Neuroscience Letters 685 (2018) 7–11

Contents lists available at ScienceDirect

Neuroscience Letters
journal homepage: www.elsevier.com/locate/neulet

Research article

Childhood trauma and emotion regulation: The moderator role of BDNF T

Val66Met
Mirela I. Bîlca, Romana Vulturara,b, Adina Chișa,b, Mădălina Buciumana, Daria Nuţua,
⁎
Ioana Buneaa, Aurora Szentágotai-Tătarc, Andrei C. Miua,
a
Cognitive Neuroscience Laboratory, Department of Psychology, Babeș-Bolyai University, Cluj-Napoca, Cluj, Romania
b
Department of Molecular Sciences, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Cluj, Romania
c
Department of Clinical Psychology and Psychotherapy, Babeș-Bolyai University, Cluj-Napoca, Cluj, Romania

A R T I C LE I N FO A B S T R A C T

Keywords: Emotion regulation difficulties have been involved in multiple forms of psychopathology and may represent an
Gene-environment interaction important focus for current efforts to understand the biological mechanisms underlying transdiagnostic symp-
Childhood trauma toms. The present study investigated a gene-environment interaction (G × E) in reappraisal, a form of emotion
Emotion regulation regulation that has been extensively linked to psychopathology. In light of recent meta-analytic evidence of its
Psychopathology
consistent role in depression and anxiety disorders, this study focused on the Val66Met (rs6265) single-nu-
cleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene and examined its moderator role in
the relation between childhood trauma and reappraisal. A sample of N = 266 participants were genotyped for
BDNF Val66Met, filled in a self-report measure of childhood trauma, and underwent a cognitive task designed to
assess reappraisal ability. The results indicated that, as expected, BDNF Val66Met was a significant moderator in
the relation between childhood trauma and reappraisal. There was a negative relation between the number of
childhood traumatic events and reappraisal ability in BDNF Met carriers, but not Val homozygotes. This finding
suggests that BDNF Val66Met contributes to susceptibility to childhood stress, with long term impact on emotion
regulation.

1. Introduction findings, genetic studies have investigated whether functional poly-

Extensive evidence indicates that emotion regulation problems are
implicated in multiple mental disorders [1]. In light of this evidence
and considering that recent efforts in psychopathology research have
called for an increased focus on transdiagnostic symptoms and their
underlying biological mechanisms [2], an increasing number of studies
have started to investigate gene-environment interactions (G × E) that
may contribute to emotion regulation [for review see 3,4]. This work
may shed light on the genetic factors moderating the relation between
environmental adversities and emotion regulation difficulties, which
may in turn contribute to risk for psychopathology [5].
One of the candidate genes that have been examined in relation to
emotion regulation is the brain-derived neurotrophic factor (BDNF).
This gene is widely expressed in the brain and its product molecule
plays an important role in neuron survival and neuroplasticity [6].
Moreover, the level of serum BDNF is reduced in depression [7] and it
has been argued that this neurotrophic disturbance may contribute to
the pathogenesis of stress-related disorders [8]. In light of these
morphisms such as BDNF Val66Met (rs6265) are associated with
psychopathology. BDNF Val66Met is a single-nucleotide poly-
morphism (SNP) that involves an adenine to guanine substitution in
exon 2, and results in a valine (Val) to methionine (Met) replacement
at codon 66 [9]. The Met allele is associated with reduced activity-
dependent secretion of BDNF in neurons [9], and has been associated
with multiple neural [10] and cognitive [11] phenotypes. Recent
meta-analyses have indicated that there is consistent evidence across
studies on the moderator role of BDNF Val66Met in the relation be-
tween stressful events and depression [12,13], as well as suicidal
behavior [14] and response to antidepressants [15]. These G × E
interactions in multiple phenotypes related to psychopathology may
be explained by their underlying effect on a transdiagnostic me-
chanism such as emotion regulation [5].
Several studies have indeed supported the association between
BDNF Val66Met and emotion regulation. Using self-report measures of
emotion regulation, it was found that BDNF Met carriers tend to use less
efficient, emotion- rather than problem-focused strategies [16], and

