Holocaust Exposure Induced Intergenerational Effects on FKBP5 Methylation
Open accessAbstract
Background The involvement of epigenetic mechanisms in intergenerational transmission of stress effects has been demonstrated in animals but not in humans. Methods Cytosine methylation within the gene encoding for FK506 binding protein 5 (FKBP5) was measured in Holocaust survivors (n = 32), their adult offspring (n = 22), and demographically comparable parent (n = 8) and offspring (n = 9) control subjects, respectively. Cytosine-phosphate-guanine sites for analysis were chosen based on their spatial proximity to the intron 7 glucocorticoid response elements. Results Holocaust exposure had an effect on FKBP5 methylation that was observed in exposed parents as well in their offspring. These effects were observed at bin 3/site 6. Interestingly, in Holocaust survivors, methylation at this site was higher in comparison with control subjects, whereas in Holocaust offspring, methylation was lower. Methylation levels for exposed parents and their offspring were significantly correlated. In contrast to the findings at bin 3/site 6, offspring methylation at bin 2/sites 3 to 5 was associated with childhood physical and sexual abuse in interaction with an FKBP5 risk allele previously associated with vulnerability to psychological consequences of childhood adversity. The findings suggest the possibility of site specificity to environmental influences, as sites in bins 3 and 2 were differentially associated with parental trauma and the offspring's own childhood trauma, respectively. FKBP5…
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Claims the paper makes
35 of 60 cited sources checked · 21 supported · 1 flagged · accuracy not yet measured
- Premisecitation
Both bins within intron 7 appear to be equally sensitive to glucocorticoid-dependent FKBP5 demethylation in a multipotent human hippocampal progenitor cell line.
“Furthermore, both bins within intron 7 appear to be equally sensitive to glucocorticoid-dependent FKBP5 demethylation in a multipotent human hippocampal progenitor cell line (38).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [38] Klengel, 2013, Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions, Nat Neurosci source
The Results report dexamethasone-induced demethylation in intron 7 of human hippocampal progenitor cells, but say the bin affected by early trauma showed the strongest demethylation—not that the bins were equally sensitive. The Methods also describe three CpG bins in intron 7, rather than two. (LLM, conf=0.82)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
- Premisecitation
Reporter gene assays established that methylation of the sites affected FKBP5 gene expression.
“Second, reporter gene assays established that methylation of the sites affected FKBP5 gene expression (38).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [38] Klengel, 2013, Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions, Nat Neurosci source
- Premisecitation
Klengel et al. demonstrated that only intron 7 CpG sites were differentially methylated in response to early abuse in the presence of FKBP5 rs1360780 risk allele.
“After extensive investigation of all relevant regions in the FKBP5 gene that had GR-binding signals including the promoter regions and introns 2, 5, and 7 (31,39), Klengel et al. (38) demonstrated that only intron 7 CpG sites were differentially methylated in response to early abuse in the presence of FKBP5 rs1360780 risk allele.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [38] Klengel, 2013, Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions, Nat Neurosci source
- Premisecitation
FKBP5 site-specific demethylation occurs with age.
“since FKBP5 site-specific demethylation occurs with age (49).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [49] Blair, 2013, Accelerated neurodegeneration through chaperone-mediated oligomerization of tau, J Clin Invest source
- Premisecitation
Using a multipotent human hippocampal progenitor cell line, four of these sites (3 to 6) were shown to be demethylated by glucocorticoid administration.
“Third, using a multipotent human hippocampal progenitor cell line, four of these sites (3 to 6) were shown to be demethylated by glucocorticoid administration (38).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [38] Klengel, 2013, Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions, Nat Neurosci source
The Results report that dexamethasone caused significant demethylation of FKBP5 intron 7 CpGs in a multipotent human hippocampal progenitor cell line. They identify three CpGs in the most strongly affected bin, but do not establish that four sites numbered 3–6 were demethylated. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Premisecitation
An experiment using chromatin conformation capture revealed that intron 7 is in direct physical contact with the FKBP5 transcriptional start site.
“First, an experiment using chromatin conformation capture revealed that intron 7 is in direct physical contact with the FKBP5 transcriptional start site (38).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [38] Klengel, 2013, Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions, Nat Neurosci source
- Premisecitation
Klengel et al. and other investigators focusing on early childhood trauma effects and gene-by-early-life-environment interactions on methylation did not assess the contribution of parental experiences, particularly trauma exposure.
“Klengel et al. (38) and other investigators (51,52) focusing on early childhood trauma effects and the influence of the gene 3 early life environment interactions on methylation did not assess the contribution of parental experiences, particularly trauma exposure.”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [38] Klengel, 2013, Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions, Nat Neurosci source
- cites [51] Turecki, 2016, Effects of the social environment and stress on glucocorticoid receptor gene methylation: A systematic review, Biol Psychiatry source
The Conclusion describes Klengel et al.’s finding on childhood maltreatment, FKBP5 genotype and methylation. The Results discuss parental stress in a separate group of studies, but do not establish that Klengel et al. or the other investigators named in the citing sentence failed to assess parental trauma exposure. (LLM, conf=0.78)
Experimental — accuracy not yet measured - cites [52] Daskalakis, 2014, Site-specific methylation changes in the glucocorticoid receptor exon 1F promoter in relation to life adversity: Systematic review of contributing factors, Front Neurosci source
The sections on GR-1F promoter site-specific methylation and possible transgenerational effects distinguish studies of childhood adversity from work assessing parental trauma or PTSD, and note that the two influences are difficult to disentangle (page unavailable). The review does not establish that Klengel et al. or all the other investigators cited failed to assess parental experiences, so that categorical part is unsupported. (LLM, conf=0.73)
Experimental — accuracy not yet measured
- Interpretationcitation
These results partially replicate previous findings in which bin 2 demethylation was associated with physical and sexual abuse, the FKBP5 risk allele, and their interaction in two separate large cohorts.
“These results partially replicate previous findings (38) in which bin 2 demethylation was associated with physical and sexual abuse, the FKBP5 risk allele, and their interaction in two separate large cohorts.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [38] Klengel, 2013, Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions, Nat Neurosci source
The Results (page unavailable) report that intron 7 bin 2 methylation was associated with childhood abuse, FKBP5 risk genotype, and their interaction in the first cohort. In the second cohort, methylation correlated with physical abuse among risk-genotype carriers, but not with sexual abuse. The claim therefore overstates the findings across both cohorts; the methylation analyses involved 76 and 56 participants, respectively, rather than two large samples. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Premisecitation
Alterations in methylation at bins 1, 2, and 3 affect GR-induced FKBP5 gene transcription.
“alterations in methylation at bins 1, 2, and 3 affect GR-induced FKBP5 gene transcription as shown by reporter-gene assay (38).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [38] Klengel, 2013, Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions, Nat Neurosci source
The Results ('Functional effects of intron 7 demethylation'; page unavailable) report that methylating an intron 7 reporter construct reduced its dexamethasone-induced activity. The Methods identify bins 1, 2, and 3 in that region, but the assay methylated the construct as a whole; it did not show that alterations in each bin individually affect transcription. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Premisecitation
Lower methylation leading to higher FKBP5 messenger RNA and protein levels has been linked to decreased GR sensitivity.
“Lower methylation leading to higher FKBP5 messenger RNA and protein levels has been linked to decreased GR sensitivity (38)”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [38] Klengel, 2013, Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions, Nat Neurosci source
The Results (page not available in our copy) link lower intron 7 methylation to greater glucocorticoid-induced FKBP5 expression and increased glucocorticoid receptor resistance. They do not establish that lower methylation raises FKBP5 protein levels, and report no association with baseline FKBP5 expression. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Interpretationcitation
Both bins 2 and 3 appear to be functionally important in this sample, as previously reported.
“Despite different associations with methylation at bins 2 and 3, both appear to be functionally important in this sample, as previously reported (38).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [38] Klengel, 2013, Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions, Nat Neurosci source
- Premisecitation
The GREs in FKBP5 intron 7 come into contact with the transcriptional start site of FKBP5 via chromatin interactions.
“These GREs come into contact with the transcriptional start site of FKBP5 via chromatin interactions”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [38] Klengel, 2013, Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions, Nat Neurosci source
- Findingown data
Offspring methylation at bin 2/sites 3 to 5 was associated with childhood physical and sexual abuse in interaction with an FKBP5 risk allele previously associated with vulnerability to psychological consequences of childhood adversity.
“In contrast to the findings at bin 3/site 6, offspring methylation at bin 2/sites 3 to 5 was associated with childhood physical and sexual abuse in interaction with an FKBP5 risk allele previously associated with vulnerability to psychological consequences of childhood adversity.”
Quote in the paperSubstantial claim - Findingown data
In Holocaust offspring, methylation at bin 3/site 6 was lower in comparison with control subjects.
“Interestingly, in Holocaust survivors, methylation at this site was higher in comparison with control subjects, whereas in Holocaust offspring, methylation was lower.”
Quote in the paperSubstantial claim - Findingown data
A linear regression confirmed that parental Holocaust exposure was the salient predictor of offspring's bin 3/site 6 methylation.
“A linear regression confirmed that parental Holocaust exposure was the salient predictor of offspring's bin 3/site 6 methylation (β 5 2.368, p 5 .034).”
Quote in the paperSubstantial claim - Findingown data
No differences between Holocaust survivors and F0 control subjects were apparent for bins 1 and 2.
“No differences between Holocaust survivors and F0 control subjects were apparent for bins 1 and 2.”
Quote in the paperNot a substantial claim - Findingown data
For protective genotype carriers (n = 13), physical and sexual abuse were positively associated with bin 2 methylation.
“For protective genotype carriers (n 5 13), physical and sexual abuse were positively associated with bin 2 methylation (r 5 .698,p 5 .008).”
Quote in the paperSubstantial claim - Findingnone given
Holocaust survivors differed from control subjects in presence and severity of current PTSD as anticipated.
“Holocaust survivors differed from control subjects in presence and severity of current PTSD as anticipated.”
Quote in the paperNot a substantial claim - Findingown data
This association was also significant without covariation.
“This association was also significant without covariation (r 5 2.432, n 5 22, p 5 .044; Figure 5).”
Quote in the paperNot a substantial claim - Findingown data
A multivariate analysis of covariance comparing Holocaust survivors and F0 control subjects on intron 7 methylation showed 10% higher levels in bin 3/site 6 in survivors.
“A multivariate analysis of covariance comparing Holocaust survivors and F0 control subjects on intron 7 methylation showed 10% higher levels in bin 3/site 6 in survivors (control subjects: 51.33 6 2.10, survivors: 56.39 6 1.03; F 1,31 5 4.34, p 5 .046; Figure 2A).”
Quote in the paperSubstantial claim - Findingown data
FKBP5 methylation averaged across the three bins examined was associated with wake-up cortisol levels.
