Methylation of the oxytocin receptor gene and oxytocin blood levels in the development of psychopathy

Abstract

Child conduct problems (CPs) are a robust predictor of adult mental health; the concurrence of callous-unemotional (CU) traits confers specific risk for psychopathy. Psychopathy may be related to disturbances in the oxytocin (OXT) system. Evidence suggests that epigenetic changes in the OXT receptor gene (OXTR) are associated with lower circulating OXT and social-cognitive difficulties. We tested methylation levels of OXTR in 4- to 16-year-old males who met DSM criteria for a diagnosis of oppositional-defiant or conduct disorder and were stratified by CU traits and age. Measures were DNA methylation levels of six CpG sites in the promoter region of the OXTR gene (where a CpG site is a cytosine nucleotide occurs next to a guanine nucleotide in the linear sequence of bases along its lenth, linked together by phosphate binding), and OXT blood levels. High CU traits were associated with greater methylation of the OXTR gene for two cytosine nucleotide and guanine nucleotide phosphate linked sites and lower circulating OXT in older males. Higher methylation correlated with lower OXT levels. We conclude that greater methylation of OXTR characterizes adolescent males with high levels of CU and CPs, and this methylation is associated with lower circulating OXT and functional impairment in interpersonal empathy. The results add genetic evidence that high CU traits specify a distinct subgroup within CP children, and they suggest models of psychopathy may be informed by further identification of these epigenetic processes and their functional significance.

Oxytocin Receptor Gene Methylation: Converging Multilevel Evidence for a Role in Social Anxiety

“…OXTR methylation in social anxiety C Ziegler et al Previously, decreased baseline oxytocin plasma levels were observed to be associated with SAD (Hoge et al, 2012), and intranasal application of oxytocin adjunct to psychotherapy significantly improved self-reported speech performance in SAD patients (Guastella et al, 2009). Assuming decreased OXTR methylation resulting in increased OXTR mRNA expression (see Introduction; Dadds et al, 2014;Gregory et al, 2009;Kusui et al, 2001;Mamrut et al, 2013), the present finding of OXTR hypomethylation being associated with SAD as well as with social phobia-related dimensional measures may reflect a compensatory mechanism leading to an upregulation of oxytocin receptor expression against the background of pathologically low oxytocin levels in SAD and social phobia-related phenotypes. This interpretation is reciprocally analogous to studies showing oxytocin-induced OXTR desensitization as evidenced by downregulated OXTR mRNA (Phaneuf et al, 2000), and is furthermore consistent with significantly decreased OXTR methylation 90 min after stress exposure (TSST) potentially indicating a compensatory upregulation of the oxytocin system serving to buffer social stress (Unternaehrer et al, 2012; for review see Marazziti et al, 2014).…”

“…The OXTR gene contains a CpG island spanning exons 1 to 3 (Chr3:8 808 962-8 811 280, GRCh37/hg19) , with evidence for increased OXTR methylation to confer decreased OXTR expression: in hepatoblastoma cells, methylation of this OXTR CpG island significantly suppressed OXTR mRNA expression by 70% (Kusui et al, 2001). Accordingly, Gregory et al (2009) observed methylation of two CpG sites within this island to result in a 20% reduction in OXTR mRNA expression, and lower plasma oxytocin levels were associated with increased OXTR methylation in peripheral blood (Dadds et al, 2014). Also, in murine cell lines, negative correlations between OXTR methylation and mRNA expression were observed (Mamrut et al, 2013).…”

“…Also, in murine cell lines, negative correlations between OXTR methylation and mRNA expression were observed (Mamrut et al, 2013). So far, OXTR methylation of this CpG island has been investigated with regard to several phenotypes related to social cognition and functioning: in a sample of male adolescents with oppositional-defiant or conduct disorder, increased OXTR methylation in peripheral blood was associated with callous-unemotional traits (Dadds et al, 2014). In autism, significantly increased OXTR methylation was observed in peripheral blood mononuclear cells and temporal cortex tissue (Gregory et al, 2009).…”

Developmental Perspectives on Oxytocin and Vasopressin

“…The methylation status of the OXTR gene has also been explored in conduct disorder (Dadds et al, 2014), a developmental antecedent to psychopathic traits in adulthood. Significantly higher methylation status of OXTR was observed in older children aged 9-16 years with comorbid callous-unemotional traits compared with the same age individuals with low callous-unemotional traits.…”

Short Review on the Aggressive Behaviour: Genetical, Biological Aspects and Oxytocin Relevance

“…the vasopressin/oxytocin signalling systems are involved in a variety of functions such as reproduction, immunity and thermoregulation, but with focus on the social manifestations connected with affiliation and aggression [42]) and lately, there is increased interest in understanding the role of (especially intranasal) oxytocin on the main neuropsychiatric disorders such as autism [45], schizophrenia [46], anxiety [47], depression, Prader Willi syndrome [48] or even psychopathy [49] and the variety of behaviours exhibited by the relevant central areas, including aggression [50][51][52].…”