Oxytocin Receptor Polymorphisms Research Articles

Roles of the Oxytocin Receptor (OXTR) in Human Diseases.

The oxytocin receptor (OXTR), encoded by the OXTR gene, is responsible for the signal transduction after binding its ligand, oxytocin. Although this signaling is primarily involved in controlling maternal behavior, it was demonstrated that OXTR also plays a role in the development of the nervous system. Therefore, it is not a surprise that both the ligand and the receptor are involved in the modulation of behaviors, especially those related to sexual, social, and stress-induced activities. As in the case of every regulatory system, any disturbances in the structures or functions of oxytocin and OXTR may lead to the development or modulation of various diseases related to the regulated functions, which in this case include either mental problems (autism, depression, schizophrenia, obsessive-compulsive disorders) or those related to the functioning of reproductive organs (endometriosis, uterine adenomyosis, premature birth). Nevertheless, OXTR abnormalities are also connected to other diseases, including cancer, cardiac disorders, osteoporosis, and obesity. Recent reports indicated that the changes in the levels of OXTR and the formation of its aggregates may influence the course of some inherited metabolic diseases, such as mucopolysaccharidoses. In this review, the involvement of OXTR dysfunctions and OXTR polymorphisms in the development of different diseases is summarized and discussed. The analysis of published results led us to suggest that changes in OXTR expression and OXTR abundance and activity are not specific to individual diseases, but rather they influence processes (mostly related to behavioral changes) that might modulate the course of various disorders. Moreover, a possible explanation of the discrepancies in the published results of effects of the OXTR gene polymorphisms and methylation on different diseases is proposed.

Polymorphisms in the oxytocin receptor and their association with apathy and impaired social cognition in Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disorder characterized by cognitive, motor, and neuropsychiatric manifestations. Oxytocin is a neuropeptide studied for its role as a neuromodulator regulating multiple behaviors linked to social cognition. Genetic variation of oxytocin receptor (OXTR) might interact in the etiology and development of several impaired social behaviors. Our aim was to study OXTR polymorphisms and their relationship with apathy and social cognition in HD. OXTR was sequenced in 21 cases and 22 controls. We assessed apathy, anxiety, depression, and irritability (Hospital Anxiety and Depression Scale-Snaith Irritability scale, HADS-SIS) and social cognition (Ekman 60 faces test), motor symptoms and functionality with the total functional capacity (TFC), and the Unified HD rating Scale (UHDRS). We identified ten variants in OXTR. Three variants were classified as possibly damaging (p.Arg40Gly) or probably damaging (p.Leu46Pro, p.Thr102Asn). Subjects carrying the wild-type genotype of the synonymous variant p.Val45 showed a significantly lower score in the HADS-SIS scale, related to lower irritability (p = 0.013). The only subject carrying the heterozygous genotype of the synonymous variant p.Leu62 showed a significantly higher score on Ekman scale, compared to wild-type (p = 0.049); however, this finding was not confirmed after bootstrapping. Variations in OXTR could have a relevant role in the correct development of social and cognitive functions. Future approaches will include the molecular study of p.Arg40Gly, p.Leu46Pro, and p.Thr102Asn to confirm their pathogenicity, as well as the validation of the influence of p.Val45 and p.Leu62 variants for their involvement in irritability and social cognition in HD.

Impact of OXTR Polymorphisms on Subjective Well-Being: The Intermediary Role of Attributional Style.

Polymorphisms in the oxytocin receptor (OXTR) gene are related to individual differences in negative emotions, such as depressive symptoms and anxiety. However, it remains unclear what the potential roles of OXTR polymorphisms are in subjective well-being (SWB), which is negatively correlated with depressive symptoms. We examined attributional styles as mediator between SWB and five polymorphisms of the oxytocin receptor gene (OXTR rs53576, rs2254298, rs1042778, rs2268494, and rs2268490) among 627 full-time college freshmen (M age = 20.90, SD = 0.82 for male; M age = 20.81, SD = 0.92 for female) using structural equation modeling. The results showed that individuals with the OXTR rs2254298 AA genotype and rs53576 AA/GA genotype reported higher scores on SWB, which suggested that individuals with this genotype experienced more happiness. Moreover, external attributional style partially mediated the association between OXTR rs2254298 polymorphism and SWB (β = 0.019, 95%CI [0.001, 0.036], p = 0.035). In conclusion, our findings demonstrated that the genetic variations of OXTR played a role in the individual differences of SWB, and external attribution style could mediate the association.

