DNA methylation differences at the glucocorticoid receptor gene in depression are related to functional alterations in hypothalamic-pituitary-adrenal axis activity and to early life emotional abuse
Abstract
Depression is associated with alterations in hypothalamic-pituitary-adrenal (HPA) axis activity. A proposed mechanism to explain these alterations are changes in DNA methylation levels, secondary to early life adversity (ELA), at stress-related genes. Two gene regions that have been implicated in the literature, the glucocorticoid receptor gene (NR3C1) exon 1F and the FKBP5 gene intron 7 were examined in 67 individuals (33 depressed patients and 34 controls). We investigated whether cortisol concentrations, evaluated in 25 depressed patients and 20 controls, and measures of ELA were associated with the degree of methylation at these candidate gene regions. Mean NR3C1 exon 1F DNA methylation levels were significantly increased in the depressed cohort and the degree of methylation was found to be positively associated with morning cortisol concentrations. DNA methylation levels at specific CG sites within the NR3C1 exon 1F were related to childhood emotional abuse severity. DNA methylation at CG38 was related to both HPA axis and childhood emotional abuse measures in the depressed group. No FKBP5 differences were revealed. Our findings suggest that hypermethylation at the NR3C1 exon 1F may occur in depression. This locus-specific epigenetic change is associated with higher basal HPA axis activity, possibly reflecting acquired glucocorticoid receptor resistance.
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Mean exon 1F methylation and NGFI-A binding site methylation positively correlate with increased morning cortisol levels and average morning cortisol output in depressed patients.
“mean exon 1 F methylation and NGFI-A binding site methylation positively correlated with increased levels of morning cortisol levels and average morning cortisol output in depressed patients (Farrell et al., 2018)”
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 Farrell et al., 2018
Table 5 (p. 27) reports positive correlations of CG38 methylation, at the NGFI-A binding site, with both waking cortisol and average morning cortisol output. Mean exon 1F methylation correlates significantly with average morning output, but not waking cortisol (p=0.12). These correlations were calculated across all participants, not specifically depressed patients. (LLM, conf=0.90)
Experimental — accuracy not yet measuredAt the level of NR3C1 there is consistent evidence on a positive correlation between childhood adversity and DNAm in Borderline PD and MDD and some clinical outcomes, and a negative correlation with anxiety and PTSD.
“at the level of NR3C1 there is consistent evidence on a positive correlation between CA and DNAm in Borderline PD and MDD and some clinical outcomes (Farrell et al., 2018; Martin-Blanco et al., 2014; Perroud et al., 2011; Radtke et al., 2015), and a negative correlation with anxiety and PTSD (Labonte, Azoulay, Yerko, Turecki, & Brunet, 2014; Schechter et al., 2015; Wang et al., 2017; Yehuda et al.”
From Can epigenetics shine a light on the biological pathways underlying major mental disorders? (2022) · cites this paper as Farrell et al., 2018
The Results (p. 13) report a positive association between childhood emotional abuse severity and methylation at two NR3C1 exon 1F sites, but only among depressed participants who reported early-life adversity. The paper does not establish the broader claim for childhood adversity generally: it found no association with the other forms of adversity measured. Its Conclusion (p. 18) also links NR3C1 methylation to morning cortisol activity in MDD. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIncreased NGFI-A binding site methylation is linked to the severity of experienced emotional abuse, but not physical abuse and/or emotional/physical neglect during childhood, exclusively in depressed individuals and not in healthy probands.
“increased NGFI-A binding site methylation was linked to the severity of experienced emotional abuse, but not physical abuse and/or emotional/physical neglect during childhood exclusively in depressed individuals, but not in healthy probands (Farrell et al., 2018)”
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 Farrell et al., 2018
NR3C1 1F promoter methylation in whole blood is significantly higher in depressed individuals than in healthy probands.
