The Dopamine D4 Receptor Gene Shows a Gender-Sensitive Association With Cognitive Empathy: Evidence From Two Independent Samples

Abstract

Increasing evidence points to a role of dopaminergic pathways in modulating social behavior. Specifically, a polymorphic region in the third exon of the Dopamine D4 receptor (DRD4) has been associated with a host of social behaviors, often in an environment-sensitive manner. Empathy is thought to be an important motivator of prosocial behaviors and can be seen as multifaceted, combining cognitive empathy (CE) and emotional empathy (EE). In the current study, we analyzed the association between DRD4 and the 2 aspects of empathy, as well as the effect of gender on this association. In Study 1, a large sample of adult participants (N = 477) was inventoried for general empathy, CE, and EE and genotyped for the DRD4 exon 3 polymorphism. Women scored higher than men on all empathy measures and no main effect of genotype was observed. It is important that a significant interaction between genotype and gender emerged specifically for CE, with women carriers of the 7R-allele scoring higher than noncarriers, whereas in men 7R-carriers scored lower than -7R. Notably, these findings were replicated in an independently recruited sample (N = 121) in Study 2. The current report shows that the DRD4 exon3 polymorphism is associated with CE and the direction of the association is gender-sensitive. (PsycINFO Database Record (c) 2014 APA, all rights reserved).

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Emotion
The Dopamine D4 Receptor Gene Shows a
Gender-Sensitive Association With Cognitive Empathy:
Evidence From Two Independent Samples
Florina Uzefovsky, Idan Shalev, Salomon Israel, Shany Edelman, Yael Raz, Nufar
Perach-Barzilay, David Mankuta, Simone G. Shamay-Tsoory, Ariel Knafo, and Richard P.
Ebstein
Online First Publication, May 26, 2014. http://dx.doi.org/10.1037/a0036555
CITATION
Uzefovsky, F., Shalev, I., Israel, S., Edelman, S., Raz, Y., Perach-Barzilay, N., Mankuta, D.,
Shamay-Tsoory, S. G., Knafo, A., & Ebstein, R. P. (2014, May 26). The Dopamine D4 Receptor
Gene Shows a Gender-Sensitive Association With Cognitive Empathy: Evidence From Two
Independent Samples. Emotion. Advance online publication.
http://dx.doi.org/10.1037/a0036555

The Dopamine D4 Receptor Gene Shows a Gender-Sensitive Association
With Cognitive Empathy: Evidence From Two Independent Samples
Florina Uzefovsky
Hebrew University Idan Shalev
Pennsylvania State University
Salomon Israel
Duke University Shany Edelman and Yael Raz
Hebrew University
Nufar Perach-Barzilay
University of Haifa David Mankuta
Hadassah Medical Organization, Jerusalem, Israel
Simone G. Shamay-Tsoory
University of Haifa Ariel Knafo
Hebrew University
Richard P. Ebstein
National University of Singapore
Increasing evidence points to a role of dopaminergic pathways in modulating social behavior. Specifi-
cally, a polymorphic region in the third exon of the Dopamine D4 receptor (DRD4) has been associated
with a host of social behaviors, often in an environment-sensitive manner. Empathy is thought to be an
important motivator of prosocial behaviors and can be seen as multifaceted, combining cognitive
empathy (CE) and emotional empathy (EE). In the current study, we analyzed the association between
DRD4 and the 2 aspects of empathy, as well as the effect of gender on this association. In Study 1, a large
sample of adult participants (N⫽477) was inventoried for general empathy, CE, and EE and genotyped
for the DRD4 exon 3 polymorphism. Women scored higher than men on all empathy measures and no
main effect of genotype was observed. It is important that a significant interaction between genotype and
gender emerged specifically for CE, with women carriers of the 7R-allele scoring higher than noncarriers,
whereas in men 7R-carriers scored lower than ⫺7R. Notably, these findings were replicated in an
independently recruited sample (N⫽121) in Study 2. The current report shows that the DRD4 exon3
polymorphism is associated with CE and the direction of the association is gender-sensitive.
Keywords: cognitive empathy, emotional empathy, dopamine, DRD4
Supplemental materials: http://dx.doi.org/10.1037/a0036555.supp
Human beings have an incredible ability to understand and
relate to the emotional experiences of others. This capacity is often
referred to as empathy; it is central to smooth social interaction and
is believed to underlie much of moral development and prosocial
behavior (Batson et al., 1988; Hoffman, 2008). The literature
differentiates between the cognitive and emotional components of
empathy, which often occur in tandem, yet are conceptually dis-
tinct. Cognitive empathy (CE) is the ability to understand what the
Florina Uzefovsky, Psychology Department, Hebrew University, Je-
rusalem, Israel; Idan Shalev, Department of Biobehavioral Health,
Pennsylvania State University; Salomon Israel, Department of Psychol-
ogy and Neuroscience and Institute for Genome Sciences and Policy,
Duke University; Shany Edelman and Yael Raz, Neurobiology, Hebrew
University; Nufar Perach-Barzilay, Department of Psychology, Univer-
sity of Haifa, Haifa, Israel; David Mankuta, Hadassah Medical Orga-
nization, Department of Labor and Delivery, Jerusalem, Israel; Simone
G. Shamay-Tsoory, Department of Psychology, University of Haifa;
Ariel Knafo, Psychology Department, Hebrew University; Richard P.
Ebstein, Psychology Department, National University of Singapore,
Singapore.
