Differential Glucocorticoid Receptor Exon 1B, 1C, and 1H Expression and Methylation in Suicide Completers with a History of Childhood Abuse
Open accessAbstract
Background Childhood abuse alters hypothalamic-pituitary-adrenal (HPA) function and increases the risk of suicide. Hippocampal glucocorticoid receptor (GR) activation regulates HPA activity, and human GR expression (hGR) is reduced in the hippocampus of suicide completers with a history of childhood abuse compared with controls. The abuse-related decrease in hGR expression associates with increased DNA methylation of the promoter of the hGR(1F) variant in the hippocampus.Methods In this study, we investigated the expression and methylation levels of other hGR splice variants in the hippocampus and anterior cingulate gyrus in suicide completers with and without a history of childhood abuse and in controls. Expression levels were quantified using quantitative reverse-transcriptase polymerase chain reaction and promoter methylation was assessed by pyrosequencing.Results In the hippocampus, the expression of total hGR and variants 1(B), 1(C), and 1(H) was decreased in suicide completers with histories of abuse compared with suicides with no histories of abuse and with control subjects. In the anterior cingulate gyrus, however, no group differences in hGR total or variant expression were found. Site-specific methylation in hGR1(B) and 1(C) promoter sequences were negatively correlated with total hGR messenger RNA, as well as with hGR1(B) and 1(C) expression. Luciferase assay showed that methylation in hGR promoter decreases transcriptional activity. In contrast, total and site-specific methylation in the hGR1(H) promoter was positively correlated with total hGR messenger RNA and hGR1(H) expression.Conclusion These findings suggest that early-life events alter the expression of several hGR variants in the hippocampus of suicide completers through effects on promoter DNA methylation.
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In the hippocampus, total GR expression and the 1B, 1C, 1H GR RNA variant levels decreased with history of childhood trauma.
“In the hippocampus, total GR expression, and the 1B,1C, 1H GR RNA variant levels decreased with history of childhood trauma.”
From Epigenetic Modifications in Stress Response Genes Associated With Childhood Trauma (2019) · cites this paper as [143]
The Results (p. 1) report decreased hippocampal total hGR and 1B, 1C, and 1H expression in suicide completers with histories of childhood abuse, compared with suicide completers without such histories and controls. The claim omits that study population and uses the broader term “childhood trauma,” whereas the reported comparison concerns childhood abuse. (LLM, conf=0.84)
Experimental — accuracy not yet measuredChildhood maltreatment, including abuse and neglect, represents a sustained early-life stressor associated with long-term biological and behavioral changes across generations.
“Childhood maltreatment, including abuse and neglect, represents a sustained early-life stressor associated with long-term biological and behavioral changes across generations.”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [120]
The Discussion (p. 6) links childhood abuse to long-lasting changes in HPA-axis regulation, gene expression, and DNA methylation in suicide completers. The introduction (p. 1) also discusses behavioral alterations after early-life adversity. The paper does not establish the claim for neglect or show that these changes persist across generations. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAltered methylation of genes involved in HPA-axis feedback and glucocorticoid homeostasis, including NR3C1 and FKBP5, has been reported in individuals with histories of abuse or neglect.
“Altered methylation of genes involved in HPA-axis feedback and glucocorticoid homeostasis, including NR3C1 and FKBP5, has been reported in individuals with histories of abuse or neglect (118–120).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [120]
The Results (pp. 2–4) report site-specific methylation differences in the hippocampal glucocorticoid receptor gene (NR3C1) among suicide completers with histories of childhood abuse. This supports the NR3C1 portion of the claim, but the paper does not report FKBP5 methylation or findings specifically about neglect. (LLM, conf=0.87)
Experimental — accuracy not yet measuredEvidence suggests involvement of stress-response regulation, neurodevelopmental and emotional processing pathways, and epigenetic remodeling processes in shaping intergenerational outcomes.
