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Theory and research both point at epigenetic processes affecting both parenting behavior and child functioning. However, little is known about the convergence of mother and child’s epigenetic patterns in families. Therefore, the current study investigated epigenetic covariance in mother–child dyads’ methylation levels regarding four stress-regulation related genes (5HTT, NR3C1, FKBP5, and BDNF). Covariance was tested in a general population sample, consisting of early adolescents (Mage = 11.63, SDage = 2.3) and mothers (N = 160 dyads). Results showed that mother and offspring 5HTT and NR3C1 methylation patterns correlated. Furthermore, when averaged across genes, methylation levels strongly correlated. These findings partially supported that child and parent methylation levels covary. It might be important to consider this covariance to understand maladaptive parent–child relationships.
Epigenetics in Families: Covariance between Mother and Child
Methylation Patterns
Tanya Van Aswegen 1, 2, , Guy Bosmans 3 ,*, , Luc Goossens 4, Karla Van Leeuwen 5, Stephan Claes 6,
Wim Van Den Noortgate 7,8 and Benjamin L. Hankin 9
Citation: Van Aswegen, T.; Bosmans,
G.; Goossens, L.; Van Leeuwen, K.;
Claes, S.; Van Den Noortgate, W.;
Hankin, B.L. Epigenetics in Families:
Covariance between Mother and
Child Methylation Patterns. Brain Sci.
2021,11, 190.
Academic Editor: María JoséRodrigo
Received: 22 December 2020
Accepted: 29 January 2021
Published: 4 February 2021
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1Department of Psychiatry, University of Stellenbosch, 7505 Cape Town, Tygerberg, South Africa;
2Department of Clinical Psychology, VU University Amsterdam, 1081 BT Amsterdam, The Netherlands
3Clinical Psychology, Faculty of Psychology and Educational Sciences, KU Leuven, 3000 Leuven, Belgium
4School Psychology and Development in Context, Faculty of Psychology and Educational Sciences,
KU Leuven, 3000 Leuven, Belgium;
5Parenting and Special Education, Faculty of Psychology and Educational Sciences, KU Leuven,
3000 Leuven, Belgium;
6University Psychiatric Center & Department of Neurosciences, KU Leuven, 3000 Leuven, Belgium;
Faculty of Psychology and Educational Sciences; KU Leuven Campus Kulak Kortrijk, 8500 Kortrijk, Belgium;
8ITEC, IMEC research group at KU Leuven, 8500 Kortrijk, Belgium
9Department of Psychology, University of Illinois at Urbana-Champaign, Champaign, IL 61820, USA;
Joint First Author.
Theory and research both point at epigenetic processes affecting both parenting behavior
and child functioning. However, little is known about the convergence of mother and child’s
epigenetic patterns in families. Therefore, the current study investigated epigenetic covariance
in mother–child dyads’ methylation levels regarding four stress-regulation related genes (5HTT,
NR3C1,FKBP5, and BDNF). Covariance was tested in a general population sample, consisting of early
adolescents (M
= 11.63, SD
= 2.3) and mothers (N= 160 dyads). Results showed that mother and
offspring 5HTT and NR3C1 methylation patterns correlated. Furthermore, when averaged across
genes, methylation levels strongly correlated. These findings partially supported that child and
parent methylation levels covary. It might be important to consider this covariance to understand
maladaptive parent–child relationships.
DNA methylation; epigenetics; stress-related genes; shared environments; early adolescence
1. Introduction
In recent years, researchers have become increasingly aware of epigenetic changes,
that is, changes in the expression of genes due to environmental influences (i.e., pesticides,
bacteria, basic nutrients, etc.), which have a strong impact on people’s health, behavior,
and disease [
]. Although epigenetic effects have been found in both parent and child
development [
], little is known about potential epigenetic covariance at the level of
mother–child dyads. Several mechanisms are known to epigenetically regulate genetic
expression. One popular epigenetic mechanism is DNA methylation; methyl groups are
added to the promoter region of genes, changing gene expression by blocking transcription
factors’ access to the promoter region of the gene [
]. Methylation levels are affected by
environmental stress, toxins [
], diet [
], and they influence—amongst others—the stress-
regulation system [
]. The difficulty of regulating stress is known to increase maladaptive
parenting [
] and increase child behavioral problems [
]. Maladaptive parenting and child
behavior problems are known to be robustly correlated [
]. Since epigenetic effects have
Brain Sci. 2021,11, 190.
Brain Sci. 2021,11, 190 2 of 11
been reported in both adults’ and children’s problematic behavior, this raises the question of
whether parents and children could have similar levels of methylation of stress-regulation
related genes. However, research on DNA methylation covariance in parent child dyads is
largely lacking.
Nevertheless, current theories of epigenetics imply covariance between parent and
child methylation [
]. First, both mothers and children are exposed to the same environ-
mental factors known to affect epigenetic changes peri- and post-partum [
]. They have a
very similar diet and are to some extent exposed to the same stressors, such as the same
bacteria and pollution. In addition, variation in methylation levels differs depending on
genotypes that parents and children share [
]. This enhances the likelihood that their
methylation levels would covary. Second, both theoretical and animal models suggest
that epigenetic patterns might be inherited and passed on from parent to offspring [
Research shows that the methylation in some genes can be duplicated during mitosis [
Although the underlying mechanisms are still the focus of research, some animal studies do
suggest that offspring might inherit epigenetic patterns that parents developed in response
to certain environments [
]. In sum, it seems reasonable to assume that parents and
children might have comparable methylation levels. Finding evidence for parent–child
methylation covariance might contribute to our understanding of the complex processes
explaining parent–child interactions. To our knowledge, just a single study investigated
the correlation between parent and child methylation levels. This study found a small
but significant correlation in Holocaust survivors [
]. However, the study had four key
limitations: (a) it focused on methylation in a single gene (FK506 binding protein or FKBP5),
(b) it relied on a small sample (N= 22 dyads only), (c) offspring methylation was measured
in adulthood, and (d) surviving the holocaust is a very specific and severe type of distress
that is difficult to generalize to other populations.
