Early-life adversity severity, timing, and context type are associated with SLC6A4 methylation in emerging adults: results from a prospective cohort study
Open accessAbstract
Background Epigenetic modifications, including DNA methylation (DNAm), can play a role in the biological embedding of early-life adversity (ELA) through serotonergic mechanisms. The current study examines methylation of the CpG island in the promoter region of the stress-responsive serotonin transporter gene (SLC6A4) and is the first to jointly assess how it is influenced by ELA severity, timing, and type-specifically, deprivation and threat.Methods We use data from 627 Youth Emotion Project study participants, recruited from two US high schools. Using adjusted linear regressions, we analyze DNA collected in early adulthood from 410 participants and ELA based on interviewer-rated responses from concurrent Childhood Trauma Interviews, adjusting for survey-measured covariates.Results ELA robustly predicted mean CpG island SLC6A4 DNAm percent across 71 CpG sites. Each additional major-severity ELA event was associated with a 0.121-percentage-point increase (p<0.001), equating to a 0.177 standard deviation (sd) higher DNAm level (95 % CI: 0.080, 0.274) with each 1-sd higher adversity score. When modeled separately, both childhood and adolescent ELA predicted SLC6A4 DNAm. When modeled jointly, adolescent ELA was most strongly predictive, and child adversity remained significantly associated with DNAm through indirect associations via adolescent adversity. Additionally, the ELA-SLC6A4 DNAm association may vary by adversity type. Across separate models for childhood and adolescent exposures, deprivation coefficients are positive and statistically significant. Meanwhile, threat coefficients are positive and not significantly significant but do not statistically differ from deprivation coefficients. In models including all ELA dimensions, one major adolescent deprivation event is associated with a 0.222-percentage-point increased SLC6A4 DNAm (p<0.05), or a 1-sd higher deprivation score with a 0.157-sd increased DNAm.Conclusion Results further implicate epigenetic modification on serotonergic neurotransmission via DNAm in the downstream sequelae of ELA-particularly adolescent deprivation-and support preventive interventions in adolescence to mitigate biological embedding.
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Methylation changes in BDNF and SLC6A4 promoters have been linked to diminished neurotrophic support and altered serotonergic tone, respectively, both correlating with suicidal ideation.
“Likewise, methylation changes in BDNF and SLC6A4 promoters have been linked to diminished neurotrophic support and altered serotonergic tone, respectively, both correlating with suicidal ideation (60, 61).”
From Exploring the neurobiological markers of suicidal behaviors in pediatric population: a narrative review (2026) · cites this paper as [61]
Methylation alterations in CRH, SKA2, BDNF, and SLC6A4 have also been implicated in suicidal behavior.
“Methylation alterations in corticotropin-releasing hormone (CRH), spindle and kinetochore-associated complex subunit 2 (SKA2), brain-derived neurotrophic factor (BDNF), and SLC6A4 have also been implicated in suicidal behavior.”
From Exploring the neurobiological markers of suicidal behaviors in pediatric population: a narrative review (2026) · cites this paper as [61]
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“Likewise, methylation changes in BDNF and SLC6A4 promoters have been linked to diminished neurotrophic support and altered serotonergic tone, respectively, both correlating with suicidal ideation (60, 61).”
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- Authors
- Koning, S. M., Kessler, C. L., Canli, T., Duman, E. A., Adam, E. K., Zinbarg, R., Craske, M. G., Stephens, J. E., & Vrshek-Schallhorn, S.
- Affiliations
- University of Nevada, Reno (US)
- Stony Brook University (US)
- Acıbadem University (TR)
- Northwestern University (US)
- University of California, Los Angeles (US)
- Corresponding author
- Koning, Stephanie M.
- ORCID
- Venue
- Psychoneuroendocrinology
- Publisher
- Elsevier BV
- Published
- 2024-12
- Volume
- 170
- Pages
- 107181
- ISSN
- 0306-4530 (ISSN-L)
- OpenAlex
- W4402547000
- Cited by
- 8
- References
- 77
- Citations by year
- 2026: 4 · 2025: 4
- FWCI
- 3.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (am, 291 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Psychoneuroendocrinology (acceptedVersion)
- PubMed (publishedVersion)
- Funders
- Institute of Education Sciences (R305B140042)
- National Science Foundation (BCS-0843346)
- National Institute of Mental Health (R01-MH065652, R01-MH065651)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (F32- HD102152)
- Northwestern University
- William T. Grant Foundation
- U.S. Department of Education
- 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 › Clinical Psychology › Child and Adolescent Psychosocial and Emotional Development
- Keywords
- childhood adversity, serotonin transporter, DNA methylation, biological embedding, adolescent adversity, deprivation, threats, emerging adults, serotonergic system
- MeSH terms
- Adverse Childhood Experiences, Adolescent, Adult, Child, Female, Humans, Male, Promoter Regions, Genetic, Prospective Studies, Stress, Psychological, CpG Islands, DNA Methylation, Epigenesis, Genetic, Serotonin Plasma Membrane Transport Proteins, Young Adult
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.
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 ›
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