“DNA methylation of the NR3C1 1 F promoter in whole blood samples was significantly higher in depressed individuals (n=33) compared to healthy probands (n=34)”
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 Farrell et al., 2018
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Cites
Hamilton, M. (1960) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.23.1.56 · Cited by 32,817 · see citing works
Kessler, R. C., Berglund, P., Demler, O., Jin, R., Merikangas, K. R., & Walters, E. E. (2005) · Archives of General Psychiatry · doi:10.1001/archpsyc.62.6.593 · Cited by 20,391 · see citing works
Epigenetic programming by maternal behavior
Weaver, I. C. G., Cervoni, N., Champagne, F. A., D'Alessio, A. C., Sharma, S., Seckl, J. R., Dymov, S., Szyf, M., & Meaney, M. J. (2004) · Nature Neuroscience · doi:10.1038/nn1276 · Cited by 6,177 · see citing works
Self-citationEpigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse
McGowan, P. O., Sasaki, A., D'Alessio, A. C., Dymov, S., Labonté, B., Szyf, M., Turecki, G., & Meaney, M. J. (2009) · Nature Neuroscience · doi:10.1038/nn.2270 · Cited by 3,531 · see citing works
Epigenetic modifications and human disease
Portela, A., & Esteller, M. (2010) · Nature Biotechnology · doi:10.1038/nbt.1685 · Cited by 2,843 · see citing works
Childhood adversities and adult psychopathology in the WHO World Mental Health Surveys
Kessler, R. C., McLaughlin, K. A., Green, J. G., Gruber, M. J., Sampson, N. A., Zaslavsky, A. M., Aguilar-Gaxiola, S., Alhamzawi, A. O., Alonso, J., Angermeyer, M., et al. (2010) · British Journal of Psychiatry · doi:10.1192/bjp.bp.110.080499 · Cited by 2,640 · see citing works
Shonkoff, J. P., Boyce, W. T., & McEwen, B. S. (2009) · JAMA · doi:10.1001/jama.2009.754 · Cited by 2,326 · see citing works
Sheehan, D., Lecrubier, Y., Harnett Sheehan, K., Janavs, J., Weiller, E., Keskiner, A., Schinka, J., Knapp, E., Sheehan, M., & Dunbar, G. (1997) · European Psychiatry · doi:10.1016/s0924-9338(97)83297-x · Cited by 2,149 · see citing works
The HPA axis in major depression: classical theories and new developments
Pariante, C. M., & Lightman, S. L. (2008) · Trends in Neurosciences · doi:10.1016/j.tins.2008.06.006 · Cited by 2,009 · see citing works
Ambiguity and the process of knowledge transfer in strategic alliances
Simonin, B. L. (1999) · Strategic Management Journal · doi:10.1002/(sici)1097-0266(199907)20:7 · Cited by 1,967 · see citing works
(2010) · Oxford University Press eBooks · doi:10.1093/acref/9780199571123.001.0001 · Cited by 1,633 · see citing works
Validity of the Childhood Trauma Questionnaire in an Adolescent Psychiatric Population
BERNSTEIN, D. P., AHLUVALIA, T., POGGE, D., & HANDELSMAN, L. (1997) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1097/00004583-199703000-00012 · Cited by 1,574 · see citing works
Allele-specific FKBP5 DNA demethylation mediates gene–childhood trauma interactions
Klengel, T., Mehta, D., Anacker, C., Rex-Haffner, M., Pruessner, J. C., Pariante, C. M., Pace, T. W. W., Mercer, K. B., Mayberg, H. S., Bradley, B., et al. (2013) · Nature Neuroscience · doi:10.1038/nn.3275 · Cited by 1,447 · see citing works
Oberlander, T. F., Weinberg, J., Papsdorf, M., Grunau, R., Misri, S., & Devlin, A. M. (2008) · Epigenetics · doi:10.4161/epi.3.2.6034 · Cited by 1,432 · see citing works
The cortisol awakening response (CAR): Facts and future directions
Fries, E., Dettenborn, L., & Kirschbaum, C. (2009) · International Journal of Psychophysiology · doi:10.1016/j.ijpsycho.2008.03.014 · Cited by 1,188 · see citing works