The aim of the current study was to remedy some of the shortcomings of the previous
study of Yehuda et al. [
]—specifically, examining methylation covariance between moth-
ers and children in several genes, in a larger sample, with offspring methylation measured
at a younger age, and with participants from the general population presumably exposed
to normative levels of daily distress. The covariance of methylation patterns for four genes
related to the stress-regulation system was tested. The stress regulating system is regulated
by the Hypothalamus–Pituitary–Adrenal (HPA) axis. Stress activates the HPA axis, which
releases glucocorticoids (such as cortisol) to protect the body from harm by promoting
fight–flight responses to distress. The HPA axis gets deactivated when the glucocorticoids
activate glucocorticoid receptors (GR) in the hippocampus, which decreases arousal as
one element of adequate stress regulation [17]. Methylation of the genes that manage this
stress-regulation system can modulate levels of cortisol in response to stress, which trans-
lates into variation in self-regulation [
]. In the current study, we tested the correlation
between mother’s and children’s methylation of these genes. More specifically, we looked
at the methylation of 5HTT, NR3C1,FKBP5, and BDNF [
]. The serotonin transporter
(5HTT) re-introduces the neurotransmitter serotonin from the synaptic cleft into presynap-
tic neurons [
]. The glucocorticoid receptor (NR3C1) is among the most studied GR genes
and functions as a transcription factor that binds to glucocorticoid response elements in
the promoters of glucocorticoid-responsive genes to inhibit HPA axis activity [
]. FKBP5
acts as a co-chaperone that modulates, amongst others, glucocorticoid receptor activity
in response to stressors [
]. Finally, the brain-derived neurotrophic factor (BDNF) regu-
lates the development of the nervous system and the formation of appropriate synaptic
connections in particular. BDNF expression occurs in the hippocampus, hypothalamus,
and pituitary [
], which are three structures highly involved in the HPA axis activity
and regulation. For all the above-mentioned genes, theory suggests that more exposure
to adverse environments leads to higher levels of methylation, which may modulate the
regulation negative affect and self-regulation [26].
To test the hypothesis that mother and child methylation levels for these genes are
correlated, we used data of the ** study (Genes, Environment, Mood [27]), which focused
Brain Sci. 2021,11, 190 3 of 11
on biological and family processes in the development of children’s depression. First, we
investigated the covariance between mother and child methylation at the level of individual
genes. Second, we looked at covariance between their overall methylation levels across
these genes. So far, no research has investigated whether different environmental influences
have specific effects on selected genes. Therefore, we tested the correlation between the
factor scores that summarized the methylation scores across the four genes for mothers and
children separately. Finally, although children in the GEM study were on average 11 years
old, they ranged in age from 8 to 16 years. Since children increasingly spend more time in
other environments than parents do during adolescence, older children might be exposed
to different stressors or toxins than parents are. As a result, one could expect the covariance
between mothers and children to decrease as children grow older. Therefore, we tested
whether age moderated the covariance between mother and child methylation. Finally, we
investigated the extent to which recent stress accounted for the levels of maternal and child
methylation and affected their covariance.
2. Method
2.1. Participants
The sample comprised 160 dyads (mother and child; 42.5% boys and 57.5% girls).
Children ranged in age from 8 to 16 years (M= 11.63, SD = 2.3), and parents’ age was
unknown. This was a subsample of the larger GEM study sample for which both mother
and child methylation data were available. Recruitment took place at two sites: the
University ** and ** University. Parent reported that both the mother and child were
fluent in English. Moreover, participating children did not have an autism spectrum or a
psychotic disorder. All children had an IQ above 70. The sample was comparable to the
community and school districts from which recruitment took place. The sample sufficiently
represented the ethnic and racial characteristics of the overall population of the United
States: 81.6% non-Hispanic; 18.4% Hispanic; 2% American Indian; 2% Asian; 5% Black,
75% White; 9% other; 7% multi-racial.
2.2. Measures
2.2.1. Methylation Procedure
To determine DNA methylation levels, we used quantitative bisulfite pyrosequencing
by EpigenDx. Pyrosequencing for allele quantification (PSQ H96A, Qiagen Pyrosequencing)
is a real-time sequencing-based DNA analysis. This analysis quantifies multiple and con-
secutive CpG sites (regions of DNA where a cytosine nucleotide is followed by a guanine
nucleotide) individually as artificial T/C SNPs (a single nucleotide polymorphism) [
In short, 500 ng of sample DNA was bisulfate treated with the Zymo DNA Methylation
Kit (Zymo Research, Orange, CA, USA). Bisulfate treated DNA is eluted in 20
L volume,
and 1
L of it is used for each PCR. For the PCRs, we used the standard pyrosequencing
recommended PCR condition: 10
PCR buffer, 1.5 mM MgCl
, 200
M of each dNTP,
M each of forward and reverse primers, HotStar DNA polymerase (Qiagen Inc.) 1.25 U,
and 1
L of bisulfite converted DNA per 30
L reaction. PCR cycling conditions were
C 15 min; 45 cycles of 94
C 30 s; 46
C 30 s; 72
C 30 s; 72
C 5 min; then, products
were held at 4
C. We used the Pyrosequencing PSQ96 HS System (PSQ H96A, Qiagen
Pyrosequencing, Colorado, USA) to sequence the PCR products (each 10
L). During
this process, we fully followed the manufacturer’s instructions. Each locus’ methylation
status was analyzed individually as a T/C SNP using QCpG software (PSQ H96A, Qiagen
Pyrosequencing, Colorado, USA) [30].
For NR3C1 methylation, human GCR Exon1F methylation assays covers 39 CG din-
ucleotides in the promoter region ranging from approximately
630 to
354 from the
transcriptional start site based on Ensembl ID ENST00000231509. ADS749FS covers 7 CpG
sites in the Exon1F region. For 5HTTP methylation, human solute carrier family 6 (sero-
tonin transporter) methylation assays covers 20 CG dinucleotides sites in the promoter
reverse strand region ranging from approximately
69 to
213 from the transcriptional
Brain Sci. 2021,11, 190 4 of 11
start site based on Ensembl ID ENSG00000108576. ADS580FS2 covers 16 CpG sites in the
promoter region. For FKBP5 methylation, human FK506 binding protein 5 methylation
assays covers 10 CG dinucleotides sites in the promoter reverse strand region ranging
from approximately
3092 to
3020 from the transcriptional start site based on Ensembl
ID ENSG00000096060. ADS2500FS2 covers all 10 CpG sites in the promoter region. For
BDNF methylation, human brain-derived neurotrophic factor (BDNF) methylation as-
says covers 8 CG dinucleotides sites in the Intron 1 region ranging from approximately
+61111 to +61129 from the transcriptional start site based on Ensembl ID ENSG00000525950.
ADS2107-FS covers all 8 CpG sites in the Intron 1 region.
2.2.2. Recent Stress
To measure stress in the child, we administered two measures. First, we adminis-
tered the Youth Life Stress Interview to the children (YLSI [
]). The YLSI is a reliable,
semi-structured contextual stress interview that validly assesses ongoing stress level in
adolescents. The YLSI’s reliability and validity is excellent [
]. Coding occurred in line
with the procedure described by Rudolph and Flynn [
]. This is the procedure that is most
often used. To derive stress severity information, responses to the related questions were
coded by a team of three or more blind raters. They came to an agreed upon severity score.
