Epigenetic regulation of the oxytocin receptor gene: implications for behavioral neuroscience
Open accessAbstract
Genetic approaches have improved our understanding of the neurobiological basis of social behavior and cognition. For instance, common polymorphisms of genes involved in oxytocin signaling have been associated with sociobehavioral phenotypes in healthy samples as well as in subjects with mental disorders. More recently, attention has been drawn to epigenetic mechanisms, which regulate genetic function and expression without changes to the underlying DNA sequence. We provide an overview of the functional importance of oxytocin receptor gene (OXTR) promoter methylation and summarize studies that have investigated the role of OXTR methylation in behavioral phenotypes. There is first evidence that OXTR methylation is associated with autism, high callous-unemotional traits, and differential activation of brain regions involved in social perception. Furthermore, psychosocial stress exposure might dynamically regulate OXTR. Given evidence that epigenetic states of genes can be modified by experiences, especially those occurring in sensitive periods early in development, we conclude with a discussion on the effects of traumatic experience on the developing oxytocin system. Epigenetic modification of genes involved in oxytocin signaling might be involved in the mechanisms mediating the long-term influence of early adverse experiences on socio-behavioral outcomes.
AI snapshot
Written from the paper’s full text.
TL;DR
This mini-review summarizes evidence that DNA methylation of the oxytocin receptor gene (OXTR) promoter, especially the MT2 region, can suppress OXTR transcription and is associated with autism, callous-unemotional traits, social-perception brain activation, and acute psychosocial stress. It argues OXTR methylation may link early adverse experience to long-term socio-behavioral outcomes, but current human evidence is preliminary and mostly from peripheral blood.
Key findings
- Functionally, Kusui et al. found that an unmethylated reporter construct including the OXTR CpG island had about 2-fold higher transcriptional activity than a construct lacking most of the CpG island; methylation reduced activity by 19% without the CpG island versus 70% with it, and deleting the MT2 region rescued methylated full-length construct activity to 68%.
- In autism, Gregory et al. reported increased methylation at CpGs −860, −934, and −959 in PBMCs from 20 autistic individuals versus 20 matched controls, with a similar pattern in temporal cortex; an independent sample of 10 autistic and matched controls showed increased methylation at CpGs −860, −901, −924, and −934 and reduced OXTR mRNA expression by 20%.
- In social perception, Jack et al. (n = 42) found that higher OXTR methylation at CpG −934 was associated with greater activation in superior temporal gyrus/supramarginal gyrus and dorsal anterior cingulate cortex during viewing of biological-motion-like stimuli.
- In callous-unemotional traits, Dadds et al. studied 69 boys with conduct problems and found no overall methylation–CU association, but higher OXTR methylation was associated with elevated CU traits in older boys (9–16 years) and not younger boys (3–8 years). Unternaehrer et al. (n = 76) found mean OXTR methylation increased immediately after the Trier Social Stress Test and decreased below baseline 90 min post-stress, with mean changes of 0.38 and 1.04%.
Methods
- Narrative mini-review; no new primary data are presented. It summarizes functional OXTR methylation studies and human behavioral, neuroimaging, and stress studies.
- Reviewed studies used DNA methylation from peripheral blood/PBMCs or temporal cortex, and methods included luciferase reporter assays, case-control methylation comparisons, fMRI, and the Trier Social Stress Test.
- No systematic review or meta-analysis is described; the synthesis is qualitative.
Limitations
- Stated: all included human studies measured DNA methylation from whole blood; because blood is heterogeneous, group differences may be confounded by cellular composition, and it is unknown whether peripheral OXTR methylation reflects central nervous system OXTR methylation.
- Stated: the stress findings should be interpreted cautiously because methylation was assessed in whole blood, stress can rapidly change leukocyte composition, and observed mean changes were small (0.38 and 1.04%); Dadds et al. lacked longitudinal data, so causality remains unclear.
- Evident from the text: the evidence base is small and preliminary, with several cited samples small (e.g., 20 + 20, 10 + 10, 69 boys, 42, 76), and the authors state there is no published human research on early environmental influences on differential OXTR methylation.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 34 cited sources checked · 0 supported · 0 flagged
- Premisecitation
Oxytocin plays a key role in the regulation of social cognition and behavior.
“Research across species has shown that the neuropeptide oxytocin plays a key role in the regulation of social cognition and behavior.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Meyer-Lindenberg et al., 2011
Not checked in the free run.
- Study design and conductcitation
Changes in blood cell composition might partially account for the observed differences in methylation levels after acute stress.
“As the composition of the circulating leukocyte pool can rapidly change in response to stress (Richlin et al., 2004), changes in blood cell composition might partially account for the observed differences in methylation levels.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Richlin et al., 2004
Not checked in the free run.
- Premisecitation
The MT2 region of the OXTR CpG island is responsible for the majority of DNA methylation-induced silencing of the reporter constructs.
“Importantly, Kusui et al. identified a region of the OXTR CpG island (termed MT2; see Figure 1A) that appears to be responsible for the majority of DNA methylation-induced silencing of these constructs.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Kusui et al., 2001
Not checked in the free run.
