Oxytocin Receptor Gene Methylation Research Articles

Exploring the role of OXTR gene methylation in attachment development: A longitudinal study.

The current study explored longitudinally whether oxytocin receptor gene methylation (OXTRm) changes moderated the association between parental sensitivity changes and children'sattachment changes over three waves. Six hundred six Flemish children (10-12 years, 42.8%-44.8% boys) completed attachment measures and provided salivary OXTRm data on seven CpG sites. Their parents reported their sensitive parenting. Results suggest that OXTRm changes hardly link to attachment (in)security changes after the age of 10. Some support was found for interaction effects between parental sensitivity changes and OXTRm changes on attachment changes over time. Effects suggest that for children with increased OXTRm in the promotor region and decreased methylation in the inhibitor region over time, increased parental sensitivity was associated with increased secure attachment and decreased insecure attachment over time.

Endogenous oxytocin levels in children with autism: Associations with cortisol levels and oxytocin receptor gene methylation

Alterations in the brain’s oxytocinergic system have been suggested to play an important role in the pathophysiology of autism spectrum disorder (ASD), but insights from pediatric populations are sparse. Here, salivary oxytocin was examined in the morning (AM) and afternoon (PM) in school-aged children with (n = 80) and without (n = 40) ASD (boys/girls 4/1), and also characterizations of DNA methylation (DNAm) of the oxytocin receptor gene (OXTR) were obtained. Further, cortisol levels were assessed to examine links between the oxytocinergic system and hypothalamic-pituitary-adrenal (HPA) axis signaling. Children with ASD displayed altered (diminished) oxytocin levels in the morning, but not in the afternoon, after a mildly stress-inducing social interaction session. Notably, in the control group, higher oxytocin levels at AM were associated with lower stress-induced cortisol at PM, likely reflective of a protective stress-regulatory mechanism for buffering HPA stress activity. In children with ASD, on the other hand, a significant rise in oxytocin levels from the morning to the afternoon was associated with a higher stress-induced cortisol release in the afternoon, likely reflective of a more reactive stress regulatory release of oxytocin for reactively coping with heightened HPA activity. Regarding epigenetic modifications, no overall pattern of OXTR hypo- or hypermethylation was evident in ASD. In control children, a notable association between OXTR methylation and levels of cortisol at PM was evident, likely indicative of a compensatory downregulation of OXTR methylation (higher oxytocin receptor expression) in children with heightened HPA axis activity. Together, these observations bear important insights into altered oxytocinergic signaling in ASD, which may aid in establishing relevant biomarkers for diagnostic and/or treatment evaluation purposes targeting the oxytocinergic system in ASD.

Oxytocin receptor gene methylation as a molecular marker for severity of depressive symptoms in affective disorder patients

BackgroundOxytocin (OXT) is a neuropeptide and hormone involved in emotional functioning and also seems to play a role in moderating the stress response. Both preclinical and clinical studies point to an increased methylation status of the Oxytocin receptor (OXTR) promoter region with concomitant deficits in social, cognitive and emotional functioning. We hypothesize that methylation levels (%) of the oxytocin receptor promoter region correlate with the severity of depression symptoms and/or with the severity of childhood trauma within this present sample of affective disorder patients.MethodologyEight hundred forty six (846) affective disorder patients of Central European origin were recruited at the Department of Psychiatry and Psychotherapy of the Medical University Vienna, the Karl Landsteiner University for Health and Science and Zentren für seelische Gesundheit, BBRZ-Med Leopoldau. Psychiatric assessment included a semi-structured diagnostic interview (Schedules for Clinical Assessment in Neuropsychiatry), the Hamilton Depression Scale and the Childhood Trauma Questionnaire. Concomitantly DNA samples of peripheral blood cells were collected for Multiplexed and Sensitive DNA Methylation Testing.ResultsOur data suggests a positive but not significant association between OXTR promoter Exons 1–3 methylation levels and severity of depression symptoms as well as severity of emotional neglect in affective disorder patients and no association with childhood trauma.ConclusionsOur findings contribute to elucidate the role of OXTR in affective disorders, but further longitudinal studies in particular are necessary to broaden the current state of knowledge.

Pathways linking childhood trauma to rural, unmarried, African American father involvement through oxytocin receptor gene methylation.