This score could range from 1 (little/no stress), 2 (average/normal stress), 3 (moderate
stress), 4 (serious stress), to 5 (severe stress). The interview results in sum scores for stress
severity and chronicity on several domains related to for example financial or academic
stress. Second, we administered the Adolescent Life Events Questionnaire (ALEQ [
This questionnaire is designed to measure the occurrence of a broad range of negative
events that typically occur during adolescence. For example, this included school prob-
lems (e.g., “You got in trouble with the teacher or principal”) or relationship difficulties
(e.g., “You found out your boyfriend/girlfriend was cheating on you”). Adolescents rated
each of the 37 events for frequency in the past 3 months on a Likert scale ranging from
A (never) to E (always). Reliability and validity for the ALEQ has been established in
past studies [
]. The three indicators of stress in the child were highly correlated
0.46 < r< 0.60
ps < 0.001
), suggesting that it was better to combine all measures to reduce
the number of analyses. To combine both stress measures, we calculated a sum score to
express general child stress with higher scores indicating more stress. To measure stress
in the parent, we administered an adult version of the ALEQ to calculate one sum score
expressing parent stress.
2.2.3. Procedure
Saliva samples were collected from all study participants using the Oragene (DNA
Genotek, Ottawa, ON, Canada) collection kits. The stress measures were administered at
the time when the saliva was collected. All study measures and procedures were approved
by University of Denver’s Internal Review Board.
3. Plan of the Analysis
All analyses were conducted using SPSS, version 27. First, we conducted prelim-
inary analyses to evaluate whether child gender and age were directly linked to child
methylation levels. Then, for Research Question 1, we calculated correlations to assess
mother–child methylation covariance per gene. For Research Question 2, we used principal
component analysis (PCA) on the four gene’s methylation scores for children and mothers
separately. These PCAs allowed calculating a methylation component score per member of
the dyad. Then, we assessed with a bivariate correlation analysis whether there is a general
association between mother and child methylation independent of the specific genes. For
Research Question 3, we evaluated the moderating effect of age on the association between
mother and child methylation levels using Hayes’s [
] PROCESS tool for SPSS (Model
1). Separate analyses were performed for each individual gene and for the methylation
component score. For Research Question 4, we first conducted correlation analyses to
Brain Sci. 2021,11, 190 5 of 11
evaluate the association between maternal stress and maternal methylation levels, and
then between child stress and child methylation levels. Finally, we conducted multiple
regression analyses to evaluate the association between maternal and child methylation
levels while controlling for the mother and child stress scores.
4. Results
Preliminary Analyses: Gender and Age Effects
No methylation data were missing. For 30 children, interview data were partially
incomplete. When calculating the sum score, we used mean imputation. After that, less
than 3% of the data was missing (one child stress score, four parent stress scores), which
were pairwise deleted. Effects of children’s age and gender were tested separately. No
significant correlations were found between children’s age and methylation. Analysis of
variance indicated that also child gender was not significantly linked to methylation.
Research Question 1: Covariance at the Level of Individual Genes.
Table A1 of Appendix Ashows significant correlations between the methylation
levels of 5HTT, NR3C1,FKBP5, and BDNF within each member of the dyad. In addition,
the results showed significant correlation between mother and child methylation levels.
However, Bonferroni correction for multiple testing requires p-values to be lower than
0.0125 (
/4 tests), due to which the transgenerational correlations for FKBP5 and BDNF no
longer reached significance (p= 0.044 and p= 0.046 respectively).
Research Question 2: Covariance of Methylation across Genes
Principal component analyses (PCAs) were conducted for children and mothers
separately on the methylation scores for the four genes. PCA for the children resulted in
one component with an eigenvalue higher than 1 (2.25), explaining 56% of the variance,
and revealing factor loadings >0.60. PCA for the mothers resulted in one component with
an eigenvalue higher than 1 (2.90), explaining 74% of the variance, revealing factor loadings
>0.83. The adequacy of combining methylation levels across genes was further supported
by reliability analysis (Cronbach αchildren = 0.72; Cronbach αmothers: 0.87).
Using the results of the PCAs, we computed factor scores for children and mothers
separately. We found a significant correlation between the two factor scores, r(160) = 0.37,
p< 0.001, reflecting a moderate association between child and mother methylation levels.
Research Question 3: Moderating Effect of Children’s Age on Mother–Child Methyla-
tion Covariance
To investigate moderation by age in the relationship between maternal and children’s
methylation patterns, we first looked at the interaction for each of the four individual
gene and then moved on to investigate the interaction for the methylation across genes
component. No moderating effects for age were found for NR3C1 (b= 0.07, t(156) = 1.28,
p= 0.20)
;5HTTP (b=
0.03, t(156) =
0.63, p= 0.53); FKBP5 (b=
0.05, t(156) =
p= 0.31
) and BDNF (b=
0.01, t(156) =
0.11, p= 0.91). In addition, age did not moderate
the relationship between mother and child (b=0.07, t(156) = 1.27, p= 0.21).
Research Question 4: Stress and Mother–Child Methylation Covariance
Preliminary inspection of the stress scores showed that they had a skewed distri-
bution. For mothers’ stress: M= 4.58; SD = 3.42; Skewness = 86, SE(Skewness) = 0.19;
Kurtosis = 0.44
, SE(Kurtosis) = 0.38. For children’s stress: M= 157.79; SD = 22.48. Moreover,
data distribution was skewed: Skewness =
1.13, SE(Skewness) = 0.19; Kurtosis = 5.10,
SE(Kurtosis) = 0.38. First, we calculated correlations between each mother’s and children’s
recent stress and their methylation levels both at the level of each individual gene and at
the component level. Table A2 shows only one significant correlation: stress of the child
was related to higher child BDNF methylation levels. However, Bonferroni correction
for multiple testing requires p-values to be lower than 0.01 (
/5 tests), due to which the
correlation between BDNF methylation and child stress no longer reached significance
p= 0.025
). Moreover, this correlation was no longer significant after excluding scores
differing more than two SDs from the child stress mean, r= 0.05, p= 0.51.