- Study design and conductnone given
All studies included in the review measured DNA methylation from whole blood.
“For instance, all studies included here measured DNA methylation from whole blood.”
Quote in the paperSubstantial claim - Premisecitation
In adult women with a history of childhood abuse, cerebrospinal fluid oxytocin concentrations were decreased compared to women without such experience.
“In a sample of adult women with a history of early abuse, decreased oxytocin concentrations in cerebrospinal fluid (CSF) were found in women reporting exposure to childhood abuse as compared to women without such experience (Heim et al., 2009).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Heim et al., 2009
Not checked in the free run.
- Premisecitation
The epigenome is sensitive to a wide variety of environmental influences, including diet, toxins, and maternal care.
“Indeed, the epigenome seems sensitive to a wide variety of environmental influences, including diet, toxins, and maternal care (Zhang et al., 2010; Walker and Gore, 2011; Dominguez-Salas et al., 2012).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Zhang et al., 2010
Not checked in the free run.
- cites Walker and Gore, 2011
Not checked in the free run.
- cites Dominguez-Salas et al., 2012
Not checked in the free run.
- Premisecitation
A similar pattern of OXTR methylation differences was observed in temporal cortex tissue.
“Importantly, a similar pattern of methylation differences was observed in temporal cortex tissue.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Gregory et al., 2009
Not checked in the free run.
- Premiseown data
Individuals with higher levels of OXTR methylation derived from PBMCs demonstrated significantly greater activation in two clusters: the superior temporal gyrus into supramarginal gyrus at the temporal parietal junction, and the dorsal anterior cingulate cortex.
“Whole-brain analysis showed that individuals with higher levels of OXTR methylation derived from PBMCs demonstrated significantly greater activation in two clusters. The first extended from the superior temporal gyrus into supramarginal gyrus at the temporal parietal junction, and the second was in the dorsal anterior cingulate cortex (dACC).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Jack et al., 2012
Not checked in the free run.
- Premisecitation
Transcriptional activity of an unmethylated reporter construct including the OXTR CpG island is about 2-fold higher than that of a construct including the core promoter but lacking the majority of the CpG island.
“Transcriptional activity of an unmethylated reporter construct including the CpG island (−2860 to +1342 bp relative to the transcription start site) was about 2-fold higher compared to the construct including the core promoter but lacking the majority of the CpG island (−2860 to +144 bp).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Kusui et al., 2001
Not checked in the free run.
- Interpretationown data
DNA methylation status of a gene involved in stress regulation might be sensitive to acute stress exposure.
“While this investigation provides first evidence that DNA methylation status of a gene involved in stress regulation might be sensitive to acute stress exposure, these results should nevertheless be interpreted with caution.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Unternaehrer et al., 2012
Not checked in the free run.
- Premisecitation
Dadds et al. provide first evidence that OXTR promoter methylation is associated with CU traits in males.
“Dadds et al. (in press) provide first evidence that OXTR promoter methylation is associated with CU traits in males.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Dadds et al., in press
Not checked in the free run.
- Interpretationcitation
OXTR CpG island methylation functionally suppresses transcription, at least in the investigated hepatoblastoma cell line.
“This indicates that OXTR CpG island methylation functionally suppresses transcription, at least in the investigated hepatoblastoma cell line.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Kusui et al., 2001
Not checked in the free run.
- Premisecitation
OXTR SNPs are associated with structural and functional alterations in limbic circuitry involving the amygdala, hypothalamus, and cingulate gyrus.
“Imaging genetic studies show that OXTR SNPs are associated with structural and functional alterations in limbic circuitry involving the amygdala, the hypothalamus and the cingulate gyrus”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Meyer-Lindenberg and Tost, 2012
Not checked in the free run.
- Premisecitation
In 69 boys with conduct problems, there was no significant overall association between OXTR methylation and CU traits.
“Overall, there was no significant association between methylation and CU traits.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Dadds et al., in press
Not checked in the free run.
- Premisecitation
In 20 individuals with autism and 20 matched controls, autistic probands showed significantly increased methylation at CpGs −860, −934, and −959.
“Significantly increased methylation in autistic probands was observed for CpGs −860, −934, and −959 (numbering according to translation start site +1).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Gregory et al., 2009
Not checked in the free run.
- Premisecitation
The OXTR CpG island has significant promoter activity.
“Using a luciferase reporter gene assay, it was shown that the CpG island had significant promoter activity.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Kusui et al., 2001
Not checked in the free run.
- Premisecitation
Post-institutionalized children reared in severely depriving conditions showed lower peripheral oxytocin levels after physical interactions with their adoptive mothers compared to children reared in a typical home environment.
“Compared to children reared in a typical home environment, the adopted children showed lower peripheral oxytocin levels after physical interactions with their adoptive mothers.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Wismer Fries et al., 2005
Not checked in the free run.
- Interpretationreasoning
Differential methylation of a CpG island in the OXTR promoter seems functionally important for OXTR expression.
“Differential methylation of a CpG island in the OXTR promoter seems to be functionally important for OXTR expression, and differences in the degree of methylation have been observed in childhood disorders characterized by impairments in social cognition.”