We are grateful to all the participants and to the research assistants
who recruited them. Financial support (RPE) from the National Uni-
versity of Singapore, Ministry of Education at Singapore, the AXA
research foundation and the Templeton Foundation are gratefully ac-
knowledged. F. Uzefovsky was funded by the Arianne de Rothschild
fellowship.
Correspondence concerning this article should be addressed to Florina
Uzefovsky, Psychology Department, The Hebrew University of Jerusalem,
Jerusalem 91501, Israel. E-mail: florina.uzefovsky@mail.huji.ac.il
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Emotion © 2014 American Psychological Association
2014, Vol. 14, No. 3, 000 1528-3542/14/$12.00 http://dx.doi.org/10.1037/a0036555
1

other is feeling (a construct which is sometimes termed affective
Theory of Mind). Emotional empathy (EE), on the other hand, is
the ability to share the feelings of another, or to experience a
similar emotion, while still maintaining a self-other distinction
(Davis, 1983; Decety & Lamm, 2006; however, see Preston &
Hofelich, 2012). Although it is clear that during a typical empathic
response both the emotional and cognitive aspect of empathy come
into play, the distinction between CE and EE has nevertheless been
strongly supported by neuroimaging and neuropsychological
and clinical findings; for example, anorexia nervosa and autism
spectrum disorder (ASD) are associated with deficits in CE but
not in EE (Calderoni et al., 2013; Jones, Happé, Gilbert, Bur-
nett, & Viding, 2010), whereas anti-social personality disorder
(ASPD), is associated with deficits in EE but not in CE (Jones
et al., 2010). Although much remains to be learned regarding
the neurobiological underpinnings of CE and EE, evidence from
both neuroimaging and lesion studies also support a dual system
model of distinct, albeit somewhat overlapping, brain pathways
(reviewed in Blair, 2005; Shamay-Tsoory, 2011)). It has been
suggested that the broadly defined human Mirror Neuron Sys-
tem (hMNS) is associated with the feeling of emotional empa-
thy. The hMNS is activated both when one experiences a certain
feeling and when one perceives another person experiencing the
same feeling (e.g., pain matrix activated when feeling pain and
when perceiving another feeling pain). For example, activation
in the anterior cingulate cortex and in the anterior insula (both
part of the hMNS) is positively correlated with reported levels
of emotional empathy (Singer et al., 2004). On the other hand,
the mentalizing network (including the ventromedial prefrontal
cortex and the temporoparietal junction) underlies CE; that is,
the ability to understand what another is feeling (Saxe &
Kanwisher, 2003; Shamay-Tsoory, Aharon-Peretz, & Perry,
2009). This network is engaged when participants are asked to
make judgments on the mental states of others (Singer, 2006).
In the current study, we aimed to provide further understanding
into the neurobiological underpinnings of empathy and its two
facets by examining the association between common genetic
variation in an important gene from the dopaminergic system and
individual differences in overall empathy, as well as separately for
cognitive and emotional empathy. It is important that any discus-
sion of individual differences is not complete without examining
the role of gender in empathy. Therefore, we will first discuss the
association between gender and empathy and then turn to the
neurogenetic architecture of empathy.
Gender and Empathy
Gender has been repeatedly reported as a salient predictor of
empathy (Baron-Cohen & Wheelwright, 2004; Mehrabian & Ep-
stein, 1972), with females scoring higher than males on most
empathy measures. Disorders associated with deficits in empathy
such as ASD and ASPD are more prevalent in men than in women,
while disorders that are associated with higher empathy, such as
anxiety and depression, are more prevalent in women than in men
(Baron-Cohen, 2004; Moran, 1999; Zahn-Waxler, Shirtcliff, &
Marceau, 2008). Such gender differences may be explained simply
by hormonal factors, by culturally established gender roles, or by
both culture and hormones; and evidence for all views exists
(Baron-Cohen, 2004; Baron-Cohen, Knickmeyer, & Belmonte,
2005; Ickes, Gesn, & Graham, 2000; Karniol, Gabay, Ochion, &
Harari, 1998; Sagi & Hoffman, 1976). Therefore, irrespective of
whether the underlying mechanisms are social or biological, gen-
der differences must be examined in every investigation into
empathy.
Genetics of Empathy
Given the importance of empathy to social functioning and the
marked individual differences in this trait, it is of considerable
interest to understand the genetic architecture of empathy. Indeed,
similar to other complex psychological traits, a meta-analysis of
twin studies indicates that the ability to empathize is moderately
heritable. It is important that when emotional and CE were con-
sidered separately, genetic effects of similar magnitude were ob-
served for both CE and EE, but a different pattern of environmen-
tal effects emerged, with individual variability in CE partially
explained by shared-environment effects (17%), and no such effect
for EE (Knafo & Uzefovsky, 2013).
The moderate heritability of empathizing ability suggests that a
search for candidate genes partially contributing to this phenotype
is worthwhile, and a good starting point is the neural pathways that
underlie social cognition in the brain.
Dopamine and Social Behavior
Dopamine is an important neurotransmitter in the “social brain”
neural network, with major influences on animal and human social
behavior (Skuse & Gallagher, 2009). It has been argued that
dopamine is crucial for empathy-motivated prosocial behavior,
which has evolutionary roots in offspring care (Preston, 2013). The
social hormones oxytocin (OT) and arginine vasopressin (AVP)
play a role in modulating dopaminergic receptors in the striatum,
orbitofrontal cortex, and other brain areas involved in social cog-
nition. Together with dopamine they comprise an integrated sys-
tem of social and communication skills (Skuse & Gallagher,
2009). Evidence suggests that social interactions are accompanied
by OT and AVP release, which in turn modulates dopaminergic
activity in the brain reward system. Thus, dopamine activity con-
tributes to experiencing social interactions as positive (Skuse &
Gallagher, 2009).