Brain Sci. 2021,11, 190 6 of 11
Second, we used multiple regression analysis to test whether mother–child methyla-
tion covariance survived controlling for mother and child stress. The mother–child methyla-
tion associations remained significant for all the analyses: 5HTT:R
= 0.06,
F(3, 152) = 2.98
p= 0.03, with
= 0.20, p= 0.04; NR3C1:R
= 0.13, F(3, 152) = 7.62, p< 0.001,
= 0.33, p< 0.001; FKBP5:R
= 0.03, F(3, 152) = 4.10, p= 0.008, with
βFKBP5mother = 0.16
,p= 0.044; BDNF:R
= 0.08, F(3, 152) = 7.62, p< 0.001, with
βBDNFmother = 0.15
p= 0.43; methylation component scores: R
= 0.16, F(3, 152) = 9.94, p< 0.001, with
βmethylation_mother = 0.36, p< 0.001.
5. Discussion
This study investigated covariance between children’s and mothers’ levels of methyla-
tion for stress-regulation system-related genes. At the level of single genes, methylation
in all four genes significantly correlated across the mothers and the children. However,
the correlations for FKBP5 and BDNF did not survive Bonferroni correction. The results of
the current study regarding FKBP5 were weaker than what Yehuda et al. [
] observed in
Holocaust survivors. One reason why the size of the effect found in the current study was
smaller could be the fact that the current study’s dyads were not exposed to the extreme
distress that Holocaust survivors experienced. Nevertheless, the trend-like effect we found
in the current study is in line with Yehuda’s study showing transgenerational covariance
between mother and child methylation levels. Moreover, the current study added to the
literature by investigating mother–child methylation covariance for additional genes and
by investigating covariance at the same point in time. In line with expectations, methyla-
tion levels correlated between generations (mother–child) for HTT5 and NR3C1. Results
also showed that within the children and within the mothers, methylation between the
genes correlated. In addition, results showed a significant correlation between mothers’
and children’s methylation component scores. Against our expectations, we found no
evidence suggesting that the covariance between mothers and children declined as children
grow older.
With regard to the covariance between mother and child methylation levels, correla-
tions robustly supported our hypothesis. These findings suggest that the environment and
the genetic background shared by children and mothers similarly affect the methylation
patterns of both members of the dyad. The current findings call for more research to explain
the causes of this covariance. Most straightforwardly, the covariance might reflect the
immediate impact of the environment at the time of the study [
]. However, there was
hardly any support for a correlation between methylation levels and stress. One reason for
the lack of correlations between the stress measures and the methylation measures might be
lack of variance at the level of stress in the current sample. Supporting this interpretation,
the one observed association between child stress and BDNF methylation disappeared
when removing more extreme scores. Moreover, ours is not the first study that struggled to
find clear correlations between stress and methylation levels in humans [
]. In contrast
to what is known about the epigenetic impact of chemical exposures, more research is
needed to understand how and when stress exposure affects methylation [
]. For example,
it might be that the shared methylation within each mother–child dyad we found in the
current study reflects the ongoing effect of shared past exposure to chemical exposures [
Furthermore, recent research on the epigenetic clock [
] and on the Developmental Origins
on Health and Disease model [
] suggest that methylation levels are to a substantial extent
established earlier in life, making it harder to find significant correlations between ongoing
stress and methylation levels at later ages. In addition, we could not correct for genetics
in the analyses. Genotype can affect the likelihood that genes are methylated. Therefore,
it might be that we could not find associations between stress and methylation because
methylation levels and methylation covariance were driven by genetic covariance [
which is an explanation we cannot rule out in the current study because we had no genetic
data. Harder to test but impossible to rule out is the possibility that the covariance could
also reflect epigenetic inheritance [44].
Brain Sci. 2021,11, 190 7 of 11
The fact that methylation levels correlated significantly within mothers and children
and the fact that we also found evidence for covariance between mother and child methy-
lation levels across all genes suggests that the factors affecting methylation might not
be gene-specific. Instead, one possibility might be that shared exposure to a toxic versus
healthy environment does result in similar methylation levels for different genes in both the
mothers and the children. So far, little research investigated whether specific toxins affect
methylation levels of specific genes. More research is needed to test whether methylation
patterns are gene-specific or not.
For our hypothesis that age would moderate the association between mother and
child methylation levels, we found no support. This suggests that the covariance be-
tween mothers’ and children’s methylation levels is not altered when their environments
increasingly start to differ. It might be that the age range in the current study was too
limited and that such age effects could emerge if children enter into adulthood themselves.
Nevertheless, these results suggest that the covariance we identified in the current study
was established earlier in life. One critical period could be during pregnancy or imme-
diately post-partum, which is a time when children are considered most vulnerable to
environmental influences [
]. Existing findings highlight the critical impact of prenatal
environmental factors on DNA methylation as a mechanism by which early childhood
experiences may become biologically embedded [
]. Another explanation might be
that the covariance expresses at least to some extent epigenetic inheritance. However,
recent attempts to establish epigenetic inheritance in humans were little successful [
Therefore, it is too premature to firmly draw such conclusions based on our data.
Further motivating caution when interpreting the findings is the small but significant
association we found between recent child stress and the children’s BDNF methylation. This
suggests that recent stress continues to have an effect on methylation levels, which could
eventually lead to reduced mother–child methylation covariance later in life. Nevertheless,
it is important to note that the child–mother covariance for BDNF methylation remained
significant after accounting for the current stress effect and to note that the significant
correlation did not survive Bonferroni correction. Therefore, this could just reflect statistical
coincidence. In addition, to better evaluate whether mother and child methylation levels
diverge when children grow older, it might be better for future research to account for
more adverse sources of recent stress. For example, Romens et al. [
] found that child
NR3C1 methylation levels were linked with exposure to physical maltreatment, displaying
a specific change in the NR3C1 receptor gene. Hence, accounting for recent physical
maltreatment could have decreased the mother–child covariance in the current study.
In sum, more research is needed to better understand the nature of the mother–child
covariance we demonstrated in this study.
Although the current findings provide some first evidence that studying methylation
patterns in human dyads could move epigenetic research significantly forward, the inter-
pretation of the findings should consider important limitations. First, families consist of
more than two family members. Therefore, a more encompassing study of family epigenet-
ics should take into account father and sibling information as well. Research has shown
differential effects of maternal versus paternal contribution to offspring methylation [
Secondly, in the current study, there was a substantial lack of information about the current
rearing environment. It would have been important to know more about the number of
siblings and the composition of the family. Higher number of siblings and families with
divorced parents, single parents, or recomposed families are known to be more stressful
for children, and this could have better explained the mother–child covariance. In addition,
there was a lack of information on the mothers’ environment and medical conditions before
and during pregnancy, and on children’s current medical conditions such as hypercorti-
solism or other endocrinological abnormalities that could have affected the covariance.