Oxytocin receptor polymorphism influences characterization of harm avoidance by moderating susceptibility to affectionless control parenting.

IntroductionOxytocin receptor (OXTR) gene polymorphism reportedly moderates effects of negative environments during childhood on mental function and behavior such as depressive symptoms and externalizing problems. This study examined OXTR gene polymorphism effects on personality traits in healthy participants, considering interaction effects of polymorphism with affectionless control (AC) parenting which is one of the dysfunctional and pathogenic parenting styles.MethodsFor 496 Japanese volunteers, personality was evaluated using the Temperament and Character Inventory. The Parental Bonding Instrument, which has subscales of care and protection, was used to assess perceived parental rearing. AC parenting was defined as low care and high protection. A/G polymorphism of the OXTR gene (rs53576) was detected using TaqMan SNP Genotyping Assay.ResultsTwo‐way analysis of covariance revealed significant interaction effects between the genotype and the number of AC parents on scores of harm avoidance, with no significant main effect of genotype on any personality. Post‐hoc analysis revealed that the harm avoidance scores were increased in a stepwise manner with respect to the increase of the number of AC parents in the A allele carriers. No similar association was observed in the A allele noncarriers.ConclusionThe results of this study suggest that OXTR polymorphism influences characterization of harm avoidance by moderating susceptibility to AC parenting.

Gene–environment interaction: Oxytocin receptor (OXTR) polymorphisms and parenting style as potential predictors for depressive symptoms

Depression is a common mental health problem that is thought to develop through a combination of genetic, psychological, and environmental factors, including parental behaviours and parental mental health. The present study investigated the potential interaction between oxytocin receptor (OXTR) single nucleotide polymorphisms (SNPs) (rs53576, rs237880, rs237887, rs237889, rs237898, rs1042778, rs2268490, rs2268491, rs4686302, rs6770632, rs13316193) and parenting style in adolescence in relation to depressive symptoms among young adults. The sample consisted of 1,098 Caucasian participants (63.6% females) and their parents. The present study included data from the Survey of Adolescent Life Cohort study collected in 2012 at wave I (mage 14.4 years; DNA collection), 2015 at wave II (mage 17.36 years; Estimation of parenting style, depressive symptoms, and parental depression) and 2018 at wave III (mage 20.19 years; Depressive symptoms). Evidence for an interaction effect between OXTR SNP rs6770632 and negative parenting style on depressive symptoms among young adults was found with support for the diathesis–stress theory. The rs6770632 was associated with depressive symptoms at higher levels of negative parenting, with A:A allele carriers reporting higher levels of depressive symptoms than C:C and C:A allele carriers. The present study provides preliminary knowledge about the potential moderation effects of perceived negative parenting on the effect of OXTR SNPs on depressive symptoms among young adults, independent of sex, previous reports of depressive symptoms, and parental depression.

OXTR moderates adverse childhood experiences on depressive symptoms among incarcerated males

ObjectivesThis study examined the moderation of an oxytocin receptor (OXTR) gene in the link between childhood adversity and depressive symptoms among incarcerated males. MethodsQuestionnaires about adverse childhood experiences and depressive symptoms, as well as genomic DNA from blood were collected among 608 incarcerated males (Mage = 32.4 years, SD = 9.41, 18–74 years). Moderation analysis was applied to examine the interaction between adverse childhood experiences (including abuse, neglect, and household dysfunction) and the OXTR polymorphisms (rs2254298, rs53576) in predicting depressive symptoms. ResultsIncarcerated males had relatively higher prevalence of childhood adversity (70.2%) and depressive symptoms (49.8%). Higher childhood adversity was associated with increased depressive symptoms, and the effect was more pronounced in the GG homozygotes of OXTR rs2254298 (b = 0.406, p < .001), as compared with the AA/AG carriers (b = 0.236, p < .001). By contrast, the OXTR rs53576 did not interact with childhood adversity in predicting depressive symptoms. ConclusionsChinese incarcerated males with the GG genotype of OXTR rs2254298 have higher vulnerability in the effect of childhood adversity on depressive symptoms.