⁎
Correspondence to: 37 Republicii Street, 400015 Cluj-Napoca, Cluj, Romania.
E-mail address: andreimiu@psychology.ro (A.C. Miu).

https://doi.org/10.1016/j.neulet.2018.07.018
Received 29 January 2018; Received in revised form 9 July 2018; Accepted 10 July 2018
Available online 11 July 2018
0304-3940/ © 2018 Elsevier B.V. All rights reserved.
M.I. Bîlc et al.
show, for instance, enhanced anxious preoccupation [17] and avoid-
ance [18] in stressful situations. These individuals also display an in-
creased tendency to ruminate [19,20], a maladaptive emotion regula-
tion strategy that has been linked to depression. Importantly, the
highest levels of habitual rumination have been found in BDNF Met
carriers with a history of more stressful events [19], which underscores
the moderator role of this polymorphism in the relation between stress
and emotion regulation.
Recent developments in the emotion regulation field have tried to
overcome the limits of self-report measures, which may be increasingly
prone to recall or reporting biases [21]. For instance, cognitive tasks
have been designed in order to assess the ability of participants to
implement a specific emotion regulation strategy such as reappraisal,
which involves changing emotional responses by reformulating the
meaning of a situation [22]. Lower use of reappraisal is known to
characterize psychopathology [23] and it is this emotion regulation
strategy that is targeted in cognitive-behavioral psychotherapy in de-
pression and anxiety disorders [24]. Using a cognitive task, Miu et al.
[25] have recently reported for the first time that reappraisal ability is
reduced in BDNF Met carriers with a history of child maltreatment.
Provided that it is replicated, this result may have implications for
understanding G × E interactions that influence emotion regulation
and may contribute both to vulnerability for psychopathology, and
response to psychotherapy.
The present study was designed to replicate and extend, in an in-
dependent sample, the previous BDNF Val66Met × childhood stressful
events in emotion regulation. In addition to child maltreatment, other
types of childhood trauma were also assessed in order to explore the
extent of this effect. As previously [25], a reappraisal ability task was
used to evaluate emotion regulation, but the images used in this study
had higher resolution and were chosen to be more realistic.
2. Material and methods
2.1. Participants
Two hundred and sixty-six volunteers (218 women), aged 18–44
(M = 20.57, SD = 3.76 years), participated in this study. Participants
were recruited through campus and online advertisements and they
were all students at Babeș-Bolyai University. None of the participants
included in this replication sample were part of the prior study [25]. All
participants were Caucasians of European descent and Romanian was
their first language. The study protocol followed the recommendations
of the Declaration of Helsinki regarding participant safety and was
approved by the Ethics Committee of Babeș-Bolyai University.
2.2. Measures
2.2.1. Genotyping
DNA was extracted from buccal epithelial cells using the MasterPure
Complete DNA & RNA Purification Kit (Epicenter, Madison, USA) and
kept at −20 °C. BDNF Val66Met genotyping was performed using tetra
primer amplified refractory mutation system (ARMS)-PCR method [26],
as previously described [25]. Considering that the BDNF Met allele is
relatively rare (i.e., approximately 19%) in European samples [27], we
aimed at comparing Met carriers (i.e., Val/Met, Met/Met) and Val
homozygotes (i.e., Val/Val).
2.2.2. Childhood trauma
The Childhood Traumatic Events Scale [28] was used to investigate
the history of traumatic events before age 17: (1) violent events such as
physical abuse, mugging or assault; (2) sexual abuse, such as rape or
sexual molestation; (3) major parental conflicts; (4) death of a family
member or a very close person; (5) severe illness or injury; and (6) other
traumatic events, which were perceived as a major influence on per-
sonality and life trajectory. Participants reported whether or not they
8
Neuroscience Letters 685 (2018) 7–11
experienced each type of event and if they had, the approximate age at
which the event occurred, and they also rated its severity on a 7-point
Likert scale (1 = not at all traumatic, to 7 = extremely traumatic).
When other traumatic events were reported, participants described the
event and also rated its traumatic intensity. This measure of childhood