In addition, it would have been important to know maternal age as well as the mothers
and children’s broader mental health conditions. Accounting for this information would
have allowed giving a more precise indication of the mother–child epigenetic covariance in
Brain Sci. 2021,11, 190 8 of 11
this sample. However, at first sight, it seems that these sources of variation should have
suppressed the effect rather than artificially increased the effect. So, it seems promising
that we still found such a substantial correlation. Since we cannot rule out that covariance
might have been inflated by such factors, we think it is safest to say that the current study
represents a new important step in the study of epigenetic patterns within families and that
the current findings should motivate the future setup of better designed studies aimed at
further unraveling mother–child covariance. Third, we could not present valid information
on the mothers’ and children’s self-regulatory capacity nor on the participants’ cortisol
responses to stress. Such information would have further strengthened the point that trans-
generational epigenetic covariance might explain part of the transmission stress-regulation
difficulties in parent–child dyads. Mothers did report on their children’s inhibitory control
using the Early Adolescent Temperament questionnaire [
], but unfortunately, the internal
consistency was insufficient as reported previously [
]. Fourth, we only focused on the
stress-response system, and our findings might not generalize to epigenetics as applied to
other biological systems. Finally, data collection was cross-sectional in nature. As a result,
it is impossible to draw conclusions about causal mechanisms nor about any synergistic
interactions between children and mothers’ methylation patterns.
In sum, the current study found evidence for covariance in mothers’ and children’s
methylation levels of stress-regulation related genes. This finding could prove relevant,
because methylation covariance could be one understudied factor explaining the previously
established covariance between mothers’ and children’s ability to regulate distress [
For example, a better understanding of the role of epigenetics in the association between
problematic mother and child self-regulatory behavior could improve our understanding of
treatment-resistant transgenerational vulnerabilities found in multi-problem families [
and the therapeutic needs of family members that developed unhealthy family relation-
ships [57].
6. Conclusions
This study investigated the covariance between children’s and mothers’ levels of
methylation for stress-regulation system-related genes. Results supported the transgener-
ational covariance for 5HTT and NR3C1 and for methylation component scores derived
from all the methylation data across the genes we tested. More research is needed to evalu-
ate the robustness of these findings and to uncover why parent–child methylation levels
covary. Future research should investigate whether this covariance can help understand
parent–child dynamics and child development. For example, parent–child methylation
covariance could contribute to explain well-known transgenerational correlational pat-
terns within families such as the association between parenting and the development of
children’s emotional and behavioral problems. It might be that the shared methylation
of genes involved in stress regulation might increase inadequate parenting (that requires
well-developed stress-regulation capacities) and at the same time increase children’s emo-
tional and behavior problems (which are also a marker of stress-regulation problems).
Similarly, parent–child methylation covariance could help explain phenomena such as
biobehavioral synchrony, resilience transmission, and transgenerational transmission in
other domains of development (e.g., attachment). Clinically, more research similar to this
could help soften professional caregivers’ blame-the-parent-like views on parenting and
child psychopathology, because is it hard to blame parents for methylation covariance.
A more positive view on parents who struggle with a child displaying stress-regulation
problems can eventually improve therapist alliance and treatment outcomes.
Author Contributions:
Conceptualization, G.B., T.V.A., and B.L.H.; methodology, B.L.H.; software,
G.B., and T.V.A.; formal analysis, G.B., T.V.A., and B.L.H.; investigation, B.L.H.; resources, B.L.H.; data
curation, B.L.H.; writing—original draft preparation, G.B., T.V.A., and B.L.H.; writing—review and
editing, L.G., K.V.L., S.C., W.V.D.N.; visualization, T.V.A.; supervision, B.L.H.; project administration,
B.L.H.; funding acquisition, B.L.H., L.G., G.B., K.V.L., W.V.D.N. All authors have read and agreed to
the published version of the manuscript.
Brain Sci. 2021,11, 190 9 of 11
This research has been supported by NIMH grants R01MH077195, R01MH105501, and
R21MH102210 assigned to B.L. Hankin, by grants G075718 and G0D6721 of the Research Foundation
Flanders (FWO) assigned to G. Bosmans, and by grant C14/16/040, from the Research Fund KU
Leuven, Belgium awarded to L. Goossens, G. Bosmans, K. Van Leeuwen, S. Claes, and W. Van
Den Noortgate.
Institutional Review Board Statement:
The study was conducted according to the guidelines of the
Declaration of Helsinki, and approved by the University of Denver Institutional Review Board, code
2008-0810 on 22 June 2009
Informed Consent Statement:
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement: All data can be obtained from the corresponding author.
Conflicts of Interest: The authors declare no conflict of interest.
Appendix A
Table A1. Correlations, means, and standard deviations of the key variables.
Measure 1 2 3 4 5 6 7 8
1. 5HTT 1
2. NR3C1 0.61 ** 1
3. FKBP5 0.31 ** 0.34 ** 1
4. BDNF 0.39 ** 0.51 ** 0.30 ** 1
5. 5HTTmother 0.20 * 0.33 * 0.10 0.14 1
6. NR3C1mother 0.29 ** 0.34 ** 0.18 * 0.13
0.74 **
7. FKBP5mother 0.27 ** 0.42 ** 0.16 * 0.19 *
0.63 ** 0.65 **
8. BDNFmother 0.24 ** 0.44 ** 0.05 0.16 *
0.68 ** 0.70 ** 0.58 **
M1.89 0.26 0.46 1.67 2.08 0.31 0.48 1.70
SD 1.18 0.72 0.70 0.90 1.16 0.75 0.73 0.91
Note. Mean = mean score of methylation patterns across CpG sites; Correlations for the same gene for children
and mothers are underlined and in bold. ** p< 0.01. * p< 0.05.
Table A2.
Correlations between mothers’ and children’s recent stress and their respective methylation
Mother Stress Child Stress
1. 5HTT 0.06 0.06
2. NR3C1 0.05 0.04
3. FKBP5 0.05 0.07
4. BDNF 0.08 0.18 *
5. Methylation component scores 0.07 0.11
Note: * p< 0.05.
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... We then went on to look at the relationship between this early NR3C1 methylation signature, in terms of overall methylation and that of specific CpG islands as reported in our previous study (10,15) and child behavior 4-years later during school age (5-9 years). One stimulus to write this paper was the publication of a recent study that investigated epigenetic covariance in mother-child dyads' degrees of methylation among four stress-regulation related genes (5HTT, NR3C1, FKBP5, and BDNF) in a sample of 160 typical peri-pubertal youth (ages [8][9][10][11][12][13][14][15][16] and their mothers (16). Results showed that mother and offspring NR3C1 methylation signatures were significantly correlated in that latter study. ...
