Looking on the bright side: biased attention and
the human serotonin transporter gene
Elaine Fox*, Anna Ridgewell and Chris Ashwin
Department of Psychology, University of Essex, Wivenhoe Park, Colchester CO4 3SQ, UK
Humans differ in terms of biased attention for emotional stimuli and these biases can confer differential
resilience and vulnerability to emotional disorders. Selective processing of positive emotional information,
for example, is associated with enhanced sociability and well-being while a bias for negative material is
associated with neuroticism and anxiety. A tendency to selectively avoid negative material might also be
associated with mental health and well-being. The neurobiological mechanisms underlying these cognitive
phenotypes are currently unknown. Here we show for the first time that allelic variation in the promotor
region of the serotonin transporter gene (5-HTTLPR) is associated with differential biases for positive and
negative affective pictures. Individuals homozygous for the long allele (LL) showed a marked bias to
selectively process positive affective material alongside selective avoidance of negative affective material.
This potentially protective pattern was absent among individuals carrying the short allele (S or SL). Thus,
allelic variation on a common genetic polymorphism was associated with the tendency to selectively
process positive or negative information. The current study is important in demonstrating a genotype-
related alteration in a well-established processing bias, which is a known risk factor in determining both
resilience and vulnerability to emotional disorders.
Keywords: cognitive bias; serotonin transporter gene; selective attention; well-being; anxiety;
Clinical populations diagnosed with disorders such as
depression and anxiety are characterized by a persistent
bias to attend towards negative events relative to positive
or neutral events (Bar-Haim et al. 2007). This research
indicates that biased attention for negative emotional
stimuli is a significant risk factor in the aetiology and
maintenance of abnormal mood states. A causal link is
likely in that the experimental induction of biases to attend
either towards or away from the negative material in
healthy populations results in differential degrees of
emotional reactivity to subsequent stressful tasks
(MacLeod et al. 2002). To date, research has focused on
negative biases. However, selective processing of positive
material, as well as the selective avoidance of negative
material, is likely to play an important role in determining
mental health and well-being (Fox 1993; Davidson 2004).
For example, an inability to experience positive affective
states (e.g. optimism, joy) is an important component of
serious psychiatric conditions such as depression
Biased attention towards negative or positive material is
auseful cognitiveendophenotype that is easy to obtain and
correlates strongly with normal variations in personality
traits that are linked to emotional resilience and vulner-
ability. While some correlative evidence is available
regarding the neural mechanisms that might mediate
these biases (Whittle et al. 2006), little is known about the
precise neurobiological mechanisms that lead to selective
processing. While controversial (Abbot 2008), the candi-
date gene approach indicates that a useful way forwards is
to identify genes known to influence biological pathways
that are implicated in emotional disorders (Canli et al.
2006; Caspi & Moffitt 2006; Canli & Lesch 2007). Instead
of assessing variations in genes in relation to a clinical
diagnosis such as depression or anxiety, the focus is on
intermediate endophenotypes (e.g. self-reported neuroti-
cism, cognitive biases, neural activity) that are known to
confer a higher risk of developing a range of emotional
disorders. Advocates of this approach have focused on
genes that influence serotonin (5-hydroxytryptamine;
5-HT) function in the brain, since variation in 5-HT
function is important in modulating mood states and is
implicated in depression and anxiety disorders (Heils et al.
1996; Hariri & Holmes 2006).
In 1996, a common polymorphism was identified in the
promotor region (5-HTTLPR) of the human serotonin
transporter gene (5-HTT, SERT, SLC6A4). Carrying the
short form of this polymorphism (S allele) modulates
the synaptic availability of serotonin (Heils et al. 1996),
and is also associated with higher levels of self-reported
neuroticism (Lesch et al. 1996). Subsequent work has
shown that the precise effects of the S allele on 5-HT brain
function are complex (Hariri & Holmes 2006; Canli &
Lesch 2007) and indeed the association with self-reported
neuroticism is not always found (Willis-Owen et al. 2005).
