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Regular article
Oxytocin receptor and vasopressin receptor 1a genes are respectively
associated with emotional and cognitive empathy
F. Uzefovsky
a,b,
⁎, I. Shalev
c
, S. Israel
a
,S.Edelman
a
,Y.Raz
d
, D. Mankuta
e
,A.Knafo-Noam
a
,R.P.Ebstein
f
a
Psychology Department, Hebrew University, Jerusalem 91501, Israel
b
Autism Research Centre, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
c
Department of Biobehavioral Health, Pennsylvania State University, University Park, PA, USA
d
Neurobiology, Hebrew University, Jerusalem, Israel
e
Hadassah Medical Organization, Department of Labor and Delivery, Jerusalem, Israel
f
Psychology Department, National University of Singapore, Singapore
abstractarticle info
Article history:
Received 10 June 2014
Revised 28 October 2014
Accepted 8 November 2014
Available online 1 December 2014
Keywords:
Cognitive empathy
Emotional empathy
Oxytocin receptor
Arginine vasopressin receptor
Gene
Empathy is the ability to recognize and share in the emotions of others. It can be considered a multifaceted
concept with cognitive and emotional aspects. Little is known regarding the underlying neurochemistry of
empathy and in the current study we used a neurogenetic approach to explore possible brain neurotransmitter
pathways contributing to cognitive and emotional empathy. Both the oxytocin receptor (OXTR) and the arginine
vasopressin receptor1a (AVPR1a) genes contribute to social cognition in both animals and humansand hence are
prominent candidates for contributing to empathy. The following research examined the associations between
polymorphisms in these two genes and individual differences in emotional and cognitive empathy in a sample
of 367 young adults. Intriguingly, we found that emotional empathy was associated solely with OXTR, whereas
cognitive empathy was associated solely with AVPR1a. Moreover, no interaction was observed between the
two genes and measures of empathy. The current findings contribute to our understanding of the distinct
neurogenetic pathways involved in cognitive and emotional empathy and underscore the pervasive role of
both oxytocin and vasopressin in modulating human emotions.
© 2014 Elsevier Inc. All rights reserved.
The human ability to automatically connect and comprehend others,
termed empathy, seems an intangible gift, yet it is deeply rooted
in Homo sapiens' evolutionary history (Preston and de Waal, 2003). It
is considered to be a primary building block in the creation and mainte-
nance of social groups, and drives many aspects of social behavior, from
child care(Preston and de Waal, 2003), to moral sense (Hoffman, 2001),
to prosocial behavior towards kin and even strangers (Batson et al.,
1988). Empathy can be conceptualized as the ability to understand
and share in others' emotions, while maintaining a self-other distinction
(Davis, 1980; Decety and Jackson, 2004). Considerable research points
to a differentiation between the cognitive (i.e., cognitive empathy—
CE) and emotional (i.e., emotional empathy—EE) facets of empathy. CE
is the ability to recognize what the other is feeling (e.g., seeingsomeone
cry and realizing they are upset), whereas EE is the sharing in others'
emotions (e.g., seeing someone cry and feeling sad for them) (Davis,
1980; Zaki and Ochsner, 2012). The distinction between the cognitive
and the emotional aspects of empathy is not only theoretical but
is supported by a considerable body of empirical research. First, a
meta-analysis showed that CE and EE have different etiologies, while
both EE and CE are moderately heritable, shared environment was
found to affect only cognitive and not emotional empathy (Knafo and
Uzefovsky, 2013). Second, recently, it has been shown that a gene cod-
ing for the dopamine D4 receptor is specifically associated with CE but
not EE (Uzefovsky et al., 2014). Third, neuroimaging and lesion studies
point to two different, albeit interconnected, brain networks underlying
CE and EE. CE is associated with the “mentalizing network,”which is
generally thought to include the ventromedial prefrontal cortex, the
temporo-parietal junction and the temporal poles (Schnell et al.,
2011; Shamay-Tsoory et al., 2009b; Zaki and Ochsner, 2012). On the
other hand, the human mirror neuron system is arguably considered
to be the basis for EE (Shamay-Tsoory, 2011a,2011b). This system is
activated both when we experience an emotion and when the “other”
experiences the same emotion and includes the inferior parietal lobule
and the amygdala, among others (Cox et al., 2011; Shamay-Tsoory
et al., 2004, 2009b). Notwithstanding the empirical distinction that
can be made between CE and EE, it is important to note that during
normal empathic processing both systems are activated (Schnell et al.,
2011; Zaki and Ochsner, 2012).
