The ability to attribute mental states to others is called theory of mind (ToM) and is a substantial component of social cognition. This ability is abnormally developed in individuals with autism spectrum disorder (ASD). Several studies over the past decade have identified the oxytocin receptor gene (OXTR) and its variants as promising components for explaining the molecular mechanisms underlying Theory of Mind (ToM). The main aim of this study is to examine the association between rs2268498 and rs53576, two functional single nucleotide polymorphisms (SNPs), and verbal and non-verbal ToM in children and adolescents with ASD and a group of typically developing youth.
The study involved 44 children and adolescents with high-functioning ASD aged 8 to 18 years old and 44 TD individuals who were matched on age and sex. In all participants, blood samples were collected and rs2268498 and rs53576 were genotyped. Happe\'s Strange Stories test and the moving shapes paradigm were used to measure verbal and non-verbal ToM in all participants.
The results of permutation tests and logistic regression suggested that in TD group, rs2268498 AA carriers showed significant higher scores in variables representing verbal ToM (ToM stories and appropriateness score) whereas, in ASD group, rs53576 AA carriers exhibited significant better performance in parameters related to non-verbal ToM (ToM general rule and intentionality score). The results of hierarchical clustering in both groups support the findings by distinguishing between language-related and language-independent aspects of ToM.
In the present study, we examined the association between rs2268498 and rs53576 and social functioning in individuals with ASD and TD group. We found preliminary evidence that rs2268498 and rs53576 are associated with ToM related abilities in healthy individuals as well as in autistic individuals. Accordingly, rs2268498 and rs53576 may play an important role in predicting ToM capabilities. It will be necessary to conduct further research to address the association of genetic variants with a deficit in ToM in individuals with ASD.

Background: CD38 is a transmembrane glycoprotein that regulates oxytocin (OT) production and influences social interactions. The oxytocin receptor (OXTR) has been studied intensively regarding its association with human psychosocial functions. Many studies have demonstrated a link between CD38 rs3796863 and OXTR rs53576 polymorphic regions and psychosocial characteristics as well as various psychiatric disorders in adolescents. Some studies, however, have reported null findings. Methods: The Strengths and Difficulties Questionnaire (SDQ) is a brief psychopathologic screening tool recommended for detecting psychosocial problems and psychiatric disorders in adolescents. The current field school-based study, conducted among urban Siberian adolescents (n = 298 aged 12-18), explored the SDQ scales in relation to polymorphisms of the CD38 and the OXTR genes (rs3796863 and rs53576, respectively). Results: None of the studied genotypes were associated with the SDQ results for the complete sample with presumed statistical power as 0.80 to detect a medium-size effect (Cramer\'s V = 0.3) at α = 0.0083. Post-hoc analysis in subgroups showed that OT pathway high activity may cause some negative consequences, such as emotional instability in older (aged 15-18) adolescent boys who are carriers of the rs53576 GG variant. Conclusion: Variations at the CD38 rs3796863 and OXTR rs53576 loci were not associated with psychosocial characteristics of adolescents assessed with the SDQ. In studies with a similar design, we recommend replication with larger samples and greater power to detect small effects, especially in age-sex subgroups of adolescents.

The single nucleotide polymorphism rs53576 of the oxytocin receptor (OXTR) gene is involved in forming and maintaining relationships in various social contexts. However, this has not been studied in the childhood peer context. The present study followed 359 children (51.6% girls) from age 9 to 12 to explore associations between OXTR rs53576 genotype (i.e., AA, AG or GG genotype) and three indicators of children\'s relationships with peers: likability and dis-likability among, and friendship with, classroom peers. Our results showed that OXTR rs53576 was associated with likability among boys, but not with dis-likability and friendship or among girls. Boys with an A and a G allele (i.e., AG genotype) became increasingly more liked by their peers across the four-year studied period than those with two A alleles or two G alleles (i.e., AA and GG genotype). This study indicates that OXTR rs53576 genotype might influence children\'s peer relationships, particularly their likeability among peers. Associations between OXTR rs53576 and peer relationships may differ depending on children\'s sex and the specific type of peer-relationship under scrutiny.

The human oxytocin system is implicated in social behavior and stress recovery. Polymorphisms in the oxytocin receptor gene (OXTR) may interact with attachment style to predict stress-related psychopathology like posttraumatic stress disorder (PTSD). The objective of this study was to examine independent and interactive effects of the OXTR single nucleotide polymorphism (SNP) rs53576, which has been associated with stress reactivity, support-seeking, and PTSD in prior studies, and attachment style on risk for PTSD in a nationally representative sample of 2163 European-American (EA) U.S. military veterans who participated in two independent waves of the National Health and Resilience in Veterans Study (NHRVS). Results revealed that insecure attachment style [adjusted odds ratio (OR) = 4.29; p < 0.001] and the interaction of rs53576 and attachment style (OR = 2.58, p = 0.02) were associated with probable lifetime PTSD. Among individuals with the minor A allele, the prevalence of probable PTSD was significantly higher among those with an insecure attachment style (23.9%) than those with a secure attachment style (2.0%), equivalent to an adjusted OR of 10.7. We attempted to replicate these findings by utilizing dense marker data from a genome-wide association study of 2215 high-risk civilians; one OXTR variant, though not rs53576, was associated with PTSD. Exploratory analyses in the veteran sample revealed that the interaction between this variant and attachment style predicting probable PTSD approached statistical significance. Results indicate that polymorphisms in the OXTR gene and attachment style may contribute to vulnerability to PTSD in U.S. military veterans.

