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European Archives of Psychiatry and Clinical Neuroscience (2020) 270:541–551
https://doi.org/10.1007/s00406-019-01013-0

O R I G I N A L PA P E R

Maternal verbal aggression in early infancy and child’s internalizing
symptoms: interaction by common oxytocin polymorphisms

Laetitia J. C. A. Smarius1,2,3  · Thea G. A. Strieder4 · Theo A. H. Doreleijers3 · Tanja G. M. Vrijkotte1 ·
M. Hadi Zafarmand1,5 · Susanne R. de Rooij1,5

Received: 29 October 2018 / Accepted: 16 April 2019 / Published online: 7 May 2019
© The Author(s) 2019

Abstract
Genetic predisposition of social sensitivity might affect vulnerability to develop psychopathology after early life stress
exposure. This study examined whether maternal verbally aggressive behavior in early infancy interacts with oxytocin
polymorphisms in developing internalizing symptoms at ages 5–6 and 11–12. In the Amsterdam-Born-Children-and-their-
Development (ABCD) study, a large observational, population-based birth cohort, maternal verbally aggressive behavior
was assessed in the 13th postnatal week by a self-report questionnaire. Internalizing symptoms at age 5–6 were assessed by
maternal report (N = 969) and internalizing symptoms at age 11–12 were assessed by self-report (N = 750). Data on oxytocin
receptor polymorphisms rs53576 and rs2268498 and oxytocin polymorphisms rs2740210 and rs4813627 were collected.
If the child was carrier of rs2740210 CA/AA polymorphism, exposure to maternal verbally aggressive behavior (10.6%)
was positively associated with general anxiety at age 5–6 and emotional symptoms at age 11–12 (p for interaction = 0.011
and p = 0.015, respectively). If the child was carrier of rs4813627 GG (wild type), exposure to maternal verbally aggressive
behavior was negatively associated with anxiety sensitivity and emotional symptoms at age 11–12 (p for interaction = 0.011
and p = 0.022, respectively). After exposure to maternal verbally aggressive behavior in early infancy, oxytocin polymor-
phisms may partly determine a child’s vulnerability to internalizing symptoms.

Keywords Verbal abuse · rs53576 · rs2268498 · rs2740210 · rs4813627 · Infant

Introduction

Since vocalizations may be as important as touch to the
neuroendocrine regulation of social bonding [1], maternal
verbally aggressive behavior can be considered stressful to
the infant. The developing brain is most vulnerable for envi-
ronmental influences at periods of rapid growth and develop-
ment, such as early infancy. The striatum, part of the dopa-
mine, serotonin, glucocorticoid, GABA-nergic, and affiliated
oxytocin pathways, can be considered as a central entry port
for processing emotional/motivational information [2]. The
striatum and its massive projections from the frontal cortex,
amygdala ,and hippocampus [3, 4] are involved in detecting
attachment-relevant cues, in appraising their valence, and in
guiding action by coding the affective attributes of stimuli
[5, 6]. Synaptogenesis in the striatum is most rapid between
2–4 months of age and total gray matter volume reaches
adult size at about 4 months of age [7], both of which impli-
cate the relevance of stress in this period of life. The stria-
tum consists of the ventral striatum (nucleus accumbens and

Electronic supplementary material The online version of this
article (https ://doi.org/10.1007/s0040 6-019-01013 -0) contains
supplementary material, which is available to authorized users.

* Laetitia J. C. A. Smarius
laetitiasmarius@online.nl

1 Department of Public Health, Amsterdam Public
Health Research Institute, Academic UMC, University
of Amsterdam, PO Box 22660, 1100 DD Amsterdam,
The Netherlands

2 Academic Center for Child and Adolescent Psychiatry de
Bascule, Amsterdam, The Netherlands

3 Department of Child and Adolescent Psychiatry, Amsterdam
UMC, location VU University Medical Center, Amsterdam,
The Netherlands

4 Arkin Institute for Mental Health, Amsterdam,
The Netherlands

5 Department of Clinical Epidemiology, Biostatistics
and Bio-informatics, Amsterdam UMC, University
of Amsterdam, Amsterdam, The Netherlands

http://orcid.org/0000-0002-6145-8037

http://crossmark.crossref.org/dialog/?doi=10.1007/s00406-019-01013-0&domain=pdf

https://doi.org/10.1007/s00406-019-01013-0

542 European Archives of Psychiatry and Clinical Neuroscience (2020) 270:541–551

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olfactory tubercle) and dorsal striatum (caudate nucleus and
putamen) and is activated by unexpected or intense stimuli
[8]. The impact of maternal verbally aggressive behavior on
child development during this early infancy period could be
considerable.