... We then went on to look at the relationship between this early NR3C1 methylation signature, in terms of overall methylation and that of specific CpG islands as reported in our previous study (10,15) and child behavior 4-years later during school age (5-9 years). One stimulus to write this paper was the publication of a recent study that investigated epigenetic covariance in mother-child dyads' degrees of methylation among four stress-regulation related genes (5HTT, NR3C1, FKBP5, and BDNF) in a sample of 160 typical peri-pubertal youth (ages [8][9][10][11][12][13][14][15][16] and their mothers (16). Results showed that mother and offspring NR3C1 methylation signatures were significantly correlated in that latter study. ...
... Van Aswegen et al. also pointed to the importance of considering this maternal-child relationship in the context of problematic mother-child relationships (16). Indeed, in our previous study, we showed maternal methylation of the NR3C1 promoter region as negatively and significantly associated with parenting stress, which is a known marker of parentchild relationship disturbance and is predictive of both child internalizing (i.e., anxiety and depression) and externalizing problems (i.e., disruptive behavior disorder symptoms such as those of attention deficit hyperactivity, oppositional defiant and disruptive mood dysregulation disorder) (10,18). ...
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Introduction Interpersonal violent (IPV) experiences when they begin in childhood and continue in various forms during adulthood often lead to chronic post-traumatic stress disorder (PTSD) that is associated in multiple studies with hypocortisolism and lower percentage of methylation of the promoter region of the gene coding for the glucocorticoid receptor (NR3C1). This prospective, longitudinal study examined the relationship of NR3C1 methylation among mothers with IPV-related PTSD and their toddlers and then looked at the relationship of maternal NR3C1 methylation and child psychopathology at school age. Methods Forty-eight mothers were evaluated for life-events history and post-traumatic stress disorder via structured clinical interview when their children were ages 12–42 months (mean age 26.7 months, SD 8.8). Their children's psychopathology in terms of internalizing symptoms and externalizing behaviors was evaluated using the Child Behavior Checklist at ages 5–9 years (mean age 7 years, SD 1.1). Percentage of methylation for the NR3C1 gene promoter region was assessed from DNA extracted from maternal and child saliva using bisulfite pyrosequencing. Data analysis involved parametric and non-parametric correlations and multiple linear and logistic regression modeling. Results Logistic regression models using child NR3C1 methylation as the dependent variable and maternal NR3C1 methylation and PTSD group status as predictors, as well as the interaction indicated that all three of these significantly predicted child NR3C1 methylation. These findings remained significant when controlling for child age, sex and maternal child abuse history. Overall, maternal NR3C1 methylation when children were toddlers was negatively and significantly associated with child externalizing behavior severity at school age. Discussion We found that correlations between mothers and their children of NR3C1 methylation levels overall and at all individual CpG sites of interest were significant only in the IPV-PTSD group. The latter findings support that NR3C1 methylation in mothers positively and statistically significantly correlates with NR3C1 methylation in their children only in presence of IPV-PTSD in the mothers. This maternal epigenetic signature with respect to this glucocorticoid receptor is significantly associated with child behavior that may well pose a risk for intergenerational transmission of violence and related psychopathology.
... This indicates the involvement of other epigenetic mechanisms when considering shared mother-child genes in neglectful contexts. Studies with target genes found significant motherchild correlation of stress-related genes in a single gene FKBP5, in Holocaust survivors (Yehuda et al., 2016) and in 5HTT and NR3C1 genes in a general population sample (Van Aswegen et al., 2021). In contrast, differential methylation of the OXTR and IGR oxytocin-related regions was only observed in the mothers exposed to perinatal depression compared to non-affected mothers, but differential methylation on those genes was not found in their children (King et al., 2017). ...
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Studies of DNA methylation have revealed the biological mechanisms by which life adversity confers risk for later physical and mental health problems. What remains unknown is the “biologically embedding” of maternal adverse experiences resulting in maladaptive parenting and whether these epigenetic effects are transmitted to the next generation. This study focuses on neglectful mothering indexed by a severe disregard for the basic and psychological needs of the child. Using the Illumina Human Methylation EPIC BeadChip in saliva samples, we identified genes with differentially methylated regions (DMRs) in those mothers with ( n = 51), versus those without ( n = 87), neglectful behavior that present similar DMRs patterns in their children being neglected versus non-neglected ( n = 40 vs. 75). Mothers reported the emotional intensity of adverse life events. After covariate adjustment and multiple testing corrections, we identified 69 DMRs in the mother epigenome and 42 DMRs in the child epigenome that were simultaneously above the α = 0.01 threshold. The common set of nine DMRs contained genes related to childhood adversity, neonatal and infant diabetes, child neurobehavioral development and other health problems such as obesity, hypertension, cancer, posttraumatic stress, and the Alzheimer’s disease; four of the genes were associated with maternal life adversity. Identifying a shared epigenetic signature of neglect linked to maternal life adversity is an essential step in breaking the intergenerational transmission of one of the most common forms of childhood maltreatment.
... Since epigenetic effects have been reported in literature in both adults' and children's problematic behavior, this raises the question of whether parents and children could have similar levels of methylation of stress-regulation-related genes. Therefore, Van Aswegen et al. [24] tested the convergence of mother and child epigenetic patterns in families, and their findings at least partially supported that child and parent methylation levels covary. ...
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Human parenting is a fundamental educational context including complex caregiving tasks finalized to nurture and protect young children [...]
Background: Although developmental supportive care is an effective approach to improve the long-term psychomotor and/or neurobehavioral function of preterm infants, very limited studies have focused on the impact of after-discharge developmental support. The underlying epigenetic changes are unclear. Purpose: This study aimed to explore the preliminary effect of an evidence-based Postdischarge Developmental Support Program (PDSP) on preterm infant neurodevelopment and underlying epigenetic changes, including brain-derived neurotrophic factor (BDNF) gene-related DNA methylation and expression. Methods: In this randomized controlled pilot trial, the preterm infant-parent dyads were randomized into either the intervention group/PDSP group (n = 22) or the control group/usual care group (n = 22). The neurodevelopmental outcomes of preterm infants were measured by Ages & Stages Questionnaires. Urine BDNF concentration level was tested by the enzyme-linked immunosorbent assay. Infant saliva specimens were collected to analyze the methylation level of BDNF gene promoter I at pre- and postintervention test. Results: After PDSP intervention, the total neurodevelopmental and the 5 domain scores of the PDSP group were all significantly higher than those of the control group (P< .05). The BDNF levels decreased significantly only within control group (P = .01). The difference in BDNF concentration and methylation levels between groups was not statistically significant. Implications for practice and research: Postdischarge Developmental Support Program may promote the neurodevelopment of preterm infants but has no effect on BDNF's expression and gene methylation level at 3 months of corrected age. The epigenetic mechanism of PDSP needs further study using a larger sample and longer follow-up.