BACKGROUND: Oxytocin receptor (OXTR) gene polymorphisms are related to individual differences in emotional processing of social cues. However, whether OXTR polymorphisms affect emotional processing of nonsocial cues remains unclear. The present study investigated the relationship between the OXTR rs53576 polymorphism and emotional processing of social cues and nonsocial cues.
METHODS: Event-related potentials were recorded from 88 male participants while images of humans and images of objects were presented as social cues and nonsocial cues, respectively.
RESULTS: First, the results showed that GG carriers of OXTR rs53576 showed more negative N1 (50-200 ms) than AA carriers in response to images of both humans and objects. Second, GG carriers showed more negative N2 (200-320 ms) than AA carriers in response to images of humans but not in response to images of objects. Third, GG carriers showed more negative N2 in response to images of humans than images of objects, whereas AA carriers showed the opposite pattern. Fourth, we observed no difference in late positive potential (600-1000 ms) to images of humans or objects that depended on the OXTR rs53576 polymorphism.
CONCLUSIONS: These results suggest that the OXTR rs53576 polymorphism affects emotional processing of not only social cues but also nonsocial cues in the very early stage (reflected in N1); however, the data also suggest that the OXTR rs53576 polymorphism is related specifically to increased emotional processing of social cues in the middle stage (reflected in N2).

In the light of contradictory results concerning OXTR polymorphism rs53576 and depression, we decided to verify the potential association between the two on 1) a large, ethnically homogenous sample of 1185 individuals who completed the Beck Depression Inventory (BDI), as well as on 2) a sample of 763 suicide victims. In the population sample, AA males showed significantly lower BDI scores (p=0.005, pcor=0.030). Exploratory analyses suggested that this effect was limited to a subgroup within 0-9 BDI score range (p=0.0007, U-Mann Whitney test), whereas no main effect on depressive symptoms (BDI>9) was found. In the suicide sample no association with rs53576 genotype was present. Exploratory analyses in suicides revealed higher blood alcohol concentration (BAC) among AA than GG/GA males (p=0.014, U-Mann Whitney test). Our results show that the OXTR rs53576 variant modulates the mood in male individuals and may positively correlate with alcohol intake among male suicides, but is not associated with suicide or depression. The study adds to the growing knowledge on rs53576 genotype characteristics.

Oxytocin is an important regulator of social relationships and has been implicated in development of substance use and addiction. We examined the association of a variance in the oxytocin receptor gene (OXTR rs53576 polymorphism) with alcohol use in a population-representative sample, and potential moderation by social functioning.
The analysis was carried out on the older birth cohort of the longitudinal Estonian Children Personality Behaviour and Health Study (ECPBHS), a cohort of initially 15 years old children (original n=593) recalled at ages 18 and 25. In all data collection waves the participants reported the frequency of consuming alcoholic beverages. Psychiatric interview was carried out at age 25 to assess the lifetime prevalence of substance use disorders. Adverse social interactions with teachers, classmates and family members were self-reported at ages 15 and 18. The minor (A) allele frequency was 0.37.
Males homozygous for the A allele (suggested to be associated with less efficient oxytocinergic functioning) were more frequent alcohol consumers at ages 15 and 18 and also more likely to have had alcohol abuse or addiction by age 25 compared to male G allele carriers. Alcohol use was not associated with the OXTR genotype in females. Both male and female AA homozygotes who had reported less favourable relations with their teachers at age 15 more likely had alcohol use disorder.
OXTR rs53576 polymorphism is associated with alcohol use and prevalence of alcohol use disorders in males, and this may be moderated by inferior interpersonal relationships.

Brain oxytocin and dopamine systems interact to modulate social cognitive behavior. Whether the interactions are modulated by oxytocin receptor (OXTR) gene variations remains unclear. Considering the dopamine transporter (DAT) availability as an endophenotype and the degree of dopamine-mediated neuroticism as a phenotype of the OXTR genotypes, the current molecular imaging study used [(99m)Tc]TRODAT-1 single photon emission computed tomography (SPECT) to measure the striatal DAT availability and the 57-item Maudsley Personality Inventory to measure neuroticism personality traits in healthy individuals to investigate (A) the correlation between the rs53576 (G/A) of OXTR and the striatal DAT availability, (B) the correlation between the peripheral oxytocin level and striatal DAT availability among different OXTR rs53576 (G/A) genotypes, and (C) whether neuroticism traits could be modified by oxytocin in certain OXTR rs53576 genotypes. The results showed that the striatal DAT availability in the AG+GG group was significantly lower than that in the AA group (2.08±0.47 vs. 1.90±0.32, p=0.04). Only individuals with one or two copies of the G allele of rs53576 showed a negative correlation between DAT availability and oxytocin level (r=-0.41, p=0.002). Furthermore, the oxytocin×DAT interaction was significantly correlated with the MPI neuroticism score in the AA group. Further analyses showed that the DAT availability was correlated with the neuroticism score only in the AA group with a low oxytocin level (r=0.74, p=0.002). The results indicated that the OXTR rs53576 is connected with the striatal DAT availability in vivo and modulates the interactions between the oxytocinergic and dopaminergic systems. Carriers with a specific rs53576 OXTR genotype may present a greater biological sensitivity as well as stress reactivity in terms of environmental adaptation.