Quote in the paperSubstantial claim - Interpretationown data
Differences in the degree of OXTR methylation have been observed in childhood disorders characterized by impairments in social cognition.
“Differential methylation of a CpG island in the OXTR promoter seems to be functionally important for OXTR expression, and differences in the degree of methylation have been observed in childhood disorders characterized by impairments in social cognition.”
Quote in the paperSubstantial claim - Interpretationcitation
Variation of OXTR influences social cognition and behavior by modulating neural circuits for processing of social information and negative affect.
“suggesting that variation of OXTR influences social cognition and behavior by modulating neural circuits for processing of social information and negative affect (Meyer-Lindenberg and Tost, 2012)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Meyer-Lindenberg and Tost, 2012
Not checked in the free run.
- Interpretationreasoning
Epigenetic modification of genes involved in oxytocin signaling might be involved in the mechanisms mediating the long-term influence of early adverse experiences on socio-behavioral outcomes.
“Epigenetic modification of genes involved in oxytocin signaling might be involved in the mechanisms mediating the long-term influence of early adverse experiences on socio-behavioral outcomes.”
Quote in the paperSubstantial claim - Interpretationcitation
Regulation of OXTR is sensitive to methylation within the MT2 region of the CpG island.
“This suggests that regulation of OXTR is sensitive to methylation within the MT2 region of the CpG island, and points toward functional significance of this region.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Kusui et al., 2001
Not checked in the free run.
- Premisecitation
Deletion of the MT2 region in the full length construct led to a relative rescue of transcriptional activity of the methylated construct to 68%.
“Deletion of the MT2 region in the full length construct led to a relative rescue of transcriptional activity of the methylated construct to 68%.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Kusui et al., 2001
Not checked in the free run.
- Premisecitation
Genes involved in oxytocinergic signaling are important in explaining individual differences in sociobehavioral phenotypes in both healthy samples and patient groups.
“Several association studies have shown that genes involved in oxytocinergic signaling are important in explaining individual differences in sociobehavioral phenotypes in both healthy samples and patient groups.”
Quote in the paperSubstantial claim - Premisecitation
Oxytocin signaling is impaired in mental disorders associated with social deficits, including autism, borderline personality disorder, and social anxiety disorder.
“Based on oxytocin administration studies and measurements of peripheral oxytocin levels, it has been suggested that signaling of oxytocin is impaired in mental disorders associated with social deficits, including autism (Andari et al., 2010; Guastella et al., 2010), borderline personality disorder (Simeon et al., 2011), and social anxiety disorder (Guastella et al., 2009; Labuschagne et al., 2010)”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Andari et al., 2010
Not checked in the free run.
- cites Guastella et al., 2010
Not checked in the free run.
- cites Simeon et al., 2011
Not checked in the free run.
- Classified as probably not a substantial claim. 4
- May combine two claims. 9
Classified as probably not a substantial claim.
Study design and conductnone givenIt is currently unknown whether differences in OXTR methylation obtained from peripheral tissues reflect variation in central nervous nuclei expressing OXTR.
“It is currently unknown whether differences in OXTR methylation obtained from peripheral tissues reflect variation in central nervous nuclei expressing OXTR.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationMean OXTR methylation status increased immediately after acute stress and then decreased to below baseline levels 90 min post-stress.
“Mean methylation status increased immediately after stress, and then decreased to below baseline levels 90 min post-stress.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Unternaehrer et al., 2012
Not checked in the free run.
Probably not a substantial claim: may not pass S4 (based).
Interpretationnone givenPsychosocial stress exposure might dynamically regulate OXTR.
“Furthermore, psychosocial stress exposure might dynamically regulate OXTR.”
Quote in the paperNot a substantial claimMay combine two claims.
Premiseown dataThe mean change in OXTR methylation from pre- to post-stress was 0.38, and from post-stress to follow-up was 1.04%.
“The mean change from pre- to post-stress was 0.38, and 1.04% from post-stress to follow-up, although individual CpGs showed larger differences.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Unternaehrer et al., 2012
Not checked in the free run.
May combine two claims.
PremisecitationMethylation reduces transcriptional activity of the OXTR reporter construct lacking the CpG island by 19% and suppresses activity of the construct including the CpG island by 70%.
“Following methylation, transcriptional activity of the reporter gene construct lacking the CpG island was reduced by 19%, whereas activity of the construct including the CpG island was suppressed by 70% when methylated.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Kusui et al., 2001
Not checked in the free run.
May combine two claims.
InterpretationreasoningOXTR methylation influences relatively low-level processes involved in social perception and may contribute more generally to interindividual differences in social cognition and behavior.
“These results suggest that OXTR methylation influences relatively low-level processes involved in social perception and may contribute more generally to interindividual differences in social cognition and behavior.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Jack et al., 2012
Not checked in the free run.
- Rests on an assumption: OXTR methylation measured in peripheral tissues reflects OXTR methylation in central nervous nuclei expressing OXTR.
May combine two claims.
InterpretationreasoningDifferential methylation of OXTR might be important in explaining individual differences in social behavior and cognition more broadly, and might provide a mechanism for biological embedding of early experience.