“FKBP5 methylation averaged across the three bins examined was associated with wake-up cortisol levels, indicating functional relevance of the methylation measures.”
Quote in the paperSubstantial claim - Findingown data
In Holocaust survivors, methylation at bin 3/site 6 was higher in comparison with control subjects.
“Interestingly, in Holocaust survivors, methylation at this site was higher in comparison with control subjects, whereas in Holocaust offspring, methylation was lower.”
Quote in the paperSubstantial claim - Findingown data
Bin 3/site 6 methylation was not associated with the FKBP5 risk allele.
“Bin 3/site 6 methylation was not associated with the FKBP5 risk allele and could not be attributed to the offspring's own trauma exposure, their own psychopathology, or other examined characteristics that might independently affect methylation of this gene.”
Quote in the paperSubstantial claim - Findingown data
Holocaust exposure had an effect on FKBP5 methylation that was observed in exposed parents as well as in their offspring.
“Holocaust exposure had an effect on FKBP5 methylation that was observed in exposed parents as well in their offspring.”
Quote in the paperSubstantial claim - Findingown data
Intron 7 FKBP5 bin average methylation was negatively correlated with wake-up cortisol, controlling for age, gender, and current mood/anxiety disorder.
“Intron 7 FKBP5 bin average methylation was negatively correlated with wake-up cortisol (r 5 2.630, df 5 16, p 5 .005,controlling for age, gender, and current mood/anxiety disorder).”
Quote in the paperSubstantial claim - Findingown data
In each of these models, parental exposure remained a significant predictor of offspring bin 3/site 6 methylation.
“In each of these, however, parental exposure remained a significant predictor (respectively, β 5 2.461, p 5 .054;β 5 2.362, p 5 .043).”
Quote in the paperSubstantial claim - Findingown data
For risk allele carriers (n = 18), there were significant negative associations with bin 2 methylation.
“For risk allele carriers (n 5 18), there were significant negative associations with bin 2 methylation (r 5 2.479, p 5 .044).”
Quote in the paperSubstantial claim - Findingown data
F0 intron 7 bin 3/site 6 methylation was correlated with F1 methylation at the same site.
“F0 intron 7 bin 3/site 6 methylation was correlated with F1 methylation at the same site (r 5 .441,n 5 33, p 5 .010; Figure 4).”
Quote in the paperSubstantial claim - Findingown data
Despite the potential limitations of the cross-sectional approach, a significant effect of severe parental trauma was observed in both generations at the same site of a transcriptionally relevant region of a stress-related gene.
“Despite the potential limitations of our cross-sectional approach, a significant effect of severe parental trauma was observed in both generations at the same site of a transcriptionally relevant region of a stress-related gene.”
Quote in the paperSubstantial claim - Findingown data
The correlations of bin average methylation with bedtime cortisol were not significant.
“The correlations of bin average methylation with bedtime cortisol were not significant (r 5 2.216, df 5 13, ns, and r 5 2.137, n 5 19, ns, respectively).”
Quote in the paperNot a substantial claim - Findingown data
The correlations at site 3 with physical abuse differed significantly according to the presence of the risk allele.
“The correlations at site 3 with physical abuse differed significantly according to the presence of the risk allele (z 5 3.89, p , .001; Figure 3).”
Quote in the paperSubstantial claim - Findingown data
F0 methylation did not alter the significance of parental Holocaust exposure as a predictor of bin 3/site 6 methylation in F1.
“F0 methylation did not alter the significance of parental Holocaust exposure as a predictor of bin 3/site 6 methylation in F1 (β 5 2.418, p 5 .022).”
Quote in the paperSubstantial claim - Findingown data
Methylation levels for exposed parents and their offspring were significantly correlated.
“Methylation levels for exposed parents and their offspring were significantly correlated.”
Quote in the paperSubstantial claim - Findingown data
There was no significant main effect of F0 PTSD diagnosis on bin 3/site 6 methylation.
“There was no significant main effect of F0 PTSD diagnosis on bin 3/site 6 methylation (F 1,31 5 .33,not significant [ns]).”
Quote in the paperNot a substantial claim - Findingown data
Significantly lower intron 7 methylation (7.7% difference) was observed at bin 3/site 6 in Holocaust offspring than comparison subjects.
“When a similar analysis was performed for F1, significantly lower intron 7 methylation (7.7% difference) was observed at bin 3/site 6 in Holocaust offspring than comparison subjects (control subjects: 57.58 6 1.63, offspring: 53.13 6 1.00; F 1,25 5 5.03, p 5 .034; Figure 2B).”
Quote in the paperSubstantial claim - Findingown data
This association was primarily driven by the Holocaust-exposed families.
“This association was primarily driven by the Holocaust-exposed families (r 5 .569,n 5 23, p 5 .005for Holocaust-exposed compared with r 5 .370,n 5 10, ns for control subjects).”
Quote in the paperSubstantial claim - Findingown data
Further analysis indicated that the effect was driven by physical abuse-induced site 3 demethylation in FKBP5 risk allele carriers.
“Further analysis indicated that the effect was driven by a physical abuse induced site 3 demethylation in FKBP5 risk allele carriers.”
Quote in the paperSubstantial claim - Findingown data
In this study, there was a negative correlation between F1 intron 7 bin average methylation and wake-up cortisol levels.
“as supported in this study by the negative correlation between F1 intron 7, bin average methylation and wake-up cortisol levels.”
Quote in the paperSubstantial claim - Findingown data
The effects were relatively small, with 10% or less difference in DNA methylation.
“While the effects were relatively small, with 10% or less difference in DNA methylation”
Quote in the paperSubstantial claim - Findingown data
This minority contributed clinically relevant variance to CTQ scores for physical and sexual abuse.
“However, this minority contributed clinically relevant variance to CTQ scores for physical and sexual abuse.”
Quote in the paperNot a substantial claim - Findingown data
Only a small minority of offspring in this study would be considered traumatized according to previously reported criteria.
“and only a small minority of offspring in this study would be considered traumatized according to previously reported criteria.”
Quote in the paperNot a substantial claim - Findingown data
Two sites anticipated to operate similarly to regulate FKBP5 gene expression were demonstrated to have different environmental influences.
“Two sites anticipated to operate similarly to regulate FKBP5 gene expression were demonstrated to have different environmental influences.”
Quote in the paperSubstantial claim - Premisecitation
FKBP5 is an important regulator of GR sensitivity.
“We focused on FKBP5, an important regulator of GR sensitivity (26), alterations of which have been associated with both PTSD and intergenerational effects (27,28).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [26] Binder, 2009, The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders, Psychoneuroendocrinology source
- Premisecitation
Parental trauma exposure has been linked with offspring trauma, particularly childhood emotional abuse.
“Since parental trauma exposure has been linked with offspring trauma, particularly childhood emotional abuse (25), it has been difficult to disentangle effects of parental exposure from those potentially conferred by the offspring's early experiences (24).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [25] Yehuda, 2001, Childhood trauma and risk for PTSD: Relationship to intergenerational effects of trauma, parental PTSD, and cortisol excretion, Dev Psychopathol source
- Premisecitation
Higher 11β-HSD-2 activity was noted in Holocaust offspring.
“However, higher 11β-HSD-2 activity was noted in Holocaust offspring (20).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] Bierer, 2014, Elevation of 11beta-hydroxysteroid dehydrogenase type 2 activity in Holocaust survivor offspring: Evidence for an intergenerational effect of maternal trauma exposure, Psychoneuroendocrinology source
- Interpretationnone given
F0 and F1 control subjects differed substantially in age (F0: 75 years vs. F1: 45 years).
“F0 and F1 control subjects differed substantially in age (F0: 75 years vs. F1: 45 years)”
Quote in the paperSubstantial claim - Study design and conductown data
The finding of higher bin 3/site 6 methylation in Holocaust survivors remained significant when the presence of PTSD was entered as an additional covariate.
“The finding remained significant when the presence of PTSD was entered as an additional covariate (p 5 .049).”
Quote in the paperSubstantial claim - Interpretationown data
This is the first demonstration of an association of preconception parental trauma with epigenetic alterations that is evident in both exposed parent and offspring.
“This is the first demonstration of an association of preconception parental trauma with epigenetic alterations that is evident in both exposed parent and offspring, providing potential insight into how severe psychophysiological trauma can have intergenerational effects.”
Quote in the paperSubstantial claim - Study design and conductown data
There were significant differences between Holocaust offspring and comparison groups in a composite score of depression and anxiety self-ratings.
“However, there were significant differences in a composite score of depression and anxiety self-ratings.”
Quote in the paperNot a substantial claim - Interpretationown data
Bin 3/site 6 methylation could be attributed to Holocaust exposure in the F0.
“Yet, it could be attributed to Holocaust exposure in the F0.”
Quote in the paperSubstantial claim - Study design and conductown data
It was not possible to disentangle the influence of parental gender, including gamete or in utero effects, since 21 of 22 Holocaust parents were survivors.
“It was not possible to disentangle the influence of parental gender, including gamete or in utero effects, since 21 of 22 Holocaust parents were survivors.”
Quote in the paperSubstantial claim - Study design and conductown data
Covariation for the presence of the FKBP5 risk allele in both generations did not substantially alter the association of bin 3/site 6 methylation between survivors and offspring or within the Holocaust-exposed families.
“Covariation for the presence of the FKBP5 risk allele in both generations did not substantially alter the association of bin 3/site 6 methylation between survivors and offspring (r 5 .438,df 5 29, p 5 .014)or within the Holocaustexposed families (r 5 .559,df 5 19, p 5 .008).”
Quote in the paperSubstantial claim - Interpretationreasoning
The Holocaust effects in F0 and F1 methylation are not likely driven by respective differences in control subjects.
“The Holocaust effects in F0 and F1 methylation are not likely driven by respective differences in control subjects.”
Quote in the paperSubstantial claim - Interpretationreasoning
It is not possible to infer mechanisms of transmission from these data.
“It is not possible to infer mechanisms of transmission from these data.”
Quote in the paperSubstantial claim - Interpretationcitation
The age difference between F0 and F1 control subjects could explain their 12% methylation difference at bin 3/site 6.
“which could explain their 12% methylation difference at bin 3/site 6”
Quote in the paperSubstantial claim - Interpretationown data
The association between FKBP5 methylation averaged across the three bins and wake-up cortisol levels indicates functional relevance of the methylation measures.
“FKBP5 methylation averaged across the three bins examined was associated with wake-up cortisol levels, indicating functional relevance of the methylation measures.”
Quote in the paperSubstantial claim - Interpretationreasoning
There are likely specific immune cell subtypes with more pronounced effects.
“Therefore, there are likely specific immune cell subtypes with more pronounced effects.”
Quote in the paperNot a substantial claim - Interpretationown data
Our data support an intergenerational epigenetic priming of the physiological response to stress in offspring of highly traumatized individuals.