Retrospective evidence shows that verbal abuse during
childhood has been associated with various psychiatric dis-
orders in adulthood: mood and anxiety disorders, eating
disorders, substance abuse disorders, personality disorders,
and schizophrenia [9]. Moreover, in a study of 9–12 year old,
any level of maternal verbal aggression greater than one or
two instances per year has been associated with depressive
symptoms, delinquency, peer overt and relational victimiza-
tion, and low self-esteem in pre-adolescence [10]. Impor-
tantly, parental threatening, hostile, and rejecting behaviors
have been shown to predict overall anxiety sensitivity (AS)
[11], which is an important contributor in the association
between abuse and the development of borderline personal-
ity disorder symptoms [12]. Verbal abuse may particularly
influence risk for internalizing disorders, as verbal abuse
influences the development of a self-critical style [13].

Although verbal abuse is an important aetiopathogenic
factor in the development of several psychiatric phenotypes,
children are affected in various ways; some children even
show remarkable resilience. Differences in vulnerability or
resilience are related to protective environmental factors dur-
ing development, including parental or non-parental support,
and biological inborn differences in genetic profile [14]. The
extent to which maternal verbally aggressive behavior in
infancy is experienced as stressful and hereby potentially
affects internalizing symptoms might partly depend on
infant’s genetic make-up. Candidates for gene-environment
interaction would be a number of single-nucleotide poly-
morphisms (SNPs) in the oxytocin (OXT) gene and oxytocin
receptor (OXTR) gene, due to their differential associations
with social sensitivity.

G-allele carriers of rs53576, located in the third intron
of the OXTR gene, have been associated with increased
empathic abilities [15]. Recently, the rs53576 G-allele has
been associated with increased amygdala responsiveness to
emotional facial expressions [16], compared to the A-allele,
implying differences in arousal depending on OXTR variant.
Of note, evidence of gene-environment interaction of early
life stress and rs53576 is contradictory and solely based on
retrospective recall. After several kinds of maltreatment in
childhood (emotional, physical or sexual abuse; emotional
or physical neglect), G-allele carriers have shown increased
depressive symptoms [17, 18], and conduct problems (in
females only) [19] and GG carriers showed a higher risk
of emotional dysregulation [20], compared to A-carriers.
However, a study on adults with clinically diagnosed depres-
sion and anxiety disorders showed no interaction of rs53576
with one or more types of childhood maltreatment [21].

Another candidate OXTR polymorphism is rs2268498.
Compared to those carrying C alleles, T-allele (TT/TC)
carriers have been demonstrated to have better recognition
of facial emotion [22] and self-reported empathy [23, 24].
In addition, two specific OXT polymorphisms, rs2740210,
and rs4813627, located in an intron, have been found associ-
ated with maternal infant-directed vocalizing (duration) or
exaggerated prosodic cues [25]. It is unclear which infant’s
phenotype is associated with these OXT polymorphisms,
because their phenotypes have only been investigated in
mothers. Although speculative, it is plausible that rs2740210
and rs4813627 are not only related to social functions in
the mothers, but to social functions in the infants as well.
In the present study, it is hypothesized that infants might
experience maternal verbally aggressive behavior differently
depending on OXTR or OXT polymorphisms. We specifi-
cally expected that infants carrying OXTR rs53576 GG or
rs2268498 TT/TC variant, who are more apt at recognizing
facial emotions, experience more stress in response to mater-
nal verbally aggressive behavior and display more internal-
izing symptoms both at age 5–6 and at age 11–12, compared
to infants carrying, respectively, GA/AA or CC variant. We
also explored whether exposed infants carrying one of the
different variants of OXT rs2740210 or rs4813627 were
more or less vulnerable to internalizing symptoms, com-
pared to exposed infants carrying the other variant.

Materials and methods

Participants

The study sample is part of a large prospective, obser-
vational, population-based multiethnic birth cohort, the
Amsterdam Born Children and their Development (ABCD)
study, which started in 2003. Extensive information about
the cohort and procedures regarding data collection has
been published elsewhere [26]. Approval of the study was
obtained from the Central Committee on Research involving
Human Subjects in The Netherlands, the Medical Ethical
Committees of participating hospitals, and the Registration
Committee of the Municipality of Amsterdam. Approval of
the ABCD-Genetic Enrichment (ABCD-GE) study, a sub-
study of 1192 white children, was obtained from the Medi-
cal Ethical Committees of the Academic Medical Centre in
Amsterdam. For the ABCD-GE study, an opt out procedure
was followed. Written informed consent was obtained from
all participating mothers and from children aged 12 or older.