Assessment of the cortisol awakening response: Expert consensus guidelines
Stalder, T., Kirschbaum, C., Kudielka, B. M., Adam, E. K., Pruessner, J. C., Wüst, S., Dockray, S., Smyth, N., Evans, P., Hellhammer, D. H., et al. (2016) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2015.10.010 · Cited by 967 · see citing works
GUNNAR, M. R., & VAZQUEZ, D. M. (2001) · Development and Psychopathology · doi:10.1017/s0954579401003066 · Cited by 900 · see citing works
The International Standard Classification of Education 2011
Schneider, S. L. (2013) · Comparative social research · doi:10.1108/s0195-6310(2013)0000030017 · Cited by 898 · see citing works
Nemeroff, C. B., Heim, C. M., Thase, M. E., Klein, D. N., Rush, A. J., Schatzberg, A. F., Ninan, P. T., McCullough, J. P., Weiss, P. M., Dunner, D. L., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2336126100 · Cited by 829 · see citing works
Major depressive disorder and hypothalamic-pituitary-adrenal axis activity
Vreeburg, S. A., Hoogendijk, W. J. G., van Pelt, J., DeRijk, R. H., Verhagen, J. C. M., van Dyck, R., Smit, J. H., Zitman, F. G., & Penninx, B. W. J. H. (2009) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2009.50 · Cited by 792 · cited 2× · see citing works
“Although not all previous studies have been consistent (Gunnar and Vazquez, 2001), elevated wakening cortisol levels have often been found in a significant number of previous studies examining the CAR tests in depression (Bhagwagar et al., 2005; Suzuki et al., 2013;Vreeburg et al., 2009).”
Perroud, N., Paoloni-Giacobino, A., Prada, P., Olié, E., Salzmann, A., Nicastro, R., Guillaume, S., Mouthon, D., Stouder, C., Dieben, K., et al. (2011) · Translational Psychiatry · doi:10.1038/tp.2011.60 · Cited by 516 · see citing works
Radtke, K. M., Ruf, M., Gunter, H. M., Dohrmann, K., Schauer, M., Meyer, A., & Elbert, T. (2011) · Translational Psychiatry · doi:10.1038/tp.2011.21 · Cited by 511 · see citing works
The HPA – Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain
Bellavance, M.-A., & Rivest, S. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00136 · Cited by 419 · see citing works
Gibb, B. E., Chelminski, I., & Zimmerman, M. A. (2006) · Depression and Anxiety · doi:10.1002/da.20238 · Cited by 389 · see citing works
Childhood adversities and adult depression: Basic patterns of association in a US national survey
Kessler, R. C., & Magee, W. J. (1993) · Psychological Medicine · doi:10.1017/s0033291700025460 · Cited by 379 · see citing works
Palma-Gudiel, H., Córdova-Palomera, A., Leza, J. C., & Fañanás, L. (2015) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2015.05.016 · Cited by 347 · see citing works
DNA-Binding Specificity of NGFI-A and Related Zinc Finger Transcription Factors
Swirnoff, A. H., & Milbrandt, J. (1995) · Molecular and Cellular Biology · doi:10.1128/mcb.15.4.2275 · Cited by 310 · see citing works
Williams, L. M., Debattista, C., Duchemin, A.-M., Schatzberg, A. F., & Nemeroff, C. B. (2016) · Translational Psychiatry · doi:10.1038/tp.2016.61 · Cited by 293 · see citing works
Increased salivary cortisol after waking in depression
Bhagwagar, Z., Hafizi, S., & Cowen, P. J. (2005) · Psychopharmacology · doi:10.1007/s00213-005-0062-z · Cited by 281 · see citing works
Consensus paper of the WFSBP Task Force on Biological Markers: Biological Markers in Depression
Mößner, R., Mikova, O., Koutsilieri, E., Saoud, M., Ehlis, A., Müller, N., Fallgatter, A. J., & Riederer, P. F. (2007) · The World Journal of Biological Psychiatry · doi:10.1080/15622970701263303 · Cited by 248 · see citing works
