Neuroscience 164 (2009) 4354

REVIEW
GENETICS OF EMOTION REGULATION
T. CANLI,a,b* J. FERRIa AND E. A. DUMANa

Catechol-O-methyltransferase (COMT) val158met

Monoamine oxidase A (MAOA)
Endophenotypes of attention to emotional stimuli
Behavioral endophenotypes
Neural endophenotypes
Integration and extension
Endophenotypes of reappraisal and suppression
Behavioral studies
Neural endophenotypes
Integration and extension
Discoveries ahead
Conclusion
Acknowledgments
References

Department of Psychology, Building B, Stony Brook University, Stony

Brook, NY 11794-2500, USA
b
Graduate Program In Genetics, Stony Brook University, Stony Brook,
NY 11794-2500, USA

AbstractEmotions can be powerful drivers of behavior that

may be adaptive or maladaptive for the individual. Thus, the
ability to alter ones emotions, to regulate them, should be
beneficial to an individuals success of survival and fitness.
What is the biological basis of this ability? And what are the
biological mechanisms that impart individual differences in
the ability to regulate emotion? In this article, we will first
introduce readers to the construct of emotion regulation, and
the various strategies that individuals may utilize to regulate
their emotions. We will then point to evidence that suggests
genetic contributions (alongside environmental contributions) to individual differences in emotion regulation. To date,
efforts to identify specific genetic mechanisms involved in
emotion regulation have focused on common gene variants
(i.e. variants that exist in >1% of the population, referred to
as polymorphisms) and their association with specific emotion regulation strategies or the neural substrate mediating
these strategies. We will discuss these efforts, and conclude
with a call to expand the set of experimental paradigms and
putative molecular mechanisms, in order to significantly advance our understanding of the molecular mechanisms by
which genes are involved in emotion regulation. 2009
IBRO. Published by Elsevier Ltd. All rights reserved.

THE CONSTRUCT OF EMOTION REGULATION

Individuals differ greatly in their responses to emotional
experiences. For example, extroversion and neuroticism
represent two fundamental personality traits that reflect,
respectively, individual differences in positive and negative
feeling states, cognitive styles and attitudes (Costa and
McCrae, 1980). Maladaptive responses to emotional stimuli may render individuals vulnerable to various forms of
psychopathology. For example, individuals who score high
in neuroticism are vulnerable to mood disorders (Kendler
et al., 1993a,b). Thus, individuals can benefit greatly from
behaviors that regulate emotions to maximize adaptive
responses and minimize maladaptive responses to emotional experiences.
Gross proposed a conceptual framework of emotion
regulation that considers the temporal aspects of emotion
(Gross, 1998). Using this framework, Gross identified antecedent-focused strategies, which an individual may utilize to regulate emotions before they arise, and responsefocused strategies, which an individual may utilize once an
emotion has begun to unfold. Emotion regulation strategies may involve either automatic/unconscious or voluntary/conscious processes.
We will briefly discuss behavioral data from three emotion regulation strategies, for which there are relevant genetic data (discussed in the next sections). As an example
of a form of emotion regulation that is often automatic/
unconscious, we will discuss studies assessing attentional
bias to emotional stimuli. As two examples of emotion
regulation that usually require voluntary/conscious effort,
we will discuss studies assessing the costs and benefits
of cognitive reappraisal (an antecedent-focused strategy)
and suppression (a response-focused strategy). A comprehensive review of this literature is well beyond the
scope of this article (interested readers are referred to

Key words: emotion regulation, neuroimaging, gene polymorphism, prefrontal cortex, amygdala, 5-HT transporter.
Contents
The construct of emotion regulation
Attention to emotional stimuli
Reappraisal and suppression
Genetic contributions to emotion regulation
Heritability
Molecular psychology
Candidate gene polymorphisms
5-HT transporter-linked polymorphic region(5-HTTLPR)

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*Correspondence to: T. Canli, Department of Psychology, Building B,

Stony Brook University, Stony Brook, NY 11794-2500, USA. Tel: 1631-632-7803.
E-mail address: turhan.canli@sunysb.edu (T. Canli).
Abbreviations: COMT, catechol-O-methyltransferase; DLPFC, dorsolateral prefrontal cortex; DTI, diffusion tensor imaging; GE, gene-byenvironment; HR, heart rate; MAOA, monoamine oxidase A; met,
methionine; OFC, orbitofrontal cortex; pACC, perigenual anterior cingulate cortex; PFC, prefrontal cortex; rACC, rostral anterior cingulate
cortex; SL, heterozygous short allele carrier; SNP, single nucleotide
polymorphism; SS, homozygous short allele carrier; val, valine;
VLPFC, ventrolateral prefrontal cortex; VNTR, variable number of
tandem repeats; WM, white matter; 5-HTT, 5-HT transporter; 5HTTLPR, 5-HT transporter-linked polymorphic region.

0306-4522/09 $ - see front matter 2009 IBRO. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.neuroscience.2009.06.049

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T. Canli et al. / Neuroscience 164 (2009) 4354

authoritative reviews elsewhere (e.g. Gross and Levenson,

1993, 1997; Gross, 1998, 2002, 2007), as is a comprehensive discussion of the patient and animal literature. Instead, the studies discussed below serve as an illustration
of the various paradigms that have been used in the study
of emotion regulation mostly in non-patient populations
and highlight some of the salient findings that have accrued in this literature to date.
Attention to emotional stimuli
A number of studies have investigated individual differences in attentional bias to emotional stimuli using paradigms that assess automatic/unconscious processes. For
example, studies using an emotional version of the Stroop
task, in which participants are timed to indicate the color in
which presented words are printed, have reported that
subjects who score high in trait anxiety or neuroticism
respond slower to negatively valenced words than to neutral words (Richards et al., 1992; Wells and Matthews,
1994; Derryberry and Reed, 1998), which is interpreted as
an attentional bias towards negative stimuli. In anxious
individuals (compared to depressed or healthy individuals),
this bias can be observed regardless of whether stimuli
are presented subliminally or supraliminally (Mogg et al.,
1993). In sub-clinical populations, anxiety is correlated with
biased Stroop processing of anxiety-related words only for
subliminal stimuli (Yovel and Mineka, 2005). There is also
evidence supporting a more complex interplay of trait and
state variables. For example, one study using an emotional
Stroop task found no evidence for state or trait effects on
Stroop interference, but did find an interactive effect, such
that only high-trait anxiety individuals showed a positive
correlation between state anxiety and Stroop interference
(Egloff and Hock, 2001).
Another example is the dot-probe paradigm, in which
pairs of target stimuli (usually differing in valence) are
presented, followed by presentation of a probe stimulus
placed in the same location as one of the preceding target
stimuli. Measures of participants reaction times to localize
the probe or of their overt orienting responses using eyetracking methods indicate to which item of the target pair
participants attended. This work has found that individuals
with high state or trait anxiety exhibit an orienting bias
towards threatening facial expressions (Bradley et al.,
2000; Mogg et al., 2000). More recent work has extended
these findings to show that high-anxious individuals, compared to low-anxious individuals, exhibit a similar attentional bias for both intense fear-related and threat-related
facial expressions (Mogg et al., 2007). A recent study
(Cooper and Langton, 2006) suggests that low-anxious
individuals may also exhibit attentional biases for threatening faces, if they are probed 100 ms after stimulus
presentation but not if they are probed 500 ms after stimulus presentation (which is a standard parameter used in
dot probe studies).
Electrophysiological evidence for attentional bias comes
from studies using event related potentials (ERPs). For
example, one study using a spatial cueing task (Fox et al.,
2008), in which individuals who were either high or low in

trait anxiety viewed valenced (happy and angry) alongside

neutral face stimuli. Only high-anxiety individuals exhibited
biased attentional processing, as measured by an enhanced N2-posterior-contralateral component, which is believed to represent attentional processes during visual
search.
Taken together, there is ample evidence across paradigms that there are individual differences in subjects
automatic/unconscious attentional bias towards emotional
stimuli. The next section will discuss complementary studies that have used paradigms requiring voluntary/conscious effort in emotion-related reappraisal and suppression.
Reappraisal and suppression
Behavioral studies have used a wide range of experimental paradigms to study the emotional, physiological, cognitive, and social consequences of emotion reappraisal and
suppression. Reappraisal refers to the strategy of changing ones interpretation of stimuli or situations that may
elicit strong (usually negative) emotions in a manner that
reduces or alters the emotional experience. Suppression
refers to the strategy of inhibiting the behavioral (e.g. facial) expression of ones emotional experience. Perhaps
the most seminal contribution to the study of these processes has been made by Gross and colleagues. In the
first study of this kind, Gross and Levenson, (1993) presented a film clip selected to elicit strong feelings of disgust
and had participants either watch the film without further
instruction or with the instruction to suppress the outward
expression of their feeling state. The suppression condition
was effective in reducing outward expression of emotion,
but not in reducing the emotional experience per se; suppression was also associated with evidence for increased
sympathetic arousal. Later work replicated and extended
these findings to show dissociable consequences of emotion suppression, compared to cognitive reappraisal, during presentation of emotional films and pictures (Gross,
1998). This work discovered that, although both strategies
were effective in reducing the expression of emotion, only
reappraisal was also effective in reducing the experience
of negative emotion.
Studies of the physical consequences of different
emotion regulation strategies have found that emotion
suppression leads to increased sympathetic activation
of the cardiovascular system (Davidson, 1993; Gross
and Levenson, 1993, 1997; Gross, 1998). On the other
hand, cognitive reappraisal is associated with reduced
cardiovascular responding. For example, individuals who
scored high in reappraisal exhibited a more adaptive cardiovascular response following an anger provocation paradigm, compared to individuals who scored low in reappraisal (Mauss et al., 2007).
A major cognitive consequence of emotion suppression, but not reappraisal, is the impairment of memory for
the details of negative film clips or images (Richards and
Gross, 2000, 2006). Indeed, the extent to which memory
during emotion suppression is diminished is comparable to
a condition in which participants are instructed to distract