“In summary, our data support an intergenerational epigenetic priming of the physiological response to stress in offspring of highly traumatized individuals.”
Quote in the paperSubstantial claim- Rests on an assumption: The observed associations between parental Holocaust exposure and offspring FKBP5 methylation reflect intergenerational transmission of epigenetic effects rather than preconception or postnatal influences or offspring recalibration of glucocorticoid regulation.
- Premisecitation
Parental trauma exposure has been shown to result in an increased prevalence of childhood abuse, most strongly emotional abuse, in offspring.
“Indeed, parental trauma exposure has been shown to result in an increased prevalence of childhood abuse, most strongly emotional abuse, in offspring (25).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [25] Yehuda, 2001, Childhood trauma and risk for PTSD: Relationship to intergenerational effects of trauma, parental PTSD, and cortisol excretion, Dev Psychopathol source
- Interpretationreasoning
There is reason to believe that methylation at individual sites in the FKBP5 gene may contribute to transcriptional and functional effects.
“there is reason to believe that methylation at individual sites in the FKBP5 gene may contribute to transcriptional and functional effects.”
Quote in the paperSubstantial claim - Premisecitation
Small differences of around 1% to 2% have been previously associated with differential gene expression of the closest gene in a mixed tissue with many cell subtypes, such as peripheral blood.
“small differences of around 1% to 2% have been previously associated with differential gene expression of the closest gene in a mixed tissue with many cell subtypes, such as peripheral blood (53).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [53] Mehta, 2013, Childhood maltreatment is associated with distinct genomic and epigenetic profiles in posttraumatic stress disorder, Proc Natl Acad Sci U S A source
- Interpretationreasoning
These changes may contribute to the increased risk for psychopathology in the F1 generation.
“These changes may contribute to the increased risk for psychopathology in the F1 generation.”
Quote in the paperSubstantial claim- Rests on an assumption: The observed associations between parental Holocaust exposure and offspring FKBP5 methylation reflect intergenerational transmission of epigenetic effects rather than preconception or postnatal influences or offspring recalibration of glucocorticoid regulation.
- Study design and conductnone given
The study was unable to disentangle functional effects of methylation at distinct CpGs in intron 7.
“Although we were unable to disentangle functional effects of methylation at distinct CpGs in intron 7”
Quote in the paperNot a substantial claim
- Classified as probably not a substantial claim. 18
- May combine two claims. 20
Classified as probably not a substantial claim.
PremisecitationEnduring behavioral responses to stress and epigenetic alterations in adult offspring have been demonstrated to be mediated by changes in gametes, in utero effects, variations in early postnatal care, and/or other early life experiences influenced by parental exposure.
“Enduring behavioral responses to stress and epigenetic alterations in adult offspring have been demonstrated to be mediated by changes in gametes (10)(11)(12)(13), in utero effects (14), variations in early postnatal care (15,16), and/or other early life experiences (17) that are influenced by parental exposure (18).”
Quote in the paperSubstantial claim4 of 7 sources checked- cites [10] Dias, 2014, Parental olfactory experience influences behavior and neural structure in subsequent generations, Nat Neurosci source
- cites [11] Zaidan, 2013, Prereproductive stress to female rats alters corticotropin releasing factor type 1 expression in ova and behavior and brain corticotropin releasing factor type 1 expression in offspring, Biol Psychiatry source
- cites [12] Franklin, 2010, Epigenetic transmission of the impact of early stress across generations, Biol Psychiatry source
- cites [13] Rodgers, 2013, Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation, J Neurosci source
- cites [14] Boersma, 2014, Prenatal stress decreases Bdnf expression and increases methylation of Bdnf exon IV in rats, Epigenetics source
- cites [15] Champagne, 2006, Maternal care associated with methylation of the estrogen receptor-alpha1b promoter and estrogen receptor-alpha expression in the medial preoptic area of female offspring, Endocrinology source
- cites [16] Weaver, 2004, Epigenetic programming by maternal behavior, Nat Neurosci source
May combine two claims.
PremisecitationDifferential methylation of the glucocorticoid receptor gene associated with maternal behavior has been observed in F1 rodents at Nr3c1 exon 1 7 promoter and in human offspring with parental PTSD at the ortholog NR3C1 exon 1 F promoter.
“Differential methylation of the glucocorticoid receptor (GR) gene associated with maternal behavior has been observed in F1 in rodents at Nr3c1 exon 1 7 promoter (16) and in human offspring with parental PTSD at the ortholog NR3C1 exon 1 F promoter (24).”
Quote in the paperNot a substantial claim1 of 2 sources checkedClassified as probably not a substantial claim.
PremisecitationAnimal models have demonstrated that stress exposure can result in epigenetic alterations in the next generation.
“Animal models have demonstrated that stress exposure can result in epigenetic alterations in the next generation, and such mechanisms have been hypothesized to underpin vulnerability to symptoms in offspring of trauma survivors (6)(7)(8)(9).”
Quote in the paperSubstantial claim1 of 4 sources checked- cites [6] Gapp, 2014, Early life epigenetic programming and transmission of stress-induced traits in mammals: How and when can environmental factors influence traits and their transgenerational inheritance?, Bioessays source
- cites [7] Yehuda, 2009, The relevance of epigenetics to PTSD: Implications for the DSM-V, J Trauma Stress source
The section “Cytosine Methylation in Response to Variations in Maternal Care: A Behavioral Model” (page unavailable) reports altered DNA methylation in rat pups receiving different levels of maternal care and says associated biological effects were transmitted to a third generation. It does not clearly demonstrate that stress exposure in one generation caused epigenetic alterations in the next; the animal model described is one of variation in maternal care. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [8] Bale, 2015, Epigenetic and transgenerational reprogramming of brain development, Nat Rev Neurosci source
- cites [9] Dias, 2015, Epigenetic mechanisms underlying learning and the inheritance of learned behaviors, Trends Neurosci source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationLower 11β-HSD-2 activity was observed in Holocaust survivors compared with control subjects, presumably reflecting an enduring adaptive response to extreme nutritional deprivation.
“For example, lower 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD-2) activity was observed in Holocaust survivors compared with control subjects, presumably reflecting an enduring adaptive response to extreme nutritional deprivation (19).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [19] Yehuda, 2009, Enduring effects of severe developmental adversity, including nutritional deprivation, on cortisol metabolism in aging Holocaust survivors, J Psychiatr Res source
May combine two claims.
PremisecitationFKBP5 effectively decreases glucocorticoid binding to GR, impeding GR translocation to the nucleus.
“FKBP5 effectively decreases glucocorticoid binding to GR, impeding GR translocation to the nucleus (29,30).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [29] Pratt, 1997, Steroid receptor interactions with heat shock protein and immunophilin chaperones, Endocr Rev source
- cites [30] Wochnik, 2005, FK506-binding proteins 51 and 52 differentially regulate dynein interaction and nuclear translocation of the glucocorticoid receptor in mammalian cells, J Biol Chem source
The Discussion reports reduced hormone binding and demonstrates that FKBP51 delays GR nuclear translocation. But it describes impaired translocation as an additional effect: the 'FKBP51 Inhibits Nuclear Translocation of GR' section finds a delay even at saturating hormone concentrations, when the binding-affinity effect is excluded. The claim's implication that reduced binding causes the translocation delay is therefore too broad. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
PremisecitationEarly abuse induced demethylation in the presence of the FKBP5 risk allele was demonstrated for three of the sites (3 to 5) in adult peripheral blood.
“Early abuse induced demethylation in the presence of the FKBP5 risk allele was demonstrated for three of the sites (3 to 5) in adult peripheral blood (38).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [38] Klengel, 2013, Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions, Nat Neurosci source
May combine two claims.
InterpretationreasoningEpigenetic effects in maternal or paternal gametes are a potential explanation for epigenetic effects in offspring, but blood samples will not permit ascertainment of gamete-dependent transmission.
“Epigenetic effects in maternal or paternal gametes are a potential explanation for epigenetic effects in offspring (10-13), but blood samples will not permit ascertainment of gamete-dependent transmission.”
Quote in the paperNot a substantial claim3 of 4 sources checked- cites [10] Dias, 2014, Parental olfactory experience influences behavior and neural structure in subsequent generations, Nat Neurosci source
- cites [11] Zaidan, 2013, Prereproductive stress to female rats alters corticotropin releasing factor type 1 expression in ova and behavior and brain corticotropin releasing factor type 1 expression in offspring, Biol Psychiatry source
- cites [12] Franklin, 2010, Epigenetic transmission of the impact of early stress across generations, Biol Psychiatry source
- cites [13] Rodgers, 2013, Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation, J Neurosci source
Classified as probably not a substantial claim.
PremisecitationFKBP5 single nucleotide polymorphisms interact with early trauma to predict both PTSD and major depression.
“FKBP5 single nucleotide polymorphisms have additionally been shown to interact with early trauma to predict both PTSD and major depression (36,37), possibly through involvement of allelespecific, environmentally dependent changes in methylation of specific cytosine-phosphate-guanine (CpG) sites (38).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [36] Binder, 2008, Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults, JAMA source
The COMMENT reports that FKBP5 SNPs interacted with child abuse to predict adult PTSD symptoms. The “FKBP5 and Child Abuse Interaction” section reports no significant genotype-by-child-abuse interaction for depression outcome after correction for multiple testing. This source therefore supports the PTSD part, but not the claim about major depression. (LLM, conf=0.90)
Experimental — accuracy not yet measured - cites [37] Koenen, 2010, FKBP5 polymorphisms modify the effects of childhood trauma, Neuropsychopharmacology source
The main text reports that FKBP5 SNP rs9470080 interacted with childhood adversity to predict PTSD risk in African-American participants; the interaction was not significant in European Americans. It does not report an FKBP5–early-trauma interaction predicting major depression. The depression study listed in the References concerns CRHR1, not FKBP5. (LLM, conf=0.87)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationAlterations of FKBP5 have been associated with both PTSD and intergenerational effects.
“alterations of which have been associated with both PTSD and intergenerational effects (27,28).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [27] Lehrner, 2014, Maternal PTSD associates with greater glucocorticoid sensitivity in offspring of Holocaust survivors, Psychoneuroendocrinology source
The Results report an association between maternal PTSD and offspring glucocorticoid sensitivity, and the Discussion considers possible intergenerational mechanisms. Neither section identifies FKBP5 or links alterations of it to PTSD or intergenerational effects (searched: FKBP5 and FK506-binding protein 5). (LLM, conf=0.72)
Experimental — accuracy not yet measured - cites [28] Daskalakis, 2013, Endocrine aspects of post-traumatic stress disorder and implications for diagnosis and treatment, Endocrinol Metab Clin North Am source
May combine two claims.
