Oxytocin receptor genetic and epigenetic variations: Association with child abuse and adult psychiatric symptoms
Open accessAbstract
Childhood abuse can alter biological systems and increase risk for adult psychopathology. Epigenetic mechanisms, alterations in DNA structure that regulate the gene expression, are a potential mechanism underlying this risk. While abuse associates with methylation of certain genes, particularly those in the stress response system, no study to date has evaluated abuse and methylation of the oxytocin receptor (OXTR). However, studies support a role for OXTR in the link between abuse and adverse adult outcomes, showing that abuse can confer greater risk for psychiatric symptoms in those with specific OXTR genotypes. This study therefore sought to (a) assess the role of epigenetics in the link between abuse and psychopathology and (b) begin to integrate the genetic and epigenetic literature by exploring associations between OXTR genotypes and DNA CpG methylation. Data on 18 OXTR CpG sites, 44 single nucleotide polymorphisms, childhood abuse, and adult depression and anxiety symptoms were assessed in 393 African American adults (age = 41 ± 12.8 years). Overall, 68% of genotypes were associated with methylation of nearby CpG sites, with a subset surviving multiple test correction. Child abuse associated with higher methylation of two CpG sites yet did not survive correction or serve as a mediator of psychopathology. However, abuse interacted with CpG methylation to predict psychopathology. These findings suggest a role for OXTR in understanding the influence of early environments on adult psychiatric symptoms.
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Experiences of childhood abuse lead to increased methylation downstream of exon 3 of OXTR.
“Moreover, it has been described that experiences of childhood abuse lead to increased methylation downstream of exon 3, supporting the notion of differential effects of preand postnatal stressors”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as Smearman et al., 2016
The Results section reports an association between childhood abuse and higher methylation at two OXTR CpG sites, but locates both sites within exon 3, not downstream of it. Neither association survived correction for multiple testing, and the observational finding does not establish that abuse caused the increase. (LLM, conf=0.89)
Experimental — accuracy not yet measuredHypomethylation within exon 1 and hypermethylation downstream of exon 3 in combination with severe childhood abuse was associated with higher adult ratings of anxiety and depression symptoms.
“Hypomethylation within exon 1 and hypermethylation downstream of exon 3 in combination with severe childhood abuse was associated with higher adult ratings of anxiety and depression symptoms (Smearman et al., 2016).”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as Smearman et al., 2016
The Results section on OXTR methylation as a moderator of abuse reports higher adult depression and anxiety symptoms with lower exon 1 methylation or higher intron 3 methylation among people reporting abuse. The claim’s restriction to severe childhood abuse is not established: the Study Cohort and Statistical Analysis sections include both moderate and severe abuse, and the reported interaction is described for a history of abuse generally. No page numbers are available in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredOnly an interaction of environmental trauma and methylation downstream of exon 3 and within exon 1 predicted adult psychopathological symptoms in 393 adult participants.
“while only an interaction of environmental trauma and methylation downstream of exon 3 and within exon 1 predicted adult psychopathological symptoms in 393 adult participants (Smearman et al., 2016).”
From The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention (2020) · cites this paper as Smearman et al., 2016
The Results section on OXTR methylation as a moderator reports that childhood abuse interacted with methylation at sites in exon 1 and intron 3 to predict adult depression and anxiety symptoms. The Methods (Participants) gives a sample of 393 adults. The claim broadens the measured exposure from childhood abuse to environmental trauma generally. (LLM, conf=0.84)
Experimental — accuracy not yet measured
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- Authors
- Smearman, E. L., Almli, L. M., Conneely, K. N., Brody, G. H., Sales, J. M., Bradley, B., Ressler, K. J., & Smith, A. K.
- Affiliations
- Emory University (US)
- United States Department of Veterans Affairs (US)
- Harvard University (US)
- Corresponding author
- Smith, Alicia K
- ORCID
- Venue
- Child Development
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-01-01
- Volume
- 87
- Issue
- 1
- Pages
- 122-134
- ISSN
- 0009-3920 (ISSN-L)
- 1467-8624
- PMC
- PMC4733885
- OpenAlex
- W2253842536
- Cited by
- 173
- References
- 49
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 11 · 2023: 19 · 2022: 18 · 2021: 19 · 2020: 33 · 2019: 18 · 2018: 19 · 2017: 17 · 2016: 10
- FWCI
- 28.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Child Development (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (MH071537, HD071982, MH096764, MH085806, GM008169, 1008188, 19233, MH085506, P30 DA027827)
- American Psychoanalytic Association Psychoanalytic Research Fund (HD071982, GM008169, 1008188, 19233, MH085506, P30 DA027827)
- T32 (GM008169)
- Burroughs Wellcome Fund (1008188)
- NARSAD (HD071982, 19233, MH085506, P30 DA027827)
- Howard Hughes Medical Institute
- American Foundation for Suicide Prevention
- Schering Plough Pharmaceuticals
- Conquer Cancer Foundation
- AFSP
- Topics
- Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Keywords
- oxytocin receptor, childhood abuse, child abuse, DNA methylation, CpG sites, single nucleotide polymorphisms, depression, anxiety, epigenetics, gene-environment interaction, African American adults, early life environment, stress response
- MeSH terms
- Adolescent, Adult, Aged, Anxiety, Black or African American, Depression, Female, Genotype, Humans, Male, Middle Aged, Receptors, Oxytocin, CpG Islands, DNA Methylation, Polymorphism, Single Nucleotide, Epigenesis, Genetic, Adult Survivors of Child Abuse, Young Adult
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