Collectively, the findings on the role of dopamine in social
interactions suggest that dopaminergic genes might play a crucial
role in empathy. Among the few genes encoding for synaptic
elements of brain dopaminergic activity, the Dopamine D4 Recep-
tor gene (DRD4) is a particularly attractive candidate. First, the
DRD4 gene is expressed in regions that have been shown to play
a role in empathy (Decety & Lamm, 2006), such as the amygdala
and the prefrontal cortex (Oak, Oldenhof, & Van Tol, 2000).
Second, converging evidence from molecular genetics studies sug-
gest that this candidate gene is associated with social cognition
(Kang, Namkoong, & Kim, 2008; Reiner & Spangler, 2011; Skuse
& Gallagher, 2009; Zhong et al., 2010). Most research on the
genetics of DRD4 focuses on a 16 amino acid repeat region (48 bp)
in exon 3 that has functional consequences (Van Craenenbroeck et
al., 2011). The most common repeat in Caucasian populations is 4
(4R), while the second most common variant is the 7 (7R) (Chang,
Kidd, Livak, Pakstis, & Kidd, 1996) that is characterized by a less
efficient receptor. The DRD4 exon3 repeat is robustly associated in
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2UZEFOVSKY ET AL.

most but not all studies as a risk allele for attention-deficit/
hyperactivity disorder (ADHD; Faraone, Doyle, Mick, & Bieder-
man, 2001), a disorder that was linked with empathy deficits
(Uekermann et al., 2010). Furthermore, in adults the 4R polymor-
phism has been associated with questionnaire measures of altruism
(Bachner-Melman et al., 2005) and with laboratory-based incen-
tivized “sense of fairness” using the ultimatum game (Zhong et al.,
2010).
It is interesting that the association between DRD4 and social
behavior is often contingent on an environmental context. That is,
carriers of the 7R allele seem to be more susceptible to the effects
of the environment on social behavior, and that is also the case
with prosocial behavior. Several studies have reported that a
child’s relationship with his or her parent is associated with proso-
cial behavior only for DRD4-7R carriers. Specifically, one study
showed that securely attached children donated more to UNICEF,
but only if they were carriers of the 7R-allele (Bakermans-
Kranenburg & van Ijzendoorn, 2011). In another study, positive
parenting was associated with mother-rated prosocial behavior,
and unexplained punishment was associated with self-initiated
prosocial behavior, only among 7R carriers (Knafo, Israel, &
Ebstein, 2010). Another study showed that religion priming in-
creased participants willingness to volunteer, but only when par-
ticipants were carriers of the susceptibility alleles (defined as the 7
or 2 repeat alleles; Sasaki et al., 2013). These findings are in line
with a relatively recent line of research that points to a unique role
of the 7R allele as an allele that confers higher sensitivity to
environmental effects:for better or for worse” (Belsky & Pluess,
2009). Notably, the prosocial behaviors associated with the DRD4
gene are likely underpinned by empathy (Batson et al., 1988;
Preston, 2013). Indeed, one study directly examined the associa-
tion between DRD4 and empathy in children, finding that maternal
negativity interacted with the DRD4 genotype to influence chil-
dren’s empathic response to an experimenter feigning physical
pain (Knafo & Uzefovsky, 2013). Taken together, these findings
suggest not only that the DRD4 gene likely contributes to empathy,
but that its role is complex and is modulated by both the internal
(hormonal) and external environment.
It is interesting that it seems that the effects of the DRD4
genotype on behavior are also moderated by gender. Several
studies report on gender-specific effects of the gene (that is,
the gene is associated with a behavior in one of the gender but not
the other) or on gender-contingent effects (that is, the effect of the
gene is different depending on gender; Froehlich et al., 2007;
Laucht, Becker, El-Faddagh, Hohm, & Schmidt, 2005; Laucht,
Becker, & Schmidt, 2006; Tammimäki & Männistö, 2011; Wang,
He, Chen, Huang, & Yeh, 2012; Zhong et al., 2010). These reports,
together with the crucial role that gender plays in individual
differences in empathy, suggests that the two factors (DRD4 and
gender) must be investigated jointly to better understand their
association with empathy.
The likely role of dopamine pathways in empathy as well as the
key role that the DRD4 plays in DA synaptic transmission provide
a promising avenue for research into the genetic architecture of
empathy. However, the complex role of DRD4 in social cognition
combined with the complex nature of empathy itself makes pre-
diction of direction of DRD4 on CE and/or EE uncertain. Never-
theless, the concept of cognitive flexibility (the ability to mentally
switch between different concepts) may be informative. It has been
shown that cognitive, but not emotional empathy is associated with
cognitive flexibility both in clinical (Shamay-Tsoory et al., 2007)
and nonclinical populations (Shamay-Tsoory, Tomer, Goldsher,
Berger, & Aharon-Peretz, 2004). Cognitive flexibility is consid-
ered to be a functional component of empathy and is primarily
associated with the ability to take the mental perspective of the
other; that is, CE (Decety & Jackson, 2004). Given that there is
evidence that the dopaminergic system underlies cognitive flexibly
(Müller et al., 2007), it is possible that the dopaminergic system
also predominantly underlies the cognitive, compared with the
emotional aspects of empathy. Supporting this notion is the recent
study implicating the dopaminergic system, and the DRD4 exon3
polymorphism specifically, in the development of Theory of Mind
(Lackner, Sabbagh, Hallinan, Liu, & Holden, 2012). However, a
direct investigation of the association between DRD4 exon3 and
cognitive and emotional aspects of empathy has not yet been
conducted, and that is a main aim of the current study.