Between January 2003 and March 2004, all pregnant
women living in Amsterdam were asked to participate in the
ABCD study during their first prenatal visit to an obstetric
care provider. Figure 1 shows a flow chart of characteristics
of the participants included in the present study. Multiple

543European Archives of Psychiatry and Clinical Neuroscience (2020) 270:541–551

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Age 5-6 health checks

N= 3287 (40%)

ABCD-Genetic Enrichment study in
Dutch children

N=1192 (14%)

————————————————-PHASE I —————————————————-

————————————————-PHASE II —————————————————

————————————————-PHASE III ————————————————–

————————————————-PHASE IV ————————————————–

* attrition at this stage due to withdrawal, infant or maternal death, and unknown address or emigration

Pregnancy questionnaire

N= 8266 (100%)

Permission for follow-up

N= 6735 (81%)

Excluding: Liveborn multiples

N= 132

Infancy questionnaire singleton

N= 5131 (62%)

Mothers retrieved after 5 years*

N= 6161 (75%)

Maternal reports at age 5

N= 4488 (54%)

Maternal reports (both infancy and age 5-6)

N= 3781 (46%)

Excluding: prematures (N=176),

congenital diseases (N=124)

Complete data

N= 969 (12%) at age 5-6

N=750 (9%) SDQ emotional symptoms at age 11-12

N=689 (8%) anxiety sensitivity at age 11-12

Maternal report at age 11-12: N= 2997

Child self-report at age 11-12: N= 3018

Fig. 1 Flow chart of participants included for analysis; * attrition at this stage due to withdrawal, infant or maternal death, and unknown address
or emigration

544 European Archives of Psychiatry and Clinical Neuroscience (2020) 270:541–551

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births were excluded from the cohort preceding the third
phase. For the ABCD-GE study, blood of the child was col-
lected from a simple finger prick during the 5-year health
check-up. DNA was extracted from the dried blood spots.
Data on the first three measurements (pregnancy, infancy,
and early childhood) had to be available to be included in
the present study. We excluded preterm births (gestational
age < 37 weeks) and congenital diseases (N = 969 included). At age 11–12, 689 children and mothers were included in anxiety sensitivity analyses and 750 in SDQ emotional symptoms analyses.

Maternal verbally aggressive behavior in infancy

Maternal verbally aggressive behavior was assessed by
maternal self-report completed in the 13th week after birth
(mean 13th week, range 11–25 weeks, and SD 2 weeks),
by a question on frequency of speaking angrily on a six
point scale: ‘Have you ever spoken angrily to your baby to
diminish the crying?’ The score was dichotomized [speaking
angrily (frequency ≤ 1 or ≥ 2)]. Maternal verbally aggres-
sive behavior was considered present if speaking angrily had
been present at least twice [27].

Internalizing symptoms at age 5–6 and at age 11–12

Emotional symptoms were assessed by maternal report at
age 5–6 and by self-report at age 11–12, using the emotional
symptoms subscale of the Dutch translation of Goodman’s
Strengths and Difficulties Questionnaire (SDQ) [28], a short-
screening questionnaire suitable for 4–16 years. Children’s
general anxiety at age 5–6 was assessed by maternal report,
using the generalized anxiety subscale of the validated Pre-
school Anxiety Scale (PAS) [29]. Pre-adolescent anxiety
sensitivity was assessed by self-report at age 11–12, using
the anxiety sensitivity subscale of the Substance Use Risk
Profile Scale (SURPS) [30].

Genotyping

DNA samples were genotyped using the Illumina Human
Core Exom Beadchip (Illumina, San Diego, CA, USA),

which includes over 540,000 genetic markers. Before
imputation, SNPs were excluded if they had high levels of
missing data (SNP call rate < 95%), strong departures from Hardy–Weinberg equilibrium (p < 1 × 10−6), or low Minor allele frequencies (MAF) ( < 1%). Individuals were excluded if mismatch in heterozygosity, gender, or relatedness existed. Genetic markers were imputed using the IMPUTE2 software and the 1000 Genomes References Panel (phase 1 release v3, build 37). Genotypes for the SNPs of interest were extracted from the imputed genome-wide association study (GWAS) data set. The final number of SNPs was 277,644. The total of SNPs after imputation was 27,448,454. We performed post- imputation quality control and removed monomorphic vari- ants (MAF = 0), as well as variants which were extremely rare in the cohort (MAF < 1%). Using the IMPUTE2-INFO metrics, the commonly used > 0.4 threshold [31] was effi-
cient to discriminate between well and poorly inferred geno-
types at the MAF ≥ 1 in our sample. Based on literature on
sample size, statistics, and selection of SNPs in genetic epi-
demiologic studies [32–35], a maximum of four SNPs were
selected. These SNPs have previously been associated with
either recognition of facial emotions or vocalizing and have
a MAF > 0.25, hereby suiting the power of our study. A car-
rier model was chosen to compare the variants differentially
known to be associated with recognition of facial emotions
[OXTR rs53576 (GG vs. GA/AA) or rs2268498 (TT/TC
vs. CC)] or duration of vocalizing (OXT rs2740210 (CC vs.
CA/AA) or rs4813627 (GG vs. GA/AA). The mean quality
of the imputed genotypes (r2) of the 4 SNPs included in this
study (rs53576, rs2268498, rs2740210, and rs4813627) was
0.82, ranging from 0.75 to 0.87 (Table 1). Using a whole
genome association analysis Java-based toolset (PLINK),
none of the selected SNPs were in pairwise linkage dise-
quilibrium (R2 = 0.31 and 0.28 for rs53576/rs2268498 and
rs2740210/rs4813627, respectively).