Father involvement contributes uniquely to children's developmental outcomes. The antecedents of father involvement among unmarried, African American fathers from rural areas, however, have been largely overlooked. The present study tested a conceptual model linking retrospective reports of childhood trauma and early adulthood social instability to father involvement among unmarried, African American men living in resource-poor, rural communities in the southeastern United States. We hypothesized these factors would influence father involvement indirectly, via DNA methylation of the oxytocin receptor gene (OXTR). A sample of 192 fathers participated in 3 waves of data collection in early adulthood. Fathers reported on social instability at Wave 1; OXTR methylation was assessed via saliva samples at Wave 2; and measures of father involvement, retrospective childhood trauma, and quality of the fathers' relationships with their children's mothers were collected at Wave 3. Structural equation modeling indicated that childhood trauma was related directly to reduced levels of father involvement and to increased social instability. Social instability was associated with elevated levels of OXTR methylation, which in turn predicted decreased father involvement. The indirect effect from social instability to father involvement via OXTR methylation was significant. These associations did not operate through fathers' relationship with the child's mother and remained significant even accounting for associations between interparental relationship quality and father involvement. Findings suggest that OXTR methylation might be a biological mechanism linking social instability to father involvement among unmarried, African American fathers in vulnerable contexts and underscore the detrimental influence of childhood trauma on father involvement. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Childhood Adversity, Socioeconomic Instability, Oxytocin-Receptor-Gene Methylation, and Romantic-Relationship Support Among Young African American Men

Men’s emerging adult romantic relationships forecast downstream relationship behavior, including commitment and quality. Accumulating evidence implicates methylation of the oxytocin-receptor-gene (OXTR) system in regulating relationship behavior. We tested hypotheses regarding the links between (a) childhood adversity and (b) socioeconomic instability in emerging adulthood on supportive romantic relationships via their associations with OXTR methylation. Hypotheses were tested using path analysis with data from 309 participants in the African American Men’s Project. Consistent with our hypotheses, results showed that OXTR methylation proximally predicted changes in relationship support during a 1.5-year period. Childhood adversity was not directly associated with OXTR methylation but, rather, with contemporaneous socioeconomic instability, which in turn predicted elevated OXTR methylation. Findings suggest that early adversity is indirectly associated with OXTR methylation by links with downstream socioeconomic instability. Findings must be considered provisional, however, because preregistered replications are needed to establish more firmly the relations among these variables.

The interaction between oxytocin receptor gene methylation and maternal behavior on children's early theory of mind abilities.

Theory of mind, the ability to represent the mental states of others, is an important social cognitive process, which contributes to the development of social competence. Recent research suggests that interactions between gene and environmental factors, such as oxytocin receptor gene (OXTR) polymorphisms and maternal parenting behavior, may underlie individual differences in children's theory of mind. However, the potential influence of DNA methylation of OXTR remains unclear. The current study investigated the roles of OXTR methylation, maternal behavior, and their statistical interaction on toddlers' early emerging theory of mind abilities. Participants included a community sample of 189 dyads of mothers and their 2- to 3-year-old children, whose salivary DNA was analyzed. Results indicated that more maternal structuring behavior was associated with better performance, on a battery of three theory of mind tasks, while higher OXTR methylation within exon 3 was associated with poorer performance. A significant interaction also emerged, such that OXTR methylation was related to theory of mind among children whose mothers displayed less structuring, when controlling for children's age, sex, ethnicity, number of child-aged siblings, verbal ability, and maternal education. Maternal structuring behavior may buffer the potential negative impact of hypermethylation on OXTR gene expression and function.

Interactions between oxytocin receptor gene methylation and callous-unemotional traits impact socioaffective brain systems in conduct-disordered youth

Interactions between oxytocin receptor gene methylation and callous-unemotional traits impact socioaffective brain systems in conduct-disordered youth

P.1.14 Oxytocin receptor gene methylation as a molecular marker for severity of depressive symptoms in mood disorder patients

P.1.14 Oxytocin receptor gene methylation as a molecular marker for severity of depressive symptoms in mood disorder patients

Oxytocin receptor gene methylation in male and female PTSD patients and trauma-exposed controls