Associations between the oxytocinergic system genes, perinatal complications and interpersonal relationships in patients with schizophrenia

To search for the associations between genes of the oxytocinergic pathway and psychosocial functioning in schizophrenia, namely, the ability of schizophrenic patients to form interpersonal relationships, taking into account the influence of such an environmental factor as perinatal complications. The study included 383 people (140 women and 243 men, mean age 32.6±11.4 years), of whom 107 had a history of perinatal complications, and 276 did not. Psychosocial functioning was assessed using the Personal and social relationships domain of The Personal and Social Performance scale (PSP). Polymorphisms rs53576, rs4686302, rs1042778 in the oxytocin receptor gene (OXTR) and polymorphism rs3796863 in the transmembrane glycoprotein (CD38) gene were genotyped. There is the association between the OXTR rs53576 polymorphism and scores on the interpersonal relations domain (p=0.005). Significant differences are found between carriers of the GG genotype and carriers of the A allele (p=0.003). In the group without perinatal complications, the genotype does not have a significant effect on PSP score. There are no associations between other polymorphisms and the level of interpersonal relationships in any of the studied groups. The results are in accordance with the notions accepted on the basis of numerous evidences that link the genes of the oxytocinergic system with social behavior. We obtained new data on the influence of the known polymorphism OXTR rs53576 on the phenotype, which has not been studied previously in this aspect - the ability to form interpersonal relationships in patients with schizophrenia, while it was shown that the effect of the genotype depends on the environmental risk factor (perinatal complications).

Lack of association of common polymorphisms linked to empathic behavior with self-reported trait empathy in healthy volunteers

BackgroundIn a previously specified sample of 421 healthy subjects, we found associations of a common oxytocin receptor (OXTR) polymorphism with self-reported trait empathy. In this study, we used this sample to explore polymorphisms in other genes which have been frequently linked to empathic behavior for associations with self-reported trait empathy: CD38 (CD38), involved in oxytocin secretion, the serotonin transporter (SLC6A4), the Catechol-O-Methyltransferase (COMT) and the corticotropin releasing hormone receptor 1 (CRHR1). MethodsWe genotyped our sample for the following common polymorphisms: rs3796863 in the CD38 gene, 5-HTTLPR in the SLC6A4 gene, rs4680 in the COMT gene and rs242924 in the CRHR1 gene. Dispositional empathy was tested using Davis' Interpersonal Reactivity Index (IRI). We used a Bonferroni corrected alpha level of p = 0.002 to adjust for multiple comparisons. ResultsNone of the genotypes were associated with any of the IRI scales for the complete sample (n = 421) or for the sub-groups of male (n = 213) and female (n = 190) participants. Our sample of 421 participants achieved 95% power to detect effects greater than r = ±0.18. For smaller effects, however, false negatives could not be rejected with equal confidence as false positives. ConclusionsWe conclude that an association between the four polymorphisms with trait empathy measured by the IRI may not be present. We propose that the associations that have been found in other studies can be largely explained by differences in empathy-related constructs and measurements.

Oxytocin receptor gene polymorphism (rs53576) and digit ratio associates with aggression: comparison in seven ethnic groups