Covariates

Infant characteristics included sex, birth weight, gestational
age, and excessive crying [36]. The following maternal char-
acteristics were assessed during pregnancy: age, parity (0
or ≥ 1), cohabitation status (single or living with partner),

Table 1 Oxytocin
polymorphism variants and
imputation quality

MAF minor allele frequency, HWE Hardy–Weinberg equilibrium

Chr rs_id Bp position Minor/
major
allele

MAF Coded allele Quality of
imputation

Certainty HWE

p value

3 rs53576 8804371 A/G 0.35 G 0.87 0.925 0.52
3 rs2268498 8812411 C/T 0.45 C 0.87 0.916 0.91
20 rs2740210 3053255 A/C 0.30 A 0.75 0.866 0.73
20 rs4813627 3055513 A/G 0.50 G 0.77 0.851 0.19

545European Archives of Psychiatry and Clinical Neuroscience (2020) 270:541–551

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and level of education (years after primary school). During
infancy, maternal smoking at home (yes or no), maternal
depressive symptoms (Center for Epidemiologic Studies
Depression Scale (CES-D), total score [37], and maternal
physical aggressive behavior [27] were included. Pleasure
in infant care was measured using five questions on a four
point scale [27].

Covariates at age 5 included: authoritarian parenting
style [12-items subscale of the short version of the Parent-
ing Styles and Dimensions Questionnaire (PSDQ)] [38, 39],
maternal parenting stress (9 items on attachment derived
from the 123 items of the ‘Nijmeegse Ouderlijke Stress
Index’ (NOSI-K) [40] and maternal depressive symptoms
(depression severity subscale of the Depression Anxiety
Stress Scales (DASS 21) [41], all of which were analyzed
continuously. Whether the child was being raised in an
intact family (a family in which the child lives with both
biological parents in the same house: yes or no) was assessed
by one item, both at age 5–6 and age 11–12. Covariates
at age 11–12 included: Tanner’s pubertal stage, maternal
authoritarian parenting style (PSDQ), and parenting stress
(NOSI-K).

Statistical analyses

Associations between descriptive characteristics and
maternal verbally aggressive behavior were tested using
ANOVA and Chi-square tests. Associations between the
different polymorphisms and maternal verbally aggressive
behavior were tested using Chi-square tests. Medians of
general anxiety, anxiety sensitivity, and both SDQ emo-
tional symptoms at age 5–6 and at age 11–12 according
to genotype variant were examined using Mann–Whitney
test. As the distribution of the outcome variables was
highly skewed, and transformation did not normalize this,
we analyzed the rank variables of general anxiety, anxi-
ety sensitivity, and SDQ emotional symptoms scores by
means of rank regression [42]. Because the results of rank
regression analyses are difficult to interpret, we showed
the results of the multivariable linear regression of the
outcome variables in Supplementary Tables as well.
Potential confounders were selected a priori from Table 2
and included in the regression model using a forced-entry
method. We always corrected for sex. In addition, we
selected covariates, which were significantly associated
with maternal verbally aggressive behavior. We decided
to select authoritarian parenting style and parenting stress
at age 5–6 only, because we expected those variables to be
more relevant in the development of internalizing symp-
toms than those variables at age 11–12. After initial testing
in a univariate model (Crude Model), the following covar-
iates were added to an adjusted model (Model 1): sex,
maternal depressive symptoms, pleasure in infant care, and

physically aggressive behavior in infancy. Finally, authori-
tarian parenting style, maternal depression, and parenting
stress at the age of 5–6 were added to the fully adjusted
model (Model 2). Interaction terms of maternal verbally
aggressive behavior and variants of OXTR rs53576 (GG
vs. GA/AA) or rs2268498 (TT/TC vs. CC) and maternal
verbally aggressive behavior and OXT rs2740210 (CC vs.
CA/AA) or rs4813627 (GG vs. GA/AA) were added to
the fully adjusted model to investigate gene-environment
interaction. In addition, the data were stratified into two
groups: presence or absence of the risk alleles and ana-
lyzed separately according to the above model. The sig-
nificance level we used in the study was 5%.

Results

Subjects’ characteristics

The characteristics of both mothers and children are pre-
sented in Table 2. Of the 969 included children, 103 (10.6%)
had been exposed to maternal verbally aggressive behavior.
Compared to mothers of non-exposed children, mothers
of exposed children reported more depressive symptoms,
less pleasure in infant care, and more physical aggressive
behaviour in infancy, and prevalence of bipolar disorder or
a history of depressive or anxiety disorder was higher. At
the child’s age of 5–6, mothers of exposed children reported
more depressive symptoms, more parenting stress, and
more often used an authoritarian parenting style, compared
to mothers of non-exposed children. At the child’s age of
11–12, mothers of exposed children reported more parenting
stress, and more often used an authoritarian parenting style,
compared to mothers of non-exposed children.

