Oxytocin receptor genetic variation relates
to empathy and stress reactivity in humans
Sarina M. Rodriguesa,b,1,2, Laura R. Saslowc,1,2, Natalia Garciac, Oliver P. Johna,c, and Dacher Keltnerc
aInstitute of Personality and Social Research, University of California, Berkeley, CA 94720; bDepartment of Psychology, Oregon State University, Corvallis,

OR 97331; and cDepartment of Psychology, University of California, Berkeley, CA 94720
Edited by Michael I. Posner, University of Oregon, Eugene, OR, and approved October 9, 2009 (received for review August 24, 2009)

emotional 兩 polymorphism 兩 social

O

xytocin is a peptide of nine amino acids that is produced in
the hypothalamus and released into both the brain andbloodstream. Functioning as both a neurotransmitter and hormone, oxytocin’s targets are widespread and include the hypothalamus, amygdala, hippocampus, brainstem, heart, uterus, andregions of the spinal cord that regulate the autonomic nervous
system, especially the parasympathetic branch (1, 2). Oxytocin’srole in reproductive functions is well known, and its contribution
to pair-bond formation has been systematically studied (3, 4).
Oxytocin also appears to modulate broad profiles of social andemotional behaviors in both males and females (5, 6). One
hypothesis is that oxytocin supports affiliative behavior. Indeed,
injections of oxytocin increase prosocial behaviors in a variety of
species, including primates, voles, rats, and sheep (7). In humans,
intranasal administration of oxytocin increases generosity (8),trust (9), eye gaze (10), and the ability to infer the affective
mental states of others (11). Furthermore, assessments of plasma
oxytocin in humans find that oxytocin levels relate to parent–child bonding behaviors (12), feelings of romantic love and trust(13), and empathy and subsequent generosity toward strangers (14).
A second hypothesis is that oxytocin interacts with the hypothalamo-pituitary-adrenal axis to attenuate the stress response(6, 15), which has pervasive influences throughout the body andthe brain (16, 17). Notably, oxytocin has been shown to induce
potent physiological anxiolytic effects, by decreasing cortisol
levels (18, 19), inhibiting cardiovascular responses to stress (19),and attenuating amygdala responsivity to emotional stimuli (20).
Given these literature findings, we derived two a priori
hypotheses about the social-emotional functions of oxytocin. We
examined individual differences at a polymorphic site in theoxytocin receptor (OXTR) gene, which is localized in single copy
to chromosome 3 of the human genome (4). Interestingly, OXTR
knockout mice display a variety of aberrant social and emotional
behaviors, including increased aggression and deficits in nurturing and social memory (21, 22), that are in keeping with the two
hypothesized functions of oxytocin tested here. In humans, asingle-nucleotide polymorphism (SNP) of an adenine (A) or
www.pnas.org兾cgi兾doi兾10.1073兾pnas.0909579106

guanine (G) within intron 3 of the OXTR gene (rs53576) has
been associated with autism (23), a disorder characterized by
impairments in social interactions and communication. This
genetic variation has also been associated with the degree ofwarm and empathic parenting displayed toward offspring (24).
Thus, individuals with one or two copies of the A allele, whencompared to those homozygous for the G allele, have an
increased likelihood of an autism diagnosis (23) and display lessparental sensitivity (24).
These studies suggest that genetic variation of the OXTR
could systematically explain variation in two basic socioemotional processes in humans—empathy and stress reactivity. We
hypothesized that rs53576 variations would be related to bothbehavioral and self-report measures of empathy and to both
physiological and self-report measures of stress reactivity. Morespecifically, we predicted that individuals homozygous for the G
allele (GG) would have higher levels of empathy and lower levelsof stress reactivity than individuals with one or two copies of the
A allele (AA and AG).
Results
As it has been proposed that oxytocin evolved to influence socialand stress profiles of males and females differently (25), we
verified that there were no significant interactions of rs53576
with gender in our analyses and display our findings for males
and females separately for illustrative purposes.
To assess individual variation in a behavioral measure of
empathic accuracy, participants completed the ‘‘Reading theMind in the Eyes’’ Test (RMET), which tests for the empathic
ability to infer the emotional states of others (11, 26–29).
Previous studies have documented that impaired performanceon the RMET predicts higher scores on a measure of autistic
traits in both clinical and control groups (27, 29). Moreover, ina healthy population, intranasal administration of oxytocin wasshown to improve empathic accuracy scores (11). As predicted,
we found that GG individuals performed significantly better on
this behavioral measure of empathy (Fig. 1A), being 22.7% lesslikely to make a mistake on the RMET than AA/AG individuals[F (1, 177) ⫽ 8.18, P ⫽ 0.005, Cohen’s d ⫽ 0.49, GG (M ⫽ 20.55%
incorrect, standard error [SE] ⫽ 1.43), AA/AG (M ⫽ 25.22%
incorrect, SE ⫽ 0.86)].
Dispositional empathy was assessed with a well-validated
self-report scale that reflects the core facets of other-oriented
empathic behavior (30). Consistent with the findings from thebehavioral measure of empathy, GG individuals reported higher
levels of dispositional empathy (Fig. 1B) than AA/AG individAuthor contributions: S.M.R., L.R.S., and O.P.J. designed research; S.M.R., L.R.S., and N.G.
performed research; S.M.R. and L.R.S. analyzed data; and S.M.R., L.R.S., O.P.J., and D.K.
wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
1S.M.R and L.R.S. contributed equally to this work.
2To whom correspondence may be addressed. E-mail: sarina.rodrigues@oregonstate.edu

