OXTR Methylation Research Articles

Grandmotherhood is associated with reduced OXTR DNA methylation

In mammals, both parental and alloparental care are associated with increased brain oxytocin signaling. Grandmothers are important alloparents in many human families. Based on animal model research showing that peripheral Oxtr methylation is associated with Oxtr expression in the nucleus accumbens, we investigated whether grandmaternal caregiving is associated with lower peripheral OXTR methylation. Results reveal several regions within OXTR where grandmothers have lower DNA methylation compared with non-grandmother controls, and no regions where grandmothers have higher OXTR DNA methylation. Among grandmothers, OXTR methylation was most strongly correlated with the grandmother’s assessment of the degree of positive feelings between her and the grandchild, which in turn predicted caregiving engagement. Although there was little evidence that grandmaternal OXTR methylation modulated grandmaternal neural responses to viewing photos of the grandchild within brain regions involved in caregiving motivation, it was negatively correlated with the neural response to an unknown grandchild. Thus, while OT signaling may not be essential for activating grandmaternal brain reward systems in our low-stress experimental context, it may support caregiving motivation towards unrelated children. Future longitudinal research should determine whether the transition to grandmotherhood is associated with a reduction in OXTR methylation.

A dog's life: Early life histories influence methylation of glucocorticoid (NR3C1) and oxytocin (OXTR) receptor genes, cortisol levels, and attachment styles.

Early life deprivation and stress can contribute to life-long, problematic consequences, including epigenetic variations related to behavior and health. Domestic dogs share human environments and social-cognitive traits, making them a promising comparative model to examine developmental plasticity. We examined 47 owner-dog dyads, including dogs rescued from abusive or neglectful environments, and matched control dogs for changes in DNA methylation of glucocorticoid (NR3C1) and oxytocin (OXTR) receptor genes previously shown to be affected by early life stress in other species including humans. We used an attachment paradigm, which included a separation event to examine cortisol levels and owner-dog attachment styles. Overall, dogs with adverse histories had different NR3C1 methylation patterns as a function of age and less OXTR methylation than comparison dogs. Dogs with adverse histories did not differ in their cortisol change from baseline to poststressor from comparison dogs, but the change in cortisol was associated with NR3C1 methylation. In addition, dogs with a history of early life stress had more insecure attachment styles; for every unit increase of OXTR methylation, the odds increased for insecure attachment style. This study demonstrates that adverse life histories lead to methylation differences, resulting in the hypothalamic-pituitary-adrenal (HPA) axis's dysregulation and differences in behavioral phenotypes.

Methylation of the Oxytocin, Oxytocin Receptor, and Vasopressin Gene Promoters in Tobacco Use Disorder during Cessation

Introduction: Vasopressin (AVP) and oxytocin (OT) exert sex-specific effects on social pair bonding and stress reactions while also influencing craving in substance use disorders. In this regard, intranasal oxytocin (OT) and AVP antagonists present potential treatments for tobacco use disorder (TUD). Since transcription of both hormones is also regulated by gene methylation, we hypothesized sex-specific changes in methylation levels of the AVP, OT, and OT receptor (OXTR) gene during nicotine withdrawal. Methods: The study population consisted of 49 smokers (29 males, 20 females) and 51 healthy non-smokers (25 males, 26 females). Blood was drawn at day 1, day 7, and day 14 of smoking cessation. Craving was assessed with the questionnaire on smoking urges (QSU). Results: Throughout cessation, mean methylation of the OT promoter gene increased in males and decreased in females. OXTR receptor methylation decreased in females, while in males it was significantly lower at day 7. Regarding the AVP promoter, mean methylation increased in males while there were no changes in females. Using mixed linear modeling, CpG position, time point, sex, and the interaction of time point and sex as well as time point, sex, and QSU had a significant fixed effect on OT and AVP gene methylation. The interaction effect suggests that sex, time point, and QSU are interrelated, meaning that, depending on the sex, methylation could be different at different time points and vice versa. There was no significant effect of QSU on mean OXTR methylation. Discussion: We identified differences at specific CpGs between controls and smokers in OT and AVP and in overall methylation of the AVP gene. Furthermore, we found sex-specific changes in mean methylation levels of the mentioned genes throughout smoking cessation, underlining the relevance of sex in the OT and vasopressin system. This is the first study on epigenetic regulation of the OT promoter in TUD. Our results have implications for research on the utility of the AVP and OT system for treating substance craving. Future studies on both targets need to analyze their effect in the context of sex, social factors, and gene regulation.