While much is known regarding the activation of brain structures
during empathy eliciting tasks, less research has focused on the neuro-
chemical pathways and specific neurotransmitters involved in empathy.
Hormones and Behavior 67 (2015) 60–65
⁎Corresponding author at: Autism Research Centre, University of Cambridge, Douglas
House, 18B Trumpington Road, Cambridge CB2 8AH.
E-mail address: fr316@cam.ac.uk (F. Uzefovsky).
http://dx.doi.org/10.1016/j.yhbeh.2014.11.007
0018-506X/© 2014 Elsevier Inc. All rights reserved.
Contents lists available at ScienceDirect
Hormones and Behavior
journal homepage: www.elsevier.com/locate/yhbeh
Two neuropeptides, oxytocin and vasopressin, are biologically plausible
candidates to mediate the neural pathways underlying empathy. Oxyto-
cin (OT) and arginine vasopressin (AVP) play a crucial role in vertebrate
social signaling with a long evolutionary history from fish to primates
(Donaldson and Young, 2008). Animal studies have established a role
for these two social neuropeptides in a wide range of affiliative behaviors
(Bosch and Neumann, 2012; Hammock and Young, 2004; Young and
Wang, 2004). Human studies using intranasal administration of both
neuropeptides have demonstrated their role in a variety of social behav-
iors including trust (Kosfeld et al., 2005), generous giving (Zak et al.,
2007) and emotion recognition (Domes et al., 2006; Uzefovsky et al.,
2011). Several studies reported on associations between plasma levels
and a range of affiliative behaviors, including parenting and romantic
bonds (Feldman, 2012; Feldman et al., 2011; Schneiderman et al.,
2012). Additionally, genetic studies found associations with individual
differences in prosocial behavior (Israel et al., 2009; Knafo et al., 2008)
and with social deficits in autism (Lerer et al., 2008; Yirmiya et al., 2006).
Most of the phenotypes examined with respect to OT-AVP genetic
pathways are reliant on empathy, yet little research has been dedicated
to direct examination of empathy and its two facets. The few studies to
examine the role of this system in empathy have focused on the OXTR
gene and very little attention has been given to AVPR1a (Chakrabarti
et al., 2009; Lucht et al., 2013; Montag et al., 2012; Rodrigues et al.,
2009; Schneiderman et al., 2012; Wu et al., 2012) (See Supporting
Material Table 1). No study to date has investigated the combined ef-
fects of these two important genes. In addition, previous genetic studies
were characterized by small samples and the findings have been mixed
prompting us in the current investigation to simultaneously examine
both OXTR and AVPR1a common polymorphisms in a larger sample of
367 subjects.
To minimizeissues of multiple testing, we selected for analysis a sin-
gle polymorphic region within the OXTR and the AVPR1a.ForOXTR,the
rs53576 SNP was selected for analysis. This SNP is located within intron
3oftheOXTR gene and constitutes a G →A change. A considerable body
of research shows associations between this rs53576-GG genotype and
increases in social cognition, including empathy (Rodrigues et al., 2009),
in both clinical and non-clinical subjects (Bakermans-Kranenburg and
van IJzendoorn, 2008; Chen et al., 2011; Costa et al., 2009; Kogan
et al., 2011;Park et al., 2010). Similarly, for the AVPR1a gene, we selected
for analysis the well-studied RS3 polymorphic repeat region located in
the promoter, and in particular, we targeted the second most common
repeat allele (termed 327 or 334 bp allele, depending on genotyping
method). The 327 repeat allele may be functionally significant since car-
riers of the 327-repeat risk allele showed higher amygdala activation
(Meyer-Lindenberg et al., 2008). This repeat allele was also associated
with lower partner bonding in men (Walum et al., 2008), lower
altruistic giving (Avinun et al., 2011) and autism (Kim et al., 2002). In
summary, we examined the OXTR rs53576 SNP and the AVPR1a-327
polymorphic repeat region for their roles in contributing to CE and EE
in a non-clinical student population. Finally, based on these investiga-
tions, we hypothesized that the presence of the rs53576-A allele in
the OXTR gene and the presence of the 327-repeat allele in the AVPR1a
gene both independently would predict lower empathy scores.