“Furthermore, differential methylation of OXTR might be important in explaining individual differences in social behavior and cognition more broadly, and might provide a mechanism for biological embedding of early experience.”
Quote in the paperSubstantial claim- Rests on an assumption: OXTR methylation measured in peripheral tissues reflects OXTR methylation in central nervous nuclei expressing OXTR.
May combine two claims.
PremisecitationSingle nucleotide polymorphisms in OXTR are associated with empathy, positive affect, and sensitivity to social support.
“single nucleotide polymorphisms (SNPs) in OXTR have been associated with empathy (Rodrigues et al., 2009), positive affect (Kogan et al., 2011; Montag et al., 2011) and sensitivity to social support (Chen et al., 2011)”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Rodrigues et al., 2009
Not checked in the free run.
- cites Kogan et al., 2011
Not checked in the free run.
- cites Chen et al., 2011
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoningIt is unclear to what extent DNA methylation differences between groups could be confounded by differences in the cellular composition of blood samples.
“Since blood is a heterogeneous tissue, it is unclear to what extent DNA methylation difference between groups could be confounded by differences in the cellular composition of the samples.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationcitationOXTR promoter methylation has functional importance with regard to gene regulation, and possibly the etiology of autism.
“Although investigated in a small sample, these findings suggest functional importance of OXTR promoter methylation with regard to gene regulation, and possibly the etiology of autism.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Gregory et al., 2009
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDNA methylation is recognized as an important epigenetic factor influencing gene expression.
“In concert with other regulators, DNA methylation is recognized as an important epigenetic factor influencing gene expression (Moore et al., 2013).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Moore et al., 2013
Not checked in the free run.
May combine two claims.
Interpretationnone givenThere is first evidence that OXTR methylation is associated with autism, high callous-unemotional traits, and differential activation of brain regions involved in social perception.
“There is first evidence that OXTR methylation is associated with autism, high callous-unemotional traits, and differential activation of brain regions involved in social perception.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationIn the older sample (9-16 years) but not the younger sample (3-8 years), higher OXTR methylation was associated with elevated CU traits.
“Whereas there was no relation between methylation and CU traits in the younger sample (3–8 years), higher methylation of OXTR was associated with elevated CU traits in the older sample (9–16 years).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Dadds et al., in press
Not checked in the free run.
The paper relies on this without support.
The effect sizes of single nucleotide polymorphisms are usually small.
“It is worth noting, however, that the effect sizes of single SNPs are usually small.”
The paper relies on this without support.
OXTR methylation measured in peripheral tissues reflects OXTR methylation in central nervous nuclei expressing OXTR.
“It is currently unknown whether differences in OXTR methylation obtained from peripheral tissues reflect variation in central nervous nuclei expressing OXTR.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Published case studies and anecdotal evidence suggest off-label prescriptions of oxytocin are already a common practice by treating clinicians, despite concerns about pediatric use outside of a clinical trial setting.
“Both published case studies 67 and anecdotal evidence 68 suggest off-label prescriptions of oxytocin are already a common practice by treating clinicians, despite concerns about pediatric use outside of a clinical trial setting.69”
From Beyond the hype and hope: critical considerations for intranasal oxytocin research in autism spectrum disorder (2017) · cites this paper as [68]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Not all reviewed methylation measurements used blood
MinorThe paper says all included studies measured DNA methylation from whole blood, but its autism section reports methylation differences measured in temporal cortex tissue.
“For instance, all studies included here measured DNA methylation from whole blood.”
“Importantly, a similar pattern of methylation differences was observed in temporal cortex tissue.”
Cites
Child abuse: Adolescent records vs. adult recall
Femina, D. D., Yeager, C. A., & Lewis, D. O. (1990) · Child Abuse & Neglect · doi:10.1016/0145-2134(90)90033-p · Cited by 8,820 · see citing works
Jaenisch, R., & Bird, A. (2003) · Nature Genetics · doi:10.1038/ng1089 · Cited by 6,325 · see citing works
DNA methylation and its basic function
Moore, L. D., Le, T., & Fan, G. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2012.112 · Cited by 4,906 · see citing works
Burden and consequences of child maltreatment in high-income countries
Gilbert, R., Widom, C. S., Browne, K., Fergusson, D., Webb, E., & Janson, S. (2009) · The Lancet · doi:10.1016/s0140-6736(08)61706-7 · Cited by 3,876 · see citing works
Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse
McGowan, P. O., Sasaki, A., D'Alessio, A. C., Dymov, S., Labonté, B., Szyf, M., Turecki, G., & Meaney, M. J. (2009) · Nature Neuroscience · doi:10.1038/nn.2270 · Cited by 3,531 · see citing works
CpG islands in vertebrate genomes.