Maternal verbally aggressive behavior and child’s
OXTR and OXT variants

Maternal verbally aggressive behavior in infancy was neither
associated with infant’s OXTR nor OXT variants (Table 3).

OXTR, OXT variants, and median score
of internalizing symptoms at age 5–6 and age 11–12

Median scores of general anxiety, anxiety sensitivity and
SDQ emotional symptoms at age 5–6 and age 11–12 are
shown in Table 3. Only genotype variant rs4813627 AA
was significantly associated with a lower median score of
SDQ emotional symptoms at age 11–12 (Mann–Whitney
p = 0.009).

546 European Archives of Psychiatry and Clinical Neuroscience (2020) 270:541–551

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Maternal verbally aggressive behavior
and internalizing symptoms at age 5–6 and age
11–12

Results from the rank regression showed that maternal verbally
aggressive behavior was not associated with general anxiety,
neither univariably (Crude model) (B = 29.8; 95% CI [(− 22.4;
82.0]), nor multivariable (Model 2) (B = 22.5; 95% CI [− 33.3;
78.4]). Maternal verbally aggressive behavior was neither
associated with SDQ emotional symptoms at age 5–6, neither
univariably (Crude model) (B = 0.0; 95% CI [− 52.5; 52.5]),
nor multivariable (Model 2) (B = − 20.6; 95% CI [− 76.2;
35.0]) nor at age 11–12, neither univariably (Crude model)

(B = − 2.6; 95% CI [− 51.1; 45.9]), nor multivariable (Model 2)
(B = − 4.2; 95% CI [− 55.6; 47.2]). Finally, maternal verbally
aggressive behavior was not associated with anxiety sensitivity
at age 11–12, neither univariably (Crude model) (B = 3.3; 95%
CI [− 43.7; 50.4]), nor multivariable (Model 2) (B = 0.7; 95%
CI [− 48.7; 50.1]) (Table S1).

OXTR and OXT variants, maternal verbally
aggressive behavior, and internalizing symptoms
at age 5–6

Results from the rank regression showed that exposed carri-
ers of rs2740210 CA/AA showed increased general anxiety

Table 2 Characteristics of 969 Dutch women and their children according to maternal verbally aggressive behavior in early infancy (N = 103)

N 969 Full sample
% or mean (SD)

No maternal verbal
aggression to infant
N = 866 (89.4%)

Maternal verbal aggres-
sion to infant
N = 103 (10.6%)

p value

Child characteristics
 Gender (% female) 504 52.0 52.1 51.5 0.91
 Birth weight (g) 969 3568 (477) 3561 (479) 3626 (459) 0.19
 Gestational age (weeks) 969 39.7 (1.2) 39.7 (1.2) 39.7 (1.1) 0.89
 Excessive crying (% yes) 17 1.8 1.6 2.9 0.34

Maternal characteristics
 Parity (% primipara) 535 55.2 54.7 59.2 0.39
 Maternal age (years) 969 33.0 (4.0) 33.1 (4,0) 32.5 (4.0) 0.13
 Cohabitancy (% living with partner) 899 93.0 92.9 93.1 0.94
 Education (years after primary school) 967 10.7 (3.0) 10.8 (2.9) 10.4 (3.0) 0.25

Maternal psychiatric history
 Autistic disorder 968 0.0 0.0 0.0 n.a.
 ADHD 967 0.6 0.0 0.7 0.51
 Schizophrenia 967 0.1 0.1 0.0 0.89
 Bipolar disorder 968 0.5 0.2 2.9 0.01
 Depressive disorder 968 15.3 14.1 25.2 0.004
 Anxiety disorder 966 6.8 6.0 13.6 0.007

Maternal factors in infancy
 Depressive symptoms 968 7.8 (6.3) 7.4 (6.1) 11.1 (7.1) < 0.001  Pleasure in infant care 964 5.9 (1.4) 5.8 (1.4) 6.5 (1.7) < 0.001  Smoking at home (% yes) 37 3.8 4.0 1.9 0.29  Physically aggressive behavior 969 3.0 (0.2) 3.0 (0.1) 3.2 (0.5) < 0.001

Child age 5–6
 Intact family (% yes) 867 89.6 90.0 85.4 0.15
 Authoritarian parenting style 941 4.7 (2.6) 4.7 (2.6) 5.3 (2.8) 0.03
 Maternal depressive symptoms 941 0.9 (1.8) 0.8 (1.7) 1.5 (2.4) < 0.001  Parenting stress 834 11.5 (2.7) 11.4 (2.7) 12.1 (3.0) 0.01

Child age 11–12 years
 Puberty, Tanner stage 3 48 6.9 40 (6.5) 8 (9.9) 0.31

Child age 11–12
 Authoritarian parenting style 709 1.3 (0.2) 1.3 (0.2) 1.4 (0.2) 0.001
 Parenting stress 707 24.2 (7.2) 23.9 (7.0) 26.8 (8.7) 0.001
 Intact family (% yes) 612 79.3 79.6 76.5 0.291