Methods
Participants
A total of 367 young adults (52% female; mean age, 24.40 ± 2.80
years) were recruited by advertisements on campus bulletin boards
for a study on personality and genetics. All subjects were aged 18–35
years, had no self-report history of psychiatric disorders, chronic illness
or drug taking and were non-smokers. All participants were of Jewish
descent (56.1% Ashkenazi Jews, 21.0% Sephardic Jews and 22.6% of
mixed Jewish descent). This sample was analyzed previously as Study
1inUzefovsky et al.( 2014), in relation to the dopamine D4 receptor
gene. The project was approved by the S. Herzog Hospital IRB commit-
tee and the Israeli Ministry of Health.
Measures
To ensure a complete measurement of empathy, each participant
filled out three widely used and highly validated self-report measures
of empathy online: the Interpersonal Reactivity Index (IRI) (Davis,
1980), the Empathy Quotient (Baron-Cohen and Wheelwright, 2004)
and the Questionnaire Measure of Emotional Empathy (QMEE)
(Mehrabian and Epstein, 1972). Participants' scores on each of the mea-
sures were standardized and averaged out to create the total empathy
score. All these measures tap into emotional and cognitive aspects of
empathy; however, the IRI consists of four validated subscales, with
two of the subscales measuring cognitive empathy (fantasy (F) and per-
spective taking (PT)) and two subscales measuring emotional empathy
(empathic concern (EC) and personal distress (PD)). These subscales
were used to create a CE and an EE scores in the same manner as the
total empathy score (see also Uzefovsky et al., 2014).
DNA extraction and genotyping
DNA extraction was performed in the research lab of the S.
Herzog Memorial Hospital. DNA was extracted using the MasterPure
kit (Epicentre, Madison, Wisconsin, United States). Genotyping of
AVPR1a.RS3 microsatellite repeats was performed jointly at S. Herzog
Memorial Hospital and the Hadassah Medical Center, Jerusalem.
Amplification of the RS3 arginine vasopressin 1a microsatellites
(AVPR1a) was achieved using the following primers (Bachner-Melman
et al., 2005; Thibonnier et al., 2000; Wassink et al., 2004)forward
(fluorescent) 5′-CCT GTA GAG ATG TAA GTG CT-3′and reverse 5′-TCT
GGA AGA GAC TTA GAT GG-3′. Each reaction mixture contained
0.5 μM primer and 20 ng of DNA. A ReddyMix master mix
(Thermoprime plus DNA polymerase) was used (Abgene, Surrey,
United Kingdom) at a magnesium concentration of 1.5–2.5 mM
MgCl2. ReddyMix buffer consisted of 75 mM Tris–HCl(pH8.8at25°C),
20 mM (NH4)2SO4 and 0.01% (v/v) Tween 20. The sample was
initially heated at 95 °C for 5 min, followed by 30 cycles of 95 °C
(30 s), 55 °C (30 s) and 72 °C (40 s) and a final extension step of 72 °C
for 10 min. The PCR product was analyzed on an ABI 310 DNA analyzer
(Applied Biosystems, Foster City, California, United States).
Genotyping of the OXTR rs53576 SNP was performed at the National
University of Singapore. SNP genotyping was performed in multiplex
assays by MassARRAY using iPLEX Gold chemistry (Sequenom, San
Diego, California), followed by MALDI-TOF mass spectrometry. PCR
and extension primers were designed using MassARRAY Assay Design
software v4.0.0.2 and online tools available at mysequenom.com
(Sequenom) (forward: 5′-GCACAGCATTCATGGAAAGG-3′; reverse: 5′-
CTGTAGAATGAGCTTCCCAG-3′, extended primer: TCTGTGGGACTGAG
GA C(G) T(A)). Genotypes were called automatically using MassARRAY
Typer software (Sequenom).
Ambiguous and undetermined genotype results were scanned by a
researcher and determined when possible. The researcher had no
knowledge of the self-report scores. When no confident interpretation
could be made, the sample was assigned a missing value. Participants
with missing genotype information were excluded from the analysis.