Hypotheses
The current investigation was designed to test the following
hypotheses. First, we hypothesized that the DRD4 exon3 polymor-
phism contributes to individual differences in empathy. To test our
hypothesis, we measured empathy and genotyped for the DRD4
exon3 polymorphism in two independently recruited samples of
university students. Second, following recent findings (reviewed
earlier), we hypothesized that the DRD4 exon3 polymorphism
would be more likely to contribute to individual differences in CE
compared with EE. Third, we sought to look at the effect of gender
as a consistent predictor of empathy, predicting that women would
score higher than men on all empathy measures. We also hypoth-
esized that the association between DRD4 and empathy would be
contingent on gender based on numerous findings that show that
the association between this gene and behavioral traits is often
gender-specific (Froehlich et al., 2007; Kang et al., 2008; Laucht
et al., 2005; Laucht et al., 2006; Reiner & Spangler, 2011; Zhong
et al., 2010). To our knowledge, this is the largest candidate gene
study of empathy so far reported.
Method
Study 1
Participants. A total of 477 Hebrew University students (54%
women, mean age 24.42 ⫾2.67) were recruited by advertisements
on campus bulletin boards for a study on personality and genetics.
All subjects were aged 18–35; had no self-report history of psy-
chiatric disorders, chronic illness, or drug taking; and were non-
smokers. All participants were of Jewish descent. The project was
approved by the S. Herzog Hospital Institutional Review Board
committee and the Israeli Ministry of Health.
Measures. Participants came to the lab where informed con-
sent was obtained and DNA mouthwash samples were collected.
Participants were then given a demographic questionnaire and a
code name and password for an online website where they filled
out several questionnaire measures, among those three widely used
and highly validated self-report measures of empathy: (1) Inter-
personal Reactivity Index (IRI; Davis, 1980), which consists of 28
items on a 5-point scale, with a higher score conferring a better
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3
DRD4 HAS A SPECIFIC EFFECT ON EMPATHY

empathic ability, as is for all the other measures. (2) Empathy
Quotient (EQ; Baron-Cohen & Wheelwright, 2004), which con-
sists of 60 items (40 empathy items and 20 filler items) on a
4-point scale. On each empathy item a person can score 2, 1, or 0.
(3) Questionnaire Measure of Emotional Empathy (QMEE; Meh-
rabian & Epstein, 1972), which consists of 33 items on a 9-point
scale. All these measures tap into emotional and cognitive aspects
of empathy; however, the EQ and the QMEE do not differentiate
between cognitive and emotional aspects of empathy, whereas the
IRI does. The IRI has four validated subscales that tap into CE and
EE. Two of the subscales measure CE (fantasy [F] and perspective
taking [PT]) with items such as “After seeing a play or movie, I
have felt as though I were one of the characters” (F) and “I try to
look at everybody’s side of a disagreement before I make a
decision” (PT). The other two subscale of the IRI tap into emo-
tional empathy (empathic concern [EC] and personal distress
[PD]), with items such as “I often have tender, concerned feelings
for people less fortunate than me” (EC) and “When I see someone
who badly needs help in an emergency, I go to pieces” (PD). An
online version of the questionnaires was used because of its
convenience and the increased sense of anonymity such a medium
provides, without compromising reliability or validity of measures
(Hertel, Naumann, Konradt, & Batinic, 2002).
DNA extraction and genotyping. DNA was extracted from
20 ml of mouthwash samples using the Master Pure kit (Epicenter,
Madison, WI). The DRD4 polymorphism (variable number of
tandem repeats of 48bp) in exon3 was characterized by a poly-
merase chain reaction (PCR) amplification procedure with the
following primers F5=-CTTCCTACCCTGCCCGCTCATGCT-
GCTGCTCTACTGG-3=and R5=-ACCACCACCGGCAGGAC-
CCTCATGGCCTTGCGCTC–3. PCR reactions were performed
using 5 ␮l of Master Mix (Thermo scientific), 2 ␮l primers (0.5
␮mol/L), 0.6 ␮l mg/Cl2 (2.5 mM), 0.4 ␮l DMSO 5%, and 1 ␮lof
water to total of 9 ␮l total volume and an additional 1 ␮lof
genomic DNA was added to the mixture. All PCR reactions were
employed on a Biometra T1 Thermocycler (Biometra, Güttingem,
Germany). PCR reaction conditions were as follows: preheating
step at 94.0 °C for 5 min, 34 cycles of denaturation at 94.0 °C for
30s, reannealing at 55 °C for 30s, and extension at 72 °C for 90s.
The reaction proceeded to a hold at 72 °C for 5 min. The reaction
mixture was then electrophoresed on a 3% agarose gel (AMRESCO)
with ethidium bromide to screen for genotypes.
The distribution of genotype frequency was in Hardy-Weinberg
equilibrium (chi-square pvalue ⫽.791) and independent of ethnic
origin (␹(3)
2⫽5.05, p⫽.168). See Table 1 for details regarding sex
and age by genotype.