Nevertheless, a 23-year longitudinal study has found that
carriers of the S allele are at a higher risk of depression and
suicide attempts if they are exposed to major traumatic life
events (Caspi et al. 2003). The hypothesis that possession
of the S allele exaggerates the neurobiological response to
stress is supported by animal studies. Rhesus macaques
Proc. R. Soc. B (2009) 276, 1747–1751
Published online 25 February 2009
Electronic supplementary material is available at http://dx.doi.org/10.
1098/rspb.2008.1788 or via http://rspb.royalsocietypublishing.org.
*Author for correspondence (firstname.lastname@example.org).
Received 3 December 2008
Accepted 14 January 2009
This journal is q 2009 The Royal Society
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.
(Macaca mulatta) reared in a stressful environment, for
example, show increased behavioural and neuroendocrine
response to stress if they carry the S allele (Barr et al.
2004). Several human studies report increased reactivity
of the amygdala in S-allele carriers in response to negative
images, such as fearful or angry facial expressions (Hariri
et al. (2002) see Munafo et al. (2008) for recent meta-
analysis). Since the amygdala is a central part of the neural
circuitry underlying emotional vigilance and arousal
(Phelps & LeDoux 2005), this suggests that these neural
circuits mediate the association between the S allele of the
5-HTTLPR and emotional reactivity.
While intriguing, functional magnetic resonance
imaging studies are difficult to interpret as increased
amygdala reactivity is not necessarily a reliable endo-
phenotype to use as a risk factor for heightened stress
reactivity. The amygdala and associated circuits are clearly
implicated in the fear response (Phelps & LeDoux 2005),
but there is also substantive evidence that the amygdala
reacts in a more general way to novelty, incongruity and
general relevance (Sander et al. 2003). Thus, the link
no means clear. A better endophenotype might be biased
attention, which has been found to be reliably associated
with increased stress reactivity in a wide range of studies
using different methodologies (MacLeod et al. 2002;
Bar-Haim et al. 2007). Moreover, biases both towards and
away from particular classes of stimuli differentially predict
emotional vulnerability. Thus, a bias to be vigilant for
threat-related material is associated with emotional vulner-
associated with resilience (Fox 1993). Only one study has
directly examined biased attention in relation to serotonin
sample of 27 psychiatric inpatients, it was found that
carriersofthe Salleleshowed a biastowards anxiety-related
words (e.g. scared, attack). While no statistical analyses
were reported, examination of their figure 1 indicates that
to selectively avoid these same stimuli. In the current study,
we hypothesize that the S allele is indeed associated with
vigilance for threatening material but that those
homozygous for the L allele are characterized by selective
group would selectively attend to affectively positive
2. MATERIAL AND METHODS
A total of 111 participants underwent a brief interview during
which it was established that they had never received any
psychiatric diagnosis and they reported that they were taking
no medication that affects mental activity. All had normal or
corrected-to-normal vision, and gave written informed
consentto participate. Standardized
measuring state and trait anxieties (STAI: Spielberger et al.
1983), depressive characteristics (BDI: Beck et al. 1996) and
the ‘Big 5’ domains of personality, including neuroticism
and extroversion (NEO PR-I: Costa & McCrae 1992), were
completed. DNA samples (either saliva or eyebrow hair)
were obtained from all participants, but genotyping data
were available only for 97 of these participants, so data from
these 97 are reported.
Biased attention was assessed by the dot-probe paradigm that
is common in cognitive psychopathology research (Bar-Haim
et al. (2007) for review). Twenty pictures with a negative
valence, 20witha positive valence and40neutral pictureswere
selected from the International Affective Picture Set (Lang et al.
2005). All three categories (negative, positive and neutral)
were matched on arousal level so that only valence differed
between any pair of pictures presented. Each trial of the
experiment included two of these pictures, one with an
emotional valence (either positive or negative) and the other
neutral presented on either side of a central fixation point
(a cross hair in black Geneva font size 24). All pictures were
presented on a white background in grey scale and measured
3.5 cm!4 cm and subtended a visual angle of 68!88 at a
viewing distance of 57 cm. The location of the emotional and
neutral pictures was counterbalanced across the experiment.