Gardiner-Garden, M., & Frommer, M. (1987) · Journal of Molecular Biology · doi:10.1016/0022-2836(87)90689-9 · Cited by 3,462 · see citing works
Risky families: Family social environments and the mental and physical health of offspring
Repetti, R. L., Taylor, S. E., & Seeman, T. E. (2002) · Psychological Bulletin · doi:10.1037/0033-2909.128.2.330 · Cited by 2,884 · see citing works
Heinrichs, M., Baumgartner, T., Kirschbaum, C., & Ehlert, U. (2003) · Biological Psychiatry · doi:10.1016/s0006-3223(03)00465-7 · Cited by 2,091 · see citing works
Self-citationOxytocin and vasopressin in the human brain: social neuropeptides for translational medicine
Meyer-Lindenberg, A., Domes, G., Kirsch, P., & Heinrichs, M. (2011) · Nature Reviews Neuroscience · doi:10.1038/nrn3044 · Cited by 1,688 · see citing works
Self-citationOxytocin Modulates Neural Circuitry for Social Cognition and Fear in Humans
Kirsch, P., Esslinger, C., Chen, Q., Mier, D., Lis, S., Siddhanti, S., Gruppe, H., Mattay, V. S., Gallhofer, B., & Meyer-Lindenberg, A. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.3984-05.2005 · Cited by 1,639 · see citing works
Saxonov, S., Berg, P., & Brutlag, D. L. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0510310103 · Cited by 1,401 · see citing works
Oxytocin improves “mind-reading” in humans
Domes, G., Heinrichs, M., Michel, A., Berger, C., & Herpertz, S. C. (2007) · Biological Psychiatry · doi:10.1016/j.biopsych.2006.07.015 · Cited by 1,298 · see citing works
Self-citationFrick, P. J., & White, S. F. (2008) · Journal of Child Psychology and Psychiatry · doi:10.1111/j.1469-7610.2007.01862.x · Cited by 1,290 · see citing works
Charting histone modifications and the functional organization of mammalian genomes
Zhou, V. W., Goren, A., & Bernstein, B. E. (2011) · Nature Reviews Genetics · doi:10.1038/nrg2905 · Cited by 1,147 · see citing works
Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders.
Guastella, A. J., Einfeld, S. L., Gray, K. M., Rinehart, N. J., Tonge, B. J., Lambert, T. J., & Hickie, I. B. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.09.020 · Cited by 962 · see citing works
Promoting social behavior with oxytocin in high-functioning autism spectrum disorders.
Andari, E., Duhamel, J.-R., Zalla, T., Herbrecht, E., Leboyer, M., & Sirigu, A. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0910249107 · Cited by 941 · see citing works
Oxytocin receptor genetic variation relates to empathy and stress reactivity in humans
Rodrigues, S. M., Saslow, L. R., Garcia, N., John, O. P., & Keltner, D. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0909579106 · Cited by 812 · see citing works
Oxytocin, vasopressin, and human social behavior
Heinrichs, M., von Dawans, B., & Domes, G. (2009) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2009.05.005 · Cited by 799 · see citing works
Self-citationOxytocin increases gaze to the eye region of human faces
Guastella, A. J., Mitchell, P. B., & Dadds, M. R. (2008) · Biological Psychiatry · doi:10.1016/j.biopsych.2007.06.026 · Cited by 798 · see citing works
CpG methylation, chromatin structure and gene silencing—a three‐way connection
Razin, A. (1998) · The EMBO Journal · doi:10.1093/emboj/17.17.4905 · Cited by 791 · see citing works
Oxytocin attenuates amygdala responses to emotional faces regardless of valence
Domes, G., Heinrichs, M., Gläscher, J., Büchel, C., Braus, D. F., & Herpertz, S. C. (2007) · Biological Psychiatry · doi:10.1016/j.biopsych.2007.03.025 · Cited by 774 · see citing works
Self-citationA fraction of the mouse genome that is derived from islands of nonmethylated, CpG-rich DNA
Bird, A. P., Taggart, M. H., Frommer, M., Miller, O. J., & Macleod, D. (1985) · Cell · doi:10.1016/0092-8674(85)90312-5 · Cited by 714 · see citing works
CD38 is critical for social behaviour by regulating oxytocin secretion
Jin, D., Liu, H.-X., Hirai, H., Torashima, T., Nagai, T., Lopatina, O., Shnayder, N. A., Yamada, K., Noda, M., Seike, T., et al. (2007) · Nature · doi:10.1038/nature05526 · Cited by 665 · see citing works
Genomic and epigenetic evidence for oxytocin receptor deficiency in autism
Gregory, S. G., Connelly, J. J., Towers, A. J., Johnson, J., Biscocho, D., Markunas, C. A., Lintas, C., Abramson, R. K., Wright, H. H., Ellis, P., et al. (2009) · BMC Medicine · doi:10.1186/1741-7015-7-62 · Cited by 576 · see citing works
Fries, A. B. W., Ziegler, T. E., Kurian, J. R., Jacoris, S., & Pollak, S. D. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0504767102 · Cited by 570 · see citing works
Epigenetics and the environmental regulation of the genome and its function
Zhang, T.-Y., & Meaney, M. J. (2010) · Annual Review of Psychology · doi:10.1146/annurev.psych.60.110707.163625 · Cited by 565 · see citing works
Tost, H., Kolachana, B., Hakimi, S., Lemaitre, H., Verchinski, B. A., Mattay, V. S., Weinberger, D. R., & Meyer–Lindenberg, A. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1003296107 · Cited by 564 · see citing works
Oxytocin Attenuates Amygdala Reactivity to Fear in Generalized Social Anxiety Disorder
Labuschagne, I., Phan, K. L., Wood, A., Angstadt, M., Chua, P., Heinrichs, M., Stout, J. C., & Nathan, P. J. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2010.123 · Cited by 549 · cited 1× · see citing works
“, 2011), and social anxiety disorder (Guastella et al., 2009; Labuschagne et al., 2010).”