In total, three people were excluded from the analysis due to
missing genetic data. Results conform to the Hardy–Weinberg equilibri-
um for both OXTR (chi-square = .37, pvalue N.05) and AVPR1a
(chi-square = .07, pvalue N.05). The distribution of genotypes in the
sample is presented in Table 1.
Although all participants were of the same ethnic origin (Jewish)
and therefore there is little possibility for population stratification,
we tested to make sure that Jewish origin (Ahskenazi/Sephardic) was
not associated with allele frequency. For both OXTR and AVPR1a,no
61F. Uzefovsky et al. / Hormones and Behavior 67 (2015) 60–65
association between Jewish origin and allele frequency was found
(chi-square .89 and 1.71 pN.05, respectively).
Statistical analysis
Genotype of the AVPR1a.RS3 microsatellite was coded as the pres-
ence or absence of the 327-repeat allele and genotype of the OXTR
rs53576 was coded as the presence or absence of the A-minor allele,
both resulting in two-level predictor variables. Gender, OXTR genotype,
AVPR1a genotype and the interaction term of OXTR and AVPR1a
all served as predictors of questionnaire scores. All variables were
dummy coded and centered. Variables were entered into the regression
model in three steps; first—gender, second—OXTR and AVPR1a geno-
types and third—the interaction of OXTR and AVPR1a. Three regression
models were analyzed with the total empathy score, cognitive empathy
score and emotional empathy score as the dependent measures. All
results were confirmed using 1000 bootstrap samples. The bootstrap
procedure repeatedly resamples the data to create 1000 samples.
This allows to reduce uncertainty in the estimated parameters. The
bootstrapping procedure was carried out using the bootstrapping op-
tion that is available as part of a linear regression analysis in SPSS v19.
All statistical tests were carried out using SPSS v19 (Windows).
Results
The complete empathy score is based on scores of three self-report
measures of empathy: the interpersonal Reactivity Index (IRI) (Davis,
1980), the Questionnaire Measure of Emotional Empathy (QMEE)
(Mehrabian and Epstein, 1972) and the Empathy Quotient (EQ)
(Baron-Cohen and Wheelwright, 2004). Mean scores (split by gender)
and correlations between the measures are reported in Table 2. Theoret-
ical considerations (all questionnaires aim to measure empathy) were
supported by the correlations, allowing to construct a total empathy
score.
We first turned to examine the association between the total
empathy score and each of the genes, controlling for gender. We used
a linear regression model with gender entered first. OXTR and AVPR1a
genotypes were entered in the second step, and an interaction term
(centered) between OXTR and AVPR1a genotype was entered in the
third step. As expected, gender was a significant predictor of empathy
(pb.001), with women scoring higher than men. Entering the OXTR
and AVPR1a genotypes in the modelrevealed that bothsignificantly pre-
dicted empathy, and gender and genes altogether explain a total of 13%
of the variance in empathy scores. Results were confirmed with a boot-
strap analysis. As we hypothesized, the presence of the rs53576-A allele
in the OXTR gene, and the presence of the 327-repeat allele in the
AVPR1a gene, both independently predicted lower empathy scores.
The interaction between OXTR and AVPR1a genotypes was not a signifi-
cant predictor of empathy (see Table 3).
We next turned to investigate the effect of genotype on the two
empathy types. We carried out regression analyses similar to that
described above, with cognitive empathy as the dependent variable in
the first regression and emotional empathy the dependent variable in
the second. In both analyses, gender significantly predicted both CE
and EE, with women scoring higher than men (standardized βwas .18
and .32, respectively, in the complete model). The OXTR rs53576-A
allele predicted lower emotional empathy (standardized β=−.11,
p= .029), but not cognitive empathy (standardized β=−.08,
p= .10). On the other hand, the AVPR1a 327 allele predicted lower
cognitive empathy (standardized β=−.16, p= .002), but not
emotional empathy (standardized β=−.08, p= .12). The interaction
between OXTR and AVPR1a genotypes was not associated with emotional
or cognitive empathy. Results were confirmed with a bootstrap analysis
(see Tables 4 and 5 for details). These results suggest that somewhat
distinct molecular genetic and neurochemical architecture characterizes
cognitive and emotional empathy.