T. Canli et al. / Neuroscience 164 (2009) 4354

themselves from the emotional stimulus (Richards and

Gross, 2006). One explanation for this phenomenon is that
suppression taps cognitive resources by requiring the continuous monitoring and adjustment of emotion expression.
By contrast, reappraisal reframes the emotional experience early on, which consequently affects the behavioral
response and requires no additional cognitive resources
(Richards and Gross, 2000).
Other paradigms have assessed the effects of suppression on memory in the context of social interactions.
For example, one study had dating couples discuss a
relationship conflict and found that suppression was associated with reduced memory for the content of that conversation (Richards et al., 2003). A similar finding was reported in a study using a stressful speaking task, in which
participants spontaneous emotion suppression (spontaneous meaning in the absence of an explicit experimental
instruction to suppress, but instead suppression being
spontaneously used by the subject) was associated with
reduced memory for the content of a speech (Egloff et al.,
2006).
Suppression also affects the quality of social interactions. For example, suppression has been shown to have
negative effects on social dyads, such as the inhibition of
relationship formation (Butler et al., 2003). Outside the
laboratory, one prospective study followed students transitioning to college (Srivastava et al., 2009). In this study,
suppression of emotion expression, measured both as a
stable trait and as a dynamic response to the novel environment, predicted lower social support, less closeness to
others, and lower social satisfaction (Srivastava et al.,
2009).
Several studies have begun to examine whether the
consequences of emotion suppression are universal or
culturally moderated. For example, studies have demonstrated that European Americans use suppression as a
regulatory technique less frequently than do ethnic minorities; additionally, American samples of diverse ethnicity
negatively appraise suppression as inauthentic and deceitful (Gross and John, 2003; Butler et al., 2007). Some
researchers have suggested that this assessment of suppression may be culturally driven, and that Asian populations might view suppression as a prosocial method of
maintaining harmony in relationships (Wierzbicka et al.,
1994; Butler et al., 2007). When comparing the social
consequences of suppression in Asian and Western European samples and taking into account the norms and
values of their respective cultures, Butler and colleagues
(2007) found that deleterious social effects were greatly
reduced for Asian participants, primarily due to their increased responsiveness. The authors suggested that this
increase in responsiveness might be due to Asian participants ability to suppress more automatically than did
Western European individuals, thus lessening cognitive
demands of effortful suppression.
Taken together, the behavioral literature on emotion
reappraisal and suppression has identified emotional,
physiological, cognitive, and social consequences across
a range of paradigms. To the extent that there are individ-

45

ual differences in the ability to regulate emotions, which

may affect individuals biological fitness, the question
arises whether there are genetic factors that may contribute to these individual differences. We will turn to the
evidence in support of genetic contributions in the remainder of this article.

GENETIC CONTRIBUTIONS TO EMOTION

REGULATION
Heritability
There is strong evidence that individual differences in responsiveness to emotional stimuli are moderated, in part,
by genetic variables. For example, emotion-related personality traits such as extroversion and neuroticism have
heritability estimates of 40%50% (Viken et al., 1994; Jang
et al., 1996), with a similar amount of variance accounted
for by the non-shared environment. There is some evidence that the contribution of the non-shared environment
increases over the life span: one cross-sectional twin study
of individuals aged 2574 found that older adults exhibited
reduced heritability in daily affect, which the authors interpreted as evidence for an age-related increase in the
ability to regulate emotions (Neiss and Almeida, 2004).
Yet, direct evidence from twin studies for genetic contributions to emotion regulation is sparse. One study investigated heritability of emotion regulation in a set of 115
monozygotic (MZ) and 156 dizygotic (DZ) 5-month-old twin
pairs, assessing their responses to neutral and happy
facial expressions posed by their mother or by a stranger
(Soussignan et al., 2009). Behavioral measures included
motor activity level, social gaze, gaze aversion, positive
expression, negative expression, and self-comfort. It was
found that the observed variance in most behavioral responses was influenced by the non-shared environment.
The only evidence for a genetic contribution to emotion
regulation (as indicated by the latency and frequency of
gaze aversion) was observed when infants viewed the
strangers facial expressions. In this condition, the authors
determined that the observed variance was best represented by a model incorporating both additive genetic and
non-shared environmental influences, with heritability estimates ranging from 19% to 31%.
The available evidence therefore supports the notion
that individual differences in emotion regulation are, at
least in part, genetically moderated. Yet, it is clear that twin
studies would greatly benefit from incorporating a range of
paradigms used by emotion researchers to investigate
specific mechanisms of emotion regulation. For example, it
is unknown whether heritability estimates are similar for
different emotion regulation strategies, such as suppression versus reappraisal, or for automatic/unconscious versus voluntary/conscious processes. Furthermore, there is
indirect evidence from one cross-sectional study (Neiss
and Almeida, 2004) that environmental contributions to
emotion regulation skills increase with age, but these skills
have not been evaluated experimentally, nor are there any
longitudinal data to confirm this hypothesis.

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T. Canli et al. / Neuroscience 164 (2009) 4354

Molecular psychology
Whereas twin studies address questions of heritability of
emotion regulation, molecular genetic association studies
have the potential to identify specific genes associated
with emotion regulation. To the extent that the tools of
molecular biology are applied to the study of behavior, we
refer to this endeavor as molecular psychology (Canli,
2008). Before we turn our attention to specific examples
related to three forms of emotion regulation, we will briefly
review some key concepts and candidate genes.
A key concept is that of the endophenotype. Unlike
the phenotype, which traditionally represents the physical
manifestation (e.g. morphology) of an organisms genotype, the endo-phenotype is expressed at the behavioral or
physiological level, which is closer to the biological level at
which a gene operates. As a consequence, it is assumed
that the measured genetic effect sizes will be greater for
endophenotypes than for other phenotypes. Thus, the construct has been adopted in psychiatry (Gottesman and
Gould, 2003), particularly in the search for biomarkers of
psychopathology (Siever et al., 2002; New and Siever,
2003; Slaats-Willemse et al., 2003; Hasler et al., 2006),
although critics point out that the assumption of greater
genetic effect sizes is not supported by the empirical evidence (Flint and Munafo, 2007).
Another key concept is that of the polymorphism, which
is a common variant or allele (i.e. present in 1% of the
population) of a given gene. There are many different
types of polymorphisms, ranging from substitutions of
single nucleotides (single nucleotide polymorphisms, or
SNPs) to insertions or deletions (Ins/Del polymorphisms)
of nucleotide sequences, to variable numbers of repeated
nucleotide sequences (variable number of tandem repeats; VNTRs), to copy number variations (CNVs), which
may vary by many thousands of nucleotides. These polymorphisms may or may not affect a genes function. If they
do, they may alter which protein is encoded by the gene, or
the amount of a protein that is encoded, or its structural or
functional features, or the genes ability to regulate the
expression of other genes. Thus, polymorphic gene variations can activate numerous molecular mechanisms to
regulate the function of genes, and thusthrough the
genes role in shaping the structure or function of relevant
brain circuits contribute to individual differences in behavior. To date, only a very small number of gene polymorphisms have been investigated for their association
with emotion regulation. We will introduce the most prominent gene polymorphisms next.
Candidate gene polymorphisms
5-HT transporter-linked polymorphic region(5-HTTLPR).
One key regulator of the 5-HT system is the 5-HT transporter (5-HTT), which removes 5-HT released into the
synaptic cleft. The 5-HTT is encoded by a single gene
(5-HTT, SERT, SLC6A4). Transcriptional activity of the
human 5-HTT is modulated by several variations, including
a repetitive sequence, the 5-HTT-linked polymorphic region (5-HTTLPR), which is composed of a short (s) and a