Self-citationEffects of intranasal oxytocin on emotional face processing in women
Domes, G., Lischke, A., Berger, C., Grossmann, A., Hauenstein, K., Heinrichs, M., & Herpertz, S. C. (2010) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2009.06.016 · Cited by 521 · see citing works
Self-citationLower CSF oxytocin concentrations in women with a history of childhood abuse
Heim, C., Young, L. J., Newport, D. J., Mletzko, T., Miller, A. H., & Nemeroff, C. B. (2009) · Molecular Psychiatry · doi:10.1038/mp.2008.112 · Cited by 518 · see citing works
Genome-wide epigenetic regulation by early-life trauma
Labonté, B., Suderman, M., Maussion, G., Navaro, L., Yerko, V., Mahar, I., Bureau, A., Mechawar, N., Szyf, M., Meaney, M. J., et al. (2012) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2011.2287 · Cited by 488 · see citing works
Neumann, I. D. (2002) · Progress in brain research · doi:10.1016/s0079-6123(02)39014-9 · Cited by 387 · see citing works
Guastella, A. J., Howard, A. L., Dadds, M. R., Mitchell, P., & Carson, D. S. (2009) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2009.01.005 · Cited by 366 · see citing works
Labonte, B., Yerko, V., Gross, J., Mechawar, N., Meaney, M. J., Szyf, M., & Turecki, G. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.01.034 · Cited by 345 · see citing works
Neural mechanisms of social risk for psychiatric disorders
Meyer‐Lindenberg, A., & Tost, H. (2012) · Nature Neuroscience · doi:10.1038/nn.3083 · Cited by 342 · see citing works
A longitudinal study of epigenetic variation in twins
Wong, C. C. Y., Caspi, A., Williams, B. S., Craig, I., Houts, R., Ambler, A. P., Moffitt, T. E., & Mill, J. S. (2010) · Epigenetics · doi:10.4161/epi.5.6.12226 · Cited by 320 · see citing works
The contributions of oxytocin and vasopressin pathway genes to human behavior
Ebstein, R. P., Knafo, A., Mankuta, D., Chew, S. H., & Lai, P. S. (2012) · Hormones and Behavior · doi:10.1016/j.yhbeh.2011.12.014 · Cited by 283 · see citing works
Kogan, A., Saslow, L. R., Impett, E. A., Oveis, C., Keltner, D., & Rodrigues Saturn, S. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1112658108 · Cited by 279 · see citing works
Maternal Care and DNA Methylation of a Glutamic Acid Decarboxylase 1 Promoter in Rat Hippocampus
Zhang, T., Hellstrom, I. C., Bagot, R. C., Wen, X., Diorio, J. C., & Meaney, M. J. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.1039-10.2010 · Cited by 269 · see citing works
Chen, F. S., Kumsta, R., von Dawans, B., Monakhov, M., Ebstein, R. P., & Heinrichs, M. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1113079108 · Cited by 268 · see citing works
Self-citationOxytocin, stress and social behavior: neurogenetics of the human oxytocin system
Kumsta, R., & Heinrichs, M. (2012) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2012.09.004 · Cited by 265 · see citing works
Self-citationThe Detection of Contingency and Animacy from Simple Animations in the Human Brain
Blakemore, S. (2003) · Cerebral Cortex · doi:10.1093/cercor/13.8.837 · Cited by 251 · see citing works
Unternaehrer, E., Luers, P., Mill, J., Dempster, E., Meyer, A. H., Staehli, S., Lieb, R., Hellhammer, D. H., & Meinlschmidt, G. (2012) · Translational Psychiatry · doi:10.1038/tp.2012.77 · Cited by 250 · see citing works
Commentary: The seven plagues of epigenetic epidemiology
Heijmans, B. T., & Mill, J. (2012) · International Journal of Epidemiology · doi:10.1093/ije/dyr225 · Cited by 208 · see citing works
Kusui, C., Kimura, T., Ogita, K., Nakamura, H., Matsumura, Y., Koyama, M., Azuma, C., & Murata, Y. (2001) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2001.6024 · Cited by 196 · see citing works
Arginine Vasopressin and Oxytocin Modulate Human Social Behavior
Ebstein, R. P., Israel, S., Lerer, E., Uzefovsky, F., Shalev, I., Gritsenko, I., Riebold, M., Salomon, S., & Yirmiya, N. (2009) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2009.04541.x · Cited by 195 · see citing works
DNA methylation of the oxytocin receptor gene predicts neural response to ambiguous social stimuli
Jack, A., Connelly, J. J., & Morris, J. P. (2012) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2012.00280 · Cited by 192 · see citing works
Transgenerational neuroendocrine disruption of reproduction