547European Archives of Psychiatry and Clinical Neuroscience (2020) 270:541–551

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problems at age 5–6 and SDQ emotional symptoms at age
11–12, compared to unexposed carriers of rs2740210 CA/
AA (p value for interaction p = 0.011 and p = 0.015, respec-
tively) (Fig. 2a, b). Exposed carriers of rs4813627 GG (the
wild type) showed decreased anxiety sensitivity and SDQ-
emotional symptoms at age 11–12, compared to unexposed
carriers of rs4813627 GG (p value for interaction p = 0.011
and p = 0.023, respectively) (Fig. 2c, d). There was no sig-
nificant interaction between exposure and rs53576 GG or
rs2268498 TT/TC on internalizing outcomes (Table S2).

Discussion

Our study shows novel evidence, suggesting that OXT poly-
morphisms might influence the vulnerability or resilience
to develop internalizing symptoms in childhood and pre-
adolescence, after exposure to maternal verbally aggressive
behavior in early infancy. In line with our hypothesis, we
found evidence for gene-environment interaction of OXT
polymorphisms previously shown to be associated with
duration of maternal vocalization [25]. Our results suggest
that carrying OXT variant rs2740210 CA/AA increases the
risk to develop general anxiety problems at age 5–6 and
SDQ-emotional symptoms at age 11–12, after exposure to
maternal verbally aggressive behavior. Interestingly, carri-
ers of OXT variant rs4813627 GG are suggested to benefit

from maternal verbally aggressive behavior, as these carri-
ers show decreased anxiety sensitivity and SDQ emotional
symptoms at age 11–12, after exposure to maternal verbally
aggressive behavior, compared to GA/AA carriers. Thus,
both wild types of the child’s OXT variants, shown to be
associated with longer duration of vocalizing in mothers,
seem protective after exposure to maternal verbally aggres-
sive behavior. Although children’s phenotype of these OXT
SNPs is unknown until now, we would like to elaborate on
our findings in this discussion. Prosody, defined as variations
in rhythm, intonation, and pitch, is a feature of mammalian
vocalization which communicates emotional charges and
affective state [43]. Although speculative, it is possible that
carriers of the OXT wild type differ from the risk carriers
in seeking communication, in the ability to reorient to (or
filter out) salient stimuli and possibly in OXT release. Sub-
sequently, programming effects of the OXT, and communi-
cating systems, might differentially occur. Of note, no main
effect was found of maternal verbally aggressive behavior
and internalizing symptoms both at age 5–6 and age 11–12,
contrarily to other studies on parental verbal aggression in
childhood [9, 10, 11]. Importantly, we did not investigate
persistent maternal verbally aggressive behavior to the child.
On the contrary, we aimed to focus on the single stressor of
maternal verbal aggressive behavior in early infancy.

Our null findings on OXTR variants rs53576 and
rs2268498 are in contrast with our hypothesis and the studies

Table 3 OXTR and OXTP genotype variants according to maternal verbally aggressive behavior in infancy, general anxiety, SDQ emotional
symptoms by maternal report at age 5–6, and anxiety sensitivity and SDQ emotional symptoms by self-report at age 11–12

* < 0.05; ** < 0.01; *** < 0.001

N (%) No maternal verbally
aggressive behavior
N (%)

Maternal verbally
aggressive behavior
N (%)

General
anxiety
Age 5–6
Median

SDQ emotional
symptoms
Age 5–6
Median

Anxiety
sensitivity
Age 11–12
Median

SDQ
emotional
symptoms
Age 11–12
Median

OXTR rs53576
 GG (wild type) 406 (41.9) 366 (42.3) 40 (38.8) 0.0 1.0 1.8 2.0
 GA 459 (47.4) 412 (47.6) 47 (45.6) 0.0 0.0 1.8 1.0
 AA 104 (10.7) 88 (10.2) 16 (15.5) 0.0 0.0 1.8 1.0

OXTR rs2268498
 TT (wild type) 287 (29.6) 260 (30) 27 (26.2) 0.0 0.0 1.8 2.0
 TC 487 (50.3) 430 (49.7) 57 (55.3) 1.0 1.0 1.8 2.0
 CC 195 (20.1) 176 (20.3) 19 (18.4) 0.0 0.0 1.8 1.0

OXTP rs2740210
 CC (wild type) 475 (49.0) 417 (48.2) 58 (56.3) 0.0 0.0 1.8 2.0
 CA 404 (41.7) 369 (42.6) 35 (34.0) 1.0 1.0 1.8 2.0
 AA 90 (9.3) 80 (9.2) 10 (9.7) 0.0 0.0 1.7 1.0

OXTP rs4813627
 GG (wild type) 275 (28.4) 245 (28.3) 30 (29.1) 0.0 0.0 1.8 2.0
 GA 460 (47.5) 411 (47.5) 49 (47.6) 1.0 1.0 1.8 2.0
 AA 234 (24.1) 210 (24.2) 24 (23.3) 0.0 0.0 1.8 1.0*