long (l) allele resulting in differential 5-HTT expression

(Heils et al., 1996). Presence of the s allele is associated
with reduced transcriptional activity and 5-HTT expression,
relative to the l allele (Lesch et al., 1996). In addition, the
long allele contains an A/G SNP, which may render the LG
allele functionally similar to the short allele (Hu et al., 2005;
Wendland et al., 2006). Presence of the short allele is
associated with anxiety-related traits (Lesch et al., 1996;
Schinka et al., 2004; Sen et al., 2004) and with increased
activation in brain regions involved in emotion processing,
particularly the amygdala (Hariri et al., 2002; Canli et al.,
2005; Herrmann et al., 2007; Munaf et al., 2008).
Catechol-O-methyltransferase (COMT) val158met.
COMT degrades catecholamines such as dopamine. A
SNP located at codon 158 of the COMT gene leads to a
substitution of the amino acid valine (val) for methionine
(met), resulting in the substitution of the amino acid met for
val. The val allele is twice to three times as active as the
met allele (Lotta et al., 1995). Because COMT is the main
enzyme for dopamine catabolism in the frontal cortex
(Chen et al., 2004), this polymorphism is potentially relevant for moderating frontal cortical involvement in topdown emotion regulation.
Monoamine oxidase A (MAOA). MAOA regulates the
catabolism of monoamines, particularly 5-HT. Located
within the MAOA gene is a polymorphism, which is located
1.2 kb upstream of the MAOA coding sequences and
consists of a 30-bp repeated sequence present in two,
three, 3.5, four, or five copies (Sabol et al., 1998). This
VNTR polymorphism is functional: variants with 3.5 or four
copies of the repeat sequence are transcribed more efficiently (high-expression variants) than those with three or
five copies of the repeat (low-expression variants) (Sabol
et al., 1998). The MAOA gene polymorphism is an X
chromosomelinked polymorphism, meaning that only one
copy is present in males. Thus, all males will be homozygous for either the high- or low-expression variant,
whereas females (who carry two copies of MAOA) may be
homozygous or heterozygous. MAOA variation has been
linked to social behavior, particularly aggression (Caspi et
al., 2002; Newman et al., 2005) and moderates brain circuits involved in emotion and emotion regulation (Buckholtz et al., 2008; Buckholtz and Meyer-Lindenberg, 2008).
In the following sections, we will review the evidence
suggesting a role for these (and other) gene polymorphisms in the endophenotypes of three emotion regulation
strategies (attention to emotional stimuli, reappraisal, and
suppression) reviewed before.

ENDOPHENOTYPES OF ATTENTION TO
EMOTIONAL STIMULI
Behavioral endophenotypes
Several behavioral studies of attention have pointed to a
role for the 5-HTTLPR polymorphism. For example, one
study assessed emotional attentional bias in psychiatric
inpatients genotyped for 5-HTTLPR using anxiety- and
depression-related word stimuli in a dot-probe paradigm

T. Canli et al. / Neuroscience 164 (2009) 4354

(Beevers et al., 2007). It was found that short allele carriers

exhibited a significantly stronger attentional bias than did
noncarriers toward anxiety-related (but not to depressionrelated) word stimuli. Similarly, another dot-probe study
used images of spiders in healthy (i.e. not spider phobic)
individuals and reported attentional bias towards these
images in short allele carriers, but not in noncarriers (Osinsky et al., 2008).
Homozygous long allele carriers have been shown to
exhibit processing biases of their own: based on their
reaction times in a dot-probe task using valenced and
neutral images, homozygous carriers of the long allele
exhibited attentional bias toward positive, and away from
negative, stimuli (Fox et al., 2009). In contrast, carriers of
the short allele showed a (nonsignificant) tendency toward
a reverse processing bias.
Neural endophenotypes
The first fMRI study on the role of 5-HTTLPR in emotion
processing can be viewed as using a paradigm of automatic emotion processing (Hariri et al., 2002). In that study,
Hariri and colleagues scanned participants as they performed a matching task. In the experimental condition,
participants viewed angry and fearful facial expressions
and were instructed to match the facial expression of a
probe stimulus with one of two target stimuli. In the control
condition, participants viewed horizontal and vertical oval
shapes and were instructed to match stimuli accordingly. It
was found that activation of the amygdala, a region well
known to respond to facial expressions of emotion, particularly fearful faces, varied according to 5-HTTLPR genotype: activation was significantly greater in carriers of the
short allele than in noncarriers. Given that the amygdala is
believed to play a critical role in vigilance (Davis and
Whalen, 2001), this observation is consistent with the idea
that short allele carriers exhibit biased attention towards
negative stimuli.
We have made a similar observation using the emotional word Stroop task (Canli et al., 2005), for which there
is ample evidence for biased processing in high anxious or
neurotic individuals, as reviewed above. In our study, participants were scanned while they viewed negative, positive, and neutral word stimuli displayed in different colors.
Study participants were instructed to press a button indicating the color of the word, and no reference was made to
the affective characteristics of some of the stimuli. When
we compared amygdala activation in response to negative,
relative to neutral, word stimuli, we replicated Hariri and
colleagues (2002) observation that 5-HTTLPR short allele
carriers exhibited significantly greater amygdala activation
than did noncarriers.
However, we reasoned that the relative activation difference between the negative and neutral word condition
could have been driven by either increased activation to
negative or decreased activation to neutral words. To dissociate these two explanations, we conducted another set
of analyses based on relative comparisons with another
baseline condition, fixation rest, in which participants passively viewed fixation crosses. Surprisingly, relative to fix-

47

ation rest, presentation of negative words was not associated with increased amygdala activation in short allele
carriers. Instead, relative to fixation rest, presentation of
neutral words was associated with decreased amygdala
activation in short allele carriers, and this finding has since
been replicated by another group (Heinz et al., 2007).
Stated as in the previous sentence, the observation seems
counterintuitive. However, another way of stating the result
is to say that short allele carriers exhibited increased
amygdala activation during fixation rest, which may contribute to elevated levels of vigilance at times when they
are not cognitively constrained. Indeed, Raichle and colleagues (2001) have identified the amygdala as one brain
region that may be characterized by elevated resting activation as a default state of brain activity in the absence of
cognitive constraints. We therefore hypothesized thatin
the absence of cognitive constraints or external stimulus
presentationsshort allele carriers are characterized by
(trait-like) tonic amygdala activation, rather than a phasic
response to an external negative stimulus (Canli and Lesch, 2007). In a subsequent imaging study using arterial
spin labeling, we showed that resting amygdala activation,
quantified in volume of absolute blood flow, is indeed
significantly higher in short allele carriers than it is in noncarriers (Canli et al., 2006). This observation has also been
independently replicated (Rao et al., 2007), although the
interpretation of these findings remains a matter of debate
(Heinz et al., 2007).
Another imaging study focused on the role of the
COMT val158met polymorphism in emotional attention deployment (Bishop et al., 2006). The met allele of this polymorphism had previously been associated with reduced
emotion regulation in response to painful stimuli (Zubieta
et al., 2003) and with increased anxiety in some studies
(Karayiorgou et al., 1997; Woo et al., 2002, 2004; Enoch et
al., 2003, 2008; Olsson et al., 2005, 2007, but see Shioe et
al., 2003, McGrath et al., 2004 for contrary findings; for
a recent review, see Harrison and Tunbridge, 2008). In
the COMT val158met study of attention, participants
were scanned while matching images of houses in the
presence of neutral or emotional distracter images (Bishop
et al., 2006). Prior work by this group had shown that this
task is sensitive to individual differences in anxiety, with
activation in brain regions associated with cognitive control
being inversely related to individuals anxiety levels
(Bishop et al., 2004). It was therefore predicted that presence of the met allele should be inversely associated with
activation in these regions in the presence of negative
distracters. Indeed, the number of met alleles was found to
correlate inversely with activation in the ventrolateral prefrontal cortex (VLPFC) and orbitofrontal cortex (OFC) during presentation of negative distracters (no association
with amygdala activation was observed), as well as taskrelated activation in the parahippocampal place area.
These data were interpreted to suggest that the presence
of the met allele is associated with reduced top-down
regulation of distraction from negative stimuli.