PremisecitationIntron 7 sites are located within, or in proximity to, functional consensus glucocorticoid response elements and are demethylated by glucocorticoids, particularly during developmentally sensitive periods.
“Intron 7 sites are located within, or in proximity to, functional consensus glucocorticoid response elements (GREs) and are demethylated by glucocorticoids, particularly during developmentally sensitive periods (38).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [38] Klengel, 2013, Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions, Nat Neurosci source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationFKBP5 gene expression has been shown to be altered in PTSD and major depression.
“FKBP5 gene expression has been shown to be altered in PTSD and major depression (32)(33)(34)(35).”
Quote in the paperNot a substantial claim4 of 4 sources checked- cites [32] Menke, 2013, Genetic variation in FKBP5 associated with the extent of stress hormone dysregulation in major depression, Genes Brain Behav source
- cites [33] Mehta, 2011, Using polymorphisms in FKBP5 to define biologically distinct subtypes of posttraumatic stress disorder: Evidence from endocrine and gene expression studies, Arch Gen Psychiatry source
The Results and Comment sections report genotype-dependent changes in FKBP5 expression associated with PTSD symptoms, including a replicated association. The passages do not report altered FKBP5 expression in major depression, so this source supports only the PTSD part of the claim. Page numbers were not provided in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [34] Sarapas, 2011, Genetic markers for PTSD risk and resilience among survivors of the World Trade Center attacks, Dis Markers source
The genetic analysis (§3.3; page unavailable) links lower FKBP5 expression to greater PTSD symptom severity. The Discussion (§4; page unavailable) does not establish altered FKBP5 gene expression in major depression: it reports that a depression-associated genotype was not related to FKBP5 mRNA expression, although it was associated with higher protein levels. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [35] Yehuda, 2009, Gene expression patterns associated with posttraumatic stress disorder following exposure to the World Trade Center attacks, Biol Psychiatry source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationFor the NR3C1 gene, associations of individual sites with exposures to several types of adversity are increasingly recognized.
“Indeed, for the NR3C1 gene, associations of individual sites with exposures to several types of adversity are increasingly recognized (52).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [52] Daskalakis, 2014, Site-specific methylation changes in the glucocorticoid receptor exon 1F promoter in relation to life adversity: Systematic review of contributing factors, Front Neurosci source
May combine two claims.
Findingown dataHolocaust survivors and their offspring have methylation changes on the same site in a functional intronic region of the FKBP5 gene, a GR-binding sequence in intron 7, but in the opposite direction.
“The main finding in this study is that Holocaust survivors and their offspring have methylation changes on the same site in a functional intronic region of the FKBP5 gene, a GR-binding sequence in intron 7, but in the opposite direction.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataNeither parental PTSD nor the presence of the FKBP5 risk allele contributed to the model predicting offspring bin 3/site 6 methylation.
“Neither parental PTSD (β 5 .134,ns) nor the presence of the FKBP5 risk allele (β 5 2.044, ns) contributed to the model.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataEmotional abuse was not significantly associated with bin 3/site 6 methylation and did not alter the significance of Holocaust exposure at this site.
“However, like the CTQ total score, emotional abuse was not significantly associated with bin 3/site 6 methylation (β 5 .018,ns) and did not alter the significance of Holocaust exposure at this site (β 5 2.375, p 5 .045).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAdding childhood adversity as measured by the CTQ total score did not alter the predictive significance of parental exposure and was not a predictor of bin 3/site 6 methylation.
“Adding childhood adversity as measured by the CTQ total score did not alter the predictive significance of parental exposure (β 5 2.359, p 5 .049)and was not a predictor of bin 3/site 6 methylation (β 5 2.034, ns).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe intergenerational transmission of epigenetic effects at bin 3/site 6 does not appear to be mediated by childhood adversity, as is the case for bin 2.
“The mechanism of intergenerational transmission of epigenetic effects at bin 3/site 6 is not known but does not appear to be mediated by childhood adversity, as is the case for bin 2.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBin 2/sites 3 to 5 methylation was associated with offspring trauma exposure (childhood physical and sexual abuse), but the direction depended on the presence of the FKBP5 risk allele.
“In contrast to the findings at bin 3/site 6, which relate to parental exposure, bin 2/sites 3 to 5 methylation was associated with offspring trauma exposure (childhood physical and sexual abuse), but the direction depended on the presence of the FKBP5 risk allele.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingnone givenMean CTQ subscale and total scores for the Holocaust offspring were generally lower than reported in other population samples.
“It should be noted that mean CTQ subscale and total scores for the Holocaust offspring were generally lower than reported in other population samples”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationParental trauma exposure is associated with greater risk for PTSD and mood and anxiety disorders in offspring.
“Parental trauma exposure is associated with greater risk for posttraumatic stress disorder (PTSD) and mood and anxiety disorders in offspring (1,2).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
Study design and conductown dataThe finding of lower bin 3/site 6 methylation in Holocaust offspring was unchanged without covariation and when presence of lifetime PTSD in offspring or severity of childhood trauma were added as additional covariates.
“The finding was unchanged without covariation (F 1,29 5 4.91, p 5 .035)and when presence of lifetime PTSD in offspring (p 5 .036)or severity of childhood trauma (p 5 .049)were added, respectively, as additional covariates.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataBin 3/site 6 methylation could not be attributed to the offspring's own trauma exposure, their own psychopathology, or other examined characteristics that might independently affect methylation of this gene.
“Bin 3/site 6 methylation was not associated with the FKBP5 risk allele and could not be attributed to the offspring's own trauma exposure, their own psychopathology, or other examined characteristics that might independently affect methylation of this gene.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn the aforementioned study, the increase in offspring 11β-HSD-2 activity was interpreted as a protective adaptation to mitigate exposure to elevated maternal glucocorticoids associated with reduced maternal 11β-HSD-2 activity.
“in the aforementioned study, the increase in offspring 11β-HSD-2 activity was interpreted as a protective adaptation to mitigate exposure to elevated maternal glucocorticoids associated with reduced maternal 11β-HSD-2 activity (20,50).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [20] Bierer, 2014, Elevation of 11beta-hydroxysteroid dehydrogenase type 2 activity in Holocaust survivor offspring: Evidence for an intergenerational effect of maternal trauma exposure, Psychoneuroendocrinology source
- cites [50] Yehuda, 2011, Minireview: Stress-related psychiatric disorders with low cortisol levels: A metabolic hypothesis, Endocrinology source
May combine two claims.
Interpretationown dataThe addition of presence/absence of the FKBP5 risk allele as a covariate did not appreciably alter the finding, suggesting that bin 3/site 6 methylation changes in F0 were driven more by exposure than genetic variation in this single nucleotide polymorphism.
“The addition of presence/absence of the FKBP5 risk allele as a covariate did not appreciably alter the finding (p 5 .053),suggesting that bin 3/site 6 methylation changes in F0 were driven more by exposure than genetic variation in this single nucleotide polymorphism.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationWe previously reported a directional difference between parents and offspring in 11β-HSD-2 activity, which was interpreted as an accommodation in the offspring during a sensitive developmental window to the biological consequences of parental trauma exposure.
“We previously reported a directional difference between parents and offspring in 11β-HSD-2 activity, which was interpreted as an accommodation in the offspring during a sensitive developmental window to the biological consequences of parental trauma exposure (20).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] Bierer, 2014, Elevation of 11beta-hydroxysteroid dehydrogenase type 2 activity in Holocaust survivor offspring: Evidence for an intergenerational effect of maternal trauma exposure, Psychoneuroendocrinology source
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenLike FKBP5, 11β-HSD-2 is a moderator of glucocorticoid action.
“Like FKBP5, 11β-HSD-2 is a moderator of glucocorticoid action”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationreasoningThe directional difference in bin 3/site 6 methylation between Holocaust survivors and their offspring was unexpected but may reflect an intergenerational biological accommodation.
“The directional difference in bin 3/site 6 methylation between Holocaust survivors and their offspring was unexpected but may reflect an intergenerational biological accommodation.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationFKBP5 gene expression is regulated by GR binding, forming an intracellular ultrashort glucocorticoid negative-feedback loop that regulates FKBP5 and GR.
“In turn, FKBP5 gene expression is regulated by GR binding, forming an intracellular ultrashort glucocorticoid negative-feedback loop that regulates FKBP5 and GR (26,31).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [26] Binder, 2009, The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders, Psychoneuroendocrinology source
- cites [31] Jaaskelainen, 2011, Steroid up-regulation of FKBP51 and its role in hormone signaling, Curr Opin Pharmacol source
May combine two claims.
Study design and conductown dataThere were no significant differences between Holocaust survivor and comparison groups in age, gender, years of education, current anxiety or mood disorder diagnoses, or frequency of the FKBP5 risk allele.
“There were no significant differences between the groups in age, gender, years of education, current anxiety or mood disorder diagnoses, or frequency of the FKBP5 risk allele.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductown dataThere were no significant differences between Holocaust offspring and comparison groups in age, gender, years of education, childhood trauma scores, psychiatric diagnoses, frequency of the FKBP5 risk allele, or cortisol levels.
“There were no significant differences between the groups in age, gender, years of education, childhood trauma scores, psychiatric diagnoses, frequency of the FKBP5 risk allele, or cortisol levels.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe effect of Holocaust offspring status on bin 3/site 6 methylation was reduced when controlling for parental PTSD, suggesting an influence of parental PTSD symptoms.
“In contrast, the effect was reduced when controlling for parental PTSD (F 1,23 5 2.59, p 5 .121),suggesting an influence of parental PTSD symptoms.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataGenotypes of rs1360780 were in Hardy-Weinberg equilibrium.
“Genotypes of rs1360780 were in Hardy-Weinberg equilibrium (p ..05).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationEven within the same cell type, observed global changes reflect diverse changes in single cells.
“In addition, even within the same cell type, observed global changes reflect diverse changes in single cells, as has been reported in a number of articles using clone-based sequencing for methylation analysis [for example (16,17,54)].”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [16] Weaver, 2004, Epigenetic programming by maternal behavior, Nat Neurosci source
- cites [17] Murgatroyd, 2009, Dynamic DNA methylation programs persistent adverse effects of early-life stress, Nat Neurosci source
- cites [54] Yehuda, 2015, Lower methylation of glucocorticoid receptor gene promoter 1F in peripheral blood of veterans with posttraumatic stress disorder, Biol Psychiatry source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll F1 participants were raised by their biological parents.
“All F1 participants were raised by their biological parents.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataThe intra-assay and interassay coefficients of variation for cortisol were 2.3% and 6.1%, respectively.
“The intra-assay and interassay coefficients of variation were 2.3% and 6.1%, respectively.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
A major gap in the clinical literature is that parents and their adult offspring have not been studied in tandem, making it difficult to understand the origin of changes in association with parental exposure.