Oxytocin receptor gene (OXTR) DNA-methylation levels have been associated with trauma-exposure, mood- and anxiety disorders, and social processes relevant to posttraumatic stress disorder (PTSD). We hypothesized that OXTR methylation may play a role in the neurobiological underpinnings of PTSD. In the current study, we compared OXTR methylation between PTSD patients (n = 31, 14 females) and trauma-exposed controls (n = 36, 19 females). Additionally, the association between OXTR methylation and PTSD symptom severity and amygdala reactivity to an emotional faces task was assessed, as a neural hallmark of PTSD. DNA-methylation was investigated in the CpG island located at exon 3 of the OXTR, previously associated with OXTR expression. We observed a significant interaction between PTSD-status, sex and CpG-position on methylation levels. Post-hoc testing revealed that methylation levels at two specific CpG-sites were significantly higher in PTSD females compared to female trauma-exposed controls and PTSD males (CpGs Chr3:8809437, Chr3:8809413). No significant differences in methylation were observed between male PTSD patients and controls. Furthermore, within PTSD females, methylation in these CpG-sites was positively associated with anhedonia symptoms and with left amygdala responses to negative emotional faces, although this was no longer significant after stringent correction for multiple-comparisons. Though the modest size of the current sample is an important limitation, we are the first to report on OXTR methylation in PTSD, replicating previously observed (sex-specific) associations of OXTR methylation with other psychiatric disorders.

Oxytocin receptor gene methylation and substance use problems among young African American men

BackgroundStressful or supportive social environments promote biological changes with regulatory implications for future relationships and substance abuse. Recent research suggests links between adverse social environments, prosocial relationships, methylation at the oxytocin receptor gene (OXTR), and substance abuse. The potential for OXTR methylation to act as the mechanism linking social environments to substance abuse has yet to be investigated. We hypothesized that, for young African American men, childhood adversity increases, and supportive, prosocial bonds with parents, peers, partners, and community mentors decrease OXTR methylation levels, which in turn predict increases in substance-related symptoms. MethodsA sample of 358 rural African American men (age 19 at baseline) provided self-report data at three time points separated by 18 months and a genetic specimen at Time 2. ResultsEarly adversity was associated with OXTR methylation indirectly via contemporary prosocial relationships. OXTR methylation was a proximal predictor of changes in substance-related symptoms. We found no evidence for a direct association of self-reported childhood trauma with OXTR methylation status. ConclusionsFindings suggest that OXTR methylation is linked to substance use symptomatology, ostensibly resulting in increased expression of oxytocin (OT) in peripheral and central nervous systems. OXTR may act as a mechanism to explain how prosocial ties deter substance abuse and related problems. Despite conjectures in the literature that early adversity may become physiologically embedded via methylation in the OT system, direct effects were not evident. Rather, early adversity may affect OXTR methylation via influence on contemporary prosocial relationships.

Interactions Between Oxytocin Receptor Gene Methylation and Callous-Unemotional Traits Impact Socioaffective Brain Systems in Conduct-Disordered Offenders

BackgroundThe developmental trajectory of psychopathy seemingly begins early in life and includes the presence of callous-unemotional (CU) traits (e.g., perturbed socioaffective reactivity and empathy, callousness) in youths with conduct disorder (CD). Whereas oxytocin receptor gene methylation (OXTRMeth) and its downstream neuromodulatory effects are deemed relevant to CU traits, nothing is known of how OXTRMeth interacts with CU traits to impact socioaffective brain systems in youngsters with CD. MethodsHence, we uniquely probed OXTRMeth × CU trait interactions on corticolimbic activity and amygdala subregional connections during recognition and resonance of distressing socioaffective stimuli (angry and fearful faces), in juvenile offenders with CD (n = 39) versus matched healthy control youths (n = 27). ResultsRelative to healthy control youths, elevated OXTRMeth and CU levels in youths with CD essentially interacted to predict frontoparietal hyperactivity and amygdalo-frontoparietal disconnection during task performance. Specifically, increasing OXTRMeth and CU levels in youths with CD interactively predicted midcingulate hyperactivity during both emotion conditions, with insular, temporoparietal, and precuneal hyperactivity additionally emerging during emotion recognition. Interactions between high OXTRMeth and CU levels in youths with CD additionally predicted centromedial amygdala decoupling from ventromedial/orbitofrontal regions during emotion recognition, along with basolateral amygdala decoupling from precuneal and temporoparietal cortices during emotion resonance. ConclusionsThese results uniquely suggest that interactions between OXTRMeth and CU traits in youths with CD may affect brain systems critical to decoding and integrating socioaffective information. Developmental models of CU traits and psychopathy could thus possibly advance by further examining OXTR epigenetic effects, which may hold promise for indicated prevention and personalized treatment by targeting oxytocinergic function.

