Methylation matters: interaction between methylation density and serotonin transporter genotype predicts unresolved loss or trauma
Open accessAbstract
Background Do genetic or epigenetic factors play a role in making some individuals more vulnerable than others to loss of attachment figures or other traumatic experiences?Methods DNA was obtained from growth phase entrained Epstein-Barr Virus (EBV) transformed lymphoblast cell lines from 143 adopted participants. Genotype of the serotonin transporter linked polymorphic region (5HTTLPR) was determined, and methylation ratios for each of the C-phosphate-G (CpG) residues were assessed using quantitative mass spectroscopy. Unresolved loss or trauma was established using the Berkeley Adult Attachment Interview.Results Higher levels of methylation of the 5HTT promoter associated CpG island were associated with increased risk of unresolved responses to loss or other trauma in carriers of the usually protective 5HTTLPR//variant. The ss variant of 5HTTLPR predicted more unresolved loss or trauma, but only in case of lower levels of methylation. Higher levels of methylation of the ss variant were associated with less unresolved loss or other trauma.Conclusions Associations between 5HTTLPR polymorphisms and psychological problems are significantly altered by environmentally induced methylation patterns. Methylation may serve as the interface between adverse environment and the developing organism.
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SLC6A4 methylation is increased in association with lower levels of unresolved loss and trauma.
“↑ SLC6A4 methylation associated with lower levels of unresolved loss and trauma”
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 van IJzendoorn et al., 2010
The Abstract Results and Discussion report that higher methylation was associated with less unresolved loss or trauma in participants with the 5HTTLPR ss variant. The claim omits that genotype qualifier: in participants with the ll variant, higher methylation was associated with increased risk of unresolved responses. (LLM, conf=0.90)
Experimental — accuracy not yet measuredS allele carriers that experience early-life stress or trauma tend to show higher SLC6A4 promoter methylation.
“S allele carriers that experience early-life stress or trauma tend to show higher SLC6A4 promoter methylation”
From The clinical use of epigenetics in psychiatry: a narrative review of epigenetic mechanisms, key candidate genes, and precision psychiatry (2025) · cites this paper as [104]
The Discussion reports that childhood sexual or physical abuse was associated with increased 5HTTLPR methylation, but it does not say this finding was specific to S-allele carriers. The Results examine how genotype and methylation relate to unresolved loss or trauma, not whether early-life stress raises methylation in S-allele carriers. No page numbers are available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredHigher SLC6A4 promoter methylation is related to increased experiences of unresolved loss or trauma in l/l genotype carriers.
“higher degrees of promoter methylation have been related to increased experiences of unresolved loss or trauma in l/l genotype carriers (van IJzendoorn, Caspers, Bakermans-Kranenburg, Beach, & Philibert, 2010)”
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 van IJzendoorn, Caspers, Bakermans-Kranenburg, Beach, & Philibert, 2010
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- Authors
- van IJzendoorn, M. H., Caspers, K., Bakermans-Kranenburg, M. J., Beach, S. R. H., & Philibert, R.
- Affiliations
- University of Iowa (US)
- University of Georgia (US)
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2010-09
- Volume
- 68
- Issue
- 5
- Pages
- 405-407
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC2921470
- OpenAlex
- W2060345033
- Cited by
- 264
- References
- 23
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 9 · 2023: 4 · 2022: 4 · 2021: 10 · 2020: 39 · 2019: 9 · 2018: 23 · 2017: 16 · 2016: 19 · 2015: 22 · 2014: 18 · 2013: 22 · 2012: 26
- FWCI
- 10.82
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Netherlands Organization for Scientific Research (452-04-306)
- U.S. National Institute of Drug Abuse (RO 1 DA05821, R01 DA015789)
- Topics
- 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
- Social Sciences › Psychology › Clinical Psychology › Psychoanalysis and Psychopathology Research
- Keywords
- DNA methylation, serotonin transporter, 5-HTTLPR, promoter methylation, CpG islands, epigenetics, unresolved loss, trauma, attachment, genetic susceptibility, gene-environment interaction, adopted children, adult attachment
- MeSH terms
- Adoption, Cell Line, Transformed, Herpesvirus 4, Human, Female, Humans, Infant, Interview, Psychological, Male, Polymorphism, Genetic, Stress, Psychological, CpG Islands, DNA Methylation, Genetic Predisposition to Disease, Epigenesis, Genetic, Serotonin Plasma Membrane Transport Proteins, Genetic Association Studies
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