A targeted long-read sequencing approach questions the association of OXTR methylation with high-functioning autism

BackgroundDNA sequence variation and altered epigenetic regulation of the oxytocin receptor gene (OXTR) have been implicated in autism and autistic-like behaviors. While previous studies have examined subsegments of OXTR, nanopore Cas9-targeted sequencing (nCATS) allows deep characterization of entire genes with simultaneous assessment of epigenetic 5-methylcytosine (5mC) modification and without the need for prior DNA amplification or bisulfite conversion. This pilot study uses an nCATS approach to sequence the entire OXTR gene and its regulatory construct and screen for 5mC modification to compare results between individuals with high-functioning autism (HFA) and neurotypical controls (NC).MethodsUsing DNA extracted from peripheral blood, OXTR (Hg38, chr3: 8750381–8770434, 20,054 base pairs) was analyzed by nCATS. 5mC modification probabilities were calculated and visualized across the gene and differential methylation analysis was performed.ResultsTwenty adults with HFA (10 males, 10 females) and 20 age- and sex-matched NC (± 5 years) were included. There were no apparent group differences in the entire OXTR gene sequence, except for the intron variant rs918316, which was clustered in the HFA group. However, differential methylation analysis did not reveal a single significant group-dependent differentially methylated site among the 412 CpG sites captured.LimitationsLimitations of this study include the small number of samples due to the pilot nature of the study, which particularly limits the relevance of the sequence variants found. It should also be noted that the use of peripheral blood material limits the ability to draw conclusions about central processes.ConclusionsPrevious findings of autism-associated OXTR epigenetic alterations were not reproducible with our method. In our opinion, this may lead to a reconsideration of the relevance of altered methylation at individual OXTR CpG positions in autism research. However, given the pilot nature of the study, these results need to be replicated in independent cohorts and with larger sample sizes.

DNA methylation of the oxytocin receptor interacts with age to impact neural response to social stimuli.

Social isolation is one of the strongest predictors of increased risk of mortality in older adulthood. The ability to form and maintain the social relationships that mitigate this risk is partially regulated by the oxytocinergic system and one's ability to attend to and process social information. We have previously shown that an epigenetic change to the DNA of the oxytocin receptor gene (OXTR methylation) affects the salience of social information in young adults. Little is known about how the oxytocinergic system ages and what effect this aging system has on social cognitive abilities throughout the lifespan. Here we explored age-related differences in the association between neural response during selective social attention and OXTR DNA methylation in young (age 18-31) and older (age 58-81) adults. Participants underwent fMRI during a selective social attention task and provided a DNA sample for the assessment of OXTR methylation. We found that older adults activated diffuse areas of visual cortex and dorsolateral prefrontal cortex during selective social attention, consistent with the dedifferentiation and compensatory neural activation commonly reported in aging. We found a significant age-by-OXTR methylation interaction on neural response when attending to social stimuli in a complex display; young adults displayed a positive association between OXTR methylation and neural activation, replicating our prior finding that young adults with presumed diminished endogenous access to oxytocin recruit regions of the attentional cortex to a greater extent. This association did not hold for older adults. Instead, perceived social support interacted with OXTR methylation to influence neural response during selective social attention. These data suggest that environmental factors like social support moderate biological processes in aging and highlight the importance of a lifespan perspective for understanding associations between individual differences in the oxytocinergic system, neural function, and social behavior.