“Evidence suggests involvement of stress-response regulation, neurodevelopmental and emotional processing pathways, and epigenetic remodeling processes in shaping intergenerational outcomes (116–124).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [120]
The Discussion (pp. 5–6) links childhood adversity to glucocorticoid-receptor methylation and altered HPA-axis stress regulation. It does not establish neurodevelopmental or emotional-processing pathways, or show that these mechanisms shape intergenerational outcomes; its human findings concern suicide completers with histories of childhood abuse. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe first documented study of the GR promoter in humans showed higher methylation of the hippocampal GR 1F promoter in post-mortem tissue of adult suicide victims with a history of childhood abuse, similar to findings in rodent pups raised by mothers who provided low levels of licking and grooming.
“The first documented study of the GR promoter in humans showed higher methylation of the hippocampal GR 1F promoter in post-mortem tissue of adult suicide victims with a history of childhood abuse, similar to findings in rodent pups raised by mothers who provided low levels of licking and grooming 121,122 .”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [122]
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Site-specific methylation showed that methylation of variants 1B and 1C was negatively associated not only with their expression but also with total GR mRNA level.
“Site-specific methylation showed that the methylation of variants 1B and 1C was negatively associated not only with their expression but also with total GR mRNA level.”
From Epigenetic Modifications in Stress Response Genes Associated With Childhood Trauma (2019) · cites this paper as [143]
Variant 1H was associated with effects in the opposite direction.
“Variant 1H was associated with effects in the opposite direction (143).”
From Epigenetic Modifications in Stress Response Genes Associated With Childhood Trauma (2019) · cites this paper as [143]
Increased methylation of the NR3C1 promoter and reduced glucocorticoid receptor expression have been observed in hippocampal tissue of suicide completers with histories of maltreatment.
“Increased methylation of the NR3C1 promoter and reduced glucocorticoid receptor expression have been observed in hippocampal tissue of suicide completers with histories of maltreatment (119, 120).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [120]
Lower methylation of FKBP5 has been associated with structural variation in brain regions involved in emotional regulation.
“Lower methylation of FKBP5 has been associated with structural variation in brain regions involved in emotional regulation (120, 121).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [120]
The Differential DNA Methylation section (pp. 2–4) examines methylation of glucocorticoid receptor promoters, not FKBP5. Searches for FKBP5 and structural variation found no passage linking FKBP5 methylation to brain structure in our copy. (LLM, conf=0.76)
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References 55 · Cited by 345
- Authors
- Labonte, B., Yerko, V., Gross, J., Mechawar, N., Meaney, M. J., Szyf, M., & Turecki, G.
- Affiliations
- Douglas Mental Health University Institute (CA)
- McGill University (CA)
- Corresponding author
- Turecki, Gustavo
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2012-07
- Volume
- 72
- Issue
- 1
- Pages
- 41-48
- ISSN
- 0006-3223 (ISSN-L)
- OpenAlex
- W1982232439
- Cited by
- 345
- References
- 55
- Citations by year
- 2026: 3 · 2025: 14 · 2024: 9 · 2023: 13 · 2022: 13 · 2021: 29 · 2020: 28 · 2019: 22 · 2018: 39 · 2017: 28 · 2016: 34 · 2015: 30 · 2014: 48 · 2013: 25 · 2012: 10
- FWCI
- 15.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (MOP84291)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Social Sciences › Psychology › Clinical Psychology › Suicide and Self-Harm Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- glucocorticoid receptor, suicide, childhood abuse, hippocampus, anterior cingulate cortex, exon 1b, promoter methylation, hypothalamic-pituitary-adrenal axis, transcriptional regulation, childhood adversity
- MeSH terms
- Adult, Child, Child Abuse, Exons, Gyrus Cinguli, Hippocampus, Humans, Hypothalamo-Hypophyseal System, Luciferases, Male, Molecular Sequence Data, Pituitary-Adrenal System, Promoter Regions, Genetic, Quebec, Receptors, Glucocorticoid, RNA, Messenger, Suicide, Gene Expression, DNA Methylation, Reverse Transcriptase Polymerase Chain Reaction
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