Needham, B. L., Smith, J. A., Zhao, W., Wang, X., Mukherjee, B., Kardia, S. L. R., Shively, C. A., Seeman, T. E., Liu, Y., & Roux, A. V. D. (2015) · Epigenetics · doi:10.1080/15592294.2015.1085139 · Cited by 210 · see citing works
Mineralocorticoid Receptor Function in Major Depression
Young, E. A., Lopez, J. F., Murphy-Weinberg, V., Watson, S. J., & Akil, H. (2003) · Archives of General Psychiatry · doi:10.1001/archpsyc.60.1.24 · Cited by 204 · see citing works
Argentieri, M. A., Nagarajan, S., Seddighzadeh, B., Baccarelli, A., & Shields, A. E. (2017) · EBioMedicine · doi:10.1016/j.ebiom.2017.03.044 · Cited by 189 · see citing works
Increase in Concentration of Waking Salivary Cortisol in Recovered Patients With Depression
Bhagwagar, Z., Hafizi, S., & Cowen, P. J. (2003) · American Journal of Psychiatry · doi:10.1176/appi.ajp.160.10.1890 · Cited by 161 · see citing works
Epigenetics and depression: return of the repressed
Dalton, V. S., Kolshus, E., & McLoughlin, D. M. (2013) · Journal of Affective Disorders · doi:10.1016/j.jad.2013.10.028 · Cited by 134 · see citing works
Radtke, K. M., Schauer, M., Gunter, H. M., Ruf-Leuschner, M., Sill, J., Meyer, A., & Elbert, T. (2015) · Translational Psychiatry · doi:10.1038/tp.2015.63 · Cited by 128 · see citing works
O’Keane, V., Frodl, T., & Dinan, T. G. (2012) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2012.03.009 · Cited by 126 · see citing works
Self-citationAssociation between DNA Methylation in Whole Blood and Measures of Glucose Metabolism: KORA F4 Study
Kriebel, J., Herder, C., Rathmann, W., Wahl, S., Kunze, S., Molnos, S., Volkova, N. V., Schramm, K., Carstensen‐Kirberg, M., Waldenberger, M., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0152314 · Cited by 121 · see citing works
Childhood maltreatment and methylation of FK506 binding protein 5 gene (<i>FKBP5</i>)
Tyrka, A. R., Ridout, K. K., Parade, S. H., Paquette, A., Marsit, C. J., & Seifer, R. (2015) · Development and Psychopathology · doi:10.1017/s0954579415000991 · Cited by 118 · see citing works
Antonelli, G., Ceccato, F., Artusi, C., Marinova, M., & Plebani, M. (2015) · Clinica Chimica Acta · doi:10.1016/j.cca.2015.10.004 · Cited by 111 · see citing works
FKBP5 polymorphism is associated with major depression but not with bipolar disorder
Szczepankiewicz, A., Leszczyńska-Rodziewicz, A., Pawlak, J., Narozna, B., Rajewska-Rager, A., Wilkosc, M., Zaremba, D., Maciukiewicz, M., & Twarowska-Hauser, J. (2014) · Journal of Affective Disorders · doi:10.1016/j.jad.2014.04.002 · Cited by 100 · see citing works
Tozzi, L., Carballedo, A., Wetterling, F., McCarthy, H., O’Keane, V., Gill, M., Morris, D., Fahey, C., Meaney, J. F., & Frodl, T. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.170 · Cited by 97 · see citing works
Self-citationRyan, J., Chaudieu, I., Ancelin, M.-L., & Saffery, R. (2016) · Epigenomics · doi:10.2217/epi-2016-0083 · Cited by 85 · see citing works
Hohne, N., Poidinger, M., Merz, F., Pfister, H., Bruckl, T., Zimmermann, P., Uhr, M., Holsboer, F., & Ising, M. (2015) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyu087 · Cited by 74 · see citing works
Epigenetics and the glucocorticoid receptor: A review of the implications in depression
Farrell, C. M., & O’Keane, V. (2016) · Psychiatry Research · doi:10.1016/j.psychres.2016.06.022 · Cited by 72 · see citing works
Self-citationJones, R. L., Owen, L. J., Adaway, J. E., & Keevil, B. G. (2012) · Journal of Chromatography B · doi:10.1016/j.jchromb.2011.11.036 · Cited by 69 · see citing works