Walker, D. M., & Gore, A. C. (2011) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2010.215 · Cited by 167 · see citing works
Simeon, D., Bartz, J. A., Hamilton, H., Crystal, S., Braun, A. R., Ketay, S., & Hollander, E. (2011) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2011.03.013 · Cited by 167 · see citing works
Dominguez-Salas, P., Cox, S. E., Prentice, A. M., Hennig, B. J., & Moore, S. E. (2012) · Proceedings of the Nutrition Society · doi:10.1017/s0029665111003338 · Cited by 163 · see citing works
A model of differential amygdala activation in psychopathy
Moul, C., Killcross, S., & Dadds, M. R. (2012) · Psychological Review · doi:10.1037/a0029342 · Cited by 159 · see citing works
Intranasal oxytocin increases covert attention to positive social cues
Domes, G., Sibold, M., Schulze, L., Lischke, A., Herpertz, S. C., & Heinrichs, M. (2013) · Psychological Medicine · doi:10.1017/s0033291712002565 · Cited by 130 · see citing works
Self-citationIII. DEPRIVATION-SPECIFIC PSYCHOLOGICAL PATTERNS
Kumsta, R., Kreppner, J., Rutter, M. L., Beckett, C., Castle, J., Stevens, S. E., & Sonuga-Barke, E. J. S. (2010) · Monographs of the Society for Research in Child Development · doi:10.1111/j.1540-5834.2010.00550.x · Cited by 112 · see citing works
Self-citationDitzen, B., Nater, U. M., Schaer, M., La Marca, R., Bodenmann, G., Ehlert, U., & Heinrichs, M. (2013) · Social Cognitive and Affective Neuroscience · doi:10.1093/scan/nss083 · Cited by 111 · see citing works
Self-citationPolymorphisms in the oxytocin receptor gene are associated with the development of psychopathy
Dadds, M. R., Moul, C., Cauchi, A., Dobson‐Stone, C., Hawes, D. J., Brennan, J., Urwin, R., & Ebstein, R. P. (2013) · Development and Psychopathology · doi:10.1017/s0954579413000485 · Cited by 108 · see citing works
Lerer, E., Levi, S., Israel, S., Yaari, M., Nemanov, L., Mankuta, D., Yirmiya, N., & Ebstein, R. P. (2010) · Autism Research · doi:10.1002/aur.156 · Cited by 104 · see citing works
Childhood aggression, callous-unemotional traits and oxytocin genes
Beitchman, J. H., Zai, C. C. H., Muir, K. E., Berall, L. E., Nowrouzi‐Kia, B., Choi, E., & Kennedy, J. L. (2012) · European Child & Adolescent Psychiatry · doi:10.1007/s00787-012-0240-6 · Cited by 103 · see citing works
Montag, C., Fiebach, C. J., Kirsch, P., & Reuter, M. (2010) · Biological Psychiatry · doi:10.1016/j.biopsych.2010.10.026 · Cited by 97 · see citing works
Oxytocin Gene Polymorphisms Influence Human Dopaminergic Function in a Sex-Dependent Manner
Love, T. M., Enoch, M.-A., Hodgkinson, C. A., Peciña, M., Mickey, B., Koeppe, R. A., Stohler, C. S., Goldman, D., & Zubieta, J.-K. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.01.033 · Cited by 97 · see citing works
Richlin, V. A., Arevalo, J. M. G., Zack, J. A., & Cole, S. W. (2003) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2003.08.001 · Cited by 49 · see citing works
Sakai, J. T., Crowley, T. J., Stallings, M. C., McQueen, M. B., Hewitt, J. K., Hopfer, C. J., Hoft, N. R., & Ehringer, M. A. (2011) · Psychiatric Genetics · doi:10.1097/ypg.0b013e32834c0cb2 · Cited by 20 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
The impact of atypical sensory processing on social impairments in autism spectrum disorder
Thye, M. D., Bednarz, H. M., Herringshaw, A. J., Sartin, E. B., & Kana, R. K. (2018) · Developmental Cognitive Neuroscience · doi:10.1016/j.dcn.2017.04.010 · Cited by 513 · see citing works
Autism, oxytocin and interoception
Quattrocki, E., & Friston, K. (2014) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2014.09.012 · Cited by 393 · see citing works
Feldman, R., Monakhov, M., Pratt, M., & Ebstein, R. P. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.08.008 · Cited by 352 · see citing works
Does Oxytocin Increase Trust in Humans? A Critical Review of Research
Nave, G., Camerer, C., & McCullough, M. (2015) · Perspectives on Psychological Science · doi:10.1177/1745691615600138 · Cited by 309 · see citing works
Dadds, M. R., Moul, C., Cauchi, A., Dobson-Stone, C., Hawes, D. J., Brennan, J., & Ebstein, R. E. (2014) · Development and Psychopathology · doi:10.1017/s0954579413000497 · Cited by 230 · see citing works
Puglia, M. H., Lillard, T. S., Morris, J. P., & Connelly, J. J. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1422096112 · Cited by 216 · see citing works
