C., & Gotlib, I. H. (2011). Variant in oxytocin receptor gene is associated with amygdala volume. Psychoneuroendocrinology, 36, 891897.CrossRefGoogle ScholarPubMed
Gimpl, G., & Fahrenholz, F. (2001). The oxytocin receptor system: Structure, function, and regulation. Physiological Reviews, 81, 629683.CrossRefGoogle ScholarPubMed
Goodman, R. (1997). The Strengths and Difficulties Questionnaire: A research note. Journal of Child Psychology and Psychiatry and Allied Disciplines, 38, 581586.Google Scholar
Gopal Rao, V. V. N., Loffler, C., Battey, J., & Hansmann, I. (1992). The human gene for oxytocin-neurophysin I (OXT) is physically mapped to chromosome 20p13 by in situ hybridization. Cytogenetics and Cell Genetics, 61, 271273.CrossRefGoogle Scholar
Gregory, S. G., Connelly, J. J., Towers, A. J., Johnson, J., Biscocho, D., Markunas, C. A., et al. (2009). Genomic and epigenetic evidence for oxytocin receptor deficiency in autism. BMC Medicine, 7, 62.Google Scholar
Herpers, P. C., Rommelse, N. N., Bons, D. M., Buitelaar, J. K., & Scheepers, F. E. (2012). Callous–unemotional traits as a cross-disorders construct. Social Psychiatry and Psychiatric Epidemiology, 47, 20452064. doi:10.1007/s00127-012-0513-xGoogle Scholar
Holland, D., & Dadds, M. R. (1997). The Diagnostic Interview Schedule for Children, Adolescents, and Parents. Unpublished manuscript, Griffith University, Brisbane.Google Scholar
Inoue, H., Yamasue, H., Tochigi, M., Abe, O., Liu, X., Kawamura, Y., et al. (2010). Association between the oxytocin receptor gene and amygdalar volume in healthy adults. Biological Psychiatry, 68, 10661072.Google Scholar
Insel, T. R., Young, L., Witt, D. M., & Crews, D. (1993). Gonadal steroids have paradoxical effects on brain oxytocin receptors. Journal of Neuroendocrinology, 5, 619628.Google Scholar
Israel, S., Lerer, E., Shalev, I., Uzefovsky, F., Riebold, M., Laiba, E., et al. (2009). The oxytocin receptor (OXTR) contributes to prosocial fund allocations in the Dictator Game and the social value orientations task. PLoS ONE, 4(5).CrossRefGoogle ScholarPubMed
Jacob, S., Brune, C. W., Carter, C. S., Leventhal, B. L., Lord, C., & Cook, E. H. Jr. (2007). Association of the oxytocin receptor gene (OXTR) in Caucasian children and adolescents with autism. Neuroscience Letters, 417, 69.Google Scholar
Johansson, A., Westberg, L., Sandnabba, K., Jern, P., Salo, B., & Santtila, P. (2012). Associations between oxytocin receptor gene (OXTR) polymorphisms and self-reported aggressive behavior and anger: Interactions with alcohol consumption. Psychoneuroendocrinology, 37, 15461556.CrossRefGoogle ScholarPubMed
Jones, A. P., Laurens, K. R., Herba, C. M., Barker, G. J., & Viding, E. (2009). Amygdala hypoactivity to fearful faces in boys with conduct problems and callous–unemotional traits. American Journal of Psychiatry, 166, 95102.Google Scholar
Kawamura, Y., Liu, X., Akiyama, T., Shimada, T., Otowa, T., Sakai, Y., et al. (2010). The association between oxytocin receptor gene (OXTR) polymorphisms and affective temperaments, as measured by TEMPS-A. Journal of Affective Disorders, 127, 3137.Google Scholar
Kawamura, Y., Liu, X., Shimada, T., Otowa, T., Kakiuchi, C., Akiyama, T., et al. (2011). Association between oxytocin receptor gene polymorphisms and autistic traits as measured by the Autism-Spectrum Quotient in a non-clinical Japanese population. Asia-Pacific Psychiatry, 3, 128136.Google Scholar
Kim, H. S., Sherman, D. K., Sasaki, J. Y., Xu, J., Chu, T. Q., Ryu, C., et al. (2010). Culture, distress, and oxytocin receptor polymorphism (OXTR) interact to influence emotional support seeking. Proceedings of the National Academy of Sciences, 107, 1571715721.Google Scholar
Kim-Cohen, J., Caspi, A., Moffitt, T. E., Harrington, H., Milne, B. J., & Poulton, R. (2003). Prior juvenile diagnoses in adults with mental disorder: Developmental follow-back of a prospective-longitudinal cohort. Archives of General Psychiatry, 60, 709717. doi:10.1001/archpsyc.60.7.709Google Scholar
Kogan, A., Saslow, L. R., Impett, E. A., Oveis, C., Keltner, D., & Saturn, S. R. (2012). Thin-slicing study of the oxytocin receptor (OXTR) gene and the evaluation and expression of the prosocial disposition. Proceedings of the National Academy of Sciences, 109, 1808.Google Scholar