Statistical analysis. Genotype of the DRD4 exon3 repeat was
coded as the presence or absence of the 7-repeat allele, resulting in
a two-level predictor variable. Together gender, DRD4 genotype
and their interaction served as predictors of questionnaire scores.
All statistical tests were carried out using SPSS v19 (Windows).
Study 2
Participants. A total of 121 Haifa University students (62%
female, mean age 24.60 ⫾1.97) were recruited through advertise-
ments on campus bulletin boards for a study on personality and
genetics. Selection criteria were identical to those in Study 1. All
participants were of Jewish descent.
Measures and analyses. Measures and genetic analyses were
identical to those in Study 1. The distribution of genotype fre-
quency was in Hardy-Weinberg equilibrium (chi-square pvalue ⫽
.488) See Table 2 for details regarding sex and age by genotype.
Results
Study 1
The results section is planned to test our main hypotheses.
Section 1 of the results provides us with a basis for a composite
empathy score, which is used as the phenotype in the subsequent
analyses. In Section 2, we test the hypothesis that there is a
sex-contingent association between DRD4 and empathy. In Sec-
tion 3, we further analyze the role of the DRD4 exon3 polymor-
phism separately in males and females. In Section 4, we analyze
the association between DRD4 and both CE and EE.
(1) Correlation between empathy measures and computa-
tion of a composite score. Scores from all three measures
(IRI, EQ, QMEE) were standardized using Z-scores. As ex-
pected, because all three measures were designed to assess
empathy, the three variables were significantly correlated (all
correlations range from .45 to .70, p⬍.001). Therefore, an
average score was computed for each participant, which was
also standardized using Z-scores. This standardized composite
measure of empathy was used as the phenotype to test associ-
ation with DRD4.
(2) The effect of gender and genotype on composite empathy
scores. We examined the role of genotype and gender on the
composite empathy score using a 2 (7R present vs. absent) ⫻2
(male/female) analysis of variance (ANOVA). The analysis
yielded a significant effect for gender, with women scoring higher
than men, as hypothesized, F(1,402) ⫽51.77,p⬍.001. This
gender difference was qualified by a significant interaction be-
tween gender and DRD4-7R, F(1,402) ⫽5.19, p⫽.023. The main
effect of genotype was not significant, F(1,402) ⫽.07, p⫽.79;
see details in Table 3. The interaction reflects the fact that female
carriers of the 7R had higher empathy scores than noncarriers,
whereas the opposite was observed for males. Male carriers of the
7R had lower empathy scores than noncarriers (Figure 1). It is
important that the results hold when comparing 7R carriers with
4R carriers only, Gender, F(1,303) ⫽39.41, p⬍.001; Genotype,
F(1,303) ⫽.094, p⫽.76; Genotype ⫻Gender, F(1,303) ⫽10.85,
p⫽.001.
Examination of the simple effects reveals that for both genotype
groups (7R present and 7R absent) women scored significantly
higher than men (p⬍.001). Notably, the effect size (Cohen’s d),
of the difference between women and men on empathy scores was
substantially greater (d⫽1.07) in carriers of the 7R allele than
Table 1
Demographics of the Study 1 Sample by Genotype
Genotype Sex Age
7R⫺Men 157 (49.8%) 24.41 ⫾2.75
Women 158 (50.2%)
7R⫹Men 70 (45.8%) 24.48 ⫾2.66
Women 83 (54.2%)
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4UZEFOVSKY ET AL.

noncarriers (d⫽.51). Examination of the effect of genotype
separately for each sex revealed that the effect of genotype was
only marginally significant for women (p⫽.08) and not signifi-
cant for men (p⫽.15). Thus, the DRD4 genotype appears not to
have a direct across-the-board effect on empathy overall, but it
does interact with gender.
(3) The effect of genotype on cognitive and emotional
empathy. Following our second hypothesis, that the effect of the
DRD4-7R allele might be different for cognitive and emotional
empathy, we next calculated a composite score for CE and EE
separately. The separate scores were computed similarly to that of
the complete empathy score (by averaging Z-scores of the relevant
measures). The CE score was created from the two cognitive
subscales of the IRI: fantasy and perspective taking. The EE score
was created from the two emotional subscales of the IRI; empathic
concern and personal distress.
After extracting composite scores for CE and EE we tested for
an association between the DRD4 7R-allele and each facet of
empathy separately. Gender again had a main effect on both mean
scores; CE, F(1,402) ⫽16.75, p⬍.001; EE, F(1,402) ⫽44.16,
p⬍.001; and there was no main effect of DRD4 genotype; CE,
F(1,402) ⫽.63, p⫽.80; EE, F(1,402) ⫽.57, p⫽.45. Notably,
the interaction effect, DRD4 ⫻Gender, was highly significant for
CE, F(1,402) ⫽13.79, p⬍.001, but not for EE, F(1,402) ⫽.44,
p⫽.51. Repeating the analyses with only participants homozy-
gous for the 4R compared with 7R carriers (77 or 47) yielded the
same results for EE; gender, F(1,303) ⫽35.75, p⬍.001; geno-
type, F(1,303) ⫽.83, p⫽.37; Genotype ⫻Gender, F(1,303) ⫽
1.53, p⫽.22; and for CE, Gender, F(1,303) ⫽12.30, p⬍.001;
Genotype, F(1,303) ⫽.20, p⫽.65; Genotype ⫻Gender,
F(1,303) ⫽19.64, p⬍.001. Leading to the conclusion that
genotype had no main effect on empathy scores, and that the
significant interaction between gender and 7R-allele, which has
been previously observed for the overall empathy score, was
specific for CE.