“A major gap in the clinical literature is that parents and their adult offspring have not been studied in tandem, making it difficult to understand the origin of changes in association with parental exposure.”
The paper relies on this without support.
What can be detected in blood samples is parental and offspring experience-dependent epigenetic modifications.
“What can be detected in blood samples is parental and offspring experience-dependent epigenetic modifications.”
The paper relies on this without support.
The observed associations between parental Holocaust exposure and offspring FKBP5 methylation reflect intergenerational transmission of epigenetic effects rather than preconception or postnatal influences or offspring recalibration of glucocorticoid regulation.
“At present, it is not clear whether glucocorticoid programming in offspring reflects intergenerational consequences of parental exposure or offspring recalibration of glucocorticoid regulation.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
This finding tends to contradict previous findings where FKBP5 methylation has been associated with PTSD.
“This finding tends to contradict previous findings where FKBP5 methylation has been associated with PTSD (e.g., Yehuda et al., 2016;Methal et al., 2019).”
From DNA methylation of NR3C1 and FKBP5 is associated with posttraumatic stress disorder, posttraumatic growth, and resilience. (2020) · cites this paper as Yehuda et al., 2016
The Results section on Holocaust survivors and F0 comparison subjects (page unavailable) reports no significant main effect of PTSD diagnosis on FKBP5 intron 7 methylation. It attributes the observed methylation difference primarily to Holocaust exposure, rather than PTSD diagnosis. (LLM, conf=0.86)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredAcross survivor populations and their descendants, research suggests coordinated involvement of stress-response regulation, neurodevelopmental signaling, and behavioral adaptation.
“Across survivor populations and their descendants, research suggests coordinated involvement of stress-response regulation, neurodevelopmental signaling, and behavioral adaptation (7, 82–100).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [83]
The paper’s concluding discussion reports intergenerational changes in FKBP5 methylation relevant to stress regulation and proposes that they could facilitate stress adaptation. Its introductory discussion also describes behavioral responses and possible biological accommodation in offspring. It does not establish coordinated neurodevelopmental signaling and behavioral adaptation in the survivor populations and descendants studied. (LLM, conf=0.83)
Experimental — accuracy not yet measuredStudies of Holocaust survivors and their offspring demonstrate differential DNA methylation of key HPA-axis genes, including NR3C1 and FKBP5, corresponding with variation in glucocorticoid receptor sensitivity and cortisol feedback regulation.
“Studies of Holocaust survivors and their offspring demonstrate differential DNA methylation of key HPA-axis genes, including NR3C1 and FKBP5, corresponding with variation in glucocorticoid receptor sensitivity and cortisol feedback regulation (82, 83).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [83]
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 measuredVariation in FKBP5 methylation across intronic regions has been reported, with opposite directional patterns in survivors and their offspring, corresponding with differences in FKBP5 expression and glucocorticoid receptor sensitivity.
“Variation in FKBP5 methylation across intronic regions has also been reported, with opposite directional patterns observed in survivors and their offspring, corresponding with differences in FKBP5 expression and glucocorticoid receptor sensitivity (83, 84).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [83]
The intron 7 methylation results report higher methylation at bin 3/site 6 in Holocaust survivors and lower methylation at that site in their offspring, each relative to controls (pages unavailable). The Discussion links methylation to FKBP5 expression and glucocorticoid receptor sensitivity, but treats those functional implications as inferred or conceivable, not as measured differences between these groups. This study examined sites within intron 7, not variation across multiple introns. (LLM, conf=0.86)
Experimental — accuracy not yet measuredFKBP5 methylation differences have been reported across multiple trauma contexts in both survivors and offspring, raising the possibility that stress-response regulatory genes may help distinguish individuals more likely to benefit from specific interventions.
“FKBP5 methylation differences have been reported across multiple trauma contexts in both survivors and offspring, raising the possibility that stress-response regulatory genes may help distinguish individuals more likely to benefit from specific interventions (38, 66, 83, 84, 136).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [83]
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 measured
A substantial proportion of studies have focused on a limited number of stress-response genes, most notably FKBP5 and NR3C1.
“A substantial proportion of studies have focused on a limited number of stress-response genes, most notably FKBP5 and NR3C1 (55, 65, 83, 84, 121, 129).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [83]
The paper says “We focused on FKBP5” (SEE COMMENTARY ON PAGE section), so it is an example of a study centered on a stress-response gene. It also discusses research on NR3C1 (Holocaust Exposure and Intergenerational FKBP5 Methylation section). As an individual study, it does not establish that a substantial proportion of studies focus on a limited set of genes. (LLM, conf=0.84)
Experimental — accuracy not yet measuredA preliminary study examining FKBP5 intron 7 methylation in Holocaust survivors and their children demonstrated alterations at the same site within intron 7 in both parents and their children, with no specific consideration of parental gender or PTSD.
“For example, a preliminary study examining FKBP5 intron 7 methylation in Holocaust survivors and their children demonstrated alterations at the same site within intron 7 in both parents and their children, with no specific consideration of parental gender or PTSD 127 .”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [127]
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 measuredIn 32 Holocaust survivors and their 22 adult offspring compared to eight non-exposed control parents and their nine children, parental Holocaust exposure was found to predict FKBP5 intron 7 methylation in offspring.
“In 32 Holocaust survivors and their 22 adult offspring compared to eight non-exposed control parents and their nine children, parental Holocaust exposure was found to predict FKBP5 intron 7 methylation in offspring.”
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 Yehuda et al., 2016
Methylation of the third GRE in intron 7 was positively correlated with methylation at the same site in their offspring and overall average methylation of intron 7 was negatively correlated with wake-up cortisol.
“Methylation of the third GRE in intron 7 was further positively correlated with methylation at the same site in their offspring and overall average methylation of intron 7 was negatively correlated with wake-up cortisol”
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 Yehuda et al., 2016
Offspring carrying the FKBP5 rs1360780 A risk allele showed a significant negative correlation between the degree of physical and sexual childhood abuse and CpG methylation across the first GRE in intron 7, while G/G genotype carriers displayed a positive correlation.
“Furthermore, offspring carrying the FKBP5 rs1360780 A risk allele showed a significant negative correlation between the degree of physical and sexual childhood abuse and CpG methylation across the first GRE in intron 7, while G/G genotype carriers displayed a positive correlation”
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 Yehuda et al., 2016
Increased whole blood CpG methylation was observed in the third GRE of FKBP5 intron 7 in Holocaust survivors compared to contemporary Jewish controls, while children of Holocaust survivors were characterized by decreased methylation compared to control children.
“Of note, increased whole blood CpG methylation was observed in the third (of a total of three) GRE of FKBP5 intron 7 in Holocaust survivors compared to contemporary Jewish controls, while children of Holocaust survivors were characterized by decreased methylation compared to control children”
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 Yehuda et al., 2016
Potential epigenetic effects in maternal or paternal gametes could not be investigated in the Holocaust study.
“Potential epigenetic effects in maternal or paternal gametes could not, however, be investigated.”
Exposed Holocaust parents had an average of 10% higher FKBP5 methylation compared to unexposed, while exposed offspring had 7.7% lower methylation.
“Exposed parents had an average of 10% higher methylation compared to unexposed, while exposed offspring had 7.7% lower methylation.”
In the Holocaust study, Yehuda and colleagues controlled for current PTSD, childhood trauma in the offspring, and genetic variation in the gene.
“In their analysis, Yehuda and colleagues also controlled for current PTSD (51.6% of the Holocaust-exposed parents), childhood trauma in the offspring, or genetic variation in the gene.”
Holocaust exposure was associated with blood DNA methylation of the FKBP5 gene at the same transcriptionally active site in both generations, although in opposing directions.
“Holocaust exposure was associated with blood DNA methylation of the FKBP5 gene at the same transcriptionally active site in both generations, although interestingly in opposing directions.”
The majority of studies looked at only maternal transmission, four considered both maternal and paternal, and two focused only on fathers.
“The majority of the studies looked at only maternal transmission, but four considered both maternal and paternal [83,94,95,102], and two focused only on fathers [97,104].”
Of the five studies that measured FKBP5 DNA methylation, three found lower methylation in the offspring of exposed parents, one found higher methylation, and another reported no association.
“Of the five studies that measured FKBP5 DNA methylation, three found lower methylation in the offspring of exposed parents [83,94,99], one found an opposite association with higher methylation [103], and another reported no association [88].”
There were six studies of trauma or PTSD following war, including two studies of Holocaust survivors, two on the Rwandan genocide, one from the Kosovo War, and one of Vietnam veterans.
“There were six studies of trauma or PTSD following war, including two studies of Holocaust survivors [83,94,95], two studies on the Rwandan genocide [90,91], and one each from the Kosovo War [96] and Vietnam veterans [97].”
Holocaust offspring showed lower methylation at this site compared to demographically-matched controls, and Holocaust survivors demonstrated higher methylation compared to respective controls.
“However, interestingly, they were directionally distinct (when compared to their respective control groups), with Holocaust offspring showing lower methylation at this site compared to demographically-matched controls, and Holocaust survivors demonstrating higher methylation compared to respective controls.”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [127]
FKBP5 methylation in parents and their children were positively correlated.
“FKBP5 methylation in parents and their children were positively correlated.”
From Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms (2018) · cites this paper as [127]
Narrow locus selection risks overemphasizing the importance of specific genes while overlooking broader regulatory networks.
“While hypothesis-driven candidate gene studies can provide mechanistic insight, narrow locus selection risks overemphasizing the importance of specific genes while overlooking broader regulatory networks (83, 84, 121, 129).”
From Epigenetic changes associated with multi-generational trauma: characterization, mechanisms, and therapeutics (2026) · cites this paper as [83]
The Methods and Figure 1 passages describe a targeted analysis of FKBP5 intron 7, but do not say that narrow locus selection overemphasizes particular genes or overlooks broader regulatory networks. Additional searches for candidate-gene limitations and other genes or pathways found no passage making that point. The indexed passages provide no page numbers. (LLM, conf=0.74)
Experimental — accuracy not yet measuredMultiple human studies have indicated that traumas such as combat exposure, forced displacement, genocide exposure, and low maternal bonding may be passed on inter-generationally, and have been associated with both psychopathology in children and DNA methylation in the FKBP5 gene.
“Multiple human studies have indicated that traumas such as combat exposure, forced displacement, genocide exposure, and low maternal bonding may be passed on inter-generationally, and have been associated with both psychopathology in children and DNA methylation in the FKBP5 gene.45,46”
From The role of epigenetics in psychological resilience (2021) · cites this paper as [46]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Control offspring trauma total does not match its subscales
MinorThe five listed mean trauma subscale scores for comparison offspring sum to 35.6, not the reported total mean of 30.2. The gap exceeds what rounding the subscale means could explain.