P.4.e.008 - Sex-dependent differences in oxytocin receptor gene methylation between posttraumatic stress disorder patients and trauma-exposed healthy controls

P.4.e.008 - Sex-dependent differences in oxytocin receptor gene methylation between posttraumatic stress disorder patients and trauma-exposed healthy controls

Natural variation in maternal care and cross-tissue patterns of oxytocin receptor gene methylation in rats

This article is part of a Special Issue “Parental Care”. Since the first report of maternal care effects on DNA methylation in rats, epigenetic modifications of the genome in response to life experience have become the subject of intense focus across many disciplines. Oxytocin receptor expression varies in response to early experience, and both oxytocin signaling and methylation status of the oxytocin receptor gene (Oxtr) in blood have been related to disordered social behavior. It is unknown whether Oxtr DNA methylation varies in response to early life experience, and whether currently employed peripheral measures of Oxtr methylation reflect variation in the brain. We examined the effects of early life rearing experience via natural variation in maternal licking and grooming during the first week of life on behavior, physiology, gene expression, and epigenetic regulation of Oxtr across blood and brain tissues (mononucleocytes, hippocampus, striatum, and hypothalamus). Rats reared by “high” licking-grooming (HL) and “low” licking-grooming (LL) rat dams exhibited differences across study outcomes: LL offspring were more active in behavioral arenas, exhibited lower body mass in adulthood, and showed reduced corticosterone responsivity to a stressor. Oxtr DNA methylation was significantly lower at multiple CpGs in the blood of LL versus HL males, but no differences were found in the brain. Across groups, Oxtr transcript levels in the hypothalamus were associated with reduced corticosterone secretion in response to stress, congruent with the role of oxytocin signaling in this region. Methylation of specific CpGs at a high or low level was consistent across tissues, especially within the brain. However, individual variation in DNA methylation relative to these global patterns was not consistent across tissues. These results suggest that blood Oxtr DNA methylation may reflect early experience of maternal care, and that Oxtr methylation across tissues is highly concordant for specific CpGs, but that inferences across tissues are not supported for individual variation in Oxtr methylation.

Oxytocin receptor gene methylation: converging multilevel evidence for a role in social anxiety.

Social anxiety disorder (SAD) is a commonly occurring and highly disabling disorder. The neuropeptide oxytocin and its receptor (OXTR) have been implicated in social cognition and behavior. This study-for the first time applying a multilevel epigenetic approach-investigates the role of OXTR gene methylation in categorical, dimensional, and intermediate neuroendocrinological/neural network phenotypes of social anxiety. A total of 110 unmedicated patients with SAD and matched 110 controls were analyzed for OXTR methylation by direct sequencing of sodium bisulfite-converted DNA extracted from whole blood. Furthermore, OXTR methylation was investigated regarding SAD-related traits (Social Phobia Scale (SPS) and Social Interaction Anxiety Scale (SIAS)), salivary cortisol response during the Trier social stress test (TSST), and amygdala responsiveness to social phobia related verbal stimuli using fMRI. Significantly decreased OXTR methylation particularly at CpG Chr3: 8 809 437 was associated with (1) the categorical phenotype of SAD (p<0.001, Cohen's d=0.535), (2) increased SPS and SIAS scores (p<0.001), (3) increased cortisol response to the TSST (p=0.02), and (4) increased amygdala responsiveness during social phobia-related word processing (right: p(corr)<0.001; left: p(corr)=0.005). Assuming that decreased OXTR methylation confers increased OXTR expression, the present finding may reflect a compensatory upregulation for pathologically reduced oxytocin levels or a causally relevant increased OXTR activation in SAD and related traits. OXTR methylation patterns might thus serve as peripheral surrogates of oxytocin tone and aid in establishing accessible biomarkers of SAD risk allowing for indicated preventive interventions and personalized treatment approaches targeting the oxytocin system.