Oxytocin receptor gene methylation: converging multilevel evidence for a role in social anxiety
Ziegler, C., Dannlowski, U., Bräuer, D., Stevens, S., Laeger, I., Wittmann, H., Kugel, H., Dobel, C., Hurlemann, R., Reif, A., et al. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.2 · Cited by 193 · see citing works
Smearman, E. L., Almli, L. M., Conneely, K. N., Brody, G. H., Sales, J. M., Bradley, B., Ressler, K. J., & Smith, A. K. (2016) · Child Development · doi:10.1111/cdev.12493 · Cited by 173 · see citing works
Amini-Khoei, H., Mohammadi-Asl, A., Amiri, S., Hosseini, M.-J., Momeny, M., Hassanipour, M., Rastegar, M., Haj-Mirzaian, A., Mirzaian, A. H., Sanjarimoghaddam, H., et al. (2017) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2017.02.022 · Cited by 153 · see citing works
Oxytocin׳s role in anxiety: A critical appraisal
MacDonald, K., & Feifel, D. (2014) · Brain Research · doi:10.1016/j.brainres.2014.01.025 · Cited by 139 · see citing works
Oxytocin and the social brain: Neural mechanisms and perspectives in human research
Kanat, M., Heinrichs, M., & Domes, G. (2014) · Brain Research · doi:10.1016/j.brainres.2013.11.003 · Cited by 122 · see citing works
Self-citationKim, Y.-R., Kim, J.-H., Kim, M. J., & Treasure, J. (2014) · PLoS ONE · doi:10.1371/journal.pone.0088673 · Cited by 97 · see citing works
Alvares, G. A., Quintana, D. S., & Whitehouse, A. J. O. (2017) · Autism Research · doi:10.1002/aur.1692 · Cited by 91 · see citing works
Beery, A. K., McEwen, L. M., MacIsaac, J. L., Francis, D. D., & Kobor, M. S. (2016) · Hormones and Behavior · doi:10.1016/j.yhbeh.2015.05.022 · Cited by 81 · see citing works
Maternal adversities during pregnancy and cord blood oxytocin receptor (<i>OXTR</i>) DNA methylation
Unternaehrer, E., Bolten, M., Nast, I., Staehli, S., Meyer, A. H., Dempster, E., Hellhammer, D. H., Lieb, R., & Meinlschmidt, G. (2016) · Social Cognitive and Affective Neuroscience · doi:10.1093/scan/nsw051 · Cited by 75 · see citing works
Schneider-Hassloff, H., Straube, B., Jansen, A., Nuscheler, B., Wemken, G., Witt, S. H., Rietschel, M., & Kircher, T. (2016) · NeuroImage · doi:10.1016/j.neuroimage.2016.04.009 · Cited by 71 · see citing works
Genetic modulation of oxytocin sensitivity: A pharmacogenetic approach
Chen, F. S., Kumsta, R., Dvorak, F., Domes, G., Yim, O. S., Ebstein, R. P., & Heinrichs, M. (2015) · Translational Psychiatry · doi:10.1038/tp.2015.163 · Cited by 59 · see citing works
Self-citationOxytocin and anxiety disorders
Gottschalk, M. G., & Domschke, K. (2017) · Current Topics in Behavioral Neurosciences · doi:10.1007/7854_2017_25 · Cited by 61 · see citing works
Montag, C., Sauer, C., Reuter, M., & Kirsch, P. (2013) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-013-0452-x · Cited by 32 · see citing works
Preckel, K., Kanske, P., Singer, T., Paulus, F. M., & Krach, S. (2016) · BMC Psychiatry · doi:10.1186/s12888-016-1036-x · Cited by 25 · see citing works
- Authors
- Kumsta, R., Hummel, E., Chen, F. S., & Heinrichs, M.
- Affiliations
- University of Freiburg (DE)
- Corresponding author
- Kumsta, Robert
- Venue
- Frontiers in Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2013
- Volume
- 7
- Pages
- 83-83
- ISSN
- 1662-453X (ISSN-L)
- PMC
- PMC3661945
- OpenAlex
- W2011027277
- Semantic Scholar
- a853f824c5a4667125bca391a51f0a53c8b3e6e5
- Cited by
- 207
- References
- 61
- Citations by year
- 2026: 12 · 2025: 9 · 2024: 6 · 2023: 11 · 2022: 9 · 2021: 8 · 2020: 13 · 2019: 15 · 2018: 21 · 2017: 23 · 2016: 28 · 2015: 21 · 2014: 22 · 2013: 9
- FWCI
- 40.03
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Neuroscience (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion, other-oa)
- Research Bank (Australian Catholic University) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
- Funders
- Alexander von Humboldt-Stiftung
- Deutsche Forschungsgemeinschaft (KU 2479/3-1, 5310/1-1, 2479/3-1)
- Albert-Ludwigs-Universität Freiburg
- Topics
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- oxytocin receptor gene, oxytocin receptor, DNA methylation, epigenetic regulation, social behavior, autism spectrum disorder, callous-unemotional traits, social perception, psychosocial stress, childhood adversity, traumatic events, oxytocin signaling, gene expression regulation
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