or saslow@berkeley.edu.

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Oxytocin, a peptide that functions as both a hormone and neurotransmitter, has broad influences on social and emotional processing throughout the body and the brain. In this study, we tested
how a polymorphism (rs53576) of the oxytocin receptor relates to
two key social processes related to oxytocin: empathy and stress
reactivity. Compared with individuals homozygous for the G alleleof rs53576 (GG), individuals with one or two copies of the A allele(AG/AA) exhibited lower behavioral and dispositional empathy, as
measured by the ‘‘Reading the Mind in the Eyes’’ Test and another-oriented empathy scale. Furthermore, AA/AG individuals
displayed higher physiological and dispositional stress reactivity
than GG individuals, as determined by heart rate response during
a startle anticipation task and an affective reactivity scale. Our
results provide evidence of how a naturally occurring genetic
variation of the oxytocin receptor relates to both empathy andstress profiles.

Fig. 1. OXTR rs53576 polymorphism relates to behavioral and self-reportmeasures of empathy. (A) Individuals with the GG genotype perform better onan empathic accuracy task than individuals with the AA/AG genotypes, asmeasured by the ‘‘Reading the Mind in the Eyes’’ Test. (B) Individuals with the
GG genotype report higher dispositional empathy than individuals with the
AA/AG genotypes, as measured by other-oriented subscales of the DavisInterpersonal Reactivity Index. Error bars represent standard error of themean.

uals [F (1, 183) ⫽ 5.11, P ⫽ 0.025, Cohen’s d ⫽ 0.37, GG (M ⫽3.69, SE ⫽ 0.06), AA/AG (M ⫽ 3.53, SE ⫽ 0.04)].
The modulation of the acoustic startle response has beenvalidated as one of the best indexes of physiological stress
reactivity, because potentiated startle reactivity engages basic
fear-related activation in the central nervous system (31, 32). To
measure stress reactivity, participants were presented initiallywith an unanticipated white-noise burst startle stimulus. After
this, to potentiate stress reactivity, the participants were told thatthey were going to hear the loud noise two more times at the endof a 20-second countdown. During this last anticipation period,
we computed an index of heart rate (HR) reactivity by averaging
the HR of each participant during the final poststartle countdown, controlling for baseline HR taken at the beginning of theexperimental session. As predicted, GG individuals scored significantly lower on HR reactivity to the startle anticipation than
AG/AA individuals (Fig. 2A): HR [F (1, 144) ⫽ 4.97, P ⫽ 0.027,
Cohen’s d ⫽ ⫺0.52, GG (M ⫽ 72.1, SE ⫽ 0.54), AA/AG (M ⫽78.4, SE ⫽ 1.19)].
21438 兩 www.pnas.org兾cgi兾doi兾10.1073兾pnas.0909579106

Fig. 2. OXTR rs53576 polymorphism relates to physiological and self-reportmeasures of stress reactivity. (A) Individuals with the GG genotype display
lower heart-rate reactivity than individuals with the AA/AG genotypes during
an anticipation segment of a startle laboratory task. (B) Individuals with the
GG genotype report lower dispositional stress reactivity than individuals with
the AA/AG genotypes. Error bars represent standard error of the mean.

