Oxytocin Receptor Gene Methylation: Converging Multilevel Evidence for a Role in Social Anxiety

Ziegler, Christiane; Dannlowski, Udo; Bräuer, David; Stevens, S. S.; Laeger, Inga; Wittmann, Hannah; Kugel, Harald; Dobel, Christian; Hurlemann, René; Reif, Andreas; Lesch, Klaus‐Peter; Heindel, Walter; Kirschbaum, Clemens; Arolt, Volker; Gerlach, Alexander L.; Hoyer, Jürgen; Deckert, Jürgen; Zwanzger, Peter; Domschke, Katharina

doi:10.1038/npp.2015.2

Cited by 154 publications

(102 citation statements)

References 72 publications

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“…In addition to sequence variations in OT pathway genes, epigenetic modifications of the OXTR gene have recently attracted considerable attention in clinical, behavioral, and cognitive neurosciences (Kumsta et al, 2013) and have been associated with different phenotypes including maternal PPD (Bell et al, 2015; Kimmel et al, 2016), amygdala reactivity (Puglia et al, 2015), autism (Gregory et al, 2009), and social anxiety disorder (Ziegler et al, 2015) amongst others. Briefly, epigenetics encompasses a set of biochemical modifications of genome function (e.g., histone modifications, DNA methylation, or the effects of small non-coding RNAs, e.g., micro RNAs) that interfere with transcriptional or translational events and can therefore regulate gene expression.…”

Section: Gene-environment Interactions and Epigenetic Modificationmentioning

confidence: 99%

Oxytocin pathways in the intergenerational transmission of maternal early life stress

Toepfer

Heim

Entringer

et al. 2017

Neuroscience & Biobehavioral Reviews

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Severe stress in early life, such as childhood abuse and neglect, constitutes a major risk factor in the etiology of psychiatric disorders and somatic diseases. Importantly, these long-term effects may impact the next generation. The intergenerational transmission of maternal early life stress (ELS) may occur via pre-and postnatal pathways, such as alterations in maternal-fetal-placental stress physiology, maternal depression during pregnancy and postpartum, as well as impaired mother-offspring interactions. The neuropeptide oxytocin (OT) has gained considerable attention for its role in modulating all of these assumed transmission pathways. Moreover, central and peripheral OT signaling pathways are highly sensitive to environmental exposures and may be compromised by ELS with implications for these putative transmission mechanisms. Together, these data suggest that OT pathways play an important role in the intergenerational transmission of maternal ELS in humans. By integrating recent studies on gene-environment interactions and epigenetic modifications in OT pathway genes, the present review aims to develop a conceptual framework of intergenerational transmission of maternal ELS that emphasizes the role of OT.

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Section: Gene-environment Interactions and Epigenetic Modificationmentioning

confidence: 99%

Oxytocin pathways in the intergenerational transmission of maternal early life stress

Toepfer

Heim

Entringer

et al. 2017

Neuroscience & Biobehavioral Reviews

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“…Typically, an increase in DNA methylation is associated with a decrease in expression of that gene (18). Recent breakthroughs in cross-disciplinary research approaches show that epigenetic modification of OXTR, via DNA methylation, is associated with human social behavior and brain activity during social-cognitive processing (6,19,20). However, unlike genetic studies, epigenetic modifications are tissue-specific, prompting most studies of brain function to rely on DNA extracted from the proxy Significance Elucidating the genetic and biological substrates of social behavior serves to advance the way basic human nature is understood and improves the way genetic and biological markers can be used to prevent, diagnose, and treat people with impairments in social cognition and behavior.…”