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T. Canli et al. / Neuroscience 164 (2009) 4354

Integration and extension

The research on endophenotypes of attention to emotional
stimuli identifies a prominent role for the 5-HTTLPR polymorphism. Behavioral studies using the dot-probe paradigm suggest that carriers of the short allele are characterized by attentional bias toward negative stimuli and
homozygous long allele carriers by attentional bias toward
positive stimuli. Neuroimaging studies using emotional
face matching and emotional Stroop tasks (as well as
studies using many other paradigms, see for a meta-analytic review Munaf et al., 2008) point to the amygdala as
a critical region, although our emotional Stroop study
(Canli et al., 2005) also identified a large network of other
regions.
At this time, it remains to be resolved whether elevated
attentional bias to negative stimuli seen in short allele
carriers is moderated by increased phasic amygdala reactivity to external stimuli, by increased trait-like tonic activation, or both. This may not be a question that can be
resolved on the basis of neuroimaging data alone, because some have argued that elevated amygdala activation at rest reflects participants response to the undefined
environment of being inside a scanner, rather than trait-like
tonic activation (Heinz et al., 2007). However, consistent
with the view that short allele carriers are characterized by
tonic levels of (amygdala-based) emotional arousal or vigilance in the absence of cognitive constraints, data from
cortisol stress studies conducted outside the scanner show
that morning cortisol is elevated in homozygous short allele carriers (SS) (Chen et al., 2009; Wust et al., 2009), and
that there is no difference between genotype groups in
response to a social stressor (Wust et al., 2009). However,
the picture is complicated by the fact that these effects
were observed only in females and that individuals carrying both short and long alleles acted like homozygous long
allele carriers, rather than short allele carriers. Furthermore, there is evidence from one study that SS can show
greater cortisol reactivity to a stressor than individuals who
carry one or two copies of the long allele (Gotlib et al.,
2008). In any case, these studies cannot address the
question whether any of the observed effects are associated with the amygdala. Thus, more empirical evidence
across multiple paradigms will be needed to fully assess
the tonic and phasic models of 5-HTTLPR function.
Another critical extension of the discussed work will be
the assessment of other candidate gene polymorphisms.
For example, one study discussed above suggests that the
met allele of the COMT val158met polymorphism is associated with reduced top-down control of attention (Bishop
et al., 2006). Yet, data from another study suggest the
opposite conclusion: in that study, participants showed a
positive correlation between the met allele and activation in
the VLPFC and dorsolateral prefrontal cortex (DLPFC) and
limbic system (amygdala, hippocampus, and thalamus), as
well as in areas associated with visuospatial attention (fusiform gyrus and parietal lobule), when passively viewing
negative, compared to neutral, pictures (Smolka et al.,
2005). Of course, these two paradigms differ significantly

from each other, and only the former study deliberately

manipulated attentional focus. Nonetheless, discrepancies
between these findings illustrate that more studies are
needed to uncover the mechanisms by which COMT genotype (as well as any number of other candidate genes
yet untested) may be related to attentional processing of
emotional stimuli.

ENDOPHENOTYPES OF REAPPRAISAL AND

SUPPRESSION
Behavioral studies
There is scant direct empirical evidence for endophenotypes of reappraisal and suppression. One recent study
(Szily et al., 2008) focused on emotional appraisal (as
opposed to reappraisal): participants were asked to report
on a recent experience of strong sadness, fear, and joy
and to describe the situation, their subjective feelings,
physiological symptoms and behavioral expression, and
appraisal of the event. Appraisal was assessed with respect to how expected the emotion was, how pleasant or
unpleasant, how important the event was to the participants goals, how fair or unfair the event was, who was
responsible for the event, whether the participant felt able
to cope with the event, the morality of the event, and the
relation of the event to the participants self-concept (e.g.
self-esteem or self-confidence). In the description of both
fearful and of sad events, there was a significant interaction between 5-HTTLPR genotype and appraisal: carriers
of the short allele were characterized by higher scores than
were noncarriers for appraised unpleasantness and goalhindrance, and by lower scores for coping ability. In contrast, the appraisal of joyful events was not associated with
5-HTTLPR genotype.
In an experimental manipulation of emotional metacognition (Murakami et al., 2009), Japanese subjects participated in a decentered perspective manipulation, in which
they viewed negative and neutral pictures and received
feedback on their heart rate (HR) responses to the stimuli.
In the metacognition condition, participants were instructed
to observe their feelings and HR responses to emotional
pictures objectively, and not to suppress their emotions or
HR. In the control condition, participants were instructed to
watch emotional pictures as usual. Because the homozygous long allele is very rare among Asian individuals, there
were no such subjects in a sample of 24. Thus, all analyses were conducted to differentiate between homozygous
(SS) and heterozygous (SL) short allele carriers. Compared to a neutral baseline condition, presentation of negative emotional pictures produced significant increases is
self-reported anxiety in SS but not in SL subjects, regardless of emotion regulation condition. However, there was a
significant interaction effect for emotion regulation condition5-HTTLPR genotype on HR variability: in the metacognition condition only, SS but not SL subjects were
characterized by a high frequency of HR variability representing increased parasympathetic activity, indicating a
more relaxed state. These physiological data stand in contrast to the reported elevated level of anxiety from SS

T. Canli et al. / Neuroscience 164 (2009) 4354

subjects. Furthermore, this form of metacognition is known

to have opposite effects on emotional experience early in
training (when the induced state of mindfulness increases
negative emotions), compared to late in training (when the
induced state of mindfulness decreases negative emotions), but participants were only tested early in training.
Thus, the exact mechanisms by which 5-HTTLPR genotype relates to emotion regulation in this form of metacognition remain to be elucidated.
One longitudinal study explicitly tested childrens emotion regulation ability as a function of a gene-by-environment (GE) interaction of 5-HTTLPR genotype and attachment (Kochanska et al., in press). This group had
previously shown that infants attachment was associated
with a GE interaction of infants 5-HTTLPR genotype and
their mothers responsiveness to the infant at 7 months of
age (Barry et al., 2008). Specifically, infants who are carriers of the short allele (but not noncarriers) were found to
be very likely to develop insecure attachment, but only if
they experienced low responsiveness by their mothers. In
the follow-up study of the same sample (Kochanska et al.,
in press), these investigators measured childrens ability
for self-regulation across three time points (25, 38, and 52
months of age), using a battery of tasks presented to the
children as games that involved suppression of a dominant
response and adoption of a sub-dominant response. Examples of these tasks included games such as delaying a
response (e.g. reaching for candy placed under a cup or
unwrapping a gift), or suppressing or inhibiting a response
to one type of signal and producing or initiating a response
to another in a turn-taking game. It was found that children
who were carriers of the short allele and who were insecurely attached developed poor regulatory abilities. Attachment was an important moderator, because children who
were carriers of the short allele and who were securely
attached did not exhibit poor regulatory ability and performed as well as noncarriers (who performed well regardless of attachment style).
Recent work has begun to expand the search for candidate genes involved in appraisal, reappraisal or suppression beyond 5-HTTLPR. For example, one study (Wichers
et al., 2008) used an experience sampling method to collect daily measures of individuals reward experiences, as
measured by the effect of event appraisal on positive affect
(PA). Given the role of dopamine in reward experience,
and the role of the COMT val158met polymorphism in emotional processing (reviewed earlier), these investigators
assessed the role of this polymorphism in reward experience. They reported a positive correlation between the
number of met alleles and the amount of reward experience. In light of data discussed earlier, this is surprising
because the met allele has been associated with increased
anxiety and reduced emotion regulation and top-down
neural regulatory control (Karayiorgou et al., 1997; Woo et
al., 2002, 2004; Enoch et al., 2003, 2008; Zubieta et al.,
2003; Bishop et al., 2004, 2006; Olsson et al., 2005, 2007).
However, these other paradigms did not focus on processing of positive affect, nor did they use methods that assessed psychological functioning outside the laboratory.

49

One study assessed the role of genetic moderators in

the suppression versus expression of anger in pain experience (Bruehl et al., 2008). These investigators noted that
individuals differ in how they regulate anger by one of two
ways: one is trait anger-in, which refers to the management of anger by means of behavioral suppression, and
the other is anger-out, which refers to the management of
anger through physical or verbal expression. High levels of
either trait are associated with increased pain sensitivity,
but only anger-out involves opioid mechanisms. Based on
these considerations, this study investigated the role of a
polymorphism in the mu opioid receptor gene (the A118G
SNP) in moderating pain sensitivity as a function of angerout. Participants were exposed to acute pain stimuli (ischemic, finger pressure, thermal) and produced self-reported
ratings of experience sensory and affective pain, which
were summarized across stimuli. There was a significant
genotype (A118G)phenotype (trait anger-out) interaction, such that individuals who were carriers of the G allele
and who were low in anger-out reported much higher pain
sensitivity (suggesting poor endogenous opioid analgesia)
than did any other group. No significant genetic moderation was found for trait anger-in. As noted by the authors,
the mechanisms by which the 118G allele is associated
with more effective endogenous analgesia in some (high
anger-outs) but less effective endogenous analgesia in
others (low anger-outs) remain to be determined. Furthermore, it should be noted that the genetic moderation reported in this study refers to individual differences in pain
perception (in interactions with trait anger-out), and not to
a genetic contribution to trait anger-out itself. Indeed, genetic contributions to either trait anger-out or anger-in remain to be elucidated.
Neural endophenotypes
To date, there is no direct neuroimaging data for genetic
moderators of neural activation during reappraisal. However, several imaging studies have begun to identify the
neural circuitry associated with reappraisal (for more
comprehensive reviews, see Phillips et al., 2003, 2008;
Ochsner and Gross, 2005, 2007), and other imaging studies have begun to identify genetic moderators within these
circuits.
The circuitry of cognitive reappraisal is generally believed to consist of two elements: a top emotion regulatory system and a bottom emotion appraisal/generation
system (although elements of the regulatory system, specifically the VLPFC, may also be engaged in extracting
emotional meaning, Wager et al., 2008). In the first imaging study of cognitive reappraisal, Ochsner and colleagues
(2002) presented negative and neutral images and instructed participants either to experience whatever emotions a picture would generate, or to alter their interpretation of the negative images to reduce their emotional experience. Relative to the control condition, reappraisal
was associated with increased activation in the DLPFC,
VLPFC, and medial prefrontal cortex (MdPFC), and with
reduced activation in the amygdala and OFC. A similar
pattern of activation was observed in individuals who re-