BackgroundThe specific role of the oxytocin receptor (OXTR) gene polymorphisms in emotional support seeking, related to social norms and culturally normative behavior, has been discussed in several studies. Evidence on the association between aggression and OXTR polymorphisms has also been reported. The goal of the current study was to analyze the effect of the OXTR rs53576 polymorphism, prenatal testosterone effect (second-to-fourth digit ratio, or 2D:4D), and culture on aggression assessed with the Buss-Perry Aggression Questionnaire (BPAQ).MethodsThe data were collected in Russia and Tanzania and included seven ethnic groups of European, Asian, and African origin. The total sample included 1705 adults (837 males, 868 females). All the subjects were evaluated with the BPAQ. As a measure of prenatal androgenization, the second and fourth digits were measured directly from hand, and the digit ratios were calculated. All the participants provided buccal samples, from which genomic DNA was extracted, and the OXTR gene rs53576 polymorphism was genotyped. Statistical analysis was performed using SPSS version 23.0; the alpha level for all analyses was set at 0.05.ResultsThe ethnic group factor was the most significant predictor of ratings on BPAQ (medium effect size for physical aggression, anger and hostility scales, and low for verbal aggression). To study the effect of sex, the OXTR polymorphism, and prenatal androgenization, we conducted the z-score transformation for BPAQ scales and 2D:4D for each ethnic group and pooled these data into new z-score variables. According to the GLM analysis after leveling the effects of culture (z-transformation), all four scales of BPAQ demonstrated association with sex (main effects), with men scoring higher on physical and verbal aggression and women scoring higher on anger and hostility. Anger and hostility scales were also associated with OXTR polymorphism and 2D:4D of the right hand. The lowest levels of anger and hostility were observed in individuals with the AA genotype, especially in men.ConclusionsOur data suggest that both oxytocin (OXTR gene polymorphism) and fetal testosterone (2D:4D) may significantly affect emotional (anger) and cognitive (hostility) aggression in humans, given the leveling the role of culture.

Polymorphism of the Oxytocin Receptor (OXTR) Gene Affects the Circulating Oxytocin Receptor Levels in Late-Term Pregnancy in a Turkish Population

Introduction: Postterm and late-term pregnancies still remain a serious health problem, and underlying exact mechanisms are not fully elucidated. These mechanisms are influenced by many factors. Objective: The aim of this study was to investigate the relationship between plasma oxytocin and oxytocin receptor levels and oxytocin receptor polymorphisms in term and late-term pregnant women. Methods: Sixty-eight singleton pregnant women with late-term pregnancy and 83 singleton pregnant women with term parturition were included in this study. A comparison was performed between pregnancies and neonates born at term (37 0/7 and 41 6/7 weeks’ gestation). Plasma oxytocin, oxytocin receptor, estradiol, and progesterone levels were measured by using enzyme-linked immunosorbent assay kits. TaqMan® SNP Genotyping Assays and qPCR ProbesMaster were used to investigate the polymorphisms of rs237911, rs2228485, rs53576, and rs2254298. Results: There was not any difference in gene distributions of 4 common single-nucleotide polymorphisms of oxytocin receptor of rs237911, rs2228485, rs53576, and rs2254298 between subjects in late-term and term pregnancy groups. With rs53576 of the GG genotype, serum oxytocin levels were 21.50 ± 10.69 (ng/L) in the late-term group and 62.71 ± 18.01 (ng/L) in the term group (p = 0.049). Oxytocin receptor levels in the late-term and term pregnancy groups of the GG genotype were 17.92 ± 8.15 (pg/mL) and 45.77 ± 11.66 (pg/mL), respectively (p = 0.046). Conclusion: Our findings suggest that the rs53576 oxytocin receptor single-nucleotide polymorphism is associated with late-term pregnancy through acting by direct modulation of oxytocin and oxytocin receptor levels.

Do culture and oxytocin receptor polymorphisms interact to influence emotional expressivity?

Drawing on recent evidence suggesting that individuals having the G allele of the oxytocin receptor (OXTR) polymorphism are especially susceptible to socio-cultural environmental influences, including cultural norms, the present study investigated the interplay of culture and two OXTR polymorphisms (rs53576 and rs2254298) in the domain of emotional expressivity, which is culturally encouraged in Western cultures. Testing Japanese and European Canadian undergraduates, we found cultural differences in negative emotional expressivity and positive emotional expressivity. As expected, the European Canadians were greater in positive emotional expressivity than the Japanese. In contrast, the pattern was reversed in negative emotional expressivity. A series of multiple regression analyses entering gender and personality traits as control variables showed that neither culture nor the two OXTR polymorphisms interact to negative emotional expressivity and positive emotional expressivity. The present null findings suggest that continued examination with larger samples would better elucidate results on the interactions among culture, OXTR, and socioemotional behaviors.