trauma has been previously related to depressive and anxiety symptoms
[e.g., 29] and showed sensitivity to G × E interactions relevant for
psychopathology [30].
2.2.3. Reappraisal ability
Reappraisal ability was assessed using a computerized cognitive
task similar to the one used in our previous study [25], and which has
been extensively employed in previous research [e.g., 31,32]. Briefly,
participants were presented with emotionally neutral and negative
images (10 s), preceded by one of two instructions (4 s): “Look”, which
cued participants to attend naturally to the subsequent image; and
“Decrease”, which cued them to use reappraisal in order to decrease the
emotional impact of the image. Before the task, reappraisal was ex-
plained and illustrated using examples such as finding a positive
meaning (e.g., “happy-end story”), adopting an objective perspective
(e.g., “you are a doctor or firefighter”) or detaching from emotional
content (e.g., “the image is not real”). Participants then practiced re-
appraisal during 6 learning trials, in which a trained experimenter of-
fered feedback and prompted them with alternative interpretations. The
experimenter conducting the reappraisal task was blind to participants’
genotype and childhood trauma measures. The actual task included 48
trials: 16 neutral images and 16 negative images preceded by the
“Look” instruction; and another 16 negative images preceded by the
“Decrease” instruction. Order of trials was randomized at the beginning
of the experiment and remained the same for all participants. After each
image, participants rated their emotional arousal using a 9-point Likert
scale (1 = low, to 9 = high). Images were selected from the Nencki
Affective Picture System [33], based on valence and arousal norms.
Neutral stimuli had significantly lower emotional arousal (t[45.72] =
−20.86, p < .001, d = 5.68) and higher (i.e., midrange) emotional
valence (t[44.77] = 37.28, p < .001, d = 10.5) than negative stimuli.
Emotional arousal and valence scores of negative emotional stimuli in
the Look and Decrease conditions were not significantly different (both
ps > 0.960). Reappraisal ability was estimated as the mean decrease in
negative affect when using reappraisal relative to passive looking (Look
Negative – Decrease Negative) [32], such that higher scores indicated
greater reappraisal ability or decreases in negative affect due to re-
appraisal.
2.3. Statistical analysis
In a preliminary analysis, chi-square tests were used to investigate
whether the genotype distribution departed from the Hardy-Weinberg
equilibrium [34]. In addition, we checked whether reappraisal was
associated with reduced emotional responses to negative images in the
task, using repeated measures ANOVA with condition (Look Neutral vs.
Look Negative vs. Decrease Negative) as within-subject factor. Where
Mauchly’s test indicated that the assumption of sphericity was violated,
Greenhouse-Geisser corrected degrees of freedom were used.
The main analysis investigated the interaction between BDNF
Val66Met and the number of childhood traumatic events on reappraisal
ability. We focused on the number rather than perceived severity of
traumatic events in order to avoid any potential overlap between the
latter and the emotional measures in the reappraisal task [35]. In ad-
dition, we aimed to investigate the global effect of childhood trauma,
rather than that of specific types of traumatic events. In a preliminary
step, we checked the relation between genotypes and childhood
trauma, to exclude a potential gene-environment correlation. Then, the
G × E interaction was tested using multiple regression analysis. To
control for the potential confounding effect of sex, both sex and its
interactions with genotype and childhood trauma were entered in the
M.I. Bîlc et al.
regression model [36]. All analyses were run in SPSS (IBM, Armonk,
NY, USA).
3. Results
3.1. Genotype distribution
Frequencies of the BDNF Val66Met genotypes in the present sample
were as follows: 162 Val homozygotes (Val/Val); 90 heterozygotes
(Val/Met); and 14 Met homozygotes (Met/Met). These genotypes were
in Hardy Weinberg equilibrium (χ2 = 0.11, p > .05). Considering the
small frequency of the BDNF Met allele (minor allele frequency
q = 0.22), Met carriers (i.e., Val/Met and Met/Met) were compared to
Val homozygotes in all subsequent analyses.
3.2. Childhood traumatic events
Participants reported between zero and six traumatic events. While
19.18% of participants reported no childhood trauma, the rest of par-