The centre of each picture was 5 cm from fixation, with one
picture displayed on the left side of the screen and the other on
the right side. Targets consisted of two dots either vertical or
horizontal in orientation (: or..) measuring 0.5 cm in length,
which appeared in the centre of the location of either the left-
or right-hand picture. Both types of target (vertical and
horizontal) appeared equally often in the location of the
two pictures in each picture pair (left and right side),
producing eight different trial combinations for each emotion-
ally valenced picture (see figure 1 for sample trial). As there
were 40 emotional pictures, this produced 320 total trials
for the experiment, which followeda short set ofpractice trials.
Participants were tested in a quiet dimly lit testing room,
seated approximately 57 cm from a computer monitor placed
at eye level. All experimental stimuli were presented on a
17 in. monitor with a resolution of 768!1024 and connected
to a Power Macintosh G3 computer running the program
SUPERLAB (http://www.superlab.com/) to display stimuli and
record responses. A feedback sound was given for any
incorrect responses, which were rare in the experiment (the
error rate was less than 1%).
DNA samples were obtained for 111 participants, but
extraction of genotyping information was available only for
Figure 1. An illustration of a single trial in the dot-probe
paradigm. This example shows an affectively negative image
(on the left) alongside a neutral image on the right. Affective
and neutral images on each trial were matched for subjective
arousal level. The target to be responded to appears in the
location of the neutral image in this example. The actual
images used in the experiment have been replaced with
similar public domain images for this illustration to avoid
copyright infringement. The images presented here are
courtesy of www.photos8.com.
1748E. Fox et al.Biased attention and 5-HTTLPR
Proc. R. Soc. B (2009)
97 individuals. Genotyping on the serotonin transporter gene
was obtained using standard procedures as described in the
electronic supplementary material.
Table1ashowsthatthethreegenotypegroupsdid not differ
on a range of demographic and self-report measures, and
the genotypes were found to be in Hardy–Weinberg
equilibrium (c2Z0.09). Mean correct reaction time data
on the dot-probe task were computed, excluding very fast
(less than 150 ms) and very long (more than 2000 ms)
reaction times (less than 2% of the data). These mean
correct reaction times are shown in table 1b and were
analysed by means of a 2 (genotyping group: SS, SL,
LL)!2 (valence of picture: negative, positive)!2 (location
of target: same or different location from affective picture)
analysis of variance. This analysis revealed that the critical
genotyping group!valence of picture!location of target
was significant, F2,94Z9.7, p!0.001. In order to facilitate
the analysis of this interaction, an attentional bias score
was computed for both negative and positive images.
The negative bias score was derived by subtracting the mean
reaction times when targets appeared in the location of the
negativepicture,fromthemeanreaction timeswhen targets
appeared in the location of the neutral picture. Likewise,
a positive bias score was derived by subtracting the mean
reaction times when targets appeared in the location of the
positive picture, from the mean reaction times when targets
appeared in the location of the neutral picture. Thus
a positive value for either the negative or positive indices
reflects vigilance for the affective picture, whereas a negative
value indicates selective avoidance of the affective picture.
A score of 0 would indicate no bias either towards or away
from the affective picture.
The significant genotype (SS, SL, LL)!type of
picture (positive, negative) interaction with negative
and positive bias scores as the dependent variable is
illustrated in figure 2. Follow-up planned comparisons
(t-tests) were conducted for each genotype group
separately and corrected for multiple comparisons by
means of the Bonferroni correction (alpha levelZ0.025).