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.

Vasopressin, and not oxytocin, receptor gene methylation is associated with individual differences in receptive joint attention in chimpanzees (Pan troglodytes).

Joint attention (JA) is an important milestone in human infant development and is predictive of the onset of language later in life. Clinically, it has been reported that children at risk for or with a diagnosis of autism spectrum disorder (ASD) perform more poorly on measures of JA compared to neurotypical controls. JA is not unique to humans but has also been reported in great apes and to a lesser extent in more distantly related monkeys. Further, individual differences in JA among chimpanzees are associated with polymorphisms in the vasopressin and oxytocin genes, AVPR1A and OXTR. Here, we tested whether individual variation in DNA methylation of OXTR and AVPR1A were associated with performance on JA tasks in chimpanzees. We found that individual differences in JA performance was associated with AVPR1A methylation, but not OXTR methylation in the chimpanzees. The collective results provide further evidence of the role of AVPR1A in JA abilities in chimpanzees. The results further suggest that methylation values for AVPR1A may be useful biomarkers for identifying individuals at risk for ASD or related neurodevelopmental disorders associated with impairments in JA abilities.

Oxytocin receptor DNA methylation is associated with exogenous oxytocin needs during parturition and postpartum hemorrhage

BackgroundThe oxytocin receptor gene (OXTR) is regulated, in part, by DNA methylation. This mechanism has implications for uterine contractility during labor and for prevention or treatment of postpartum hemorrhage, an important contributor to global maternal morbidity and mortality.MethodsWe measured and compared the level of OXTR DNA methylation between matched blood and uterine myometrium to evaluate blood as an indicator of uterine methylation status using targeted pyrosequencing and sites from the Illumina EPIC Array. Next, we tested for OXTR DNA methylation differences in blood between individuals who experienced a postpartum hemorrhage arising from uterine atony and matched controls following vaginal birth. Bivariate statistical tests, generalized linear modeling and Poisson regression were used in the analyses.ResultsHere we show a significant positive correlation between blood and uterine DNA methylation levels at several OXTR loci. Females with higher OXTR DNA methylation in blood had required significantly more exogenous oxytocin during parturition. With higher DNA methylation, those who had oxytocin administered during labor had significantly greater relative risk for postpartum hemorrhage (IRR 2.95, 95% CI 1.53–5.71).ConclusionsWe provide evidence that epigenetic variability in OXTR is associated with the amount of oxytocin administered during parturition and moderates subsequent postpartum hemorrhage. Methylation can be measured using a peripheral tissue, suggesting potential use in identifying individuals susceptible to postpartum hemorrhage. Future studies are needed to quantify myometrial gene expression in connection with OXTR methylation.

Sex-dependent association between variability in infants’ OXTR methylation at birth and negative affectivity at 3 months

BackgroundSex-specific differences in DNA methylation of the oxytocin receptor gene (OXTR) have been shown in adults and are related to several mental disorders. Negative affectivity early in life is a trans-diagnostic risk marker of later psychopathology and is partly under genetic control. However, sex-specific variations in OXTR methylation (OXTRm) in infants and their associations with negative affectivity are still unknown. AimsHere, we explored sex differences in the association between infant OXTRm at birth and negative affectivity at 3 months of age. MethodsInfants and their mothers (N = 224) were recruited at delivery. Infants’ methylation status was assessed in 13 CpG sites within the OXTR gene intron 1 region (chr3: 8810654–8810919) in buccal cells at birth while 3-month-old infants’ negative affectivity was assessed by mothers using a well-validated temperament questionnaire. ResultsOXTRm at 12 CpG sites was higher in females than in males. Moreover, higher infants’ OXTRm at 6 specific CpG sites was associated with greater negative affectivity in males, but not in females. ConclusionsThese results provide new insights into the role of sex-dependent epigenetic mechanisms linking OXTRm with early infants’ emotional development. Understanding the degree to which epigenetic processes relate to early temperamental variations may help inform the etiology of later childhood psychopathological outcomes.