Intriguingly, for women the presence of the 7R-allele is associ-
ated with higher CE scores whereas for men the opposite is
observed and the 7R-allele is associated with lower CE scores (see
details in Table 3 and Figure 2, as well as online Supplemental
Materials Figure 1). We again turned to examine the simple effects
to better understand the interaction. In the absence of the 7R-allele
there is no significant gender effect on CE, F(1,277) ⫽.117, p⫽
.73. In contrast, the gender difference in CE in ⫹7R participants
is highly significant, F(1,125) ⫽21.54, p⬍.001, with a large
effect size (Cohen’s d⫽.83). Examination of the effect of geno-
type separately for men and women revealed that genotype was
significantly associated with CE scores for both sexes, but in
opposite directions. That is, in men, the 7R allele was significantly
associated with lower CE scores, F(1,192) ⫽8.34, p⬍.01,
Cohen’s d⫽.461; whereas for women the 7R allele was associ-
ated with higher CE scores, F(1,210) ⫽5.79, p⬍.05, Cohen’s
d⫽.348.
Study 2
To check the robustness of the findings reported in Study 1, we
recruited a second, independent sample of participants and ana-
lyzed the association between the DRD4-7R, gender and empathy.
As previously noted, the gender effect was significant (p⬍.001),
but the interaction effect (DRD4 ⫻Gender) on the total empathy
score was not significant (p⬎.05), probably because of the
smaller sample size. However, the directionality of the effect was
similar to the effect found in Study 1; males carrying the 7R score
lower than noncarriers (mean scores were ⫺.43 ⫾.74 and ⫺.15 ⫾
.99, respectively), and females carriers of the 7R score higher than
noncarriers (mean scores were .55 ⫾.86 and .33 ⫾1.11, respec-
tively).
We then turned to examine the effects of DRD4 and gender on
cognitive and emotional empathy separately. Again, as observed in
Study 1, a significant effect of gender was found for both empathy
facets; CE, F(1,121) ⫽3.71, p⫽.056; EE, F(1,121) ⫽14.87, p⬍
.001; and again, there was no main effect of DRD4 genotype; CE,
Table 2
Demographics of the Study 2 Sample by Genotype
Genotype Sex Age
7R⫺Men 33 (38.8%) 24.37 ⫾1.80
Women 52 (61.2%)
7R⫹Men 20 (47.6%) 25.05 ⫾2.26
Women 22 (52.4%)
Table 3
Means (⫾SD) of Empathy Scores by Genotype and Gender
Genotype Gender Empathy Emotional
empathy Cognitive
empathy
7R⫺Men ⫺.29 ⫾.74 ⫺.42 ⫾.93 .02 ⫾.93
Women .11 ⫾.82 .19 ⫾.98 .06 ⫾.97
7R⫹Men ⫺.46 ⫾.70 ⫺.42 ⫾.93 ⫺.39 ⫾.83
Women .32 ⫾.76 .33 ⫾.96 .41 ⫾1.08
Total Men ⫺.34 ⫾.73 ⫺.42 ⫾.93 ⫺.11 ⫾.92
Women .18 ⫾.80 .23 ⫾.97 .17 ⫾1.02
Figure 1. The effect of gender and DRD4-7R allele on empathy based on
results of Study 1. Error bars indicate SEM.
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5
DRD4 HAS A SPECIFIC EFFECT ON EMPATHY

F(1,121) ⫽.21, p⫽.65; EE, F(1,121) ⫽.002, p⫽.96. As
observed previously in Study 1, the DRD4 ⫻Gender interaction
was significant for CE, F(1,121) ⫽5.00, p⫽.03, but not for EE,
F(1,121) ⫽.288, p⫽.59. See details in Table 4. It is important
that the effects were in the same direction as Study 1, with women
carriers of the 7R-allele scoring higher than women noncarriers,
and men carriers of the 7R-allele scoring lower than men noncar-
riers (see Figure 3 and online Supporting Material Figure 2). As in
Study 1, the same results emerged when genotype was analyzed
for participants homozygous for the 4R compared with 7R carriers
(77 and 47) for EE; Gender, F(1,96) ⫽11.63, p⫽.001; Genotype,
F(1,96) ⫽.039, p⫽.85; Genotype ⫻Gender, F(1,96) ⫽.71, p⫽
.40; and similar results for CE with the exception of a nonsignif-
icant gender effect; Gender, F(1,96) ⫽2.24, p⫽.14; Genotype,
F(1,96) ⫽.42, p⫽.52; Genotype ⫻Gender, F(1,96) ⫽5.14, p⬍
.05.
Again, in the absence of the 7R-allele there is no significant
difference in CE scores by gender, F(1,82) ⫽.06,p⫽.80, whereas
the difference in CE for those men and women who carry the
DRD4 7R-allele is significant, F(1,39) ⫽8.53, p⬍.01, with a
large effect size (Cohen’s d⫽.91). A complementary analysis of
the effect of genotype within each gender revealed a significant
effect of genotype on men’s CE scores, with men carriers of the 7R
allele scoring lower than noncarriers, F(1,51) ⫽4.67, p⬍.05,
Cohen’s d⫽.63, and a nonsignificant effect in which women
7R-carriers scored higher than noncarriers on CE, F(1,70) ⫽1.43,
p⫽.24, Cohen’s d⫽.32.