Reported 30.2 · recomputed 35.6
“| Total score | 36.7 6 11.5 | 30.2 6 6.9 | F 1,30 5 2.46, ns |”
Emotional-abuse direction conflicts with the table
MinorThe discussion of this sample implies greater emotional abuse among Holocaust offspring, whereas Table 2 lists a lower mean for them than for comparison offspring.
“Since emotional abuse is reported substantially more often by Holocaust survivor offspring (25) and was reported in this sample at a trend level of significance (t 5 21.98, df 5 24.89, p 5 .059),we tested emotional abuse in the regression model.”
“| Emotional abuse | 9.0 6 5.4 | 12.0 6 3.3 | F 1,30 5 2.57, ns |”
A predictor is called significant at p = .054
MinorThe paper sets significance at p < .05 but describes parental exposure as remaining significant in a model where its reported p-value is .054.
“In each of these, however, parental exposure remained a significant predictor (respectively, β 5 2.461, p 5 .054;β 5 2.362, p 5 .043).”
“Finally, statistical significance for all analyses was set at two-tailed, p , .05.”
Offspring anxiety diagnosis differs significantly in the table
MinorThe text says psychiatric diagnoses did not differ between offspring groups, but Table 2 reports a significant difference for current anxiety disorder.
“There were no significant differences between the groups in age, gender, years of education, childhood trauma scores, psychiatric diagnoses, frequency of the FKBP5 risk allele, or cortisol levels.”
“| Current Anxiety Disorder (except PTSD) d | 8 (36.4%) | 0 (0%) | χ 2 1 5 6.56, p 5 .041 |”
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Self-citationFKBP51 and FKBP52 in signaling and disease
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Epigenetic mechanisms underlying learning and the inheritance of learned behaviors
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Self-citationMaternal Exposure to the Holocaust and Health Complaints in Offspring
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Self-citationFKBP51 regulation of AKT/protein kinase B phosphorylation
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Self-citation- Self-citation
Erratum: Dynamic DNA methylation programs persistent adverse effects of early-life stress
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Intergenerational transmission of trauma effects: putative role of epigenetic mechanisms
Yehuda, R., & Lehrner, A. (2018) · World Psychiatry · doi:10.1002/wps.20568 · Cited by 730 · see citing works
Self-citationIntergenerational Transmission of Stress in Humans
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“For instance, Holocaust survivors exhibited inverse 11β-HSD2 activity and FKBP5 methylation compared with their offspring (Yehuda et al, 2009; Bierer et al, 2014; Yehuda et al, 2015).”
BackgroundSelf-citationA paradigm shift: relationships in trauma-informed mental health services
Sweeney, A., Filson, B., Kennedy, A., Collinson, L., & Gillard, S. (2018) · BJPsych Advances · doi:10.1192/bja.2018.29 · Cited by 531 · see citing works
Racial trauma: theory, research, and healing: introduction to the special issue
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Functions and mechanisms of epigenetic inheritance in animals
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Sex Differences in Vulnerability and Resilience to Stress Across the Life Span
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“Most notably a study on the offspring of Holocaust survivors identified altered methylation status of the gene encoding FK506 binding protein, a regulator of glucocorticoid receptor sensitivity, in blood (54).”
BackgroundNeurobiology of BDNF in fear memory, sensitivity to stress, and stress-related disorders
Notaras, M. J., & van den Buuse, M. (2020) · Molecular Psychiatry · doi:10.1038/s41380-019-0639-2 · Cited by 395 · see citing works
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Self-citationBiological embedding of experience: a primer on epigenetics
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Self-citationParental Advisory: Maternal and Paternal Stress Can Impact Offspring Neurodevelopment
Chan, J. C., Nugent, B. M., & Bale, T. L. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.10.005 · Cited by 241 · see citing works
“Studies in children whose mothers survived the Holocaust suggest that one mechanism whereby maternal preconception stress may affect future generations is via alterations in DNA methylation of stress regulatory genes, such as FKBP5 and GR, which results in enhanced HPA stress axis sensitivity (73,74).”
BackgroundThe hypothalamic-pituitary-adrenal axis in PTSD: Pathophysiology and treatment interventions
Dunlop, B. W., & Wong, A. (2018) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2018.10.010 · Cited by 245 · see citing works
Epigenetics at the crossroads between genes, environment and resilience in anxiety disorders
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Self-citationPrenatal stress and epigenetics
Cao-Lei, L., de Rooij, S. R., King, S., Matthews, S. G., Metz, G. A. S., Roseboom, T. J., & Moshe Szyf, A. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.05.016 · Cited by 230 · see citing works
Dashorst, P., Mooren, T. M., Kleber, R. J., de Jong, P. J., & Huntjens, R. J. C. (2019) · European Journal of Psychotraumatology · doi:10.1080/20008198.2019.1654065 · Cited by 207 · see citing works
“The study by Yehuda et al. (2016) demonstrated methylation changes (large effect sizes) at the FKBP-5 gene, in the opposite direction, survivors had significantly higher and HSO significantly lower methylation.”
BackgroundInfluentialNindl, B. C., Billing, D. C., Drain, J. R., Beckner, M. E., Greeves, J. P., Groeller, H., Teien, H. K., Marcora, S., Moffitt, A., Reilly, T. J., et al. (2018) · Journal of science and medicine in sport · doi:10.1016/j.jsams.2018.05.005 · Cited by 195 · see citing works
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Stress, female reproduction and pregnancy
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Marzi, S. J., Sugden, K., Arseneault, L., Belsky, D. W., Burrage, J., Corcoran, D. L., Danese, A., Fisher, H. L., Hannon, E., Moffitt, T. E., et al. (2018) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2017.17060693 · Cited by 163 · see citing works
“Under the label of “adversity,” studies have focused on a diverse mix of exposures spanning maternal psychiatric disease (13), early parental loss (14), institutionalization (15), indentured child labor (16), child abuse (17), and the Holocaust (18).”
BackgroundMy grandmother’s hands: racialized trauma and the pathway to mending our hearts and bodies
Jehangir, A. (2021) · Social Work Education · doi:10.1080/02615479.2021.1976760 · Cited by 169 · see citing works
Epigenetic programming by stress and glucocorticoids along the human lifespan
Zannas, A. S., & Chrousos, G. P. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.35 · Cited by 158 · see citing works
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Losing DNA methylation at repetitive elements and breaking bad
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Post‐traumatic stress disorder and beyond: an overview of rodent stress models
Schöner, J., Heinz, A., Endres, M., Gertz, K. R., & Kronenberg, G. (2017) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.13161 · Cited by 150 · see citing works
Paternal grandfather’s access to food predicts all-cause and cancer mortality in grandsons
Vågerö, D., Pinger, P. R., Aronsson, V., & van den Berg, G. J. (2018) · Nature Communications · doi:10.1038/s41467-018-07617-9 · Cited by 150 · see citing works
Recent Genetics and Epigenetics Approaches to PTSD
Daskalakis, N. P., Rijal, C. M., King, C. D., Huckins, L. M., & Ressler, K. J. (2018) · Current Psychiatry Reports · doi:10.1007/s11920-018-0898-7 · Cited by 146 · see citing works
Self-citationThe epigenetic impacts of social stress: how does social adversity become biologically embedded?
Cunliffe, V. T. (2016) · Epigenomics · doi:10.2217/epi-2016-0075 · Cited by 141 · see citing works
The Role of Mindfulness in Reducing the Adverse Effects of Childhood Stress and Trauma
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“Remarkably, such epigenetic modifications may carry across generations, as identified in the glucocorticoid receptor related gene FKBP5 of holocaust survivors also found in their offspring [15].”
BackgroundTransgenerational epigenetics of traumatic stress
Jawaid, A., Roszkowski, M., & Mansuy, I. M. (2018) · Progress in Molecular Biology and Translational Science · doi:10.1016/bs.pmbts.2018.03.003 · Cited by 134 · see citing works
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“received considerable theoretical interest, and recent research suggests this possibility (Yehuda et al., 2016).”
Scorza, P., Duarte, C. S., Hipwell, A. E., Posner, J. E., Ortin‐Peralta, A., CANINO, G. J., Monk, C. E., & Outcomes, P. C. F. E. I. O. C. H. (2018) · Journal of Child Psychology and Psychiatry · doi:10.1111/jcpp.12877 · Cited by 135 · see citing works
Pluripotent stem cells in neuropsychiatric disorders
Soliman, M. A., Aboharb, F., Zeltner, N., & Studer, L. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.40 · Cited by 129 · see citing works
Trauma across generations and paths to adaptation and resilience
Lehrner, A., & Yehuda, R. (2018) · Psychological Trauma: Theory, Research, Practice, and Policy · doi:10.1037/tra0000302 · Cited by 129 · see citing works
Self-citationYoussef, N. A., Lockwood, L., Su, S., Hao, G., & Rutten, B. P. F. (2018) · Brain Sciences · doi:10.3390/brainsci8050083 · Cited by 125 · see citing works
“[17] study, the DNA methylation seen in the offspring was noted to be opposite from that seen in their parents.”
BackgroundGassen, N. C., Chrousos, G. P., Binder, E. B., & Zannas, A. S. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.06.003 · Cited by 124 · see citing works
“Furthermore, studies in human cohorts show that life stressrs, especially early in development, can induce lasting changes in NA methylation, both at specific candidate loci as well as on a enome-wide level (Boks et al., 2015; Brody et al., 2016a, 2016b; lengel et al., 2013; McGowan et al., 2009; Non et al., 2014; Per…”
BackgroundSelf-citationCultural trauma as a fundamental cause of health disparities
Subica, A. M., & Link, B. G. (2022) · Social Science & Medicine · doi:10.1016/j.socscimed.2021.114574 · Cited by 123 · see citing works
“, depression, metabolic syndrome, cardiovascular disease)(Bierer et al., 2014; Darity et al., 2001; Heckman and Payner, 1989; Yehuda et al., 2016).”
Tyrka, A. R., Ridout, K. K., & Parade, S. H. (2016) · Development and Psychopathology · doi:10.1017/s0954579416000870 · Cited by 119 · see citing works
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Glucocorticoids as Mediators of Adverse Outcomes of Prenatal Stress
Krontira, A. C., Cruceanu, C., & Binder, E. B. (2020) · Trends in Neurosciences · doi:10.1016/j.tins.2020.03.008 · Cited by 115 · see citing works
Self-citationMatheson, K., Foster, M. D., Bombay, A., McQuaid, R. J., & Anisman, H. (2019) · The International Journal of Ecopsychology (IJE) · doi:10.3389/fpsyg.2019.00416 · Cited by 111 · see citing works
“For example, religious beliefs might enable individuals to find meaning in their traumatic experiences (God’s will) and thereby protect against the negative effects on mental health (Ysseldyk et al., 2011).”