Kroneman, L. M., Hipwell, A. E., Loeber, R., Koot, H. M., & Pardini, D. A. (2011). Contextual risk factors as predictors of disruptive behavior disorder trajectories in girls: The moderating effect of callous–unemotional features. Journal of Child Psychology and Psychiatry and Allied Disciplines, 52, 167175.CrossRefGoogle ScholarPubMed
Lerer, E., Levi, S., Salomon, S., Darvasi, A., Yirmiya, N., & Ebstein, R. P. (2008). Association between the oxytocin receptor (OXTR) gene and autism: Relationship to Vineland Adaptive Behavior Scales and cognition. Molecular Psychiatry, 13, 980988.Google Scholar
Liu, X., Kawamura, Y., Shimada, T., Otowa, T., Koishi, S., Sugiyama, T., et al. (2010). Association of the oxytocin receptor (OXTR) gene polymorphisms with autism spectrum disorder (ASD) in the Japanese population. Journal of Human Genetics, 55, 137141.CrossRefGoogle Scholar
Lucht, M. J., Barnow, S., Sonnenfeld, C., Rosenberger, A., Grabe, H. J., Schroeder, W., et al. (2009). Associations between the oxytocin receptor gene (OXTR) and affect, loneliness and intelligence in normal subjects. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 33, 860866.Google Scholar
Malik, A. I., Zai, C. C., Abu, Z., Nowrouzi, B., & Beitchman, J. H. (2012). The role of oxytocin and oxytocin receptor gene variants in childhood-onset aggression. Genes, Brain and Behavior, 11, 545551.Google Scholar
McCarthy, M. I., Abecasis, G. R., Cardon, L. R., Goldstein, D. B., Little, J., Ioannidis, J. P. A., et al. (2008). Genome-wide association studies for complex traits: Consensus, uncertainty and challenges. Nature Reviews Genetics, 9, 356369.Google Scholar
Mendlewicz, J., Crisafulli, C., Calati, R., Kocabas, N. A., Massat, I., Linotte, S., et al. (2012). Influence of COX-2 and OXTR polymorphisms on treatment outcome in treatment resistant depression. Neuroscience Letters, 516, 8588.Google Scholar
Meyer-Lindenberg, A., Domes, G., Kirsch, P., & Heinrichs, M. (2011). Oxytocin and vasopressin in the human brain: Social neuropeptides for translational medicine. Nature Reviews Neuroscience, 12, 524538.Google Scholar
Meyer-Lindenberg, A., Polin, J. B., Kohn, P. D., Holt, J. L., Egan, M. F., Weinberger, D. R., et al. (2001). Evidence for abnormal cortical functional connectivity during working memory in schizophrenia. American Journal of Psychiatry, 158, 18091817.Google Scholar
Modahl, C., Green, L., Fein, D., Morris, M., Waterhouse, L., Feinstein, C. et al. (1998). Plasma oxytocin levels in autistic children. Biological Psychiatry, 43, 270277.Google Scholar
Montag, C., Brockman, E. M., Bayerl, M., Rujescu, D., Müller, D. J., & Gallinat, J. (2012). Oxytocin and oxytocin receptor gene polymorphisms and risk for schizophrenia: A case-control study. World Journal of Biological Psychiatry. Advance online publication. doi:10.3109/15622975.2012.677547Google Scholar
Moul, C., Killcross, S., & Dadds, M. R. (2012). A model of differential amygdala activation in psychopathy. Psychological Review, 119, 789806. doi:10.1037/a0029342Google Scholar
Norman, G. J., Hawkley, L., Luhmann, M., Ball, A. B., Cole, S. W., Berntson, G. G., et al. (2012). Variation in the oxytocin receptor gene influences neurocardiac reactivity to social stress and HPA function: A population based study. Hormones and Behavior, 61, 134139.Google Scholar
Oxford, M., Cavell, T. A., & Hughes, J. N. (2003). Callous/unemotional traits moderate the relation between ineffective parenting and child externalizing problems: A partial replication and extension. Journal of Clinical Child and Adolescent Psychology, 32, 577585.Google Scholar
Park, J., Willmott, M., Vetuz, G., Toye, C., Kirley, A., Hawi, Z., et al. (2010). Evidence that genetic variation in the oxytocin receptor (OXTR) gene influences social cognition in ADHD. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 34, 697702.Google Scholar
Pasalich, D. S., Dadds, M. R., Hawes, D. J., & Brennan, J. (2011). Do callous–unemotional traits moderate the relative importance of parental coercion versus warmth in child conduct problems? An observational study. Journal of Child Psychology and Psychiatry and Allied Disciplines, 52, 13081315.Google Scholar
Patterson, G. R., DeBaryshe, B. D., & Ramsey, E. (1989). A developmental perspective on antisocial behavior. American Psychologist, 44, 329335.CrossRefGoogle ScholarPubMed
Petersen, A. C., Crockett, L., Richards, M., & Boxer, A. (1988). A self-report measure of pubertal status: Reliability, validity, and initial norms. Journal of Youth and Adolescence, 17, 117133.Google Scholar