Discussion
The current findings demonstrate a highly specific association
between the DRD4 exon3 polymorphism and CE in a sex-specific
manner, replicated in two independently recruited groups of stu-
dents from different universities. First, we find that the repeatedly
reported gender difference in empathy scores has been replicated
in both studies, again highlighting the importance of gender to
empathy research. Second, our findings point to an even greater
role of gender in empathy. In both studies, we find that gender
markedly modulates the impact of the 7R allele on CE. In women
the presence of the 7R allele enhances CE, whereas in men the 7R
allele is significantly associated with lower CE.
The sexual dimorphism shown here for the DRD4-7R is con-
sistent with a considerable literature showing that dopaminergic
pathways are often gender-sensitive (Tammimäki & Männistö,
2011; Wang et al., 2012). Indeed, a previous study examined a
related concept-sense of fairness (modeled in the Ultimatum
Game) with participants of East-Asian origin (Zhong et al., 2010).
1
In this study, the interaction between DRD4 genotype and gender
was significant and the effect of DRD4 was more pronounced for
males than for females. Similar Gene ⫻Gender interaction effects
have been reported for other phenotypes as well, including cogni-
tive function (Froehlich et al., 2007), novelty seeking (Laucht et
al., 2006), and smoking behavior (Laucht et al., 2005). In these
studies, effects of genotype were observed in only one of the sexes.
Additional evidence stem from the association between DRD4
genotype and ADHD (Li, Sham, Owen, & He, 2006), a disorder
with a strong sex bias that is characterized by deficits in empathy
(Marton, Wiener, Rogers, Moore, & Tannock, 2009). Taken to-
gether, these findings show that the observed effects of the DRD4
genotype, and specifically the 7R-allele, are often sex-specific or
sex contingent, with the direction of the effect dependent on the
phenotype examined.
The current gender-specific findings beg further consideration
into the underlying mechanisms of the sex-contingent effects of
DRD4 exon3 on empathy. First, does the DRD4 genotype moder-
ate the effects of gender, or is it the other way around and gender
moderates the effect of DRD4? Second, what does our measure of
1
In the Asian population the 7R allele is extremely rare and the 2R allele
is the second most common allele. Studies examining social phenotypes
such as novelty seeking, other-regarding emotions and ADHD (Kang,
Namkoong, & Kim, 2008; Leung et al., 2005; Reist et al., 2007) show that
in this population, the 2R allele serves a similar role to that of the 7R allele
in Caucasian populations.
Table 4
Means (⫾SD) of Empathy Scores by Genotype and Gender
Genotype Gender Emotional empathy Cognitive empathy
7R⫺Men ⫺.28 ⫾.83 ⫺.12 ⫾.92
Women .34 ⫾1.09 ⫺.18 ⫾1.18
7R⫹Men ⫺.39 ⫾.85 ⫺.65 ⫾.78
Women .43 ⫾.93 .17 ⫾1.01
Total Men ⫺.32 ⫾.83 ⫺.32 ⫾.90
Women .36 ⫾1.04 ⫺.08 ⫾1.13
Figure 2. The effect of DRD4-7R genotype and gender on (A) cognitive empathy and (B) emotional empathy
based on results of Study 1. Error bars indicate SEM.
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6UZEFOVSKY ET AL.

sex/gender reflects (i.e., biological sex or social gender)? Alto-
gether, the currently observed Gene ⫻Gender interaction can be
interpreted in one of three ways, with each interpretation contain-
ing an underlying presupposition regarding these two questions.
First, we can consider gender as reflecting the genetic sex (i.e.,
XX or XY) of the participant. According to this view, the Gene ⫻
Gender interaction is in fact a Gene ⫻Gene interaction, making
the direction of the moderation (gene moderates sex or sex mod-
erates gene) less important.
The second possibility is to interpret gender as determining the
internal hormonal environment in which genetic products operate.
For example, women have higher levels of estrogen than men, and
these differences were shown to affect social behavior (van Anders
& Gray, 2007). Moreover, evidence suggests that sex hormones
such as estrogen affect dopamine neural pathways. Of particular
note is a study by Dreher et al. (Dreher et al., 2007), which
demonstrated augmented reactivity of the dopaminergic reward
system in women during the midfollicular phase, when estrogen is
unopposed by progesterone. In addition, behaviors associated with
addiction are mediated by dopaminergic brain reward network, and
are often different for men and women, presumably because of the
interaction between sex hormones and the dopaminergic reward
system (Becker & Hu, 2008). Thus, the Gene ⫻Gender interaction
reported in our study can be viewed as an interaction between a
gene and the internal-hormonal environment in which genes op-
erate. Future studies would benefit from examining empathy vis-
a
`-vis levels of hormones such as estrogen and testosterone, espe-
cially in light of the studies showing that empathy, facial mimicry,
and prosocial behavior are directly affected by sex hormones
(reviewed in Hastings, Zahn-Waxler, & McShane, 2006). Such
investigations can also shed more light on the direction of the
moderation observed in the current findings. For example, can a
manipulation of male hormone levels (e.g., testosterone) change
the direction of the interaction?
