Genes, Brain and Behavior (2012) 11: 398–403
Somatic markers mediate the effect of serotonin
transporter gene polymorphisms on Iowa Gambling
Task
A. C. Miu∗,† , L. G. Crişan† , A. Chiş‡ ,
L. Ungureanu§ , B. Drug㶠and R. Vulturar∗,‡
† Cognitive Neuroscience Laboratory, Department of
Psychology, Babeş-Bolyai University, ‡ Department of Cell and
Molecular Biology, Iuliu Haţieganu University of Medicine and
Pharmacy, § Department of Dermatology, Iuliu Haţieganu
University of Medicine and Pharmacy, and ¶ Institute of
Biological Research, Cluj-Napoca, Romania
*Corresponding authors: Dr A. C. Miu, 37 Republicii, 400015
Cluj-Napoca, Cluj, Romania. E-mail: andreimiu@psychology.ro;
Dr R. Vulturar, 37 Republicii, 400015 Cluj-Napoca, Cluj, Romania.
E-mail: romanavulturar@yahoo.co.uk
This study investigated whether somatic markers medi-
ate the effect of serotonin transporter genotype on Iowa
Gambling Task (IGT) performance. Participants (N = 135)
were genotyped for the insertion/deletion and single-
nucleotide (rs25531) polymorphisms in the promoter
region of the serotonin transporter gene (5-HTTLPR ).
The results of mediation analyses indicated that skin
conductance responses that anticipated IGT card selec-
tions partially (i.e. 42% of the total effect) mediated the
effect of genotype on IGT performance. In comparison
with high-functioning 5-HTTLPR genotypes, the low-
functioning genotypes were associated with higher total
IGT scores. This suggests that the higher synaptic avail-
ability of serotonin, associated with the low-functioning
5-HTTLPR genotypes, may confer differential suscepti-
bility to decision making under risk, and that almost half
of this effect is explained by facilitated somatic markers
during IGT.
Keywords: decision making, emotion, endophenotype,
5-HTTLPR, somatic marker hypothesis
Received 24 November 2011, revised 17 January 2012 and
12 February 2012, accepted for publication 16 February 2012
The Iowa Gambling Task (IGT) is extensively used in basic and
clinical research on decision making. The original success of
IGT was due to its sensitivity to ‘myopia for the future’, a type
of functional impairment displayed by patients with ventro-
medial prefrontal cortex lesions (Bechara et al . 1994). These
patients failed to develop a preference for the decks of cards
yielding lower immediate gains but also smaller future losses
during IGT, and persevered in choosing from the decks that
398
Genes, Brain and Behavior © 2012 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society
doi: 10.1111/j.1601-183X.2012.00774.
yielded higher immediate gains but also higher future losses.
In healthy controls, the preference for long-term advanta-
geous decks in IGT was paralleled by the development of skin
conductance responses (SCR) prior to the selection of cards
(Bechara et al . 1997). Anticipatory SCR were higher before
picking a card from the disadvantageous decks in healthy
controls, but not in patients with ventromedial prefrontal
cortex lesions (Bechara et al . 1999). These discoveries put
IGT in the center of the somatic marker hypothesis (Bechara
et al . 2000; Damasio 1996), which has argued that emotions,
as reflected by anticipatory SCR during IGT, guide decision
making. Although this theory has been debated (Bechara
et al . 2005; Dunn et al . 2006; Guillaume et al . 2009; Maia
& McClelland 2004), it remains highly influential in cognitive
psychology, cognitive neuroscience and neuroeconomics.
Recent interest in IGT has concerned the neurochemical
mechanisms that underlie optimal performance, with impli-
cations for understanding the decision-making dysfunctions
in various neurological and psychiatric conditions (Bechara
2004; Verdejo-Garcia & Bechara 2009). It has been hypoth-
esized that the biasing action of somatic markers (e.g.
anticipatory SCR) on IGT performance may involve changes
in neurotransmitter release in cortical and subcortical neural
structures associated with executive functioning, working
memory, emotions and the implementation of behavioral
decisions (Bechara & Damasio 2005; Li et al . 2010). One
of the candidate neurotransmitters involved in IGT is sero-
tonin. It was shown that the administration of fluvoxamine,
a selective serotonin reuptake inhibitor (SSRI), improved the
selection of advantageous choices in IGT, and this effect
was stronger in the second part of the task (Bechara et al .