Poulin, M. J., Holman, E. A., & Buffone, A. (2012). The neurogenetics of nice: Receptor genes for oxytocin and vasopressin interact with threat to predict prosocial behavior. Psychological Science, 23, 446452.Google Scholar
Rey, J. M., Singh, M., Hung, S. F., Dossetor, D. R., Newman, L., Plapp, J. M., et al. (1997). A global scale to measure the quality of the family environment. Archives of General Psychiatry, 54, 817822.Google Scholar
Rodrigues, S. M., Saslow, L. R., Garcia, N., John, O. P., & Keltner, D. (2009). Oxytocin receptor genetic variation relates to empathy and stress reactivity in humans. Proceedings of the National Academy of Sciences, 106, 2143721441.Google Scholar
Sakai, J. T., Crowley, T. J., Stallings, M. C., McQueen, M., Hewitt, J. K., Hopfer, C., et al. (2012). Test of association between 10 single nucleotide polymorphisms in the oxytocin receptor gene and conduct disorder. Psychiatric Genetics, 22, 99102.Google Scholar
Saphire-Bernstein, S., Way, B. M., Kim, H. S., Sherman, D. K., & Taylor, S. E. (2011). Oxytocin receptor gene (OXTR) is related to psychological resources. Proceedings of the National Academy of Sciences, 108, 1511815122.Google Scholar
Sturge-Apple, M. L., Cicchetti, D., Davies, P., Davies, P. T., & Suor, J. H. (2012). Differential susceptibility in spillover between interparental conflict and maternal parenting practices: Evidence for OXTR and 5-HTT genes. Journal of Family Psychology, 26, 431442. doi:10.1037/a0028302Google Scholar
Tansey, K. E., Brookes, K. J., Hill, M. J., Cochrane, L. E., Gill, M., Skuse, D., et al. (2010). Oxytocin receptor (OXTR) does not play a major role in the aetiology of autism: Genetic and molecular studies. Neuroscience Letters, 474, 163167.Google Scholar
Thompson, R. J., Parker, K. J., Hallmayer, J. F., Waugh, C. E., & Gotlib, I. H. (2011). Oxytocin receptor gene polymorphism (rs2254298) interacts with familial risk for psychopathology to predict symptoms of depression and anxiety in adolescent girls. Psychoneuroendocrinology, 36, 144147.Google Scholar
Tost, H., Kolachana, B., Hakimi, S., Lemaitre, H., Verchinski, B. A., Mattay, V. S., et al. (2010). A common allele in the oxytocin receptor gene (OXTR) impacts prosocial temperament and human hypothalamic-limbic structure and function. Proceedings of the National Academy of Sciences, 107, 1393613941.Google Scholar
Viding, E., Blair, R. J. R., Moffitt, T. E., & Plomin, R. (2005). Evidence for substantial genetic risk for psychopathy in 7-year-olds. Journal of Child Psychology and Psychiatry and Allied Disciplines, 46, 592597.Google Scholar
Viding, E., Frick, P. J., & Plomin, R. (2007). Aetiology of the relationship between callous–unemotional traits and conduct problems in childhood. British Journal of Psychiatry, 190(Suppl. 49), s33s38.Google Scholar
Viding, E., Hanscombe, K. B., Curtis, C. J. C., Davis, O. S. P., Meaburn, E. L., & Plomin, R. (2010). In search of genes associated with risk for psychopathic tendencies in children: A two-stage genome-wide association study of pooled DNA. Journal of Child Psychology and Psychiatry and Allied Disciplines, 51, 780788.Google Scholar
Viding, E., Sebastian, C. L., Dadds, M. R., Lockwood, P. L., Cecil, C. A. M., De Brito, S. A., et al. (in press). Fast and fearless: Amygdala response to pre-attentive masked fear is associated with callous–unemotional traits in children with conduct problems. American Journal of Psychiatry.Google Scholar
Wermter, A. K., Kamp-Becker, I., Hesse, P., Schulte-Körne, G., Strauch, K., & Remschmidt, H. (2010). Evidence for the involvement of genetic variation in the oxytocin receptor gene (OXTR) in the etiology of autistic disorders on high-functioning level. American Journal of Medical Genetics, 153B, 629639.Google Scholar
Wootton, J. M., Frick, P. J., Shelton, K. K., & Silverthorn, P. (1997). Ineffective parenting and childhood conduct problems: The moderating role of callous–unemotional traits. Journal of Consulting and Clinical Psychology, 65, 301308.CrossRefGoogle ScholarPubMed
Wu, N., Li, Z., & Su, Y. (2012). The association between oxytocin receptor gene polymorphism (OXTR) and trait empathy. Journal of Affective Disorders, 138, 468472.Google Scholar
Wu, S., Jia, M., Ruan, Y., Liu, J., Guo, Y., Shuang, M., et al. (2005). Positive association of the oxytocin receptor gene (OXTR) with autism in the Chinese Han population. Biological Psychiatry, 58, 7477.Google Scholar