Discussion
We have implemented a neurogenetic strategy to explorethe neuro-
chemical pathways underpinning human empathy in a relatively large
sample of young adults. We tested the contribution of polymorphisms
in the AVPR1a and OXTR genes to individual differences in empathy.
Both of these genes arevery plausible candidates for contributing to em-
pathy, a core concept in social cognition. We further investigated the
cognitive and emotional facets of empathy to gain a better understand-
ing of the contribution of OT and AVP pathways to empathy. Both the
AVPR1a 327 repeat and the OXTR rs53576 SNP variants were,as we pre-
dicted, associated with empathy and the allelic direction of association
is consistent with other investigationsof these two polymorphisms. No-
tably, OXTR rs53576-A allele solely predicted lower emotional empathy
whereas the AVPR1a 327 repeat allele solely predicted lower scores on
cognitive empathy. Interestingly, the interaction between the two
genes was not associated with either empathy measure. Altogether,
the neurogenetic approach taken in the current study allows a molecu-
lar distinction to be made betweenboth facets of empathy and identifies
at least two of the neurochemical pathways contributing to this most
human of traits.
The current results give greater traction to an increasing body of
research, suggesting that the neurochemical and neurogenetic under-
pinnings of emotional empathy are somewhat distinct from those of
cognitive empathy. Neuroimaging, brain lesion studies, genetic studies
and clinical research studies support the notion that empathy is multi-
faceted and relies on both partially distinct and yet apparently intercon-
nected, brain circuits (Shamay-Tsoory et al., 2007, 2009a, 2009b;
Shamay-Tsoory and Aharon-Peretz, 2007; Uzefovsky et al., 2014; Zaki
and Ochsner, 2012). Hence, we suggest that empathy should not be
studied simply as a monolithic concept but rather that its multifaceted
nature needs to be taken into account. Moreover, our findings based
on a neurogenetic strategy suggest the distinct involvement of
oxytocinergic neural pathways in emotional empathy and vasopressin
pathways in cognitive empathy. Although few studies have assessed
the association between these genes and empathy, one study by
Rodrigues et al. (2009) investigated the association between OXTR
rs53576 SNP and empathy as measured by the Interpersonal Reactivity
Index (IRI), finding that, as in the current study, the rs53576-A was
associated with lower empathy scores (they did not distinguish be-
tween the cognitive and emotional subscales). However, Rodrigues
et al. (2009) in the same investigation also finds an association between
the OXTR rs53576 and the Reading the Mind in the Eyes Test (RMET)
(Baron-Cohen et al., 2001), a measure of cognitive empathy, a result
Table 1
Distribution of the OXTR rs53576 and AVPR1a.RS3 genotype in the current sample, coded
for presence and absence of the risk allelein each gene.
OXTR rs53576 AVPR1a.RS3
Allele N Allele N
A present (AA/AG) 194 327 repeat present 137
A absent (GG) 173 327 repeat absent 230
Table 2
Mean scores of the individual empathy measures split by gender, and the correlations
between the measures. All correlations are significant at the pb.001 level.
Note: IRI = Interpersonal Reactivity Index; QMEE = Questionnaire Measureof Emotional
Empathy; EQ = Empathy Quotient.
Mean score—females
(N= 190)
Mean score—males
(N= 177)
Correlations
IRI QMEE EQ
IRI 97.35 90.43 1
QMEE 42.63 27.03 .70** 1
EQ 44.25 40.43 .42** .52** 1
62 F. Uzefovsky et al. / Hormones and Behavior 67 (2015) 60–65
that is in conflict with our failure to find an association between this SNP
and cognitive empathy using a self-report questionnaire. One possible
explanation for the discrepancy in the results is that the Rodrigues
et al. (2009) study included very mixed ethnicity including 35%
Caucasians, 41% Asians and 24% mixed in their smaller sample of only
192 subjects. In addition, it is also possible that the type of the task
(performance based vs. a questionnaire measure) affected this result.