Dispositional levels of stress reactivity were assessed with a
12-item scale that captures affective reactivity to stressful situations, emergencies, and crises, rather than baseline negative
affect. Consistent with the physiological startle reactivity findings, GG individuals reported lower levels of dispositional stress
reactivity (Fig. 2B) [F (1, 184) ⫽ 5.61, P ⫽ 0.019, Cohen’s d ⫽⫺0.39, GG (M ⫽ 2.47, SE ⫽ 0.08), AA/AG (M ⫽ 2.69,
SE ⫽ 0.05)].
Finally, we tested whether the rs53576 variation would relate
to self-report measures of attachment style and received parental
care. These data are important to rule out potential self-reportbiases as an alternative explanation of our self-report findings(e.g., GG individuals might simply report more positive outcomes on any self-report measure). This analysis also provided
an initial test of the alternative hypothesis that early relationships
with parents account for these effects. Replicating past research,
we found no link between rs53576 variations and attachment
style (33), nor did we find an association with received parental
care.
Rodrigues et al.

findings, we found no association between rs53576 variations andattachment style. GG individuals did not differ from AG/AA
individuals on either attachment avoidance [F (1, 104) ⫽ 1.02,
P ⫽ 0.315, G/G (M ⫽ 2.48, SE ⫽ 0.11), A/A or A/G (M ⫽ 2.35,
SE ⫽ 0.07)] or attachment anxiety [F (1, 104) ⫽ 1.20, G/G (M ⫽2.58, SE ⫽ 0.13), A/A or A/G (M ⫽ 2.75, SE ⫽ 0.08)]. Thesefindings delineate an important boundary condition of the impactof this OXTR polymorphism on interpersonal functioning.
Consistent with the attachment findings, GG individuals did
not differ from AG/AA individuals on received paternal [F (1,176) ⫽ 0.15, P ⫽ 0.699, G/G (M ⫽ 3.45, SE ⫽ 0.13), A/A or A/G(M ⫽ 3.51, SE ⫽ 0.08)] or maternal caring [F (1, 176) ⫽ .22, P ⫽0.643, Cohen’s d ⫽ 0.08, G/G (M ⫽ 4.01, SE ⫽ 0.13), A/A or A/G(M ⫽ 3.94, SE ⫽ 0.08)]. Again, this result helps us begin to ruleout positive report bias for OXTR genotype and gives someevidence that our results are not due to positive early relationships with parents.
Discussion
Our results are consistent with past research relying on intranasal administrations or plasma assays of oxytocin showing that
empathy and stress responsivity are both influenced by oxytocin(6, 11, 18, 34). Although of the functionality of the rs53576
OXTR polymorphism is unknown and its position within an
intron suggests that it is unlikely to confer any distinctive
molecular function, future work is needed to determine whether
it is related to oxytocin sensitivity and OXTR signaling pathways.
Nevertheless, our results and the findings of other groups (23,24) suggest that probing for variations at this site may be
meritorious in mixed-population gene-association studies ofindividual differences in social and emotional processing. Given
the limitations of single-gene approaches and that all socioemotional behaviors are influenced by multiple genes, future
research should determine how the OXTR gene may interact
with others involved in social and emotional processing.
Without respect to genotype, empathy and stress reactivity
measures in this study are slightly negatively correlated with eachother (average correlation: r ⫽ ⫺0.021), but such correlations do
not approach statistical significance. Therefore, the OXTR
variant analyzed in this study reveals a unique dissociation. The
empathy and stress reactivity used in this study vary systematically in healthy human populations in other studies (27, 30, 32,
35). Interestingly, previous work has shown that autistic individuals display lower scores in both the behavioral (RMET) anddispositional empathy measures (27, 29, 36) and that intranasal
oxytocin improves both RMET performance and prosocial
behaviors (8, 9, 11, 37). Furthermore, intranasal oxytocin reduces amygdala activation and cortisol increases to emotional
stimuli (20, 37). These data converge with the findings from thepresent study and lend credence to the claim that this genetic
variation of the oxytocin system influences emotional processing
and other-oriented behavior in tandem. Future work is needed
to more fully characterize the relationship between empathy andstress reactivity, as influenced by oxytocin, in both clinical andnonclinical populations.
This study demonstrates a link between OXTR variations andindividual differences in empathy and stress-related profiles. In
the present research, those individuals who are homozygous for
the G allele, compared to those with one or two copies of the A
allele, proved to be more adept at inferring the mental states ofothers and also reported experiencing tonically higher levels of
empathy. Complementing these findings, those with an A allele
showed greater cardiovascular reactivity to an imminent startle
probe and also reported higher levels of reactivity across avariety of stressful contexts. These findings are in keeping withtwo central hypotheses about the functions of oxytocin—that it
enables social affiliation and the reduction of stress. These
Rodrigues et al.