Finally, we can interpret gender as those behaviors that are
affected by social norms and perceptions regarding gender-
normative behavior, suggesting the interpretation of the interaction
as a Gene ⫻Social environment interaction. This view is sup-
ported by several findings that identify empathy as part of the
female societal gender role. For example, men and women tend to
define women in terms of relationships, and men in terms of
agency and independency (Guimond, Chatard, Martinot, Crisp, &
Redersdorff, 2006). The way gender is perceived is greatly influ-
enced by society, and therefore gender can be viewed as an
environmental factor that can in turn influence empathy. In a
meta-analysis of studies that assessed CE, it was found that only
after invoking female demand characteristics did women outper-
form men on this task (Ickes et al., 2000). A direct test of the
meta-analysis findings (Thomas & Maio, 2008) revealed that
women whose female stereotypical supremacy in CE was threat-
ened, had increased motivation to perform better at the task which
resulted in better performance when compared with women who
did not undergo the manipulation. It is interesting that when the
female gender role was evoked in men, they too perceived emo-
tions more accurately. Hence, increasing female demand charac-
teristics causes in turn an increase in motivation to perform better
in these types of tasks. From this point of view, it is possible to
consider the sex-contingent effect of DRD4 as reflecting a Gene ⫻
Environment interaction.
It is important to note here that although questionnaire measures
have the advantage of revealing a complex and stable character-
istic, they are also prone to reporter bias and demand characteris-
tics, which might have had an influence on the findings. For
example, perhaps carriers of the 7-repeat are more prone to rate
themselves (as opposed to really feel or act) according to gender
related cultural norms. Hence, future studies might employ other
measures of empathy (i.e., laboratory-based tasks) that are less
affected by these biases. Nevertheless, although cultural and ste-
reotypical differences in the role men and women take on in
society undoubtedly contribute to gender differences in empathiz-
ing ability, this influence might be moderated, as our results
suggest, by specific molecular genetic endowments. Thus, accord-
ing to this interpretation and our results, genotype enhances exist-
ing sex differences in those people who are more affected by the
environment, so that the DRD4 genotype moderates gender effects
on empathy. Indeed, future research might profit from exploring
how cultural attitudes interact with genotype in determining em-
pathizing ability.
The current finding that DRD4 interacts with gender to affect
cognitive but not emotional empathy supports the theoretical dis-
tinction between EE and CE and, furthermore suggests a biological
mechanism for this distinction. Although research in social and
developmental psychology had consistently differentiated between
the two aspects of empathy, the biological underpinnings of the
Figure 3. The effect of DRD4-7R genotype and gender on (A) cognitive empathy and (B) emotional empathy
based on results of Study 2. Error bars indicate SEM.
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7
DRD4 HAS A SPECIFIC EFFECT ON EMPATHY

two systems remained unclear. Recent advances in neuroimaging
and lesion research provided insights into the brain structures that
underlie EE and CE, but much remains to be learned. The current
findings contribute to a better understanding of the biological
mechanism of empathy by using a neurogenetic strategy. The
neurotransmitter dopamine is associated with a host of social
behaviors and emotional responses, many of them basic mecha-
nisms that do not involve higher order emotional or cognitive
processing (Preston, 2013). Therefore, it was important to under-
stand if the DRD4 gene is associated with emotional and cognitive
aspects of empathy. Indeed, the current study lends support to a
recent model that suggested dopamine as a key neurotransmitter in
cognitive but not emotional empathy (see Shamay-Tsoory, 2011
and Lackner et al., 2012). Moreover, this finding echoes our
previous finding of different etiologies for cognitive and emotional
empathy derived from a meta-analysis of twin studies, whereby
cognitive, but not emotional empathy, was found to be influenced
by shared environment (Knafo & Uzefovsky, 2013). In addition,
brain lesion studies (Shamay-Tsoory et al., 2009) and imaging
studies (Cox et al., 2011) strongly suggest that different neuronal
networks are involved in emotional and CE. This anatomical and
functional separation between emotional and CE is also supported
by some behavioral studies (Jones et al., 2010; Schwenck et al.,
2011). The current genetic evidence strengthens the notion that the
two empathy systems are distinct at the molecular and neural
levels. It is interesting that CE is both more complex and thought
to be phylogenetically more recent than emotional empathy (Pres-
ton & de Waal, 2003). It also depends on cognitive flexibility,
which is mediated by phylogenetically recent prefrontal cortices.
CE involves the ability to create a theory about the other’s mental
state and cognitively take the perspective of others, a feat almost
exclusively carried out by Homo sapiens with some possible
primate exceptions (Call & Tomasello, 2008). It is important that
the DRD4-7R allele is also considered to be a relatively recent allele
(Wang et al., 2004), perhaps explaining the specific association be-
tween this allele and the more phylogenetically advanced ability of
CE. Further research is needed to understand the intricate association
between empathy and the dopaminergic system. It is plausible that
other pathways within the dopaminergic system are associated with
the emotional aspects of empathy.
We currently identify one gene (of presumably many) under-
pinning the molecular genetic architecture of CE, providing a
partial understanding of the neural pathways likely accounting for
individual differences in this phenotype. Taken together, the cur-
rent findings not only open a window into the molecular architec-
ture of CE, but could also add to the Nature versus Nurture debate
regarding gender differences in empathizing abilities. Our findings
strengthen the argument that the sexual dimorphism observed in
empathy is at least partially genetically influenced. Moreover, they
add another possible interpretation of the gene by gender interac-
tion, fueled by recent research into Gene ⫻Environment effects,
that the term gender reflects both the biological and the social
environment. This interpretation, albeit somewhat speculative,
aims to propose another way of looking at the decades old debate
among researchers regarding the mechanisms, either biological or
social, underlying observed differences between men and women
in empathy.
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Received March 21, 2013
Revision received February 10, 2014
Accepted February 27, 2014 䡲
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This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.
10 UZEFOVSKY ET AL.