Maternal verbal aggression in early infancy and child\u2019s internalizing symptoms: interaction by common oxytocin polymorphisms

Genetic predisposition of social sensitivity might affect vulnerability to develop psychopathology after early life stress exposure. This study examined whether maternal verbally aggressive behavior in early infancy interacts with oxytocin polymorphisms in developing internalizing symptoms at ages 5–6 and 11–12. In the Amsterdam-Born-Children-and-their-Development (ABCD) study, a large observational, population-based birth cohort, maternal verbally aggressive behavior was assessed in the 13th postnatal week by a self-report questionnaire. Internalizing symptoms at age 5–6 were assessed by maternal report (N = 969) and internalizing symptoms at age 11–12 were assessed by self-report (N = 750). Data on oxytocin receptor polymorphisms rs53576 and rs2268498 and oxytocin polymorphisms rs2740210 and rs4813627 were collected. If the child was carrier of rs2740210 CA/AA polymorphism, exposure to maternal verbally aggressive behavior (10.6%) was positively associated with general anxiety at age 5–6 and emotional symptoms at age 11–12 (p for interaction = 0.011 and p = 0.015, respectively). If the child was carrier of rs4813627 GG (wild type), exposure to maternal verbally aggressive behavior was negatively associated with anxiety sensitivity and emotional symptoms at age 11–12 (p for interaction = 0.011 and p = 0.022, respectively). After exposure to maternal verbally aggressive behavior in early infancy, oxytocin polymorphisms may partly determine a child’s vulnerability to internalizing symptoms.

OXTR rs53576 polymorphism impacts interpersonal adaptability: Dispositional forgiveness as a mediator

Polymorphisms in the oxytocin receptor (OXTR) gene have been shown to be related to individual differences in social skills that are important for building and maintaining social relationships, such as the capability to efficiently process social information and regulate emotions. However, what remains unclear is the potential roles of OXTR polymorphisms in interpersonal adaptability, namely the ability to cope with the situational demands of interpersonal interactions. In this study, we examined the roles of OXTR rs53576 polymorphism in interpersonal adaptability, empathic perception, and dispositional forgiveness in a cohort of 573 college freshmen. The results indicated that the scores on interpersonal adaptability and dispositional forgiveness, apart from empathic perception, increased as functions of the number of G alleles of OXTR rs53576. Moreover, dispositional forgiveness, but not empathic perception, mediated the association between OXTR rs53576 and interpersonal adaptability. The findings highlight the influences of the OXTR gene on adaptive interpersonal interactions, especially when individuals face changing social situations.

Sex-specific association of a common GNAS polymorphism with self-reported cognitive empathy in healthy volunteers.

BackgroundIn a recent study, we found associations of a common oxytocin receptor (OXTR) polymorphism with inter-individual differences in empathy, especially with emotional empathy in women. Many other studies found specific associations of oxytocin, arginine-vasopressin, serotonin and dopamine receptor gene polymorphisms with various aspects of trait empathy. As all these receptors belong to the guanine-binding protein (G protein) coupled receptor family, it is a reasonable assumption, that alterations in genes encoding G protein subunits also influence the signal transduction in empathy related circuits. However, to the best of our knowledge, these genomic variations have not yet been studied in genetic research on empathy.MethodsHere, we analysed associations of a common polymorphism of the GNAS gene (C393T) in a previously characterized sample of 421 healthy blood donors (231 M, 190 F; age 18–74). The GNAS gene encodes the G protein adenylyl cyclase stimulator (Gαs) G protein subunit, which activates cyclic adenosine monophosphate (cAMP)-dependent pathways by stimulating the adenylyl cyclase. Cognitive and emotional aspects of dispositional empathy were tested using Davis’ Interpersonal Reactivity Index (IRI).ResultsIn the complete sample, associations of C393T genotype with IRI empathy scores, including cognitive empathy (p = 0.055) and perspective taking (p = 0.057) scores did not reach a level of significance. None of the IRI scores was near to being significantly associated with C393T genotype for men alone. In females, however, genotype was significantly associated with cognitive empathy (r = -.204, p = 0.005) and perspective taking (r = -.209, p = 0.004), accounting for 4.2% and 4.4% of variability. The association of genotype with perspective taking remained significant after adjustment for multiple comparisons (p = 0.045). The 393C-allele, which had been identified as a risk factor in several medical conditions such as hypertension, obesity and diabetes, was associated with higher cognitive empathy compared to the T allele in our sample.ConclusionsThe results suggest a significant association of GNAS C393T genotypes with the cognitive empathic capacity of perspective taking. This association could only be found in female participants.