findings have important implications for understanding how
naturally occurring variations in the oxytocin system, which can
influence neural and physiological processing (19, 20, 25, 38),
affect both social and emotional systems.
Materials and Methods
College students at the University of California, Berkeley (n ⫽ 192, 59%
female) with a mean age of 20.2 years (SE ⫽ 0.20 years) and of mixed ethnicity(35% Caucasian, 41% Asian, and 24% other or multiple ethnicities) participated in the study for partial course credit. Initial analyses confirmed thatOXTR variations did not significantly interact with gender or ethnicity for anyof the dependent variables. This research was authorized by the university’s
Committee for Protection of Human Subjects, and all participants gave informed consent before beginning each portion of the study. Participants
completed the self-report measures and the behavioral empathy task at least
1 week before taking part in the laboratory-based experimental session.
Genotyping. DNA was collected from saliva using Oragene kits (DNA Genotek,
Kanata, Ontario, Canada), which allow for long-term preservation and storage of DNA at room temperature. All DNA samples were labeled with ananonymous code designed to protect the privacy of participants and were
purified by Creative Genomics (Port Jefferson Station, NY). First, DNA samples
were heat-treated to maximize DNA yield and to ensure that nucleases arepermanently inactivated. Next, DNA samples were mixed and ice-incubatedwith Oragene DNA Purifier to remove impurities. After this, each sample wascentrifuged at room temperature and the clear supernatant was transferred
to a new tube. Tubes were centrifuged after 100% ethanol was added toprecipitate the DNA. DNA samples were then washed with ethanol, rehydrated, assayed for concentration, and sent to the University of California, San
Francisco Genomics Core to conduct the genotyping assay. The SNP marker for
rs53576 was genotyped using TaqMan SNP Genotyping Assays (Applied Biosystems, Foster City, CA) functionally tested by Applied Biosystems and available on demand. TaqMan polymerase chain reaction (PCR) reactions weredone with Universal Master Mix Amperase UNG, 0.083 ␮l Taqman 40X probe
mix, and 1.417 ␮l of water, 1 ␮l of DNA normalized to 10 ng/␮l, for a 5 ␮l total
volume. The PCR conditions for the TaqMan SNP Genotype Assays were as
follows: one enzyme activation step at 95.0 °C for 10 min, and 50 alternating
cycles of denaturation at 95.0 °C for 15 s and reannealing and extension at
60.0 °C for 1 min. All PCR reactions and allelic discrimination reactions were
performed on an ABI 7900HT Real-Time PCR System (Applied Biosystems) andanalyzed using SDS 2.3 software (Applied Biosystems).
Genotype distribution (n ⫽ 44 A/A, n ⫽ 88 A/G, n ⫽ 47 G/G) aligns withprevious reports for this variation according to the ethnic background of ourparticipants (23, 39). No sex differences could be detected (␹2 ⫽ 2.16; df ⫽ 2,
P ⫽ 0.34). Data quality was assessed by duplicating a subset of random DNA
samples and genotype data reproducibility was 100%. In all but one of ourmeasures, the AA and AG groups did not differ in statistically significant ways;
we therefore combined them in our comparative analyses to GG, as done
previously by other researchers (24).
Empathy: Behavioral Task. As an objective measure of empathy, we used theReading the Mind in the Eyes Task (11, 26 –29), which assesses individual
differences in the ability to infer the affective mental states of strangers. In thisstandardized multiple-choice test, participants are shown 36 black-and-whitephotos of the eye region of different individuals. The individual in each photo
displays a particular emotional or cognitive state. Each photo is paired withfour affective-state adjectives as response options (e.g., ‘‘terrified,’’ ‘‘upset,’’‘‘arrogant,’’ and ‘‘annoyed’’). Participants select the adjective that in their
judgment best describes what the individual in the photo is feeling or
thinking.
Empathy: Self-Report. The most commonly used self-report measure of dispositional empathy (30) consists of three core facets of other-oriented empathic
behavior, namely perspective taking (e.g., ‘‘I sometimes try to understand myfriends better by imagining how things look from their perspective’’), empathic concern (e.g., ‘‘I often have tender, concerned feelings for people lessfortunate than me’’), and fantasy (e.g., ‘‘I really get involved with the feelingsof the characters in a novel.’’), all of which are positively intercorrelated,
capture the broader concept of other-oriented empathy, and have beenshown to predict helping for altruistic reasons (40). Participants rated each
item from 1 (strongly disagree) to 5 (strongly agree). This 21-item composite
measure of dispositional empathy had a Cronbach’s alpha reliability of 0.81.
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Discriminant Validity. Attachment style. Consistent with previous

