A genome-wide methylation study reveals X chromosome and childhood trauma methylation alterations associated with borderline personality disorder
Open accessAbstract
Borderline personality disorder (BPD) is a severe and highly prevalent psychiatric disorder, more common in females than in males and with notable differences in presentation between genders. Recent studies have shown that epigenetic modifications such as DNA methylation may modulate gene × environment interactions and impact on neurodevelopment. We conducted an epigenome wide study (Illumina Infinium HumanMethylation450k beadchip) in a group of BPD patients with ( N = 49) and without ( N = 47) childhood traumas and in a control group ( N = 44). Results were confirmed in a replication cohort ( N = 293 BPD patients and N = 114 controls) using EpiTYPER assays. Differentially methylated CpG sites were observed in several genes and intragenic regions in the X chromosome ( PQBP1 , ZNF41 , RPL10 , cg07810091 and cg24395855) and in chromosome 6 (TAP2). BPD patients showed significantly lower methylation levels in these CpG sites than healthy controls. These differences seemed to be increased by the existence of childhood trauma. Comparisons between BPD patients with childhood trauma and patients and controls without revealed significant differences in four genes ( POU5F1 , GGT6 , TNFRSF13C and FAM113B ), none of them in the X chromosome. Gene set enrichment analyses revealed that epigenetic alterations were more frequently found in genes controlling oestrogen regulation, neurogenesis and cell differentiation. These results suggest that epigenetic alterations in the X chromosome and oestrogen-regulation genes may contribute to the development of BPD and explain the differences in presentation between genders. Furthermore, childhood trauma events may modulate the magnitude of the epigenetic alterations contributing to BPD.
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An EWAS study in Borderline PD found differences in methylation in GCT6, which is important in glutathione metabolism.
“Furthermore, an EWAS study in Borderline PD found differences in methylation in GCT6, which is important in glutathione metabolism (Arranz et al., 2021).”
From Can epigenetics shine a light on the biological pathways underlying major mental disorders? (2022) · cites this paper as Arranz et al., 2021
The Discussion reports differential methylation of GGT6, not “GCT6,” and identifies its role in glutathione homeostasis. The finding was specifically for BPD patients with childhood trauma compared with BPD patients without childhood trauma and controls; the citing sentence omits that distinction. (LLM, conf=0.88)
Experimental — accuracy not yet measuredOther evidence suggests a negative correlation between DNAm in genes enriched for immune pathways (such as TLR1 and TLR3) and childhood adversity in PTSD subjects; while the TNFRSF13C gene was differently methylated between Borderline PD participants with and without childhood adversity.
“Other evidence suggests a negative correlation between DNAm in genes enriched for immune pathways (such as TLR1 and TLR3) and CA in PTSD subjects (Uddin et al., 2010); while the TNFRSF13C gene was differently methylated between Borderline PD participants with and without CA (Arranz et al., 2021)”
From Can epigenetics shine a light on the biological pathways underlying major mental disorders? (2022) · cites this paper as Arranz et al., 2021
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredThree EWAS studies in BD, Borderline PD and MDD have consistently shown changes in DNAm in genes from the POU family that are associated with childhood adversity (POU6F2, POU5F1 and POU3F1 respectively), which are genes involved in myelinisation and neurogenesis.
“For instance, three EWAS studies in BD (Comes et al., 2019), Borderline PD (Arranz et al., 2021) and MDD (Lutz et al., 2017) have consistently shown changes in DNAm in genes from the POU family that are associated with CA (POU6F2, POU5F1 and POU3F1 respectively), which are genes involved in myelinisation and neurogenesis (Online Supplementary Table S1 (SM) – EWAS section).”
From Can epigenetics shine a light on the biological pathways underlying major mental disorders? (2022) · cites this paper as Arranz et al., 2021
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredA number of EWAS studies conducted in clinical samples have reported an association between exposure to childhood adversity and DNAm changes across genes involved in inflammation.
“A number of EWAS studies conducted in clinical samples have reported an association between exposure to CA and DNAm changes across genes involved in inflammation.”
From Can epigenetics shine a light on the biological pathways underlying major mental disorders? (2022) · cites this paper as Arranz et al., 2021
The Discussion (page unavailable) reports a childhood-trauma-associated methylation difference in a clinical BPD sample that includes TNFRSF13C, a gene the paper describes as regulating B cells. But this is one EWAS, not evidence that a number of clinical EWAS studies found changes across inflammation-related genes. The Results (page unavailable) place immune-response enrichment in the BPD-versus-control comparison, not the childhood-trauma comparison. (LLM, conf=0.82)
Experimental — accuracy not yet measuredIn a sample of borderline personality disorder patients, an EWAS found DNA methylation differences in the GGT6 gene associated with childhood adversity exposure.
“A recent EWAS study found differences in DNAm of the GGT6 gene that were associated with exposure to CA in a sample of Borderline PD patients”
From Can epigenetics shine a light on the biological pathways underlying major mental disorders? (2022) · cites this paper as Arranz et al., 2021
GGT6 is key for glutathione homeostasis.
“GGT6 is key for glutathione homoeostasis (Arranz et al., 2021)”
From Can epigenetics shine a light on the biological pathways underlying major mental disorders? (2022) · cites this paper as Arranz et al., 2021
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Bouchard-Boivin, M., Hudon, A., Godin, F., Désilets, M., & Cailhol, L. (2026) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2026.1820717
Xiao, Q., Shen, L., Wang, L., Zhang, S., Wen, S., Ma, Y., Liu, Y., & Xu, B. (2026) · Psychiatry Research · doi:10.1016/j.psychres.2026.117437
- Authors
- Arranz, M. J., Gallego-Fabrega, C., Martín-Blanco, A., Soler, J., Elices, M., Dominguez-Clavé, E., Salazar, J., Vega, D., Briones-Buixassa, L., & Pascual, J. C.
- Affiliations
- Universitat Autònoma de Barcelona (ES)
- Institut de Recerca Sant Pau (ES)
- Corresponding author
- Pascual, Juan Carlos
- ORCID
- Venue
- Translational Psychiatry
- Published
- 2021-01-05
- Volume
- 11
- Issue
- 1
- Pages
- 5-5
- ISSN
- 2158-3188 (ISSN-L)
- PMC
- PMC7791113
- OpenAlex
- W3120706965
- Cited by
- 17
- References
- 61
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 5 · 2023: 5 · 2022: 1 · 2021: 1
- FWCI
- 0.94
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Translational Psychiatry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (PI14/00214)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Social Sciences › Psychology › Clinical Psychology › Personality Disorders and Psychopathology
- Social Sciences › Psychology › Clinical Psychology › Psychopathy, Forensic Psychiatry, Sexual Offending
- Keywords
- borderline personality disorder, DNA methylation, X chromosome, childhood trauma, epigenetics, sex differences, neurogenesis, gene-environment interaction, TAP2, Oct4, TNFRSF13C, chromosome 6
- MeSH terms
- Borderline Personality Disorder, DNA-Binding Proteins, Female, Humans, Male, X Chromosome, CpG Islands, DNA Methylation, Epigenesis, Genetic
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