50

T. Canli et al. / Neuroscience 164 (2009) 4354

ported greater use of reappraisal in everyday life when

these individuals viewed negative pictures without being
explicitly instructed to engage in reappraisal (Drabant et
al., 2009). Whereas downregulation of negative affect is
associated with reduced amygdala activation, other studies showed that maintenance of a negative emotional response is associated with prolonged amygdala activation
(Schaefer et al., 2002), and that upregulation of negative
affect is associated with increased amygdala activation
(Ochsner et al., 2004). A reciprocal relation between regulatory cortical systems and the amygdala has been reported across several studies using cognitive reappraisal
paradigms (Ochsner et al., 2002; Urry et al., 2006; Banks
et al., 2007; Goldin et al., 2008).
Several studies have shown that the functional and
structural connectivity between the amygdala and frontal
cortical regions is moderated by 5-HTTLPR genotype. Pezawas et al., (2005) reported significant reductions in gray
matter volume in the perigenual anterior cingulate cortex
(pACC) and amygdala of short allele carriers, relative to
noncarriers. To test for a functional relationship between
these regions, they used a emotional face-matching paradigm (Hariri et al., 2002) and conducted a functional connectivity analysis between these regions, which identified
two dissociable areas within the pACC: the rostral anterior
cingulate cortex (rACC), which was positively functionally
connected with the amygdala, and the dorsal anterior cingulate cortex (dACC), which was negatively functionally
connected with the amygdala. However, the degree of
functional connectivity was moderated by 5-HTTLPR genotype: short allele carriers, relative to noncarriers, exhibited significantly reduced functional connectivity (as well as
reduced covariance in gray matter volume) between amygdala and pACC, most prominently the rACC. Importantly,
the degree of coupling was inversely related to the trait of
harm avoidance, suggesting a close link between the function of a neural regulatory emotion circuit, its moderation
by genetic variation, and their association with anxietyrelated traits.
Interestingly, another study found a positive correlation
in functional connectivity between the amygdala and another prefrontal region (VMPFC) as a function of the short
allele (Heinz et al., 2005). However, as Pezawas et al.,
(2005) point out, projections between the amygdala and
VMPFC are sparse or nonexistent and functional connectivity between these regions likely reflects indirect anatomical pathways. They therefore suggested that evidence of
increased coupling between amygdala and VMPFC could
reflect a compensatory mechanism to the primary mechanism between amygdala and pACC.
Indeed, a similar conclusion emerges from analyses of
Buckholtz et al., (2008; Buckholtz and Meyer-Lindenberg,
2008) with respect to functional and structural connectivity
moderated by the low-expressing MAOA allele, which had
been associated with aggressive behavior (Caspi et al.,
2002), and which also affects serotonergic tone by degradation of synaptic 5-HT. Their path analysis of functional
imaging data suggests that the rACC directly regulates the
amygdala through inhibitory connections. When this path-

way is impaired (as indicated by reduced connectivity,

observed both in 5-HTTLPR short allele carriers and in
MAOA low expression allele carriers), amygdala response
to emotional signals would be stronger and the VMPFC
would become activated (explaining a positive functional
connectivity between both regions) as a compensatory and
superordinate regulator supporting rACC function. However, since none of these studies explicitly used emotion
regulation paradigms to manipulate reappraisal, these hypotheses await empirical validation.
There is now evidence from a structural imaging study
of white matter (WM) connectivity for genetic moderation of
structural connectivity between amygdala and prefrontal
cortex (PFC): a diffusion tensor imaging (DTI) study investigated the microstructure of WM connections between
frontal cortical and limbic structures, as a function of 5HTTLPR genotype (Pacheco et al., 2009). Analysis of the
uncinate fasciculus (UF), a WM pathway connecting the
amygdala to the medial and orbital prefrontal cortex, revealed a negative correlation between the number of short
alleles and a measure of WM integrity (specifically, functional anisotropy). Thus, impaired WM integrity between
the amygdala and PFC as a function of 5-HTTLPR genotype may contribute to increased amygdala activation and
poor functional coupling between it and the PFC. However,
in the absence of behavioral and functional imaging data to
be correlated with DTI data, the link between poor emotion
regulation and WM impairment remains to be demonstrated.
Integration and extension
The preceding section highlights the need for behavioral
and neuroimaging endophenotype studies of reappraisal
and suppression. The work to date is largely using emotion
regulation paradigms in the absence of genetic analysis, or
genetic analysis in the absence of explicit emotion regulation paradigms.
Future genetic analyses need to be conducted with
greater attention to the causal inferences that are made
between candidate polymorphisms and behavioral or neural endophenotypes. For example, the long allele of the
5-HTTLPR contains a SNP (an A to G substitution) that
may render carriers of the LG allele functionally similar to
short allele carriers (Hu et al., 2005; Wendland et al.,
2006). The functional significance of this SNP in moderating individual differences in emotion regulation remains to
be investigated. Similarly, Wichers and colleagues (2008)
noted that the COMT val158met polymorphism shows interaction effects with other COMT polymorphisms. Thus,
future studies of the role of COMT genetic variation in
emotion regulation could benefit from genotyping for multiple COMT polymorphisms in parallel.
In light of some evidence suggesting GE interactions
by which early attachment may be an important moderator
of early environmental influences (Barry et al., 2008), and
that non-shared environmental contributions to emotion
regulation may increase over an individuals life span
(Neiss and Almeida, 2004), future work needs to focus on
the role of GE interactions in emotion regulation at the

T. Canli et al. / Neuroscience 164 (2009) 4354

behavioral and neural level. We were the first to document

a GE interaction for a specific polymorphism using neuroimaging, showing that amygdala activation was moderated by both 5-HTTLPR genotype and life stress history
(Canli et al., 2006), a finding that has recently been extended in a study of conscious versus nonconscious face
processing (Williams et al., 2009). However, neither of
these studies explicitly manipulated emotion regulation.
There is also evidence that personality traits are associated with individual differences in neural circuits involved
in emotion processing (Canli et al., 2001, 2002; Canli,
2004; Rubino et al., 2007). These traits are, to some
extent, heritable and may thus involve a host of other
genes not considered before. Furthermore, there is now
evidence that individual differences in emotion-related
brain structures are independently predicted by specific
genotypes and personality traits (Bertolino et al., 2005).
Yet to date, there is still relatively little research devoted to
the neurogenetic basis of personality traits. Given that
these traits add significantly to variability in brain circuits
relevant to emotion regulation, such research could contribute to a deeper understanding of the genetics of emotion regulation.

DISCOVERIES AHEAD
The genetics of emotion regulation is a field that is vastly
unexplored. Aside from critical extensions discussed
above, such as the need to utilize a wider range of endophenotype paradigms, investigate more candidate genes
and polymorphisms, and include assessment of environmental contributions and GE interactions to emotion regulation, perhaps the most dramatic advances may come
from conceptual changes and technical innovations.
One example, already well under way in other areas of
neuroscience, is the study of the epigenome and the related idea of epigenetic regulation. The epigenome consists of molecules that can alter gene expression, without
altering the nucleotide DNA sequence that makes up the
genome. There is now considerable evidence that certain
types of life experiences can alter epigenetic markers, as
shown in rat studies of early maternal experience (Weaver
et al., 2004, 2006; Meaney and Szyf, 2005a,b), prenatal
exposure to maternal depression (Oberlander et al., 2008),
and the impact of childhood maltreatment on gene methylation in the human brain (Ernst et al., 2009; McGowan
et al., 2009). Given that there are data suggesting an
interaction between 5-HTTLPR genotype and life experience on childrens emotion regulation (Barry et al., 2008;
Kochanska et al., in press) and on amygdala function
(Canli et al., 2006; Williams et al., in press), there is a real
need to investigate the role that epigenetic mechanisms
may play in mediating these kinds of interactions in the
context of emotion regulation.
Another example is the approach to study complex
behaviors in whole genome association studies (WGAS),
which use gene array technology to probe very large numbers of gene variants (currently about 1 million per array)
or gene expression of large numbers of human genes

51

(currently about 26,000 per array), rather than single gene

polymorphisms. Given that any one gene may contribute
only a small amount of variance to the behavior of interest,
methods that can identify very large numbers of genes
represent an attractive strategy for driving future discoveries. Although there are concerns about the number of
subjects needed to obtain reliable results, recent analytical
innovations have begun to address these concerns (Subramanian et al., 2005; Schork et al., 2008; Torkamani et
al., 2008).
One has to be mindful that array technology is based
on a selected set of molecular probes, whichalthough
covering the whole genome do not cover each nucleotide of the genome. However, affordable whole-genome
sequencing of each and every nucleotide of an individuals
genome is not far off. The hope is that the use of such
technology may dramatically accelerate the discovery of
genes related to complex behaviors including emotion regulation. However, it is very possible that knowledge of
individuals nucleotide sequence alone will prove inadequate to explain all genetic contributions to behavior. Indeed, as the work conducted on gene methylation has
already shown, epigenetic moderators of gene function will
almost certainly play a significant role, as well.