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by McQuaid [17] and Bradley [18], but in line with the study
of Tollenaar et al. [19], in which no interaction was shown
of neither rs53576 nor rs2268498 and childhood maltreat-
ment by retrospective recall. Interestingly, ample evidence
suggests possible psychological resilience in rs53576 GG
carriers, compared to A-allele carriers [44, 45], due to their
innate higher support seeking, higher levels of optimism,

mastery, self-esteem and decreased emotion-focused coping
following unsupportive responses, compared to the A-allele
carriers. Developing empathic abilities in hypothesized
OXTR risk allele carriers could help in time to overcome
stressors and induce self-regulation, in a way that G-carriers
more than in A-carriers, respectively, TT/TC carriers more
than CC carriers, feel able to cope with external demands.

Fig. 2 a General anxiety at age 5–6 (ranking scores) according to
maternal verbally aggressive behavior, stratified by rs2740210. b
SDQ-emotional symptoms at age 11–12 (ranking variables) accord-
ing to maternal verbally aggressive behavior, stratified by rs2740210.
c Anxiety sensitivity at age 11–12 (ranking variables) according
to maternal verbally aggressive behavior, stratified by rs4813627. d
SDQ-emotional symptoms at age 11–12 (ranking variables) accord-
ing to maternal verbally aggressive behavior, stratified by rs4813627.
Oxytocin peptide genotype variants influence internalizing symptoms
(ranking variables) after exposure to maternal verbally aggressive
behavior in early infancy. Carriers of rs2740210 CA/AA exposed to

maternal verbally aggressive behavior in early infancy have increased
general anxiety symptoms at age 5–6 and increased Goodman’s
Strengths and Difficulties Questionnaire (SDQ) emotional symptoms
at age 11–12, compared to carriers of rs2740210 CA/AA unexposed
to maternal verbally aggressive behavior in early infancy (interac-
tion terms, respectively, 0.011 and 0.015). Carriers of rs4813627 GG
exposed to maternal verbally aggressive behavior in early infancy
have decreased anxiety sensitivity and decreased SDQ emotional
symptoms at age 11–12, compared to carriers of rs4813627 GG unex-
posed to maternal verbally aggressive behavior in early infancy (inter-
action terms, respectively, 0.011 and 0.023)

549European Archives of Psychiatry and Clinical Neuroscience (2020) 270:541–551

1 3

Indeed, the developing mastery capacities of the hypoth-
esized OXTR risk allele carriers might explain our null
finding on internalizing symptoms, but only in the plausible
absence of cumulative maternal abuse in due time. Instead,
adolescent carriers of rs53576 GG variant with documented
maltreatment histories, on average an accumulation of 2.2
maltreatment subtypes have been shown to have higher lev-
els of internalizing symptoms and perceive lower social sup-
port compared to maltreated A-carriers [18]. Second, it is
possible that the absence of gene-environment interaction
of OXTR variants is partly due to the fact that we could not
assess the possible contribution of the developing attach-
ment style. Indeed, in adult rs53576 GG carriers, insecure
childhood attachment is associated with higher attachment
related anxiety and alexithymia, than in A-allele carriers
[46].

Strengths and limitations

Strengths of this study are the large, population-based, birth
cohort with prospective design and extensive data collec-
tion from early infancy onwards. General anxiety, anxiety
sensitivity, and SDQ-emotional symptoms cover multiple
aspects of internalizing symptoms. Since they belong to
separate high-risk groups, we excluded preterm births and
congenital disorders. We were able to control for a large
number of potentially confounding stressors, such as mater-
nal depression, authoritarian parenting style, and parent-
ing stress, as we were specifically interested in the impact
of maternal verbally aggressive behavior in early infancy.
Importantly, gonadal steroids, which rise in puberty, have a
role in the maturation of the oxytocin system [47] and endo-
crinological changes could co-exist with internalizing symp-
toms. Nevertheless, in our sample, puberty stage did not
differ between the exposed and the non-exposed children.
To follow the recommendations of Keller [48] to properly
control for potential confounders, we additionally checked
whether adding sex × G, sex × E, physical aggression × E,
and physical aggression × G to the complete model would
change the results. The p values for interaction of the SNPs
and maternal verbal aggression in association with internal-
izing symptoms minimally changed and remained signifi-
cant [rs2740210 × verbal aggression: p = 0.002 (instead of
0.011) and p = 0.002 (instead of 0.015); rs4813627 × ver-
bal aggression: p = 0.015 (instead of 0.011) and p = 0.009
(instead of 0.023)]. Possible social desirability in answering
the question of speaking angrily to the infant could lead to
underestimation of the true frequency of maternal verbally
aggressive behavior. However, self-report is the best way to
measure this as continuous observation of the mother–infant
dyad is not feasible.