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This paper presents an essay that uses an epigenetic approach to attain an inclusive and in-depth understanding of the influence of family context and quality of parenting on children’s psychological development. Based on the identification of a key developmental process in which interactions are continuously internalised, the approach draws attention to the bidirectional and systemic nature of intrafamily and parenting interactions and highlights the multiple factors that influence them, which are linked to the developmental history of the species, the individual characteristics of both the child and their parents, and contextual variables. In response to these internalised interactions, the body activates epigenetic mechanisms, such as DNA methylation, which may affect the phenotypic expression of the genome. Theoretical and methodological implications are discussed in light of the current process of identifying the biological profiles underlying negative and positive parenting practices. Some insights are offered regarding the challenges and opportunities that parents and policymakers should address in the 21st century in connection with the promotion of positive parenting, taking into account the epigenetic processes triggered by adverse environments for children and their families.
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Abstract While biological alterations associated with childhood maltreatment (CM) have been found in affected individuals, it remains unknown to what degree these alterations are biologically transmitted to the next generation. We investigated intergenerational effects of maternal CM on DNA methylation and gene expression in N = 113 mother-infant dyads shortly after parturition, additionally accounting for the role of the FKBP5 rs1360780 genotype. Using mass array spectrometry, we assessed the DNA methylation of selected stress-response-associated genes (FK506 binding protein 51 [FKBP5], glucocorticoid receptor [NR3C1], corticotropin-releasing hormone receptor 1 [CRHR1]) in isolated immune cells from maternal blood and neonatal umbilical cord blood. In mothers, CM was associated with decreased levels of DNA methylation of FKBP5 and CRHR1 and increased NR3C1 methylation, but not with changes in gene expression profiles. Rs1360780 moderated the FKBP5 epigenetic CM-associated regulation profiles in a gene × environment interaction. In newborns, we found no evidence for any intergenerational transmission of CM-related methylation profiles for any of the investigated epigenetic sites. These findings support the hypothesis of a long-lasting impact of CM on the biological epigenetic regulation of stress-response mediators and suggest for the first time that these specific epigenetic patterns might not be directly transmitted to the next generation.
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Polycyclic aromatic compounds (PACs) are known due to their mutagenic activity. Among them, 2-nitrobenzanthrone (2-NBA) and 3-nitrobenzanthrone (3-NBA) are considered as two of the most potent mutagens found in atmospheric particles. In the present study 2-NBA, 3-NBA and selected PAHs and Nitro-PAHs were determined in fine particle samples (PM 2.5) collected in a bus station and an outdoor site. The fuel used by buses was a diesel-biodiesel (96:4) blend and light-duty vehicles run with any ethanol-to-gasoline proportion. The concentrations of 2-NBA and 3-NBA were, on average, under 14.8 µg g⁻¹ and 4.39 µg g⁻¹, respectively. In order to access the main sources and formation routes of these compounds, we performed ternary correlations and multivariate statistical analyses. The main sources for the studied compounds in the bus station were diesel/biodiesel exhaust followed by floor resuspension. In the coastal site, vehicular emission, photochemical formation and wood combustion were the main sources for 2-NBA and 3-NBA as well as the other PACs. Incremental lifetime cancer risk (ILCR) were calculated for both places, which presented low values, showing low cancer risk incidence although the ILCR values for the bus station were around 2.5 times higher than the ILCR from the coastal site.
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DNA methylation is a vital modification process in the control of genetic information, which contributes to the epigenetics by regulating gene expression without changing the DNA sequence. Abnormal DNA methylation—both hypomethylation and hypermethylation—has been associated with improper gene expression, leading to several disorders. Two types of risk factors can alter the epigenetic regulation of methylation pathways: genetic factors and modifiable factors. Nutrition is one of the strongest modifiable factors, which plays a direct role in DNA methylation pathways. Large numbers of studies have investigated the effects of nutrition on DNA methylation pathways, but relatively few have focused on the biochemical mechanisms. Understanding the biological mechanisms is essential for clarifying how nutrients function in epigenetics. It is believed that nutrition affects the epigenetic regulations of DNA methylation in several possible epigenetic pathways: mainly, by altering the substrates and cofactors that are necessary for proper DNA methylation; additionally, by changing the activity of enzymes regulating the one-carbon cycle; and, lastly, through there being an epigenetic role in several possible mechanisms related to DNA demethylation activity. The aim of this article is to review the potential underlying biochemical mechanisms that are related to diet modifications in DNA methylation and demethylation.
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Background: Molecular aging biomarkers, such as epigenetic age predictors, predict risk factors of premature aging, and morbidity/mortality more accurately than chronological age in middle-aged and elderly populations. Yet, it remains elusive if such biomarkers are associated with aging-related outcomes earlier in life when individuals begin to diverge in aging trajectories. We tested if the Horvath epigenetic age predictor is associated with pubertal, neuroendocrine, psychiatric, and cognitive aging-related outcomes in a sample of 239 adolescents, 11.0-13.2 years-old. Results: Each year increase in epigenetic age acceleration (AA) was associated with 0.06 SD units higher weight-for-age, 0.08 SD units taller height-for-age, -0.09 SD units less missed from the expected adult height, 13 and 16% higher odds, respectively, for each stage increase in breast/genitals development on the Tanner Staging Questionnaire and pubertal stage on the Pubertal Development Scale, 4.2% higher salivary cortisol upon awakening, and 18 to 34% higher odds for internalizing and thought problems on the Child Behavior Checklist (p values < 0.045). AA was not significantly associated with cognition. Conclusions: Our findings suggest that already in adolescence, AA is associated with physiological age acceleration, which may index risk of earlier aging. AA may identify individuals for preventive interventions decades before aging-related diseases become manifest.
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DNA methylation is the most well studied of the epigenetic regulators in relation to environmental exposures. To date, numerous studies have detailed the manner by which DNA methylation is influenced by the environment, resulting in altered global and gene-specific DNA methylation. These studies have focused on prenatal, early-life, and adult exposure scenarios. The present review summarizes currently available literature that demonstrates a relationship between DNA methylation and environmental exposures. It includes studies on aflatoxin B1, air pollution, arsenic, bisphenol A, cadmium, chromium, lead, mercury, polycyclic aromatic hydrocarbons, persistent organic pollutants, tobacco smoke, and nutritional factors. It also addresses gaps in the literature and future directions for research. These gaps include studies of mixtures, sexual dimorphisms with respect to environmentally associated methylation changes, tissue specificity, and temporal stability of the methylation marks. Expected final online publication date for the Annual Review of Public Health Volume 39 is April 1, 2018. Please see for revised estimates.