CONCLUSION
In conclusion, we think that the application of powerful
tools developed for molecular biology, in conjunction with
sophisticated experimental paradigms developed for psychology, will synergize to dramatically accelerate discoveries in molecular psychology. We hope that this article
motivates researchers interested in the genetics of emotion regulation to play a central role in these discoveries.
AcknowledgmentsSome of the work discussed in this review
was supported by a grant from the National Science Foundation
(BCS-0224221) to T. C.

REFERENCES
Banks SJ, Eddy KT, Angstadt M, Nathan PJ, Phan KL (2007) Amygdala-frontal connectivity during emotion regulation. Soc Cogn Affect Neurosci 2:303312.
Barry RA, Kochanska G, Philibert RA (2008) G x E interaction in the
organization of attachment: mothers responsiveness as a moderator of childrens genotypes. J Child Psychol Psychiatry 49:1313
1320.
Beevers CG, Gibb BE, McGeary JE, Miller IW (2007) Serotonin transporter genetic variation and biased attention for emotional word
stimuli among psychiatric inpatients. J Abnorm Psychol 116:208
212.
Bertolino A, Arciero G, Rubino V, Latorre V, De Candia M, Mazzola V,
Blasi G, Caforio G, Hariri A, Kolachana B, Nardini M, Weinberger
DR, Scarabino T (2005) Variation of human amygdala response
during threatening stimuli as a function of 5=HTTLPR genotype and
personality style. Biol Psychiatry 57:15171525.
Bishop S, Duncan J, Brett M, Lawrence AD (2004) Prefrontal cortical
function and anxiety: controlling attention to threat-related stimuli.
Nat Neurosci 7:184 188.
Bishop SJ, Cohen JD, Fossella J, Casey BJ, Farah MJ (2006) COMT
genotype influences prefrontal response to emotional distraction.
Cogn Affect Behav Neurosci 6:6270.

52

T. Canli et al. / Neuroscience 164 (2009) 4354

Bradley BP, Mogg K, Millar NH (2000) Covert and overt orienting of

attention to emotional faces in anxiety. Cogn Emot 14:789 808.
Bruehl S, Chung OY, Burns JW (2008) The mu opioid receptor A118G
gene polymorphism moderates effects of trait anger-out on acute
pain sensitivity. Pain 139:406 415.
Buckholtz JW, Callicott JH, Kolachana B, Hariri AR, Goldberg TE,
Genderson M, Egan MF, Mattay VS, Weinberger DR, MeyerLindenberg A (2008) Genetic variation in MAOA modulates ventromedial prefrontal circuitry mediating individual differences in
human personality. Mol Psychiatry 13:313324.
Buckholtz JW, Meyer-Lindenberg A (2008) MAOA and the neurogenetic architecture of human aggression. Trends Neurosci 31:120
129.
Butler EA, Egloff B, Wilhelm FH, Smith NC, Erickson EA, Gross JJ
(2003) The social consequences of expressive suppression. Emotion 3:48 67.
Butler EA, Lee TL, Gross JJ (2007) Emotion regulation and culture: are
the social consequences of emotion suppression culture-specific?
Emotion 7:30 48.
Canli T (2004) Functional brain mapping of extraversion and neuroticism: learning from individual differences in emotion processing. J
Pers 72:11051132.
Canli T (2008) Toward a molecular psychology of personality. In:
Handbook of personality: theory and research (John OP, Robins
RW, Pervin LA, eds), pp 311327. New York: Guilford Press.
Canli T, Lesch KP (2007) Long story short: the serotonin transporter in
emotion regulation and social cognition. Nat Neurosci 10:1103
1109.
Canli T, Omura K, Haas BW, Fallgatter AJ, Constable RT, Lesch KP
(2005) Beyond affect: a role for genetic variation of the serotonin
transporter in neural activation during a cognitive attention task.
Proc Natl Acad Sci U S A 102:12224 12229.
Canli T, Qiu M, Omura K, Congdon E, Haas BW, Amin Z, Herrmann
MJ, Constable RT, Lesch KP (2006) Neural correlates of epigenesis. Proc Natl Acad Sci U S A 103:1603316038.
Canli T, Sivers H, Whitfield SL, Gotlib IH, Gabrieli JDE (2002) Amygdala response to happy faces as a function of extraversion. Science 296:2191.
Canli T, Zhao Z, Desmond JE, Kang E, Gross J, Gabrieli JDE (2001)
An fMRI study of personality influences on brain reactivity to emotional stimuli. Behav Neurosci 115:33 42.
Caspi A, McClay J, Moffitt TE, Mill J, Martin J, Craig IW, Taylor A,
Poulton R (2002) Role of genotype in the cycle of violence in
maltreated children. Science 297:851 854.
Chen J, Lipska BK, Halim N, Ma QD, Matsumoto M, Melhem S,
Kolachana BS, Hyde TM, Herman MM, Apud J, Egan MF, Kleinman JE, Weinberger DR (2004) Functional analysis of genetic
variation in catechol-O-methyltransferase (COMT): effects on
mRNA, protein, and enzyme activity in postmortem human brain.
Am J Hum Genet 75:807 821.
Chen MC, Joormann J, Hallmayer J, Gotlib IH (2009) Serotonin transporter polymorphism predicts waking cortisol in young girls. Psychoneuroendocrinology 34:681 686.
Cooper RM, Langton SRH (2006) Attentional bias to angry faces using
the dot-probe task? It depends when you look for it. Behav Res
Ther 44:13211329.
Costa PT Jr, McCrae RR (1980) Influence of extraversion and neuroticism on subjective well-being: happy and unhappy people. J Pers
Soc Psychol 38:668 678.
Davidson K (1993) Suppression and repression in discrepant selfother ratings: relations with thought control and cardiovascular
reactivity. J Pers 61:669 691.
Davis M, Whalen PJ (2001) The amygdala: vigilance and emotion. Mol
Psychiatry 6:1334.
Derryberry D, Reed MA (1998) Anxiety and attentional focusing: trait,
state and hemispheric influences. Pers Individ Dif 25:745761.

Drabant EM, McRae K, Manuck SB, Hariri AR, Gross JJ (2009)

Individual differences in typical reappraisal use predict amygdala
and prefrontal responses. Biol Psychiatry 65:367373.
Egloff B, Hock M (2001) Interactive effects of state anxiety and trait
anxiety on emotional Stroop interference. Pers Individ Dif 31:875
882.
Egloff B, Schmukle SC, Burns LR, Schwerdtfeger A (2006) Spontaneous emotion regulation during evaluated speaking tasks: associations with negative affect, anxiety expression, memory, and physiological responding. Emotion 6:356 366.
Enoch MA, White KV, Waheed J, Goldman D (2008) Neurophysiological and genetic distinctions between pure and comorbid anxiety
disorders. Depress Anxiety 25:383392.
Enoch MA, Xu K, Ferro E, Harris CR, Goldman D (2003) Genetic
origins of anxiety in women: a role for a functional catechol-Omethyltransferase polymorphism. Psychiatr Genet 13:33 41.
Ernst C, Deleva V, Deng X, Sequeira A, Pomarenski A, Klempan T,
Ernst N, Quirion R, Gratton A, Szyf M, Turecki G (2009) Alternative
splicing, methylation state, and expression profile of tropomyosinrelated kinase B in the frontal cortex of suicide completers. Arch
Gen Psychiatry 66:2232.
Flint J, Munafo MR (2007) The endophenotype concept in psychiatric
genetics. Psychol Med 37:163180.
Fox E, Derakshan N, Shoker L (2008) Trait anxiety modulates the
electrophysiological indices of rapid spatial orienting towards angry
faces. Neuroreport 19:259 263.
Fox E, Ridgewell A, Ashwin C (2009) Looking on the bright side:
biased attention and the human serotonin transporter gene. Proc
Biol Sci 276:17471751.
Goldin PR, McRae K, Ramel W, Gross JJ (2008) The neural bases of
emotion regulation: reappraisal and suppression of negative emotion. Biol Psychiatry 63:577586.
Gotlib IH, Joormann J, Minor KL, Hallmayer J (2008) HPA axis reactivity: a mechanism underlying the associations among 5-HTTLPR,
stress, and depression. Biol Psychiatry 63:847 851.
Gottesman II, Gould TD (2003) The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry
160:636 645.
Gross JJ (1998) Antecedent- and response-focused emotion regulation: divergent consequences for experience, expression, and
physiology. J Pers Soc Psychol 74:224 237.
Gross JJ (2002) Emotion regulation: affective, cognitive, and social
consequences. Psychophysiology 39:281291.
Gross JJ, ed (2007) Handbook of emotion regulation. New York:
Guilford Publications.
Gross JJ, John OP (2003) Individual differences in two emotion regulation processes: implications for affect, relationships, and wellbeing. J Pers Soc Psychol 85:348 362.
Gross JJ, Levenson RW (1993) Emotional suppression: physiology,
self-report, and expressive behavior. J Pers Soc Psychol 64:
970 986.
Gross JJ, Levenson RW (1997) Hiding feelings: the acute effects of
inhibiting negative and positive emotion. J Abnorm Psychol 106:
95103.
Hariri AR, Mattay VS, Tessitore A, Kolachana B, Fera F, Goldman D,
Egan MF, Weinberger DR (2002) Serotonin transporter genetic
variation and the response of the human amygdala. Science
297:400 403.
Harrison PJ, Tunbridge EM (2008) Catechol-O-methyltransferase
(COMT): a gene contributing to sex differences in brain function,
and to sexual dimorphism in the predisposition to psychiatric disorders. Neuropsychopharmacology 33:30373045.
Hasler G, Drevets WC, Gould TD, Gottesman II, Manji HK (2006)
Toward constructing an endophenotype strategy for bipolar disorders. Biol Psychiatry 60:93105.
Heils A, Teufel A, Petri S, Stober G, Riederer P, Bengel D, Lesch KP
(1996) Allelic variation of human serotonin transporter gene expression. J Neurochem 66:26212624.