Selective follow-up was present as in most cohort stud-
ies. However, as maternal verbally aggressive behavior did

not differ between responders and non-responders, respec-
tively, 10.6% and 9.2% (p = 0.177), possible selection bias is
estimated to be limited. Furthermore, the genotype variants
did not vary across the exposed and non-exposed children.
Therefore, no population stratification was present. Since
parents have been shown to underestimate child worry and
anxiety and overestimate optimism, compared to child self-
report in 4–11-year-old children [49], we cannot rule out
the possibility that internalizing symptoms at age 5–6 could
have been underestimated. Although we assessed internal-
izing symptoms at age 5–6 by maternal report only, we did
assess internalizing symptoms at age 11–12 by self-report.
Unfortunately, paternal report was not collected. Data on
trauma in early childhood were limited to maternal aggres-
sive behavior to the infant at the age of 3 months. The dis-
tinction between temporary, frequent, or persistent maternal
aggressive behavior to the infant, thus creating chronic stress
in the first years, could not be made based on our data. We
expect that experience of simultaneous other adverse events
will increase the gene–environment interaction effect.

Although the study population was large, the numbers
of subjects in various groups in the studied interactions
seem small (ranging from 19–44), nonetheless, comparable
to other gene-environment studies. We aimed to replicate
the results in an independent cohort, but to the best of our
knowledge, no other cohort study exists in which mater-
nal verbally aggressive behaviour at the age of 3 months
was assessed. Nevertheless, this is an exploratory analysis
and our findings on gene-environment interaction by OXT
polymorphisms should be replicated in independent sam-
ples. Furthermore, gene–environment interaction of OXTR
or OXT polymorphisms could differ between boys and girls.
Indeed, evidence of sex differences exists in brain structure,
function, and neurotransmission [50] as well as stress reac-
tivity [51]. Unfortunately, our study was underpowered for
sex-stratified interaction analyses.

Interestingly, it might be possible that the environmen-
tal stressor of verbal aggression differs from other types of
maltreatment (i.e., neglect, physical abuse, and sexual abuse)
in interaction with OXTR or OXT polymorphisms, as such
has been shown in the serotonin transporter gene [52]. In
this study of Fisher et al. (2013), gene–environment inter-
actions were found only when maltreatment was analyzed
in accumulation, or when sexual abuse or physical neglect
was analyzed separately. A separate study on gene–envi-
ronment interaction for each type of maltreatment in early
infancy might show different results. Importantly, we tested
the effect of gene–environment interaction on internalizing
symptoms along the internalizing symptoms continuum. We
were unable to examine a differential effect on prevalence of
mood or anxiety disorder because of our healthy population
sample. Future studies should incorporate clinical outcomes,
as well as sex differences in larger birth cohort samples and

550 European Archives of Psychiatry and Clinical Neuroscience (2020) 270:541–551

1 3

continue into adolescence and adulthood. Eventually, stud-
ies of possible genetic overlapping functions are warranted
to further explore the relevance of these promising genetic
markers.

This study uniquely contributes to the field. Infant’s
genetic variation of OXT polymorphisms associated with
vocalizing is shown to be a significant factor of vulnerabil-
ity or resilience in developing internalizing symptoms after
exposure to maternal verbally aggressive behavior in early
infancy. Common psychiatric disorders as mood and anxiety
disorders have been recognized as continuous phenotypes
in the population. Therefore, aetiopathogenic mechanisms
should be detectable across a wide range of subclinical and
clinical phenotypic variants in non-clinical samples such as
the ABCD cohort.

Acknowledgements We acknowledge the large contribution and
involvement of all participating mothers and children of the ABCD
study. Genotyping was funded by the Biobanking and BioMolecular
resources Research Infrastructure The Netherlands (BBMRI-NL) Grant
Number CP2013-50.

Compliance with ethical standards

Conflict of interest The authors declare that they have no conflict of
interest.

Open Access This article is distributed under the terms of the Crea-
tive Commons Attribution 4.0 International License (http://creat iveco
mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribu-
tion, and reproduction in any medium, provided you give appropriate
credit to the original author(s) and the source, provide a link to the
Creative Commons license, and indicate if changes were made.

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• Maternal verbal aggression in early infancy and child’s internalizing symptoms: interaction by common oxytocin polymorphisms

Abstract
Introduction
Materials and methods
Participants
Maternal verbally aggressive behavior in infancy
Internalizing symptoms at age 5–6 and at age 11–12
Genotyping
Covariates
Statistical analyses
Results
Subjects’ characteristics
Maternal verbally aggressive behavior and child’s OXTR and OXT variants
OXTR, OXT variants, and median score of internalizing symptoms at age 5–6 and age 11–12
Maternal verbally aggressive behavior and internalizing symptoms at age 5–6 and age 11–12
OXTR and OXT variants, maternal verbally aggressive behavior, and internalizing symptoms at age 5–6
Discussion
Strengths and limitations
Acknowledgements
References