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confidence: 99%

Epigenetic modification of OXT and human sociability

Haas

Filkowski

Cochran

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Across many mammalian species there exist genetic and biological systems that facilitate the tendency to be social. Oxytocin is a neuropeptide involved in social-approach behaviors in humans and others mammals. Although there exists a large, mounting body of evidence showing that oxytocin signaling genes are associated with human sociability, very little is currently known regarding the way the structural gene for oxytocin (OXT) confers individual differences in human sociability. In this study, we undertook a comprehensive approach to investigate the association between epigenetic modification of OXT via DNA methylation, and overt measures of social processing, including self-report, behavior, and brain function and structure. Genetic data were collected via saliva samples and analyzed to target and quantify DNA methylation across the promoter region of OXT. We observed a consistent pattern of results across sociability measures. People that exhibit lower OXT DNA methylation (presumably linked to higher OXT expression) display more secure attachment styles, improved ability to recognize emotional facial expressions, greater superior temporal sulcus activity during two social-cognitive functional MRI tasks, and larger fusiform gyrus gray matter volume than people that exhibit higher OXT DNA methylation. These findings provide empirical evidence that epigenetic modification of OXT is linked to several overt measures of sociability in humans and serve to advance progress in translational social neuroscience research toward a better understanding of the evolutionary and genetic basis of normal and abnormal human sociability.ociability is a central feature of the human species. Through one perspective, the complex array of human social-cognition and behavior serves to differentiate humans from other animals. However, there exist several core elemental components of the human sociobiological system that are present across many animal species, which may have remained relatively conserved throughout recent evolutionary history (1). Elucidating the genetic and biological substrates of social behavior serves to advance the way basic human nature is understood and improves the way genetic and biological markers can be used to prevent, diagnose, and treat people with impairments in social cognition and behavior.Oxytocin is a neurohypophysial peptide synthesized in the hypothalamus in the brain, linked to a wide range of social behaviors in humans and other mammals. Administration of oxytocin in humans is associated with changes in social-approach behaviors, such as trust (2) and personal proximity (3). This evidence has motivated the search for genes within the oxytocin system that confer individual differences in social behavior and cognition. A burgeoning body of evidence highlights the role of several key genes within the oxytocin signaling pathway linked to sociability, including the oxytocin receptor gene (OXTR), CD38, and the structural gene for oxytocin (OXT) (4). Although mounting data strongly support the role of ...

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“…We pooled effect sizes from three recently published studies (Kim, Kim, Kim, & Treasure, 2014;Rubin et al, 2016;Ziegler et al, 2015). The average reported effect size for associations between OXTR DNA methylation and behavior was .34.…”

Section: Participantsmentioning

confidence: 99%

Epigenetic Modification of OXTR is Associated with Openness to Experience

Haas

Smith

Nishitani

2018

Personality Neuroscience

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Oxytocin is a neuropeptide known to influence social and cognitive processing across several mammalian species. There currently exists a mixed and controversial pattern of evidence that oxytocin pathway genes confer individual differences in social cognition and personality in humans. Inconsistencies across studies may in part be explained by the presence of intermediary, epigenetic, variables that exist between genotype and phenotype. This study was designed to investigate the association between epigenetic modification of the Oxytocin Receptor Gene (OXTR), via DNA methylation, and Big-5 personality traits. Genetic data were collected via saliva samples and analyzed to quantify DNA methylation within the promoter region of OXTR. The results indicate that Openness to Experience is associated with OXTR DNA methylation, while controlling for the remaining Big-5 personality dimensions (Neuroticism, Extraversion, Agreeableness, and Conscientiousness) and sex and age. This finding provides additional support for models associating oxytocin with individual differences in personality and identity in humans.In spite of the growth of the field of behavioral genetics, established links between personality traits and specific genes are currently tenuous, at best. Indeed, several recent important meta-analyses show that many published studies linking single-nucleotide polymorphisms (SNPs) with personality traits fail to replicate (De Moor et al., 2012;Montag & Reuter, 2014;Rietveld et al., 2014). One reason underlying the presence of inconsistencies across gene × personality studies may be that many studies have yet to consider epigenetic factors impacting the way genes function and are ultimately expressed (Kumsta & Heinrichs, 2013). Genes do not directly impact psychological phenomena: they initiate biochemical and physiological mechanisms. Furthermore, identical SNPs that occur in different people typically do not function in identical ways, and may result in a variety of phenotypes being expressed. Thus, investigating the association between SNPs and individual differences in human traits is limited because several intermediary factors that exist between genotype and phenotype are not typically considered. One novel way to elucidate the way genes are associated with phenotypes, such as with personality, is to use an epigenetic approach.Epigenetics is the study of how gene functioning is altered by exogenous and endogenous factors. One epigenetic process that influences the expression of genes is DNA methylation, which occurs when a methyl group forms a covalent attachment with the 5' carbon of cytosine in the context of a cytosine phosphodiester guanine (CpG) dinucleotide, commonly called a CpG site. DNA methylation regulates the expression of genes by influencing the recruitment and binding of regulatory protein to DNA. Typically, an increase in DNA methylation is associated with a decrease in expression of that gene. Although several studies show that stable genetic variants, such as SNPs, confer tendencies to...

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Oxytocin Receptor Gene Methylation: Converging Multilevel Evidence for a Role in Social Anxiety

Cited by 154 publications

References 72 publications

Oxytocin pathways in the intergenerational transmission of maternal early life stress

Oxytocin pathways in the intergenerational transmission of maternal early life stress

Epigenetic modification of OXT and human sociability

Epigenetic Modification of OXTR is Associated with Openness to Experience

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