Similar findings have been reported by Lucht et al. (2013). They exam-
ined 3 OXTR SNPs, rs53576 among them, in a group of 76 adolescents
and young adults, finding that the rs2228485 was associated with per-
formance on the RMET (rs53576 and rs2254298 did not withstand mul-
tiple testing corrections) (Lucht et al., 2013). Similarly to the Rodrigues
et al. (2009) study, several factors may explain the divergence in results;
the sample size is very small in terms of genetic research, the task mea-
sures performance and the sample included adolescents. Notwithstand-
ing, support for our current findings that the OXTR is associated with
emotional but not cognitive empathy comes from a recent study that
examined the effects of intranasal OT administration on EE and CE
(Hurlemann et al., 2010). The study showed that the administration of
OT brought on an increase in EE but not CE. Additional partial support
comes from another study that examined the association between
OXTR and empathy in individuals with Schizophrenia and controls
(Montag et al., 2012). In their study, the rs2254298, but not the
rs53576, was found to be associated with EE (specifically, the empathic
concern subscale of the IRI) only in the schizophrenia group. Although
this study does not constitute a full replication, it still supports the
notion that OXTR is associated with emotional empathy. However,
clearly, additional research with larger samples is needed to understand
the specific role of the oxytocinergic and vasopressinergic systems in
the two facets of empathy.
The current study joins an ever growing literature on the association
between the oxytocin-vasopressin system and social cognition and be-
havior, although the biological mechanism of this association is yet
largely unknown. Only a few studies examined the functionality of
these polymorphisms (Knafo et al., 2008; Meyer-Lindenberg et al.,
2008; Tansey et al., 2011; Tost et al., 2010; Wang et al., 2013). Several
neuroimaging studies have begun to explore the functional effects of
the OXTR rs53576 SNP and its association with brain areas associated
with empathy. Tost et al. (2010) showed that the G-allele is associated
with higher gray matter volume in the amygdala and hypothalamus.
In addition, the connectivity between the amygdala and hypothalamus
was associated with genotype (Tost et al., 2010). Similarly, Wang et al.
(2013) showed that the G-allele is associated with higher volume of
the amygdala. In addition, G carriers showed higher functional connec-
tivity with the prefrontal cortex (Wang et al., 2013). A recent study
revealed, using a SPECT analysis, an association between the G-allele
and lower striatal availability of the dopamine transporter gene (DAT)
(Chang et al., 2014). Taken together, these studies point to a role of
the rs53576 in moderating the functionality of brain areas involved in
social cognition. Again, studies of the functional significance of the RS3
polymorphism are scarce. The length of RS3 was previously associated
with mRNA levels of AVPR1a in the hypothalamus (Knafo et al., 2008)
and with promoter activity (Tansey et al., 2011). As mentioned,
the 327 allele was associated with amygdala activation (Meyer-
Lindenberg et al., 2008).Taken together, these studies suggest that the
observed association between OXTR and AVPR1a genes and empathy is
mediated by socio-emotional networks in the brain. However, future
research in the field of social science can greatly benefit from studies
on the basic biology of these (and other) polymorphisms in the OXTR
and AVPR1a genes.
Table 3
Linear regression analyses withgender, OXTR rs53576 genotype, AVPR1a.327 genotype and the interactionbetween OXTR and AVPR1agenotyped predicting empathyscores. Resultsshow
that (1) women havehigher empathy scoresthan men; (2) the A allele of the OXTR rs53576 and the 327 repeatallele of the AVPR1a independently predict lower empathyscores; (3) the
interaction between OXTR rs53576 and AVPR1a.327 is not predictive of empathy scores. Results were confirmed using a bootstrap procedure based on 1000 bootstrap samples.
Empathy β(standardized) Sig. Block ΔR
2
FSig. B(unstandardized) Bootstrap 95% CI
Lower Higher
Step 1 .11 44.08 pb.001
Gender .328 pb.001 .617 .425 .798
Step 2 .132 19.53 pb.001
Gender .333 pb.001 .625 .439 .807
OXTR rs53576 −.134 p= .006 .031 p= .002 −.217 −.399 −.051
AVPR1a.327 −.115 p= .018 −.261 −.443 −.064
Step 3 .130 14.62 pb.001
Gender .332 pb.001 .625 .435 .808
OXTR rs53576 −.115 p= .019 −.217 −.400 −.049
AVPR1a.327 −.134 p= .006 −.261 −.446 −.063
OXTR xAVPR1a −.010 p= .838 .000 p= .838 −.039 −.390 .351
Table 4
Linear regression analyses with gender, OXTR rs53576 genotype, AVPR1a.327 genotype and the interaction between OXTR and AVPR1a genotyped predicting emotional empathy scores.