Rare missense coding variants in oxytocin receptor (OXTR) in schizophrenia cases are associated with early trauma exposure, cognition and emotional processing

BackgroundOxytocin is a peptide hormone that influences the integration of social cognition with behavior and affect regulation. Oxytocin also prominently directs the transition of neuronal GABA neurotransmission from excitatory to inhibitory after birth. The oxytocin receptor (OXTR) is linked to schizophrenia, a heterogeneous syndrome. Relationships of OXTR polymorphisms with specific clinical features could aid in evaluating any role of oxytocin in the pathogenesis of schizophrenia. MethodSchizophrenia cases with rare missense coding OXTR single nucleotide variants (SNVs) were identified from a well-characterized sample of cases and controls who were assessed for symptoms, cognition and early life trauma. ResultsFive of 48 cases showed rare OXTR variants. Compared to the other cases they had less severe negative symptoms (deficits in emotional expression and motivation) and less severe general psychopathology scores (depression and anxiety). They demonstrated lower nonverbal (performance) than verbal intelligence due to deficient perceptual organization and slow processing speed. They also reported greater early trauma exposure (physical and sexual abuse and emotional trauma). ConclusionCases carrying rare OXTR SNVs had less negative and affective symptoms than other cases, but similar psychotic symptoms, along with specific cognitive deficits. The clinical characterization of these cases occurred in association with environmental exposure to early trauma, especially sexual abuse, which may have influenced the expression of schizophrenia in subjects harboring specific SNVs in the OXTR.

Oxytocin Receptor Polymorphisms are Differentially Associated with Social Abilities across Neurodevelopmental Disorders

Oxytocin is a pituitary neuropeptide that affects social behaviour. Single nucleotide polymorphisms (SNPs) in the oxytocin receptor gene (OXTR) have been shown to explain some variability in social abilities in control populations. Whether these variants similarly contribute to the severity of social deficits experienced by children with neurodevelopmental disorders is unclear. Social abilities were assessed in a group of children with autism spectrum disorder (ASD, n = 341) or attention deficit hyperactivity disorder (ADHD, n = 276) using two established social measures. Scores were compared by OXTR genotype (rs53576, rs237887, rs13316193, rs2254298). Unexpectedly, the two most frequently studied OXTR SNPs in the general population (rs53576 and rs2254298) were associated with an increased severity of social deficits in ASD (p < 0.0001 and p = 0.0005), yet fewer social deficits in ADHD (p = 0.007 and p < 0.0001). We conclude that these genetic modifier alleles are not inherently risk-conferring with respect to their impact on social abilities; molecular investigations are greatly needed.

Intranasal oxytocin and a polymorphism in the oxytocin receptor gene are associated with human-directed social behavior in golden retriever dogs

The oxytocin system may play an important role in dog domestication from the wolf. Dogs have evolved unique human analogue social skills enabling them to communicate and cooperate efficiently with people. Genomic differences in the region surrounding the oxytocin receptor (OXTR) gene have previously been associated with variation in dogs' communicative skills. Here we have utilized the unsolvable problem paradigm to investigate the effects of oxytocin and OXTR polymorphisms on human-directed contact seeking behavior in 60 golden retriever dogs. Human-oriented behavior was quantified employing a previously defined unsolvable problem paradigm. Behaviors were tested twice in a repeated, counterbalanced design, where dogs received a nasal dose of either oxytocin or saline 45min before each test occasion. Buccal DNA was analysed for genotype on three previously identified SNP-markers associated with OXTR. The same polymorphisms were also genotyped in 21 wolf blood samples to explore potential genomic differences between the species. Results showed that oxytocin treatment decreased physical contact seeking with the experimenter and one of the three polymorphisms was associated with degree of physical contact seeking with the owner. Dogs with the AA-genotype at this locus increased owner physical contact seeking in response to oxytocin while the opposite effect was found in GG-genotype individuals. Hence, intranasal oxytocin treatment, an OXTR polymorphism and their interaction are associated with dogs' human-directed social skills, which can explain previously described breed differences in oxytocin response. Genotypic variation at the studied locus was also found in wolves indicating that it was present even at the start of dog domestication.