OXTR DNA methylation differentiates men on the obesity spectrum with and without binge eating disorder

BackgroundThe neuropeptide oxytocin (OXT) plays a role in the regulation of eating behavior and metabolism. OXT functioning is altered in patients with eating and weight disorders, and a variant of the oxytocin receptor gene (OXTR) has been associated with impulsive eating behavior as it is seen in patients with binge eating disorder (BED). Gene × environment interactions could play a role in BED. One mechanism mediating this interaction is the epigenetic alteration of gene expression. We therefore investigated if DNA methylation of the OXTR differs between individuals with obesity depending on a comorbid BED. We analyzed DNA methylation of the OXTR in peripheral blood of 227 individuals on the obesity spectrum (mean age: 40.3 ± 13.1 yrs; mean BMI: 38.6 ± 7.3 kg/m2), 130 of which were diagnosed with BED.ResultsThere were no overall differences in OXTR methylation between participants with and those without BED (p > 0.05), while both subgroups were comparable regarding age and body mass index (BMI), but significantly differed in sex distribution (p = 0.035). We found no relationship between mean DNA methylation and BMI or self-reported eating disorder (ED) pathology. Analyzing potential sex differences revealed a significantly lower OXTR DNA methylation in male participants with BED as compared to those without BED (p = 0.017). No such difference was found in the female subsample (p > 0.05).ConclusionsClinically significant binge eating pathology might be associated with lower OXTR DNA methylation exclusively in males. The differential DNA methylation of OXTR in males with BED supports the view that BED represents a phenotype within the obesity spectrum that is characterized by specific vulnerability factors. A better understanding of the epigenetic underpinnings of the OXT system might contribute to the refinement of OXT administration approaches as potential interventions in eating and weight disorders.

Effects of Prenatal Phthalate Exposure and Childhood Exercise on Maternal Behaviors in Female Rats at Postpartum: A Role of Oxtr Methylation in the Hypothalamus.

Both the detrimental effect of prenatal exposure to di-(2-ethylhexyl)-phthalate (DEHP) and the beneficial effects of physical exercise on brain functions have been reported. The oxytocin pathway has been implicated in the onset of maternal behaviors. Epigenetic modification of the oxytocin receptor gene (OXTR) through DNA methylation has been associated with the pathogenesis of neuropsychiatric disorders. The purpose of this study was to investigate the effects of prenatal DEHP exposure on oxytocin-regulated maternal behaviors and to examine the protective effect of exercise. Pregnant rats (F0) were fed with vehicle or DEHP during gestation and the offspring females (F1) were assessed for their maternal behaviors by pup retrieval test at postpartum. The results showed that reduced pup retrieval activities without significant alteration of stress responses were observed in the prenatally DEHP-exposed females. Prenatal DEHP exposure decreased the expressions of oxytocin, Oxtr mRNA, and oxytocin receptor, and increased Oxtr methylation in the hypothalamus of postpartum female rats. There were no significant effects of exercise on behavioral, biochemical, and epigenetic measurements. These results suggest that prenatal DEHP exposure has a long-term adverse effect on maternal behaviors; Oxtr hyper-methylation may be a potential epigenetic mechanism for this alteration, which cannot be prevented by physical exercise during childhood.