The LL group showed a marked avoidance of negative
material (t(15)ZK4.6, p!0.000) alongside a vigilance
for positive material (t(15)Z2.4, p!0.015). By contrast,
the SS and SL groups showed non-significant tendencies
to orient towards negative material (t(35)!1 and
t(44)Z1.6, pZ0.07, respectively) and to selectively
pZ0.15, respectively). Further analysis revealed that the
LL group differed from the other genotype groups in
terms of both their avoidance of negative material, as
well as their vigilance for positive material (all p values
!0.001). Moreover, the direction of biased attention for
the LL group differed significantly, depending on whether
the affective material was negative or positive with
negative material eliciting avoidance (mean negative
biasZK18.3) and positive images eliciting vigilance
(mean positive biasZC23.5; t(15)ZK3.6, p!0.001).
These differences did not reach significance for either the
SS (mean negative biasZ1.4, mean positive biasZK3.6,
t(35)!1) or the SL groups (mean negative biasZ6.1,
mean positive biasZK4.6, t(45)Z1.6, p!0.06).
The current study investigated whether allelic variation on
the 5-HTTLPR gene interacts with biases in attention.
This approach attempts to capture gene effects by using
Table 1. (a) Means and standard deviations (in brackets) for
subjective ratings and demographic variables as a function
of genotyping group. (b) Mean correct reaction times
(in milliseconds) and standard deviations (in brackets) on
the attention bias (dot-probe) task as a function of genotype
group, valence of picture (negative or positive) and location of
target (valid, same location as affective picture; invalid,
opposite location to affective picture).
SS (nZ36) SL (nZ45)LL (nZ16)
attention bias score
Figure 2. Mean attentional bias scores with standard errors
as a function of genotype group and valence of the affective
picture. Grey bars indicate bias scores for pictures with a
negative valence. Positive scores (above 0) refer to vigilance,
negative scores (below 0) refer to avoidance and zero refers
to no bias.
Biased attention and 5-HTTLPR
E. Fox et al.
Proc. R. Soc. B (2009)
dependent measures that are more sensitive than self-
report (e.g. neuroticism) or clinical diagnosis (Canli et al.
2006; Caspi & Moffitt 2006; Canli & Lesch 2007).
Previous studies have used amygdala activation as the
endophenotype (Munafo et al. (2008) for meta-analysis),
while a single study using a measure of biased attention
found increased vigilance for threat-related words in
S-allele carriers among a psychiatric inpatient group
(Beevers et al. 2007). Thecurrentstudyisthefirsttoreport
gene-related variation in biased attention in the healthy
population. We found evidence for a strong positive bias in
the LL group such that vigilance for positive material was
observed among those homozygous for the L allele in
addition to a clear avoidance of negative material. This
protective pattern was completely absent in S-allele
carriers. This result is consistent with a recent report
that S-allele carriers and LL groups appear to be affected
in opposite ways by life stress. Canli et al. (2006) reported
that resting activation in the amygdala and hippocampus
increased with increasing life stress for SS and SL groups,
but decreased with increasing life stress in the LL group.
Thus, general life stress may induce resilience in some
groups (e.g. LL groups), while revealing increased
susceptibility to mood disorders in others (e.g. S-allele
carriers). As illustrated in figure 3, the current results
provide a potential mechanism for this association.
There are a couple of limitations to the current study.
First, we did not genotype two relatively new variants that
have been identified in the long version of the 5-HTTLPR
promotor (LGand LA). The LGand the S allele have
comparable levels of serotonin transporter expression
(Hu et al. 2005) and therefore it would be interesting to
assess the impact of this variant on the current results.
Since the LGis relatively rare (approx. 10%), however, it is
unlikely to have influenced the current results to any
great extent. Nevertheless, future studies on variation in
the 5-HTTLPR and attention should also take into
account the additional variants of the L allele. Second,
levels of self-reported neuroticism and extraversion did
not differ across our genotype groups, which conflicts with
some earlier reports (e.g. Lesch et al. 1996). However,
while early studies did report an association between the
S allele and higher levels of neuroticism, several large-
scale studies have failed to replicate this association
(Willis-Owen et al. 2005). The fact that our genotype
groups were matched on a range of self-report measures,
including neuroticism can be seen as a major strength.
