Glucocorticoid receptor gene (NR3C1) methylation following stressful events between birth and adolescence. The TRAILS study

Knaap, Lisette J. van der; Riese, Harriëtte; Hudziak, James J.; Verbiest, Michaël; Verhulst, Frank C.; Oldehinkel, Albertine J.; Oort, Floor V. A. van

doi:10.1038/tp.2014.22

Cited by 151 publications

(131 citation statements)

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“…However, for both NR3C1 and BDNF, maternal cortisol did not predict infant DNA methylation changes. Variation in DNA methylation within the NR3C1 1F region has been reported in both animal 15,18,19 and human [23][24][25][26][27] studies, suggesting that this epigenetic marker is developmentally sensitive to the quality of the environment. These studies have consistently reported increased DNA methylation of NR3C1 1F and our findings compliment previous reports examining the epigenetic impact of maternal depressed mood during pregnancy.…”

Section: Discussionmentioning

confidence: 96%

“…23 Increased NR3C1 1F DNA methylation has also been detected in DNA extracted from whole blood samples from young adolescents exposed to physical abuse in childhood, 24 and adolescents exposed to stressful life events or trauma. 25 This susceptibility to alterations in NR3C1 DNA methylation is also observed in response to prenatal distress. Increased NR3C1 1F DNA methylation has been found in cord blood of infants exposed to maternal depressed mood during pregnancy and this altered epigenetic state was predictive of stress responses in these infants at 3 months of age.…”

Section: Introductionmentioning

confidence: 92%

“…[23][24][25] Increased NR3C1 exon 1F methylation and decreased GR mRNA have been detected in the hippocampus of suicide victims with a history of childhood abuse. 23 Increased NR3C1 1F DNA methylation has also been detected in DNA extracted from whole blood samples from young adolescents exposed to physical abuse in childhood, 24 and adolescents exposed to stressful life events or trauma.…”

Section: Introductionmentioning

confidence: 99%

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Maternal prenatal depressive symptoms predict infantNR3C11F andBDNFIV DNA methylation

et al. 2015

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Abbreviations: BDNF, gene encoding the brain-derived neurotrophic factor protein, BPA, bisphenol A, GR, glucocorticoid receptor, HPA, hypothalamic-pituitary adrenal, NR3C1, gene encoding the glucocorticoid receptor.Prenatal maternal psychological distress increases risk for adverse infant outcomes. However, the biological mechanisms underlying this association remain unclear. Prenatal stress can impact fetal epigenetic regulation that could underlie changes in infant stress responses. It has been suggested that maternal glucocorticoids may mediate this epigenetic effect. We examined this hypothesis by determining the impact of maternal cortisol and depressive symptoms during pregnancy on infant NR3C1 and BDNF DNA methylation. Fifty-seven pregnant women were recruited during the second or third trimester. Participants self-reported depressive symptoms and salivary cortisol samples were collected diurnally and in response to a stressor. Buccal swabs for DNA extraction and DNA methylation analysis were collected from each infant at 2 months of age, and mothers were assessed for postnatal depressive symptoms. Prenatal depressive symptoms significantly predicted increased NR3C1 1F DNA methylation in male infants (b D 2.147, P D 0.044). Prenatal depressive symptoms also significantly predicted decreased BDNF IV DNA methylation in both male and female infants (b D ¡3.244, P D 0.013). No measure of maternal cortisol during pregnancy predicted infant NR3C1 1F or BDNF promoter IV DNA methylation. Our findings highlight the susceptibility of males to changes in NR3C1 DNA methylation and present novel evidence for altered BDNF IV DNA methylation in response to maternal depression during pregnancy. The lack of association between maternal cortisol and infant DNA methylation suggests that effects of maternal depression may not be mediated directly by glucocorticoids. Future studies should consider other potential mediating mechanisms in the link between maternal mood and infant outcomes.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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Maternal prenatal depressive symptoms predict infantNR3C11F andBDNFIV DNA methylation

et al. 2015

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“…However, another study has reported that there is a nonsignificant effect of perinatal stress, defined as the sum of maternal psychological problems during pregnancy or the 3 months after delivery, on NR3C1 methylation in adolescent offspring (van der Knaap et al, 2014). Incongruent findings on the methylation status of NR3C1 may be reflective of differences in methodologies or individual differences in the potential subsequent development of psychopathology in offspring.…”