The role of oxytocin signaling in depression and suicidality in returning war veterans

Many war veterans struggle with depression and suicidality, and separation from the military is a time of particularly high risk. Based on research in non-human animals, we hypothesized that reduced oxytocin signaling would mediate symptoms of depression and suicidality in war veterans recently separated from their close comrades. We also hypothesized that veterans with more frequent contact with comrades would have fewer symptoms of depression and suicidality. In this cross-sectional study, male veterans from the Iraq and Afghanistan wars (n = 86) provided blood and urine samples for measurement of peripheral oxytocin (OT) levels, as well as saliva samples for DNA extraction followed by genotyping of oxytocin receptor gene (OXTR) Single Nucleotide Polymorphisms, and CpG-methylation assessment. Participants also completed a series of mental health questionnaires and interviews. Veterans reported feeling very close to their comrades during war, and missing them greatly upon returning home. Neither peripheral OT levels nor OXTR genotypes were related to symptoms of depression or suicidality. On the other hand, methylation at OXTR CpG −924 was negatively correlated with depressive symptomology, after controlling for possible confounds. Veterans who socialized with comrades more frequently had higher levels of urinary, but not plasma OT, as well as less depressive symptomology. Social connectedness was a strong negative predictor of symptoms of both depression and suicidality, eclipsing the predictive power of other variables such as post-deployment social support, the degree to which participants reported missing their comrades, and the frequency with which they socialized with comrades. Our results suggest that veteran mental health is more impacted by lack of social connectedness than by separation from close comrades per se. While there is some evidence that OXTR methylation relates to depressive symptomology, decreased OT signaling does not appear to mediate the relationship between social disconnectedness and depression or suicidality. Sleep quality and anxiety disorders were also significantly associated with mental health symptoms, independent of social connectedness. Our findings suggest that efforts aimed at alleviating the burden of depression and suicidality in returning war veterans should focus on re-integrating veterans into society and establishing a feeling of social connectedness, as well as on treating anxiety disorders and sleep problems.

Epigenetic tuning of brain signal entropy in emergent human social behavior

BackgroundHow the brain develops accurate models of the external world and generates appropriate behavioral responses is a vital question of widespread multidisciplinary interest. It is increasingly understood that brain signal variability—posited to enhance perception, facilitate flexible cognitive representations, and improve behavioral outcomes—plays an important role in neural and cognitive development. The ability to perceive, interpret, and respond to complex and dynamic social information is particularly critical for the development of adaptive learning and behavior. Social perception relies on oxytocin-regulated neural networks that emerge early in development.MethodsWe tested the hypothesis that individual differences in the endogenous oxytocinergic system early in life may influence social behavioral outcomes by regulating variability in brain signaling during social perception. In study 1, 55 infants provided a saliva sample at 5 months of age for analysis of individual differences in the oxytocinergic system and underwent electroencephalography (EEG) while listening to human vocalizations at 8 months of age for the assessment of brain signal variability. Infant behavior was assessed via parental report. In study 2, 60 infants provided a saliva sample and underwent EEG while viewing faces and objects and listening to human speech and water sounds at 4 months of age. Infant behavior was assessed via parental report and eye tracking.ResultsWe show in two independent infant samples that increased brain signal entropy during social perception is in part explained by an epigenetic modification to the oxytocin receptor gene (OXTR) and accounts for significant individual differences in social behavior in the first year of life. These results are measure-, context-, and modality-specific: entropy, not standard deviation, links OXTR methylation and infant behavior; entropy evoked during social perception specifically explains social behavior only; and only entropy evoked during social auditory perception predicts infant vocalization behavior.ConclusionsDemonstrating these associations in infancy is critical for elucidating the neurobiological mechanisms accounting for individual differences in cognition and behavior relevant to neurodevelopmental disorders. Our results suggest that an epigenetic modification to the oxytocin receptor gene and brain signal entropy are useful indicators of social development and may hold potential diagnostic, therapeutic, and prognostic value.

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).

Epigenetic modification of the oxytocin receptor gene: implications for autism symptom severity and brain functional connectivity.