Developmental changes in social attention and oxytocin levels in infants and children

Oxytocin (OT) signalling represents one of the most critical systems involved in human social behaviour. Although several studies have examined the relationship between social functioning and peripheral OT levels, the association between OT and the development of social attention has not been well studied. Therefore, we investigated the developmental relationship between gaze fixation for social cues and OT levels during young childhood. We examined visual attention using an eye tracking system in infants and children (5–90 months of age) and measured the concentration of OT in saliva samples. We observed a negative association between age and both attention toward social cues and salivary OT levels, and a positive association between age and attention for non-social cues. We also observed that salivary OT levels were modulated by polymorphisms in oxytocin receptor (OXTR) rs53576. Our results suggest that there is an age-dependent association between visual attention for social cues and OT levels in infants and children, and that the development of visual attention to the eyes as social cues is associated with both OXTR polymorphisms and OT levels. Such findings indicate that OT and OXTR status may provide insight into the atypical development of social attention in infants and young children.

Oxytocin receptor and G-protein polymorphisms in patients with depression and separation anxiety

BackgroundThe impact of combined variants of Oxytocin Receptor (OXTR) and G protein β3 subunit genes was investigated in relation to retrospective reports of childhood as well as contemporary adult separation anxiety (SA), based on evidence of a β/γ dimer-mediated signaling for OXTR. MethodsA case-control association study (225 healthy adults and 188 outpatients with depression) was performed to establish Risk-Combined Genotype (RCG) of the studied variants (OXTR rs53576 and the functional Gβ3 subunit rs5443). Current SA was evaluated by the ASA-27 and retrospective childhood symptoms by the SASI. GG genotype of OXTR rs53576 combined with T-carrier genotype of Gβ3 rs5443 represented the RCG. ResultsCompared to non-RCG, those with RCG had significantly higher levels of childhood and adult SA. The RCG was significantly associated with childhood SA threshold score (OR=2.85, 90%CI: 1.08–7.50). Childhood SA was, in turn, strongly associated with a threshold SA score in adulthood (OR=15.58; 95% CI: 4.62–52.59). LimitationsAlthough the overall sample size is sizable, comparisons among subgroups with specific combination of alleles are based on relatively small numbers. Conclusions:Our study indicates that variations in OXTR and Gβ3 genes are specifically associated with presence and severity of SA in childhood and adulthood, but not with depression or anxiety in general. Because there is increasing interest in oxytocin in social behavior, the gene-SA associations identified have potential translational and clinical relevance.

A Precision Medicine Approach to Oxytocin Trials.

In this chapter, we introduce a new area of social pharmacology that encompasses the study of the role of neuromodulators in modulating a wide range of social behaviors and brain function, with the interplay of genetic and epigenetic factors. There are increasing evidences for the role of the neuropeptide oxytocin in modulating a wide range of social behaviors, in reducing anxiety, and in impacting the social brain network. Oxytocin also promotes social functions in patients with neuropsychiatric disorders, such as autism and reduces anxiety and fear in anxiety disorders. In this chapter, we will emphasize the importance of integrating basic research and clinical human research in determining optimal strategies for drug discoveries for social dysfunctions and anxiety disorders. We will highlight the significance of adopting a precision medicine approach to optimize targeted treatments with oxytocin in neuropsychiatry. Oxytocin effects on social behavior and brain function can vary from one individual to another based on external factors, such as heterogeneity in autism phenotype, childhood experiences, personality, attachment style, and oxytocin receptor polymorphisms. Hence, targeted therapies for subgroups of patients can help alleviating some of the core symptoms and lead to a better future for these patients and their families.