The role of epigenetics in psychological resilience
Smeeth, D., Beck, S., Karam, E. G., & Pluess, M. (2021) · The Lancet Psychiatry · doi:10.1016/s2215-0366(20)30515-0 · Cited by 108 · see citing works
Non, A. L., Hollister, B. M., Humphreys, K. L., Childebayeva, A., Esteves, K. C., Zeanah, C. H., Fox, N. A., Nelson, C. A., & Drury, S. S. (2016) · American Journal of Physical Anthropology · doi:10.1002/ajpa.23010 · Cited by 107 · see citing works
“In contrast, increased DNA methylation at intron 7 has been observed at multiple CpG sites in FKBP5 in Holocaust survivors, although lower methylation was observed in their offspring, suggesting an inter-generational biological accommodation of trauma at this gene (Yehuda et al., 2015).”
BackgroundEpigenetics as a Driver of Developmental Origins of Health and Disease: Did We Forget the Fathers?
Soubry, A. (2017) · BioEssays · doi:10.1002/bies.201700113 · Cited by 108 · see citing works
“Yehuda et al., 2016[73] Retrospective cohort 31 Holocaust offspring, 9 Jewish US citizens (demographically matched) USA Feinberg et al., 2015[93] Cohort 44 fathers with at least one autistic child 4 sites, US Northstone et al., 2014[62] Birth cohort 9886 fathers Avon, UK Soubry et al., 2013[65]…”
BackgroundDaskalakis, N. P., Cohen, H., Nievergelt, C. M., Baker, D. G., Buxbaum, J. D., Russo, S. J., & Yehuda, R. (2016) · Experimental Neurology · doi:10.1016/j.expneurol.2016.07.024 · Cited by 105 · see citing works
Self-citationGlucocorticoid receptor DNA methylation, childhood maltreatment and major depression
Bustamante, A. C., Aiello, A. E., Galea, S., Ratanatharathorn, A., Noronha, C., Wildman, D. E., & Uddin, M. (2016) · Journal of Affective Disorders · doi:10.1016/j.jad.2016.07.038 · Cited by 104 · see citing works
“Similar binning approaches have been applied to analyses of stress-related effects on other HPA axis genes, in which functionally distinct regions are grouped together in bins (e.g. FKBP5; (Klengel et al., 2013; Yehuda et al., 2015).”
MethodIntergenerational transmission of DNA methylation signatures associated with early life stress
Stenz, L., Schechter, D. S., Serpa, S. R., & Paoloni-Giacobino, A. (2018) · Current Genomics · doi:10.2174/1389202919666171229145656 · Cited by 101 · see citing works
“Interestingly, FKBP5 has been reported to interact with NR3C1 as a co-chaperone of the glucocorticoid receptor complex [82].”
BackgroundGlucocorticoids and Hippocampal Structure and Function in PTSD
Szeszko, P. R., Lehrner, A. L., & Yehuda, R. (2018) · Harvard Review of Psychiatry · doi:10.1097/hrp.0000000000000188 · Cited by 105 · see citing works
Self-citationAbnormal Epigenetic Regulation of Immune System during Aging
Jasiulionis, M. G. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00197 · Cited by 100 · see citing works
Intergenerational Mobility and Equality of Opportunity
Torche, F. (2015) · European Journal of Sociology · doi:10.1017/s0003975615000181 · Cited by 94 · see citing works
Impact of Parental Exposure on Offspring Health in Humans
Jawaid, A., Jehle, K.-L., & Mansuy, I. M. (2020) · Trends in Genetics · doi:10.1016/j.tig.2020.10.006 · Cited by 103 · see citing works
Jablonka, E. (2016) · The Sociological Review · doi:10.1111/2059-7932.12012 · Cited by 98 · see citing works
“…regulator of GR-sensitivity, FKBP5, which have been associated with both PTSD and intergenerational effects, have been demonstrated, showing a direct (inverse) relationship between induced methylation marks in traumatized parents and their descendants’ methylation profile (Yehuda et al., 2015).”
BackgroundPlasticity of the epigenome during early-life stress
Barnett-Burns, S., Szyszkowicz, J. K., Luheshi, G. N., Lutz, P.-É., & Turecki, G. (2017) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2017.09.033 · Cited by 91 · see citing works
Evidence for Stress-like Alterations in the HPA-Axis in Women Taking Oral Contraceptives
Hertel, J., König, J., Homuth, G., der Auwera, S. V., Wittfeld, K., Pietzner, M., Kacprowski, T., Pfeiffer, L., Kretschmer, A., Waldenberger, M., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-13927-7 · Cited by 91 · see citing works
Identification of dynamic glucocorticoid-induced methylation changes at the FKBP5 locus
Wiechmann, T., Röh, S., Sauer, S., Czamara, D., Arloth, J., Ködel, M., Beintner, M., Knop, L., Menke, A., Binder, E. B., et al. (2019) · Clinical Epigenetics · doi:10.1186/s13148-019-0682-5 · Cited by 81 · see citing works
Self-citationA review of epigenetic contributions to post-traumatic stress disorder
Howie, J. H., Rijal, C. M., & Ressler, K. J. (2019) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2019.21.4/kressler · Cited by 95 · see citing works
Intergenerational Effects of Maternal Holocaust Exposure on <i>FKBP5</i> Methylation
Bierer, L. M., Bader, H. N., Daskalakis, N. P., Lehrner, A., Provençal, N., Wiechmann, T., Klengel, T., Makotkine, I., Binder, E. B., & Yehuda, R. (2020) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2019.19060618 · Cited by 86 · 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
Genetics of glucocorticoid regulation and posttraumatic stress disorder -what do we know?
Castro-Vale, I., van Rossum, E. F. C., Machado, J. C., Mota-Cardoso, R., & Carvalho, D. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.02.005 · Cited by 85 · see citing works
Epigenetic legacy of parental experiences: Dynamic and interactive pathways to inheritance
Champagne, F. A. (2016) · Development and Psychopathology · doi:10.1017/s0954579416000808 · Cited by 80 · see citing works
“The persistence across generations of the effects of parental experiences has been demonstrated in humans in studies of famine and trauma exposure (Kaati, Bygren, Pembrey, & Sjostrom, 2007; Yehuda et al., 2015) and may contribute to the observed familial transmission of psychopathology (Oquendo et al.”
BackgroundMorris, G., Berk, M., Maes, M. H. J., Carvalho, A. F., & Puri, B. K. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-1498-1 · Cited by 87 · see citing works
Glucocorticoid Signaling and Epigenetic Alterations in Stress-Related Disorders
Mourtzi, N., Sertedaki, A., & Charmandari, E. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22115964 · Cited by 87 · see citing works
Understanding the epigenetic basis of sex differences in depression
Hodes, G. E., Walker, D. M., Labonté, B., Nestler, E. J., & Russo, S. J. (2016) · Journal of Neuroscience Research · doi:10.1002/jnr.23876 · Cited by 82 · see citing works
“The concept that the experience of stress in one individual can lead to altered stress sensitivity in its offspring is relatively new but has gained substantial traction in recent years (Yuan et al., 2015).”
BackgroundMatosin, N., Cruceanu, C., & Binder, E. B. (2017) · Chronic Stress · doi:10.1177/2470547017710764 · Cited by 84 · see citing works
“Even from the first possible window of stress exposure—in utero—organisms may be susceptible to epigenetic programming which persists into adult life (Table 1(a)).80 In particular, epigenetic differences in key genes that regulate the HPA axis are reported in people exposed to prenatal adversity.80 These effects are h…”
BackgroundSelf-citationThe role of DNA methylation in the pathophysiology and treatment of bipolar disorder
Fries, G. R., Li, Q., McAlpin, B. R., Rein, T., Walss‐Bass, C., Soares, J. C., & Quevedo, J. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.06.010 · Cited by 82 · see citing works
“…measure the so-called ‘non genetic intergenerational transmission’ of DNA methylation patterns over generations (Weber-Stadlbauer et al., 2016; Yehuda et al., 2015), which will in fact demonstrate whether the risk shown by populations at familial risk of BD can be modulated by such…”
BackgroundEarly Environments, Stress, and the Epigenetics of Human Health
Mulligan, C. J. (2016) · Annual Review of Anthropology · doi:10.1146/annurev-anthro-102215-095954 · Cited by 80 · see citing works
“…disorders in adulthood (Klengel et al. 2013), with Holocaust survivors and their offspring, with some cases of childhood physical and sexual abuse (Yehuda et al. 2015), with low socioeconomic status (SES) during childhood (Needham et al. 2015), and with severe social deprivation, such as…”
Matheson, K., Seymour, A. M., Landry, J., Ventura, K., Arsenault, E., & Anisman, H. (2022) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph19116455 · Cited by 88 · see citing works
“These behavioral and hormonal alterations were, in many instances, accompanied by epigenetic changes in both the survivors and their children [145], varying in relation to whether one or both parents had been survivors, as well as whether one or both parents had developed PTSD [146].”
BackgroundKlinger-König, J., Hertel, J., Van der Auwera, S., Frenzel, S., Pfeiffer, L., Waldenberger, M., Golchert, J., Teumer, A., Nauck, M., Homuth, G., et al. (2019) · Neuropsychopharmacology · doi:10.1038/s41386-019-0319-6 · Cited by 78 · see citing works
Karanikas, E., Daskalakis, N. P., & Agorastos, A. (2021) · Brain Sciences · doi:10.3390/brainsci11060723 · Cited by 78 · see citing works
Self-citationMehta, D., Bruenig, D., Carrillo‐Roa, T., Lawford, B., Harvey, W., Morris, C. P., Smith, A. K., Binder, E. B., Young, R. M., & Voisey, J. (2017) · Acta Psychiatrica Scandinavica · doi:10.1111/acps.12778 · Cited by 78 · see citing works
“including transgenerational inheritance of DNA methylation marks (71).”
BackgroundSelf-citationTransgenerational epigenetic inheritance: from phenomena to molecular mechanisms
Liberman, N., Wang, S. Y., & Greer, E. L. (2019) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2019.09.012 · Cited by 75 · see citing works
“famine during the Dutch Hunger Winter was associated with lower cytosine methylation on the imprinted insulinlike growth factor 2 (IGF2) gene [85] and decreased cytosine methylation in the FKBP5 (FK506 Binding Protein 5) gene was correlated with stress levels in the offspring of Holocaust survivors [29].”
BackgroundSchuebel, K., Gitik, M., Domschke, K., & Goldman, D. (2016) · International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyw058 · Cited by 75 · see citing works
How to Forget the Unforgettable? On Collective Trauma, Cultural Identity, and Mnemotechnologies
Aydin, C. (2017) · Identity · doi:10.1080/15283488.2017.1340160 · Cited by 73 · see citing works
“Recently, Yehuda et al. (2015) indicated that children of genocide survivors can even inherit trauma in their DNA.”