The role of oxytocin in social cognition has attracted tremendous interest in social neuroscience and psychiatry. Some studies have reported improvement in social symptoms following oxytocin treatment in autism spectrum disorders (ASD), while others point to endogenous factors influencing its efficiency and to mixed results in terms of long-term clinical benefits. Epigenetic modification to the oxytocin receptor gene (OXTR) in ASD could be an informative biomarker of treatment efficacy. Yet, little is known about the relationship between OXTR methylation, clinical severity, and brain function in ASD. Here, we investigated the relationship between OXTR methylation, ASD diagnosis (in N = 35 ASD and N = 64 neurotypical group), measures of social responsiveness, and resting-state functional connectivity (rsFC) between areas involved in social cognition and reward processing (in a subset of ASD, N = 30). Adults with ASD showed higher OXTR methylation levels in the intron 1 area compared with neurotypical subjects. This hypermethylation was related to clinical symptoms and to a hypoconnectivity between cortico-cortical areas involved in theory of mind. Methylation at a CpG site in the exon 1 area was positively related to social responsiveness deficits in ASD and to a hyperconnectivity between striatal and cortical brain areas. Taken together, these findings provide initial evidence for OXTR hypermethylation in the intron area as a potential biomarker for adults with ASD with less severe developmental communication deficits, but with impairments in theory of mind and self-awareness. Also, OXTR methylation in the exon 1 area could be a potential biomarker of sociability sensitive to life experiences.

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.

Reduced DNA Methylation of the Oxytocin Receptor Gene Is Associated With Anhedonia-Asociality in Women With Recent-Onset Schizophrenia and Ultra-high Risk for Psychosis.

Negative symptoms are recognized as a fundamental feature of schizophrenia throughout the disease course. Epigenetic alterations in the oxytocin receptor gene (OXTR) may be a key mechanism involved in social-emotional disturbances of schizophrenia. Here, we investigated OXTR methylation and its association with clinical and brain network connectivity phenotypes of negative symptoms, particularly anhedonia-asociality, in individuals with recent-onset schizophrenia (ROS) and at ultrahigh risk (UHR) for psychosis. Sixty-four ROS (39 women), 46 UHR (19 women), and 98 healthy individuals (52 women) participated in this study. OXTR methylation was quantified using the pyrosequencing method. Asubset of participants (16 ROS, 23 UHR, and 33 healthy controls [HCs]) underwent a 5.5-minute resting-state functional magnetic resonance imaging to determine the relationship between OXTR methylation and the striatal-amygdala network functional connectivity (FC) underlying anhedonia-asociality. Both men and women with ROS and UHR showed significantly decreased OXTR methylation compared to HCs. In women with ROS and UHR, decreased OXTR methylation showed a significant correlation with increased anhedonia-asociality. FC of the striatal-amygdala network, positively associated with the severity of anhedonia-asociality, showed an inverse correlation with OXTR methylation. This study suggests that epigenetic alterations of OXTR, which can be detected before the development of full-blown psychosis, confer susceptibility to schizophrenia and play a crucial role in the manifestation of anhedonia-asociality, particularly in women.

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.

DNA methylation of OXTR is associated with parasympathetic nervous system activity and amygdala morphology.

Oxytocin has anxiolytic properties whose mechanisms of action are still being identified. DNA methylation in the promoter region of the oxytocin receptor gene (OXTR), an epigenetic modification that putatively reflects a downtuning of the oxytocin system, has previously been implicated in the regulation of fear-related responses through the amygdala. In this study, we attempted to characterize the relationship between methylation of OXTR and anxiogenesis using two distinct endophenotypes: autonomic nervous system activity and subcortical brain structure. In 79 participants, we found that increased OXTR methylation is associated with attenuated resting parasympathetic tone, measured using high-frequency heart rate variability. Further, we found that this relationship is mediated by brain morphology, such that OXTR methylation is associated with increased gray matter of the central amygdala which is, in turn, associated with decreased parasympathetic tone. These results further our understanding of epigenetic regulation of the human oxytocin system and its role in anxiogenesis.