ticipants reported one (38.72%), two (21.80%), three (12.79%), four
(5.64%), five (1.50%) or six (0.37%) traumatic events. Given the lower
number of reports of more than three traumatic events, they were
collapsed in the same category. Therefore, participants with zero, one,
two, and three or more traumatic events were compared in all sub-
sequent analyses. Details on the specific types of traumatic events that
were reported, their perceived traumatic intensity and the self-reported
mean age at the time of trauma are described in the Supplementary
Material.
3.3. Reappraisal ability
A repeated measures ANOVA indicated significant differences in
emotional arousal between experimental conditions (F[1.95,
515.78] = 537.73, p < .001, ƞP2 = .67). Bonferroni post-hoc tests
showed that emotional arousal was significantly reduced in the
Decrease Negative (M = 3.98, SD = 1.61) compared to the Look
Negative (M = 4.80, SD = 1.61) condition. This confirmed that re-
appraisal of negative images reduced their emotional impact. As ex-
pected, emotional arousal was lowest in the Look Neutral condition
(M = 2.24, SD = 0.94).
3.4. Gene-environment interaction
Table 1 shows the distribution of BDNF Val66Met genotypes by
number of childhood traumatic events. The correlation between geno-
types and childhood trauma was not significant (r = 0.053, p = .387),
ruling out a potential gene-environment correlation.
The genotype × childhood trauma events in reappraisal ability was
investigated in a multiple regression model, in which BDNF Val66Met,
the number of childhood traumatic events and sex (women coded with
0; men coded with 1) were entered as predictors in the first step, and
their interactions were added in the second step (Table 2). Results in-
dicated a negative relation between sex and reappraisal ability, with
higher performance in women. While neither BDNF Val66Met, nor
Table 1
BDNF Val66Met genotypes by number of childhood traumatic events.
Number of childhood traumatic events
0 1 2 3+
BDNF Genotypes Met carriers 15 44 23 22
Val homozygotes 36 59 35 32
Note: 3+ indicates three or more childhood traumatic events.
9
Neuroscience Letters 685 (2018) 7–11
childhood trauma had a significant effect, their interaction was a sig-
nificant predictor of reappraisal ability.
A follow-up analysis, in which the mean severity of traumatic events
was used as covariate, confirmed that the BDNF Val66Met × childhood
trauma interaction remained significant: B = −0.410; SE(B) = 0.16;
p = 0.028; CI: −0.73, −0.08.
Slope analysis on the relation between childhood trauma and re-
appraisal ability in each genotype group indicated a significant negative
association between childhood trauma and reappraisal ability in BDNF
Met carriers (B = −0.304; SE(B) = 0.12; p = 0.019; CI: −0.56,
−0.04), but not Val homozygotes (B = 0.124; SE(B) = 0.09;
p = 0.205; CI: −0.06, 0.31) (Supplementary Fig. 1).
4. Discussion
The results of the present study indicate that BDNF Val66Met is a
moderator in the relation between childhood trauma and reappraisal
ability. As expected based on previous evidence, BDNF Met carriers, but
not Val homozygotes showed a negative association between the
number of childhood traumatic events and efficiency of reappraisal.
This study replicates our previous findings [25], which have shown
for the first time the interactive involvement of BDNF Val66Met and
childhood maltreatment in reappraisal. In both studies, reappraisal was
assessed using a cognitive task that has shown sensitivity to depressive
symptoms [37]. In the present study, as well as in previous research
[25,38], childhood trauma was not directly linked to reappraisal
ability. That is, only BDNF Met carriers with a history of childhood
trauma showed poor reappraisal efficiency. This may be explained by
the distal influence of childhood trauma, which may sensitize to sub-
sequent stressful events in the long term and may contribute to emo-
tional problems when acting in tandem with genetic factors [39,40]. To
date, the BDNF Val66Met × childhood stress in reappraisal ability has
been replicated in two independent samples [25; the present study] and
showed considerable statistical robustness given that different measures
of childhood stressful events and different sets of affective stimuli were
employed in the two studies. Notably, the stimuli used in the present
study have higher resolution compared to those used in our previous
work, and may have been perceived as more realistic [33]. The present