If there were differences in these personality traits among
the groups, then the biased attention results would be
difficult to interpret. As it stands, in spite of no across-
group differences in several relevant personality traits
(neuroticism, extraversion, depression, state anxiety), we
still find clear differences in attentional bias for emotional
information across the different genotype groups. This
supports our view that differences on the serotonin
transporter gene aremore likely to predict online measures
of information processing as measured here in comparison
with more general measures, such as self-report measures
of neuroticism. It is concluded that future studies on
genetic variation and psychopathology would benefit by
obtaining actual measures of selective processing as well as
self-report measures. On this point, we also note that we
measured biased attention using a standard presentation
time of 500 ms. Given that attention is a continuous
cognitive process, it is important for future studies
to assess the relationship between the 5-HTTLPR and
biases in attention at various early and late stages of
To conclude, the current study found that the presence
of positive material induced a strong bias to attend
towards this type of material in the LL, but not in either
of the SS or SL groups. By contrast, the presence of
negative material induced a selective avoidance in the LL
group, which was not apparent in S-allele carriers. These
low-level biases for affectively salient stimuli play a
powerful role in the development of beliefs and general
two variants of the 5-HTT gene
Figure 3. An illustration of how allelic variation in the transcriptional control region (TCR) of the serotonin transporter
gene (5-HTT) can influence the nature of selective attention. The affective images presented here are courtesy of
1750 E. Fox et al. Biased attention and 5-HTTLPR
Proc. R. Soc. B (2009)
reactivity to significant life events. The current results Download full-text
indicate that a genetically driven tendency to look on the
bright side of life is a core cognitive mechanism underlying
resilience to general life stress. The absence of this
protective bias in S-allele carriers is likely to be linked
with the heightened susceptibility to mood disorders
such as depression and anxiety that has been reported in
The study was approved by the University of Essex Ethics
Committee and fulfilled the guidelines for the testing of
human participants in the UK.
The study was supported by a University of Essex Research
Promotion Fund (RPF) grant to E.F. and by a Wellcome
Trust project grant (Ref: 07670/Z/05/Z) to E.F. We thank
Rachel Burrows and Claudia Aldridge for their help with
data collection, and the John Innes Centre Genome
Laboratory in Norwich, UK, for conducting the genotyping
analysis. C.A. is now at the Department of Psychology,
University of Bath, UK.
Abbot, A. 2008 Psychiatric genetics: the brains of the family.
Nature (news feature) 454, 154–157. (doi:10.1038/
Bar-Haim, Y., Lamy, D., Pergamin, L., Bakermans-
Kranenburg, M. J. & van Ijzendoorn, M. H. 2007
Threat-related attentional bias in anxious and non-
anxious individuals: a metaanalytic study. Psychol. Bull.
133, 1–24. (doi:10.1037/0033-2909.133.1.1)
Barr, C. S. et al. 2004 Sexual dichotomy of an interaction
between early adversity and the serotonin transporter
gene promoter variant in rhesus macaques. Proc. Natl
Acad. Sci. USA 101, 12 358–12 363. (doi:10.1073/pnas.
Beck, A., Steer, R. & Brown, G. 1996 Manual for beck
depression inventory-II. San Antonio, TX: Psychological
Beevers, C. G., Gibb, B. E., McGeary, J. E. & Miller, I. W.
2007 Serotonin transporter genetic variation and biased
attention for emotional word stimuli among psychiatric
inpatients. J. Abnorm. Psychol. 116, 208–212. (doi:10.
Canli, T. & Lesch, K. P. 2007 Long story short: the serotonin
transporter in emotion regulation and social cognition.
Nat. Neurosci. 10, 1103–1109. (doi:10.1038/nn1964)
Canli, T., Qiu, M., Omura, K., Congdon, E., Haas, B. W.,
Amin, Z., Herrmann, M. J., Constable, R. T. & Lesch,
K. P. 2006 Neural correlates of epigenesis. Proc. Natl
Acad. Sci. USA 103, 16 033–16 038. (doi:10.1073/pnas.