BackgroundEpigenetics of prenatal stress in humans: the current research landscape
Dieckmann, L., & Czamara, D. (2024) · Clinical Epigenetics · doi:10.1186/s13148-024-01635-9 · Cited by 84 · see citing works
“DNAm changes in FKBP5 were also reported in blood samples of adult offspring of holocaust survivors [106].”
BackgroundHow are social determinants of health integrated into epigenetic research? A systematic review
Evans, L. A., Engelman, M., Mikulas, A., & Malecki, K. M. C. (2021) · Social Science & Medicine · doi:10.1016/j.socscimed.2021.113738 · Cited by 70 · see citing works
“For example, one study examined state-sponsored persecution inflicted upon Jewish Holocaust survivors and intergenerational trauma carried forward to adult offspring (Yehuda et al., 2016) and another investigated direct exposure to the Rwandan Evans et al.”
BackgroundSuchdev, P. S., Boivin, M. J., Forsyth, B. W. C., Georgieff, M., Guerrant, R. L., & Nelson, C. A. (2017) · PEDIATRICS · doi:10.1542/peds.2016-2828e · Cited by 71 · see citing works
Nöthling, J., Malan-Müller, S., Abrahams, N., Hemmings, S. M. J., & Seedat, S. (2020) · The World Journal of Biological Psychiatry · doi:10.1080/15622975.2019.1583369 · Cited by 74 · see citing works
Neuroscience of trauma and the Russian invasion of Ukraine
Jawaid, A., Gomółka, M., & Timmer, A. (2022) · Nature Human Behaviour · doi:10.1038/s41562-022-01344-4 · Cited by 70 · see citing works
Ramo-Fernández, L., Boeck, C., Koenig, A. M., Schury, K., Binder, E. B., Gündel, H., Fegert, J. M., Karabatsiakis, A., & Kolassa, I.-T. (2019) · Scientific Reports · doi:10.1038/s41598-018-36689-2 · Cited by 67 · see citing works
Self-citationGrasso, D. J., Drury, S., Briggs-Gowan, M., Johnson, A., Ford, J., Lapidus, G., Scranton, V., Abreu, C., & Covault, J. (2020) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2020.104604 · Cited by 65 · see citing works
A Review of Psychological Stress among Students and Its Assessment Using Salivary Biomarkers
Špiljak, B., Vilibić, M., Glavina, A., Crnković, M., Šešerko, A., & Lugović‐Mihić, L. (2022) · Behavioral Sciences · doi:10.3390/bs12100400 · Cited by 68 · see citing works
“According to the literature, there is a correlation between blood cortisol levels and salivary cortisol values, observed particularly during stress [67].”
BackgroundBear, U. R., Thayer, Z. M., Croy, C. D., Kaufman, C. E., Manson, S. M., & the AI-SUPERPFP Team (2018) · Family & Community Health · doi:10.1097/fch.0000000000000205 · Cited by 67 · see citing works
Bhushan, D., Kotz, K. J., McCall, J., Wirtz, S., Gilgoff, R., Dube, S. R., Powers, C., Olson-Morgan, J., Galeste, M., Patterson, K., et al. (2020) · doi:10.48019/peam8812 · Cited by 71 · see citing works
Mehta, D., Miller, O., Bruenig, D., David, G., & Shakespeare‐Finch, J. (2020) · Journal of Traumatic Stress · doi:10.1002/jts.22472 · Cited by 66 · see citing works
FK506 binding protein 51 integrates pathways of adaptation
Rein, T. (2016) · BioEssays · doi:10.1002/bies.201600050 · Cited by 65 · see citing works
“In addition, the mentioned study on Holocaust survivors and their offspring reported higher methylation of the analyzed cytosines in intron 7 of FKBP5, but lower methylation in their offspring [109].”
BackgroundInfluentialClimate change is a major stressor causing poor pregnancy outcomes and child development
Olson, D. M., & Metz, G. A. S. (2020) · F1000Research · doi:10.12688/f1000research.27157.1 · Cited by 64 · see citing works
In utero exposure to the Great Depression is reflected in late-life epigenetic aging signatures
Schmitz, L., & Duque, V. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2208530119 · Cited by 61 · see citing works
“Hunger Winter Families Study (ntreated=348) (41–43), Project Ice Storm (ntreated=34) (44–47), or research on Holocaust survivors (ntreated=54) (48), that examined the impact of maternal nutrition or stress on DNAm changes in pre-selected CpG regions that regulate specific genes.”
BackgroundPang, T. Y., Short, A. K., Bredy, T. W., & Hannan, A. J. (2017) · Current Opinion in Behavioral Sciences · doi:10.1016/j.cobeha.2017.02.007 · Cited by 61 · see citing works
Miller, O., Shakespeare-Finch, J., Bruenig, D., & Mehta, D. (2020) · Psychological Trauma: Theory, Research, Practice, and Policy · doi:10.1037/tra0000574 · Cited by 56 · see citing works
“This finding tends to contradict previous findings where FKBP5 methylation has been associated with PTSD (e.g., DNA METHYLATION OF NR3C1 AND FKBP5 IS ASSOCIATED WITH TRAUMA RESPONSES 11 Yehuda et al., 2016; Methal et al., 2019).”
ResultStress Response Modulation Underlying the Psychobiology of Resilience
Averill, L., Averill, C. L., Kelmendi, B., Abdallah, C., & Southwick, S. (2018) · Current Psychiatry Reports · doi:10.1007/s11920-018-0887-x · Cited by 49 · see citing works
Zhou, A., & Ryan, J. (2023) · Genes · doi:10.3390/genes14081639 · Cited by 57 · see citing works
“The majority of the studies looked at only maternal transmission, but four considered both maternal and paternal [83,94,95,102], and two focused only on fathers [97,104].”
BackgroundInfluentialTherapeutic Cancer Vaccines—T Cell Responses and Epigenetic Modulation
Kartikasari, A. E. R., Prakash, M. D., Cox, M., Wilson, K., Boer, J. C., Cauchi, J. A., & Plebanski, M. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2018.03109 · Cited by 54 · see citing works
Resilience: Safety in the Aftermath of Traumatic Stressor Experiences
Matheson, K., Asokumar, A., & Anisman, H. (2020) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2020.596919 · Cited by 63 · see citing works
“An epigenetic change of the FKBP5 gene was also apparent in their offspring; however, in this case epigenetic marks were reduced (Yehuda et al., 2016; Bierer et al., 2020).”
BackgroundBraun, K., Bock, J., Wainstock, T., Matas, E., Gaisler‐Salomon, I., Fegert, J. M., Ziegenhain, U., & Segal, M. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.05.021 · Cited by 53 · see citing works
“A major development in recent years involves the realization that prenatal and preconception stress can cause long lasting epigenetic effects, mediated by DNA methylation of specific genes related to stress such as FKBP5, (Blaze and Roth, 2015; Yehuda et al., 2016).”
Psychotherapy and Genetic Neuroscience: An Emerging Dialog
Jiménez, J. P., Botto, A., Herrera, L., Leighton, C., Rossi, J. L., Quevedo, Y., Silva, J. R., Martínez, F. I., Assar, R., Salazar, L. A., et al. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00257 · Cited by 58 · see citing works
“Given that there is some evidence for the transgenerational transmission of epigenetic modifications in humans exposed to traumatic situations (Yehuda et al., 2016), it is possible to hypothesize that epigenetic changes produced by psychotherapy could also potentially be passed on to offspring.”
BackgroundEvidence for germline non-genetic inheritance of human phenotypes and diseases
Senaldi, L., & Smith-Raska, M. (2020) · Clinical Epigenetics · doi:10.1186/s13148-020-00929-y · Cited by 55 · see citing works
“These findings persisted after controlling for parental post-traumatic stress disorder (PTSD) as well as a polymorphic variant associated with altered stress response; the authors conclude that parental Holocaust exposure was a significant predictor of offspring FKBP5 methylation in this group [43].”
BackgroundLiu, H., Li, T. W., Liang, L., & Hou, W. K. (2021) · Clinical Psychology Review · doi:10.1016/j.cpr.2021.102069 · Cited by 61 · see citing works
Environment factors, DNA methylation, and cancer
Liu, J., Huang, B., Ding, F., & Li, Y. (2023) · Environmental Geochemistry and Health · doi:10.1007/s10653-023-01749-8 · Cited by 55 · see citing works
“These environmental factors include poor diet [133] and living habits [163, 164], toxic chemicals [165, 166], heavy metal exposure, ionizing radiation exposure [167], psychological adversity [168, 169], and more.”
BackgroundKalyan-Masih, P., Vega-Torres, J. D., Miles, C., Haddad, E., Rainsbury, S., Baghchechi, M., Obenaus, A., & Figueroa, J. D. (2016) · eNeuro · doi:10.1523/eneuro.0125-16.2016 · Cited by 53 · see citing works
International Norms, Moral Psychology, and Neuroscience
Price, R. M., & Sikkink, K. (2021) · Cambridge University Press eBooks · doi:10.1017/9781108966610 · Cited by 53 · see citing works
- Authors
- Yehuda, R., Daskalakis, N. P., Bierer, L. M., Bader, H. N., Klengel, T., Holsboer, F., & Binder, E. B.
- Affiliations
- James J. Peters VA Medical Center (US)
- Mount Sinai Hospital (US)
- Emory University (US)
- HolsboerMaschmeyer NeuroChemie (Germany) (DE)
- Corresponding author
- Yehuda, Rachel
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2016-09
- Volume
- 80
- Issue
- 5
- Pages
- 372-380
- ISSN
- 0006-3223 (ISSN-L)
- OpenAlex
- W1203252705
- Cited by
- 782
- References
- 60
- Citations by year
- 2026: 58 · 2025: 90 · 2024: 68 · 2023: 55 · 2022: 65 · 2021: 66 · 2020: 99 · 2019: 75 · 2018: 75 · 2017: 74 · 2016: 47 · 2015: 7 · 2014: 2
- FWCI
- 29.35
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- NIMH (R01 MH 64675-01)
- Biology of Risk and PTSD in Holocaust Survivor Offspring (1RC1MH088101-01)
- Mount Sinai General Clinical Research Center from the National Institute of Health (5 M01 RR00071)
- European Research Council starting (281338)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
- Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
- Keywords
- Holocaust survivors, intergenerational trauma, FKBP5, DNA methylation, epigenetics, glucocorticoid response element, childhood abuse, cortisol, parental trauma, site-specific methylation
- MeSH terms
- Tacrolimus Binding Protein 5, Cytosine, Female, Humans, Male, Parents, Psychiatric Status Rating Scales, Surveys and Questionnaires, Stress Disorders, Post-Traumatic, Cohort Studies, Child of Impaired Parents, Survivors, Holocaust, DNA Methylation, Tacrolimus Binding Proteins, Adult Children
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