Stress Reactivity: Physiological Task. Throughout the laboratory session, participants’ heart rate was recorded. As an index of stress reactivity, we assessed
the average heart rate of each participant during a startle anticipation task
and controlled for the average baseline heart rate during a 2-minute paced
breathing task. To make these measurements, participants were connected toa physiological measurement system (P150, Biopac Systems Inc., Santa Barbara, CA) using disposable snap electrodes (Biopac, EL503) with LEAD110
series electrode leads. Heart rate data were stored and analyzed using Acknowledge software (Biopac Systems Inc.). If any artifacts in the data wereobserved, they were repaired, if possible, or discarded from analyses. Data
averages that were more than three standard deviations below or above themean (outliers) were discarded.
In the laboratory, participants were hooked up to physiological equipment
and were given a 15-min period to rest while seated in a comfortable chair.
Next, participants were asked to relax and then engaged in a 2-minutepaced-breathing task, which guided participants through controlled breathing with their eyes closed. The task limits the variability in respiration acrossparticipants and allows for the analysis of heart rate under controlled conditions (41).
Participants were then seated directly in front of a 17‘‘ flat-screen LCD
monitor. The auditory startle probes were administered via computer-based
instructions on the screen. Instructions guided participants to put on calibrated headphones (Sennheiser HD-280) and to fixate on a large ’’X‘‘ presented in the center of the screen. Fifteen seconds later, an unanticipated loudnoise was presented through the headphones. The stimulus was a standard
white-noise burst used in previous startle experiments (500 ms, 120 dB) (42).
After this first unanticipated startle probe, the computer screen notified theparticipants that after each 20-s countdown, loud noises would be presented:’’In this part of the experiment, you will know exactly when the loud noises will
occur. You will see a countdown from 9 to 0 on the video screen. When you see‘‘0’’ the loud noise will happen. Before beginning the countdown, please
relax.‘‘ To measure stress reactivity, we averaged the participants’ heart rateduring the second (final) countdown, thus capturing the maximum effect offear-potentiated anticipation, and compared this with baseline heart rateduring the paced breathing task.

reactivity in stressful situations, emergencies, and crises, rather than baseline
negative affect. This unidimensional scale measures a general factor of stress
reactivity. On the highly reactive end, item examples include feeling apprehensive and ill at ease in emergencies, and becoming very emotional when
under a great deal of stress; on the low-reactive end, examples include
remaining calm in tense situations and being relaxed and handling stress well.
Participants rated their level of agreement from 1 (disagree strongly) to 5
(agree strongly).
Discriminant Validity. To test the boundary conditions of the impact of thers53576 OXTR polymorphism, we examined two possible confounds, i.e., thatOXTR variations are related to positive self-report bias or that they are linked
to differential early-life experiences.
Attachment Style. Some participants completed a shortened version of theExperiences in Close Relationships Inventory (43), which measures the two
major dimensions of attachment functioning in adults. Attachment avoidanceis measured with items such as ‘‘I have not felt comfortable opening up to mypartner,’’ and ‘‘I want to get close to my partner, but I find myself pulling back’’(alpha ⫽ 0.81). Attachment anxiety is measured with items such as ‘‘I haveoften worried that my partner won’t care about me as much as I care about
him/her,’’ and ‘‘I have often wanted to merge completely with my partner, andthis sometimes scared him/her away’’ (alpha ⫽ 0.80). Participants rated how
much they agreed that each item was true of their own experiences inromantic relationships, using a scale from 1 (strongly disagree) to 5 (strongly
agree).
Received Paternal and Maternal Caring. Using the caring scale of the Parental
Bonding Instrument (44), participants rated their father’s and their mother’scaregiving behavior before the participants’ age of 16; the same 12 items areworded once for rating one’s father and once for rating one’s mother, using
a five-point response scale from 1 (strongly disagree) to 5 (strongly agree).
Items include ‘‘He/She could make me feel better when I was upset’’ and‘‘He/She was affectionate to me.’’ Cronbach’s alpha was 0.94 for the paternal
caring scale and 0.95 for the maternal caring scale.

Stress-Reactivity: Self-Report. Stress reactivity was assessed with a 12-item
scale (Cronbach’s alpha ⫽ 0.86). Following Gross et al. (35), we used items fromthe broad Neuroticism personality domain that measure negative-emotion

ACKNOWLEDGMENTS. We gratefully acknowledge all of the wonderful research assistants and honors students involved in this project. This research
was supported by grants from the Metanexus Institute, the Greater Good
Science Center, and the University of California, Berkeley Swan ResearchAward.

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