Caspi, A. & Moffitt, T. 2006 Gene–environment interactions
in psychiatry: joining forces with neuroscience. Nat. Rev.
Neurosci. 7, 583–590. (doi:10.1038/nrn1925)
Caspi, A. et al. 2003 Influence of life stress on depression:
moderation by a polymorphism in the 5-HTT gene.
Science 301, 386–389. (doi:10.1126/science.1083968)
Costa Jr, P. T. & McCrae, R. R. 1992 NEO PI-R professional
Davidson, R. J. 2004 Well-being and affective style: neural
359, 1395–1411. (doi:10.1098/rstb.2004.1510)
Fox, E. 1993 Allocation of visual attention and anxiety. Cogn.
Emot. 7, 207–215. (doi:10.1080/02699939308409185)
Hariri, A. R. & Holmes, A. 2006 Genetics of emotional
regulation: the role of the serotonin transporter in neural
function. Trends Cogn. Sci. 10, 182–191. (doi:10.1016/
Hariri, A. R., Mattay, V. S., Tessitore, A., Kolachana, B. S.,
Fera, F., Goldman, D., Egan, M. F. & Weinberger, D. R.
2002 Serotonin transporter genetic variation and the
response of the human amygdala. Science 297, 400–403.
Heils, A., Teufel, A., Petri, S., Sto ¨ber, G., Riederer, P.,
Bengel, D. & Lesch, K. P. 1996 Allelic variation of human
serotonin transporter gene expression. J. Neurochem. 66,
Hu, X., Oroszi, G., Chun, J., Smith, T. L., Goldman, D. &
Schuckit, M. A. 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,
Lang, P. J., Bradley, M. M. & Cuthbert, B. N. 2005
International affective picture system (IAPS): affective
ratings of pictures and instruction manual. Technical
report A-6, University of Florida, Gainesville, FL.
Lesch, K. P. et al. 1996 Association of anxiety-related traits
with a polymorphism in the serotonin transporter gene
regulatory region. Science 274, 1527–1531. (doi:10.1126/
MacLeod, C., Rutherford, E. M., Campbell, I., Ebsworthy,
G. & Holker, L. 2002 Selective attention and emotional
vulnerability: assessing the causal basis of their association
through the experimental manipulation of attentional bias.
J. Abnorm. Psychol. 111, 107–123. (doi:10.1037/0021-
Munafo, M. R., Brown, S. M. & Hariri, A. R. 2008 Serotonin
transporter (5-HTTLPR) genotype and amygdala acti-
vation: a meta-analysis. Biol. Psychiatry 63, 852–857.
Phelps, E. A. & LeDoux, J. E. 2005 Contributions of the
amygdala to emotion processing: from animal models to
human behavior. Neuron 48, 175–187. (doi:10.1016/
Sander, D., Grafman, J. & Zalla, T. 2003 The human
amygdala: an evolved system for relevance detection. Rev.
Neurosci. 14, 303–316.
Spielberger, C. D., Gorsuch, R. L., Lushene, R. E., Vagg, P.
R. & Jacobs, G. A. 1983 Manual for the state-trait anxiety
inventory STAI ( form Y). Palo Alto, CA: Consulting
Whittle, A., Allen, N. B., Lubman, D. & Yucel, M. 2006
The neuroanatomical basis of affective temperament:
towards a better understanding of psychopathology.
Neurosci. Biobehav. Rev. 30, 511–525. (doi:10.1016/
Willis-Owen, S. A., Turri, M. G., Munafo `, M. R., Surtees,
P. G., Wainwright, N. W., Brixey, R. D. & Flint, J. 2005
The serotonin transporter length polymorphism, neuroti-
cism, and depression: a comprehensive assessment of
association. Biol. Psychiatry 58, 451–456. (doi:10.1016/
Biased attention and 5-HTTLPR
E. Fox et al.
Proc. R. Soc. B (2009)