Rao, S., Yao, Y., Ryan, J. L., Li, T., Wang, D., Zheng, C., Xu, Y. J., & Xu, Q. (2016) · Scientific Reports · doi:10.1038/srep32687 · Cited by 62 · see citing works
Early life trauma, depression and the glucocorticoid receptor gene—An epigenetic perspective
Smart, C., Strathdee, G., Watson, S., Murgatroyd, C., & McAllister-Williams, R. H. (2015) · Psychological Medicine · doi:10.1017/s0033291715001555 · Cited by 61 · see citing works
Fujii, T., Hori, H., Ota, M., Hattori, K., Teraishi, T., Sasayama, D., Yamamoto, N., Higuchi, T., & Kunugi, H. (2014) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2014.01.007 · Cited by 45 · see citing works
Suzuki, H., Belden, A. C., Spitznagel, E. L., Dietrich, R., & Luby, J. L. (2013) · Psychiatry Research · doi:10.1016/j.psychres.2013.06.038 · Cited by 31 · see citing works
Psychosocial factors in outcome in two opiate addiction treatments
Grey, C. C., Osborn, E., & Reznikoff, M. (1986) · Journal of Clinical Psychology · doi:10.1002/1097-4679(198601)42:1 · Cited by 28 · see citing works
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Schiele, M. A., Gottschalk, M. G., & Domschke, K. (2020) · Clinical Psychology Review · doi:10.1016/j.cpr.2020.101830 · Cited by 156 · see citing works
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Chami, R., Monteleone, A. M., Treasure, J., & Monteleone, P. (2019) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2018.12.009 · Cited by 66 · see citing works
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“Gene (hyper ↑ or ↓ hypo DNAm) and citation Candidate gene or EWAS Tissue Condition/sample Clinical/biological outcome CLMN*, SENP7* Clark et al. (2021) EWAS Blood Adolescents Differently methylated in CU users Immune system and inflammation ZC3H12D ↓Montano et al. (2016) EWAS Blood SCZ TCF3 ↑Montano et al. (2016) EWAS…”
BackgroundResultInfluentialHPA axis dysregulation is associated with differential methylation of CpG-sites in related genes
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- Authors
- Farrell, C., Doolin, K., O’ Leary, N., Jairaj, C., Roddy, D., Tozzi, L., Morris, D., Harkin, A., Frodl, T., Nemoda, Z., Szyf, M., Booij, L., & O'Keane, V.
- Affiliations
- Trinity College Dublin (IE)
- Otto-von-Guericke-Universität Magdeburg (DE)
- Ollscoil na Gaillimhe – University of Galway (IE)
- Semmelweis University (HU)
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- ORCID
- Venue
- Psychiatry Research
- Publisher
- Elsevier BV
- Published
- 2018-07
- Volume
- 265
- Pages
- 341-348
- ISSN
- 0165-1781 (ISSN-L)
- OpenAlex
- W2802228122
- Cited by
- 144
- References
- 51
- Citations by year
- 2026: 7 · 2025: 7 · 2024: 10 · 2023: 23 · 2022: 15 · 2021: 19 · 2020: 48 · 2019: 10 · 2018: 5
- FWCI
- 11.77
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Psychiatry Research (publishedVersion)
- PubMed (publishedVersion)
- Spectrum Research Repository (Concordia University) (acceptedVersion)
- Semmelweis University Repository (Semmelweis University) (submittedVersion)
- Funders
- Health Research Board (HRA-POR-2015-1317)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
- Keywords
- depression, DNA methylation, glucocorticoid receptor, FKBP5, hypothalamic-pituitary-adrenal axis, cortisol, childhood adversity, epigenetics, stress-related genes
- MeSH terms
- Adult, Child, Child Abuse, Cross-Sectional Studies, Major Depressive Disorder, Female, Humans, Hydrocortisone, Hypothalamo-Hypophyseal System, Male, Pituitary-Adrenal System, Receptors, Glucocorticoid, Cohort Studies, DNA Methylation, Epigenesis, Genetic
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