T. Canli et al. / Neuroscience 164 (2009) 4354

Heinz A, Braus DF, Smolka MN, Wrase J, Puls I, Hermann D, Klein S,
Grusser SM, Flor H, Schumann G, Mann K, Buchel C (2005)
Amygdala-prefrontal coupling depends on a genetic variation of
the serotonin transporter. Nat Neurosci 8:20 21.
Heinz A, Smolka MN, Braus DF, Wrase J, Beck A, Flor H, Mann K,
Schumann G, Buchel C, Hariri AR, Weinberger DR (2007) Serotonin transporter genotype (5-HTTLPR): effects of neutral and
undefined conditions on amygdala activation. Biol Psychiatry 61:
10111014.
Herrmann MJ, Huter T, Muller F, Muhlberger A, Pauli P, Reif A, Renner
T, Canli T, Fallgatter AJ, Lesch KP (2007) Additive effects of
serotonin transporter and tryptophan hydroxylase-2 gene variation
on emotional processing. Cereb Cortex 17:1160 1163.
Hu X, Oroszi G, Chun J, Smith TL, Goldman D, Schuckit MA (2005) An
expanded evaluation of the relationship of four alleles to the level
of response to alcohol and the alcoholism risk. Alcohol Clin Exp
Res 29:8 16.
Jang KL, Livesley WJ, Vernon PA (1996) Heritability of the big five
personality dimensions and their facets: a twin study. J Pers
64:577591.
Karayiorgou M, Altemus M, Galke BL, Goldman D, Murphy DL, Ott J,
Gogos JA (1997) Genotype determining low catechol-O-methyltransferase activity as a risk factor for obsessive-compulsive disorder. Proc Natl Acad Sci U S A 94:4572 4575.
Kendler KS, Kessler RC, Neale MC, Heath AC, Eaves LJ (1993a) The
prediction of major depression in women: toward an integrated
etiologic model. Am J Psychiatry 150:1139 1148.
Kendler KS, Neale MC, Kessler RC, Heath AC, Eaves LJ (1993b) A
longitudinal twin study of personality and major depression in
women. Arch Gen Psychiatry 50:853 862.
Kochanska G, Philibert RA, Barry RA (in press) Interplay of genes and
early mother-child relationship in the development of self-regulation
from toddler to preschool age. J Child Psychol Psychiatry, in press.
Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S,
Benjamin J, Muller CR, Hamer DH, Murphy DL (1996) Association
of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274:15271531.
Lotta T, Vidgren J, Tilgmann C, Ulmanen I, Melen K, Julkunen I,
Taskinen J (1995) Kinetics of human soluble and membranebound catechol O-methyltransferase: a revised mechanism and
description of the thermolabile variant of the enzyme. Biochemistry
34:4202 4210.
Mauss IB, Cook CL, Cheng JYJ, Gross JJ (2007) Individual differences in cognitive reappraisal: experiential and physiological responses to an anger provocation. Int J Psychophysiol 66:116 124.
McGowan PO, Sasaki A, DAlessio AC, Dymov S, Labonte B, Szyf M,
Turecki G, Meaney MJ (2009) Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood
abuse. Nat Neurosci 12:342348.
McGrath M, Kawachi I, Ascherio A, Colditz GA, Hunter DJ, De Vivo I
(2004) Association between catechol-O-methyltransferase and
phobic anxiety. Am J Psychiatry 161:17031705.
Meaney MJ, Szyf M (2005a) Environmental programming of stress
responses through DNA methylation: life at the interface between
a dynamic environment and a fixed genome. Dialogues Clin Neurosci 7:103123.
Meaney MJ, Szyf M (2005b) Maternal care as a model for experiencedependent chromatin plasticity? Trends Neurosci 28:456 463.
Mogg K, Bradley SD, Williams R, Mathews A (1993) Subliminal processing of emotional information in anxiety and depression. J
Abnorm Psychol 102:304 311.
Mogg K, Garner M, Bradley BP (2007) Anxiety and orienting of gaze to
angry and fearful faces. Biol Psychol 76:163169.
Mogg K, Millar NH, Bradley BP (2000) Biases in eye movements to
threatening facial expressions in generalized anxiety disorder and
depressive disorder. J Abnorm Psychol 109:695704.

53

Munaf MR, Brown SM, Hariri AR (2008) Serotonin transporter (5HTTLPR) genotype and amygdala activation: a meta-analysis. Biol
Psychiatry 63:852 857.
Murakami H, Matsunaga M, Ohira H (2009) Association of serotonin
transporter gene polymorphism and emotion regulation. Neuroreport 20:414 418.
Neiss M, Almeida DM (2004) Age differences in the heritability of mean
and intraindividual variation of psychological distress. Gerontology
50:2227.
New AS, Siever LJ (2003) Biochemical endophenotypes in personality
disorders. Methods Mol Med 77:199 213.
Newman TK, Syagailo YV, Barr CS, Wendland JR, Champoux M,
Graessle M, Suomi SJ, Higley JD, Lesch KP (2005) Monoamine
oxidase A gene promoter variation and rearing experience influences aggressive behavior in rhesus monkeys. Biol Psychiatry
57:167172.
Oberlander TF, Weinberg J, Papsdorf M, Grunau R, Misri S, Devlin AM
(2008) Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant
cortisol stress responses. Epigenetics 3:97106.
Ochsner KN, Bunge SA, Gross JJ, Gabrieli JD (2002) Rethinking
feelings: an FMRI study of the cognitive regulation of emotion. J
Cogn Neurosci 14:12151229.
Ochsner KN, Gross JJ (2005) The cognitive control of emotion. Trends
Cogn Sci 9:242249.
Ochsner KN, Gross JJ (2007) The neural architecture of emotion
regulation. In: Handbook of emotion regulation, pp 87109. New
York: Guilford Press.
Ochsner KN, Ray RD, Cooper JC, Robertson ER, Chopra S, Gabrieli
JD, Gross JJ (2004) For better or for worse: neural systems
supporting the cognitive down- and up-regulation of negative emotion. Neuroimage 23:483 499.
Olsson CA, Anney RJ, Lotfi-Miri M, Byrnes GB, Williamson R, Patton
GC (2005) Association between the COMT Val158Met polymorphism and propensity to anxiety in an Australian population-based
longitudinal study of adolescent health. Psychiatr Genet 15:109
115.
Olsson CA, Byrnes GB, Anney RJ, Collins V, Hemphill SA, Williamson
R, Patton GC (2007) COMT Val(158)Met and 5HTTLPR functional
loci interact to predict persistence of anxiety across adolescence:
results from the Victorian Adolescent Health Cohort Study. Genes
Brain Behav 6:647 652.
Osinsky R, Reuter M, Kupper Y, Schmitz A, Kozyra E, Alexander N,
Hennig J (2008) Variation in the serotonin transporter gene modulates selective attention to threat. Emotion 8:584 588.
Pacheco J, Beevers CG, Benavides C, McGeary J, Stice E, Schnyer
DM (2009) Frontal-limbic white matter pathway associations with
the serotonin transporter gene promoter region (5-HTTLPR) polymorphism. J Neurosci 29:6229 6233.
Pezawas L, Meyer-Lindenberg A, Drabant EM, Verchinski BA, Munoz
KE, Kolachana BS, Egan MF, Mattay VS, Hariri AR, Weinberger
DR (2005) 5-HTTLPR polymorphism impacts human cingulateamygdala interactions: a genetic susceptibility mechanism for depression. Nat Neurosci 8:828 834.
Phillips ML, Drevets WC, Rauch SL, Lane R (2003) Neurobiology of
emotion perception I: the neural basis of normal emotion perception. Biol Psychiatry 54:504 514.
Phillips ML, Ladouceur CD, Drevets WC (2008) A neural model of
voluntary and automatic emotion regulation: implications for understanding the pathophysiology and neurodevelopment of bipolar
disorder. Mol Psychiatry 13:829, 833 857.
Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA,
Shulman GL (2001) A default mode of brain function. Proc Natl
Acad Sci U S A 98:676 682.
Rao H, Gillihan SJ, Wang J, Korczykowski M, Sankoorikal GM,
Kaercher KA, Brodkin ES, Detre JA, Farah MJ (2007) Genetic
variation in serotonin transporter alters resting brain function in
healthy individuals. Biol Psychiatry 62:600 606.

