Elsevier

Journal of Psychiatric Research

Volume 59, December 2014, Pages 93-100
Journal of Psychiatric Research

Variation in the oxytocin receptor gene is associated with increased risk for anxiety, stress and depression in individuals with a history of exposure to early life stress

https://doi.org/10.1016/j.jpsychires.2014.08.021Get rights and content

Abstract

Background

Oxytocin is a neuropeptide that is involved in the regulation of mood, anxiety and social biology. Genetic variation in the oxytocin receptor gene (OXTR) has been implicated in anxiety, depression and related stress phenotypes. It is not yet known whether OXTR interacts with other risk factors such as early life trauma to heighten the severity of experienced anxiety and depression.

Methods

In this study, we examined genotypes in 653 individuals and tested whether SNP variation in OXTR correlates with severity of features of self-reported experience on the Depression Anxiety and Stress Scale (DASS), and whether this correlation is enhanced when early life trauma is taken into account. We also assessed the effects of OXTR SNPs on RNA expression levels in two separate brain tissue cohorts totaling 365 samples.

Results

A significant effect of OXTR genotype on DASS anxiety, stress and depression scores was found and ELS events, in combination with several different OXTR SNPs, were significantly associated with differences in DASS scores with one SNP (rs139832701) showing significant association or a trend towards association for all three measures. Several OXTR SNPs were correlated with alterations in OXTR RNA expression and rs3831817 replicated across both sets of tissues.

Conclusions

These results support the hypothesis that the oxytocin system plays a role in the pathophysiology of mood and anxiety disorders.

Section snippets

Background

Oxytocin (OXT) is a mammalian hormone that is best known for its role in lactation, parturition and maternal behavior. It is synthesized in the hypothalamic paraventricular and supraoptic nuclei, transported to the posterior pituitary and released into the general circulation. It is also found in extra-hypothalamic brain areas. OXT has been shown to exert effects on memory (de Wied et al., 1993, Lerer et al., 2008), anxiety (Heinrichs et al., 2003) and social interaction (Kosfeld et al., 2005,

Sample

A total of 1226 participants in the BRAINnet Foundation Database www.brainnet.net, (Koslow et al., 2013) which includes the Brain Resource International Database administered for scientific purposes (Gordon, 2003, Gordon et al., 2005)) have been assessed using the DASS measure (Kemp et al., 2005, Lovibond, 1995), a 42-item self report designed to measure the negative emotional states of depression, anxiety and stress. The Depression scale assesses dysphoria, hopelessness, devaluation of life,

Symptoms and early life stress

For TEST 1, we found a greater number of traumatic events was associated with greater severity of symptoms for stress (p-value = 7.604E-09), anxiety (p-value = 3.604E-06) and depression symptom scores (p-value = 2.245E-11). These results are shown in Fig. 2.

Symptoms-ELS relationship and covariates

For TEST 2, we found that none of our demographic variables (gender, age or years of education) were significant covariates (Table 1) when corrected for multiple testing. Additionally, none of these variables significantly interacted with

Discussion

The physiological role of oxytocin has been intensively investigated. Initial work demonstrated its role in labor and lactation (Thorburn and Challis, 1979). More recent work has focused on oxytocin's effects on human social behavior (Ebstein et al., 2010) including work demonstrating that intranasal administration of oxytocin increases trust in humans (Kosfeld et al., 2005) and is a potent antagonist of amygdala activation and brainstem activation in autonomic and behavioral manifestations of

Role of funding source

Genotyping was sponsored by an Australian Research Council Linkage Project grant (LP0455104) with Brain Resource Ltd as the industry partner. Data analysis was supported by NIA AG041232 and NIMH MH094759.

Disclosures

Drs. Myers, McAuley-Clark & Dobson-Stone report no competing interests. Dr. Williams has previously consulted with and held stock in Brain Resource Ltd. Dr. Gatt has previously received consultancy fees with Brain Resource Ltd for unrelated projects, and is a stock holder in Freedomsway Corp. Pte. Ltd. Dr. Schofield reports receiving speaking fees from Janssen-Cilag. This activity does not present a conflict with the current data. Dr Nemeroff consults for Xhale, Takeda, SK Pharma, Shire, Roche,

Contributors

AJM was responsible for the design, analysis and write-up of all experiments, LW manages the cohort and was involved in data collection and edited the manuscript, JMG helped with data collection and edited the manuscript, EZMC helped with data collection and edited the manuscript, CDS helped with data collection and edited the manuscript, PRS coordinated the genetic data collection and edited the manuscript, CBN edited the manuscript.

Acknowledgments

AJM is supported by NIA AG041232 and NIMH MH094759. This project was supported by an Australian Research Council Linkage Project grant (LP0455104) held by LMW and with Brain Resource Ltd as the industry partner. JMG is supported by the National Health & Medical Research Council of Australia (NHMRC) Career Development Fellowship APP1062495. CDS is supported by the National Health & Medical Research Council of Australia (NHMRC) Project Grant 630428. PRS is supported by NHMRC Program Grant 1037196

References (41)

  • G. Scantamburlo et al.

    Plasma oxytocin levels and anxiety in patients with major depression

    Psychoneuroendocrinol

    (2007)
  • K. Uvnas-Moberg

    Oxytocin may mediate the benefits of positive social interaction and emotions

    Psychoneuroendocrinol

    (1998)
  • J.A. Webster et al.

    Genetic control of human brain transcript expression in alzheimer disease

    Am J Hum Genet

    (2009)
  • S. Wu et al.

    Positive association of the oxytocin receptor gene (OXTR) with autism in the Chinese Han population

    Biol Psychiatry

    (2005)
  • B. Zhang et al.

    Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease

    Cell

    (2013)
  • E. Andari et al.

    Promoting social behavior with oxytocin in high-functioning autism spectrum disorders

    Proc Natl Acad Sci U S A

    (2010)
  • M.J. Bakermans-Kranenburg et al.

    Oxytocin receptor (OXTR) and serotonin transporter (5-HTT) genes associated with observed parenting

    Soc Cogn Affect Neurosci

    (2008)
  • J.C. Barrett

    Haploview: visualization and analysis of SNP genotype data

    Cold Spring Harb Protoc

    (2009)
  • J.C. Barrett et al.

    Haploview: analysis and visualization of LD and haplotype maps

    Bioinform

    (2005)
  • F.S. Chen et al.

    Common oxytocin receptor gene (OXTR) polymorphism and social support interact to reduce stress in humans

    Proc Natl Acad Sci U S A

    (2011)
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