findings on reappraisal are also in line with previous evidence on BDNF
Val66Met × stress in rumination [19] and less efficient emotion-fo-
cused coping [17,18].
Having assessed a diverse array of stressful events, this study ex-
tends the previous evidence by showing that childhood trauma in-
cluding sexual and physical abuse, but also more common events such
as loss of a close person, parental conflicts, and severe illness or injury
in childhood, interact with BDNF Val66Met to influence emotion reg-
ulation. This is in line with previous work on psychopathology [e.g.,
29,41], which has suggested that both interpersonal (i.e., involving
intentional harm, such as childhood abuse and neglect) and non-in-
terpersonal (e.g., death of someone close, disease) trauma are asso-
ciated with internalizing symptoms.
The finding that BDNF Met carriers may be more sensitive to early
stressful events, with long term effects on emotion regulation, could be
explained by the role of the BDNF molecule in neural development and
neuroplasticity [6]. The Met allele is associated with reduced activity-
dependent secretion of BDNF [9], which may enhance the stress vul-
nerability of developing neural structures involved in emotion regula-
tion, including emotional brain hubs such as the hippocampus, amyg-
dala and prefrontal cortex [42]. Reappraisal ability has been
consistently associated with activity in these brain areas [31,32] and
the present focus on this measure may have contributed to the success
of capturing the interaction between BDNF Val66Met and childhood
trauma. Indeed, reappraisal ability may represent an intermediate
phenotype that is more sensitive to G × E interactions than more global
symptoms or psychiatric diagnostic categories [43,44]. In addition, this
intermediate phenotype may show transdiagnostic value considering
M.I. Bîlc et al.
Table 2
Regression coefficients for the effects of BNDF Val66Met and childhood trauma on reappraisal ability.
Model
Step 1 BDNF Val66met
Number of childhood traumatic events
Sex (0 = women; 1 = men)
Step 2 BDNF Val66Met × Number of childhood traumatic events
BDNF Val66Met × Sex
Number of childhood traumatic events × Sex
BDNF Val66Met × Number of childhood traumatic events × Sex
Note: B = unstandardized regression coefficient; SE (B) = standard error ; Beta = standardized regression coefficient; R2 = proportion of variance explained.
that difficulties with reappraisal characterize multiple mental disorders
[1,23]. In light of the present findings, BDNF Met carriers may carry the
highest risk of emotion regulation difficulties following early stress, but
they may also show the highest sensitivity to interventions targeting
reappraisal, such as cognitive-behavioral psychotherapy [24]. Indeed,
our previous study has suggested that BDNF Met carriers can show both
the lowest and highest level of reappraisal ability, depending on whe-
ther they were exposed to major stressful events in childhood. Further
research on BDNF Val66Met as a “plasticity gene” [45], which could be
involved in the response to psychotherapeutic interventions [46], is
warranted in the future.
We acknowledge that the sample size in this study is not ideal for
detecting the typically small effects of genetic polymorphisms.
However, having used a performance-based measure of emotion reg-
ulation, which is more time consuming than self-report questionnaires,
precluded us from of recruiting a larger sample in this study. In defense
of the present results, we argue that the BDNF Val66Met × childhood
trauma was replicated in two independent samples [25; the present
study]. Moreover, this G × E interaction has been consistently linked to
depression in recent meta-analyses [12,13]. Finally, given that the
present measure of reappraisal ability was based on self-report ratings
of emotional arousal, which could be susceptible to desirability biases,
future studies could include a physiological correlate of emotional
arousal [37].
5. Conclusion
In conclusion, the present results suggest that BDNF Met carriers
may be particularly vulnerable to childhood trauma, showing a dose-
response effect of the number of early stressful events on emotion
regulation ability.
Acknowledgements
This work was supported by the Romanian National Authority for
Scientific Research, CNCS – UEFISCDI (grant number PN-III- ID-PCE-
2016-4- 0864).
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the
online version, at doi:https://doi.org/10.1016/j.neulet.2018.07.018.
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