54

T. Canli et al. / Neuroscience 164 (2009) 4354

Richards A, French CC, Johnson W, Naparstek J, Williams J (1992)

Effects of mood manipulation and anxiety on performance of an
emotional Stroop task. Br J Psychol 83:479 491.
Richards JM, Butler EA, Gross JJ (2003) Emotional regulation in
romantic relationships: the cognitive consequences of concealing
feelings. J Soc Pers Relat 20:599 620.
Richards JM, Gross JJ (2000) Emotion regulation and memory: the
cognitive costs of keeping ones cool. J Pers Soc Psychol
79:410 424.
Richards JM, Gross JJ (2006) Personality and emotional memory: how
regulating emotion impairs memory for emotional events. J Res
Pers 40:631 651.
Rubino V, Blasi G, Latorre V, Fazio L, dErrico I, Mazzola V, Caforio G,
Nardini M, Popolizio T, Hariri A, Arciero G, Bertolino A (2007)
Activity in medial prefrontal cortex during cognitive evaluation of
threatening stimuli as a function of personality style. Brain Res Bull
74:250 257.
Sabol SZ, Hu S, Hamer D (1998) A functional polymorphism in the
monoamine oxidase A gene promoter. Hum Genet 103:273279.
Schaefer SM, Jackson DC, Davidson RJ, Aguirre GK, Kimberg DY,
Thompson-Schill SL (2002) Modulation of amygdalar activity by the
conscious regulation of negative emotion. J Cogn Neurosci 14:
913921.
Schinka JA, Busch RM, Robichaux-Keene N (2004) A meta-analysis
of the association between the serotonin transporter gene polymorphism (5-HTTLPR) and trait anxiety. Mol Psychiatry 9:
197202.
Schork NJ, Wessel J, Malo N (2008) DNA sequence-based phenotypic
association analysis. Adv Genet 60:195217.
Sen S, Burmeister M, Ghosh D (2004) Meta-analysis of the association between a serotonin transporter promoter polymorphism (5HTTLPR) and anxiety-related personality traits. Am J Med Genet
127B:85 89.
Shioe K, Ichimiya T, Suhara T, Takano A, Sudo Y, Yasuno F, Hirano
M, Shinohara M, Kagami M, Okubo Y, Nankai M, Kanba S (2003)
No association between genotype of the promoter region of serotonin transporter gene and serotonin transporter binding in human
brain measured by PET. Synapse 48:184 188.
Siever LJ, Torgersen S, Gunderson JG, Livesley WJ, Kendler KS
(2002) The borderline diagnosis III: identifying endophenotypes for
genetic studies. Biol Psychiatry 51:964 968.
Slaats-Willemse D, Swaab-Barneveld H, de Sonneville L, van der
Meulen E, Buitelaar J (2003) Deficient response inhibition as a
cognitive endophenotype of ADHD. J Am Acad Child Adolesc
Psychiatry 42:12421248.
Smolka MN, Schumann G, Wrase J, Grusser SM, Flor H, Mann K,
Braus DF, Goldman D, Buchel C, Heinz A (2005) Catechol-Omethyltransferase val158met genotype affects processing of emotional stimuli in the amygdala and prefrontal cortex. J Neurosci
25:836 842.
Soussignan R, Boivin M, Girard A, Perusse D, Liu X, Tremblay RE
(2009) Genetic and environmental etiology of emotional and social
behaviors in 5-month-old infant twins: influence of the social context. Infant Behav Dev 32:19.
Srivastava S, Tamir M, McGonigal KM, John OP, Gross JJ (2009) The
social costs of emotional suppression: a prospective study of the
transition to college. J Pers Soc Psychol 96:883 897.
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL,
Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES,
Mesirov JP (2005) Gene set enrichment analysis: a knowledgebased approach for interpreting genome-wide expression profiles.
Proc Natl Acad Sci U S A 102:1554515550.

Szily E, Bowen J, Unoka Z, Simon L, Keri S (2008) Emotion appraisal

is modulated by the genetic polymorphism of the serotonin transporter. J Neural Transm 115:819 822.
Torkamani A, Topol EJ, Schork NJ (2008) Pathway analysis of
seven common diseases assessed by genome-wide association. Genomics 92:265272.
Urry HL, van Reekum CM, Johnstone T, Kalin NH, Thurow ME,
Schaefer HS, Jackson CA, Frye CJ, Greischar LL, Alexander AL,
Davidson RJ (2006) Amygdala and ventromedial prefrontal cortex
are inversely coupled during regulation of negative affect and
predict the diurnal pattern of cortisol secretion among older adults.
J Neurosci 26:4415 4425.
Viken RJ, Rose RJ, Kaprio J, Koskenvuo M (1994) A developmental
genetic analysis of adult personality: extraversion and neuroticism
from 18 to 59 years of age. J Pers Soc Psychol 66:722730.
Wager TD, Davidson ML, Hughes BL, Lindquist MA, Ochsner KN
(2008) Prefrontal-subcortical pathways mediating successful emotion regulation. Neuron 59:10371050.
Weaver IC, Cervoni N, Champagne FA, DAlessio AC, Sharma S,
Seckl JR, Dymov S, Szyf M, Meaney MJ (2004) Epigenetic programming by maternal behavior. Nat Neurosci 7:847 854.
Weaver IC, Meaney MJ, Szyf M (2006) Maternal care effects on the
hippocampal transcriptome and anxiety-mediated behaviors in the
offspring that are reversible in adulthood. Proc Natl Acad Sci U S A
103:3480 3485.
Wells A, Matthews G (1994) Attention and emotion: a clinical perspective. Hillsdale, NJ: Elrbaum.
Wendland JR, Martin BJ, Kruse MR, Lesch KP, Murphy DL (2006)
Simultaneous genotyping of four functional loci of human SLC6A4,
with a reappraisal of 5-HTTLPR and rs25531. Mol Psychiatry
11:224 226.
Wichers M, Aguilera M, Kenis G, Krabbendam L, Myin-Germeys I,
Jacobs N, Peeters F, Derom C, Vlietinck R, Mengelers R, Delespaul P, van Os J (2008) The catechol-O-methyl transferase
Val158Met polymorphism and experience of reward in the flow of
daily life. Neuropsychopharmacology 33:3030 3036.
Wierzbicka A, Kitayama S, Markus HR (1994) Emotion, language, and
cultural scripts. In: Emotion and culture: empirical studies of mutual
influence, pp 133196. Washington, DC: American Psychological
Association.
Williams LM, Gatt JM, Schofield PR, Olivieri G, Peduto A, Gordon E.
Negativity bias in risk for depression and anxiety: brain-body fear
circuitry correlates, 5-HTT-LPR and early life stress. Neuroimage,
in press.
Woo JM, Yoon KS, Choi YH, Oh KS, Lee YS, Yu BH (2004) The
association between panic disorder and the L/L genotype of catechol-O-methyltransferase. J Psychiatr Res 38:365370.
Woo JM, Yoon KS, Yu BH (2002) Catechol O-methyltransferase
genetic polymorphism in panic disorder. Am J Psychiatry 159:
17851787.
Wust S, Kumsta R, Treutlein J, Frank J, Entringer S, Schulze TG,
Rietschel M (2009) Sex-specific association between the 5-HTT
gene-linked polymorphic region and basal cortisol secretion. Psychoneuroendocrinology 34:972982.
Yovel I, Mineka S (2005) Emotion-congruent attentional biases: the
perspective of hierarchical models of emotional disorders. Pers
Individ Dif 38:785795.
Zubieta JK, Heitzeg MM, Smith YR, Bueller JA, Xu K, Xu Y, Koeppe
RA, Stohler CS, Goldman D (2003) COMT val158met genotype
affects mu-opioid neurotransmitter responses to a pain stressor.
Science 299:1240 1243.

(Accepted 20 June 2009)

(Available online 25 June 2009)