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Background New efficient therapies for urothelial carcinoma (UC) are urgently required. Small-molecule drugs targeting chromatin regulators are reasonable candidates because these regulators are frequently mutated or deregulated in UC. Indeed, in previous work, Romidepsin, which targets class I histone deacetylases (HDAC), efficiently killed UC cells, but did not elicit canonical apoptosis and affected benign urothelial cells indiscriminately. Combinations of HDAC inhibitors with JQ1, an inhibitor of bromodomain-containing acetylation reader proteins like BRD4, which promote especially the transcription of pro-tumorigenic genes, have shown efficacy in several tumor types. We therefore investigated the effects of combined Romidepsin and JQ1 treatment on UC and benign urothelial control cells. Results JQ1 alone induced cell cycle arrest, but only limited apoptosis in eight UC cell lines with strongly varying IC50 values between 0.18 and 10 μM. Comparable effects were achieved by siRNA-mediated knockdown of BRD4. Romidepsin and JQ1 acted in a synergistic manner across all UC cell lines, efficiently inhibiting cell cycle progression, suppressing clonogenic growth, and inducing caspase-dependent apoptosis. Benign control cells were growth-arrested without apoptosis induction, but retained long-term proliferation capacity. In UC cells, anti-apoptotic and oncogenic factors Survivin, BCL-2, BCL-XL, c-MYC, EZH2 and SKP2 were consistently downregulated by the drug combination and AKT phosphorylation was diminished. Around the transcriptional start sites of these genes, the drug combination enhanced H3K27 acetylation, but decreased H3K4 trimethylation. The cell cycle inhibitor CDKN1C/p57KIP2 was dramatically induced at mRNA and protein levels. However, Cas9-mediated CDKN1C/p57KIP2 knockout did not rescue UC cells from apoptosis. Conclusion Our results demonstrate significant synergistic effects on induction of apoptosis in UC cells by the combination treatment with JQ1 and Romidepsin, but only minor effects in benign cells. Thus, this study established a promising new small-molecule combination therapy approach for UC. Electronic supplementary material The online version of this article (10.1186/s13148-017-0434-3) contains supplementary material, which is available to authorized users.
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The present study investigated the association of perinatal depression (PD) with differential methylation of 3 genomic regions among mother and child dyads: exon 3 within the oxytocin receptor (OXTR) gene and 2 intergenic regions (IGR) between the oxytocin (OXT) and vasopressin (AVP) genes. Maternal PD was assessed at 5 time-points during pregnancy and postpartum. Four groups were established based on Edinburgh Postnatal Depression Scale (EPDS) cut-off scores: no PD, prenatal or postpartum depressive symptoms only and persistent PD (depressive symptoms both prenatally and postpartum). Salivary DNA was collected from mothers and children at the final time-point, 2.9years postpartum. Mothers with persistent PD had significantly higher overall OXTR methylation than the other groups and this pattern extended to 16/22 individual CpG sites. For the IGR, only the region closer to the AVP gene (AVP IGR) showed significant differential methylation, with the persistent PD group displaying the lowest levels of methylation overall, but not for individual CpG sites. These results suggest that transient episodes of depression may not be associated with OXTR hypermethylation. Validation studies need to confirm the downstream biological effects of AVP IGR hypomethylation as it relates to persistent PD. Differential methylation of the OXTR and IGR regions was not observed among children exposed to maternal PD. The consequences of OXTR hypermethylation and AVP IGR hypomethylation found in mothers with persistent PDS may not only impact the OXT system, but may also compromise maternal behavior, potentially resulting in negative outcomes for the developing child.
Psychiatric disorders are clinically heterogeneous and debilitating chronic diseases resulting from a complex interplay between gene variants and environmental factors. Epigenetic processes, such as DNA methylation and histone posttranslational modifications, instruct the cell/tissue to correctly interpret external signals and adjust its functions accordingly. Given that epigenetic modifications are sensitive to environment, stable and reversible, epigenetic studies in psychiatry could represent a promising approach to better understand and treat disease. In the present review, we aim to discuss the clinical opportunities and challenges arising from the epigenetic research in psychiatry. Using selected examples, we first recapitulate key findings supporting the role of adverse life events, alone or in combination with genetic risk, in epigenetic programming of neuropsychiatric systems. Epigenetic studies further report encouraging findings about the use of methylation changes as diagnostic markers of disease phenotype and predictive tools of progression and response to treatment. Next, we discuss the potential of using targeted epigenetic pharmacotherapy, combined with psychosocial interventions, for future personalized medicine of patients. Finally, we review methodological limitations that could hinder interpretation of epigenetic data in psychiatry. They mainly arise from heterogeneity at the individual and tissue level and require future strategies in order to reinforce the biological relevance of epigenetic data and its translational use in psychiatry. Overall, we suggest that epigenetics could provide new insights into a more comprehensive interpretation of mental illness and might eventually improve the nosology, treatment, and prevention of psychiatric disorders.
In utero exposure to environmental stress in both animals and humans could result in long-term epigenome alterations and which further lead to consequences for adaptation and development in the offspring. Epigenetics, especially DNA methylation, is considered one of the most widely studied and well-characterized mechanisms involved in the long-lasting effects of in utero stress exposure. In this review, we outlined evidence from animal and human prenatal research supporting the view that prenatal stress could lead to lasting, broad and functionally organized signatures in DNA methylation which, in turn, could mediate exposure-phenotype associations. We also emphasized the advantage of using stressor from quasi-randomly assigned experiments. Furthermore, we discuss challenges that still need to be addressed in this field in the future.
The present meta-analysis integrates research from 1,435 studies on associations of parenting dimensions and styles with externalizing symptoms in children and adolescents. Parental warmth, behavioral control, autonomy granting, and an authoritative parenting style showed very small to small negative concurrent and longitudinal associations with externalizing problems. In contrast, harsh control, psychological control, authoritarian, permissive, and neglectful parenting were associated with higher levels of externalizing problems. The strongest associations were observed for harsh control and psychological control. Parental warmth, behavioral control, harsh control, psychological control, autonomy granting, authoritative, and permissive parenting predicted change in externalizing problems over time, with associations of externalizing problems with warmth, behavioral control, harsh control, psychological control, and authoritative parenting being bidirectional. Moderating effects of sampling, child’s age, form of externalizing problems, rater of parenting and externalizing problems, quality of measures, and publication status were identified. Implications for future research and practice are discussed.