Section: Epigeneticsmentioning

confidence: 99%

Intergenerational Transmission of Stress in Humans

Bowers

Yehuda

2015

Neuropsychopharmacol

394

269

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The hypothesis that offspring are affected by parental trauma or stress exposure, first noted anecdotally, is now supported empirically by data from Holocaust survivor offspring cohorts and other populations. These findings have been extended to less extreme forms of stress, where differential physical, behavioral, and cognitive outcomes are observed in affected offspring. Parental stress-mediated effects in offspring could be explained by genetics or social learning theory. Alternatively, biological variations stemming from stress exposure in parents could more directly have an impact on offspring, a concept we refer to here as 'intergenerational transmission', via changes to gametes and the gestational uterine environment. We further extend this definition to include the transmission of stress to offspring via early postnatal care, as animal studies demonstrate the importance of early maternal care of pups in affecting offsprings' long-term behavioral changes. Here, we review clinical observations in offspring, noting that offspring of stress-or trauma-exposed parents may be at greater risk for physical, behavioral, and cognitive problems, as well as psychopathology. Furthermore, we review findings concerning offspring biological correlates of parental stress, in particular, offspring neuroendocrine, epigenetic, and neuroanatomical changes, in an attempt to determine the extent of parental stress effects. Although understanding the etiology of effects in offspring is currently impeded by methodological constraints, and limitations in our knowledge, we summarize current information and conclude by presenting hypotheses that have been prompted by recent studies in the field.

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“…Studies of early experiences in rats found that DNA methylation of the GR promoter region was altered by maternal care, which in turn was associated with GR expression and HPA responses to stress 12. In humans, stressful life events (e.g., trauma and abuse) have been associated with higher DNA methylation at the GR promoter region13, 14, 15, 16, 17, 18 as well as differential GR expression and biological markers of HPA‐axis activity, such as salivary cortisol 13, 14. Furthermore, GR methylation has been implicated in the development of PTSD following trauma 19.…”

Section: Introductionmentioning

confidence: 99%

Hpa Axis Related Genes and Response to Psychological Therapies: Genetics and Epigenetics

et al. 2015

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BackgroundHypothalamic–pituitary–adrenal (HPA) axis functioning has been implicated in the development of stress‐related psychiatric diagnoses and response to adverse life experiences. This study aimed to investigate the association between genetic and epigenetics in HPA axis and response to cognitive behavior therapy (CBT).MethodsChildren with anxiety disorders were recruited into the Genes for Treatment project (GxT, N = 1,152). Polymorphisms of FKBP5 and GR were analyzed for association with response to CBT. Percentage DNA methylation at the FKBP5 and GR promoter regions was measured before and after CBT in a subset (n = 98). Linear mixed effect models were used to investigate the relationship between genotype, DNA methylation, and change in primary anxiety disorder severity (treatment response).ResultsTreatment response was not associated with FKBP5 and GR polymorphisms, or pretreatment percentage DNA methylation. However, change in FKBP5 DNA methylation was nominally significantly associated with treatment response. Participants who demonstrated the greatest reduction in severity decreased in percentage DNA methylation during treatment, whereas those with little/no reduction in severity increased in percentage DNA methylation. This effect was driven by those with one or more FKBP5 risk alleles, with no association seen in those with no FKBP5 risk alleles. No significant association was found between GR methylation and response.ConclusionsAllele‐specific change in FKBP5 methylation was associated with treatment response. This is the largest study to date investigating the role of HPA axis related genes in response to a psychological therapy. Furthermore, this is the first study to demonstrate that DNA methylation changes may be associated with response to psychological therapies in a genotype‐dependent manner.

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Glucocorticoid receptor gene (NR3C1) methylation following stressful events between birth and adolescence. The TRAILS study

Cited by 151 publications

References 52 publications

Maternal prenatal depressive symptoms predict infantNR3C11F andBDNFIV DNA methylation

Maternal prenatal depressive symptoms predict infantNR3C11F andBDNFIV DNA methylation

Intergenerational Transmission of Stress in Humans

Hpa Axis Related Genes and Response to Psychological Therapies: Genetics and Epigenetics

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