Results show that emotional empathy is predicted by gender (women score higher than men) and by the OXTR rs53576 genotype (the A allele is associated with lower empathy). The
AVPR1a.327 genotype and the interaction are not predictive of emotional empathy. Results were confirmed using a bootstrap procedure based on 1000 bootstrap samples.
Emotional empathy β(standardized) Sig. Block ΔR
2
F Sig. B (unstandardized) Bootstrap 95% CI
Lower Higher
Step 1 .097 40.27 pb.001
Gender .315 pb.001 .627 .428 .821
Step 2 .11 16.01 pb.001
Gender .317 pb.001 .630 .433 .825
OXTR rs53576 −.108 p= .029 .018 p= .028 −.215 −.399 −.016
AVPR1a.327 −.077 p= .122 −.157 −.359 .051
Step 3 .11 11.98 pb.001
Gender .317 pb.001 .630 .432 .822
OXTR rs53576 −.108 p= .029 −.215 −.399 −.019
AVPR1a.327 −.077 p= .122 −.158 −.363 .047
OXTR xAVPR1a .007 p= .891 .000 p= .891 .028 −.373 .392
63F. Uzefovsky et al. / Hormones and Behavior 67 (2015) 60–65
This is the first and the largest study to examine concurrently the
role of OXTR and AVPR1a in contributing to individual differences in
both facets of empathy, EE and CE. The current results show that EE
and CE can be distinguished at the genetic level and by implication at
the neurochemical level. OXTR was associated with emotional empathy,
which we suggest is consistent with a large literature demonstrating a
role of this gene in both animal and human affiliative behaviors.
AVPR1a appears to contribute solely to cognitive empathy also consis-
tent with previous findings, suggesting a role for this gene in various
facets of social cognition and social memory (Dantzer et al., 1988;
Ferguson et al., 2002; Walum et al., 2008).
As mentioned, the current study investigated the effects of OXTR and
AVPR1a on empathy in the largest sample to date. However, a replica-
tion of the current findings is needed to establish the unique role of
OXTR and AVPR1a in individual differences in cognitive and emotional
empathy. Our findings help clarify the proximal mechanisms that are
associated with cognitive and emotional empathy and, in doing so,
may open new avenues for interventions in clinical conditions associated
with difficulties in empathy such as autism and anti-social personality
disorder.
Role of funding source
Financial support (RPE) from the National University of Singapore,
NUS grant: R-122000125133. John Templeton Foundation :ID# 21240.
Ministry of Education at Singapore, the AXA Research Foundation and
the Templeton Foundation are gratefully acknowledged. FU was funded
by the Arianne de Rothschild Fellowship. Sponsors had no role in the
study design; in the collection, analysis and interpretation of the data;
in the writing of the report; and in the decision to submit the article
for publication.
Acknowledgments
We are grateful to all the participants and to the research assistants
who recruited them.
Appendix A. Supplementary data
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.yhbeh.2014.11.007.
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Table 5
Linear regression analyses with gender, OXTR rs53576 genotype, AVPR1a.327 genotype and the interaction between OXTR and AVPR1a genotyped predicting cognitive empathy scores.
Resultsshow that cognitiveempathy is predictedby gender (women score higher than men) andby the AVPR1a.327 genotype(the 327 allele is associated with lowerempathy). The OXTR
rs53576 genotype and the interaction are not predictive of cognitive empathy. Results were confirmed using a bootstrap procedure based on 1000 bootstrap samples.
Cognitive empathy β(standardized) Sig. Block ΔR
2
F Sig. B (unstandardized) Bootstrap 95% CI
Lower Higher
Step 1 .026 10.90 p= .001
Gender .170 p= .001 .334 .141 .532
Step 2 .052 7.73 pb.001
Gender .176 p= .001 .346 .145 .543
OXTR rs53576 −.083 p= .103 .018 p= .028 −.164 −.354 .031
AVPR1a.327 −.156 p= .002 −.316 −.526 −.118
Step 3 .060 5.77 pb.001
Gender .176 p= .001 .346 .150 .544
OXTR rs53576 −.083 p= .103 −.164 −.352 .031
AVPR1a.327 −.156 p= .002 −.316 −.526 −.118
OXTR xAVPR1a .007 p= .895 .000 p= .895 .027 −.365 .436
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