2001). This part of IGT is thought to reflect decision making
under risk because, by this stage, participants have probably
acquired some subjective sense of the outcome probabili-
ties associated with the different decks of cards (Bechara
et al . 1997). Therefore, serotonin stimulation by SSRI may
specifically facilitate decision making under risk in IGT, but
this hypothesis should be further investigated considering
that the preliminary findings of Bechara et al . (2001) have
not been replicated. However, it was also observed that
enhancing serotonin activity in humans by administering
its precursor, 5-hydroxytryptophan, reduced decision-making
biases (i.e. the reflection effect) in a task similar to IGT (Mur-
phy et al . 2009). In contrast, tryptophan depletion in rats,
which effectively reduced brain serotonin synthesis, impaired
decision-making performance in a murine analog of IGT (Koot
et al . 2012). Psychopharmacological studies in animals and
humans seem to agree on the involvement of serotonin
in decision making, but it is yet unclear whether increased
© 2012 The Authors

serotonin activity has enhancing or impairing effects on IGT
(Homberg 2012; Rogers 2011).
Selective serotonin reuptake inhibitor acts on the serotonin
transporter (5-HTT), which is the key molecule responsible for
the reuptake of serotonin. The human 5-HTT is encoded by
a gene located on the chromosome 17 (17q11.1-q12). The
promoter of this gene (5-HTTLPR ) hosts two polymorphic
loci, which result in variations in 5-HTT gene expression
and 5-HTT function in the brain. An insertion/deletion
polymorphism in the human 5-HTTLPR has been first
reported (Lesch et al . 1996). This polymorphism has a short
(S ) allele comprising 14 copies of a 20–23 base pair unit,
and a long (L) allele comprising 16 copies of the same repeat
unit. The short allele is associated with reduced expression
of 5-HTT gene and consequently reduced availability of
5-HTT in the brain (Little et al . 1998; Reimold et al . 2007).
A more recently described polymorphism (rs25531) involves
the substitution of an adenine to a guanine in the L allele
of 5-HTTLPR (Hu et al . 2006). The LG allele functionally
resembles the S allele (Ehli et al . 2012; Hu et al . 2006), so
it is necessary to genotype both 5-HTTLPR polymorphisms
(i.e. triallelic 5-HTTLPR ) in order to correctly categorize the
L alleles into low-functioning (LG ) and high-functioning (LA ).
Therefore, an alternative to pharmacological manipulations
of 5-HTT by SSRI is to study the influence of low- (S and
LG ) and high-functioning (LA ) alleles of 5-HTT gene on IGT
performance.
In light of the potentially enhancing effects of SSRI on IGT,
one would expect that the low-functioning alleles of 5-HTT
facilitated decision making in this task. Genetic knockout of
5-HTT in rats was indeed associated with a higher level of
performance in a murine analog of IGT (Homberg et al . 2008).
However, the lack of 5-HTT by gene knockout in rats may
have different effects on IGT, in comparison with low 5-HTT
functioning in humans. Indeed, the findings of recent genetic
association studies on 5-HTT and IGT in healthy humans have
been heterogenous. Two studies were able to confirm that S
carriers made more advantageous choices in the first block of
IGT (Stoltenberg et al . 2011; Stoltenberg & Vandever 2010),
whereas another study found that only S carriers who also
had a certain dopamine receptor type 4 genotype displayed
IGT advantage (Ha et al . 2009). In contrast, three studies
reported that S carriers showed reduced IGT performance
(van den Bos et al . 2009; He et al . 2010; Homberg et al .
2008), and another study indicated no effect of 5-HTTLPR
on IGT (Lage et al . 2011). Similar studies in clinical samples
found that the S and LG alleles were associated with reduced
IGT performance in obsessive-compulsive disorder (da Rocha
et al . 2008), or had no influence on IGT in suicide attempters
(Jollant et al . 2007).
Clearly, additional studies are crucial in order to elucidate
the effects of 5-HTT on IGT, and set the stage for meta-
analyses. Different groups focused on various IGT outcomes
(e.g. total score, scores from a single 20-trial block and scores
from the first block vs. the other four blocks), and these vari-
ables need to be considered. The effects of 5-HTT may also
be different in clinical samples compared with healthy volun-
teers because the effects of the genotype may interact with
the duration of the disease or previous medication in patients
with emotional disorders. Moreover, only two of the previous
Genes, Brain and Behavior (2012) 11: 398–403
5-HTTLPR, somatic markers and decision making
studies in healthy participants (Ha et al . 2009; Stoltenberg
et al . 2011) genotyped for rs25531 alleles, and this may
have contributed to their success in finding positive effects
on IGT. Another unexplored aspect, which would greatly
increase the theoretical significance of this line of research,
is related to the effects of 5-HTT genotype on somatic
markers during IGT. Recent evidence confirmed that the dif-
ference between anticipatory SCR before advantageous and
disadvantageous choices predicted IGT performance, and
suggested that somatic markers and declarative knowledge
independently contribute to IGT (Guillaume et al . 2009).
This study was designed to investigate the effects of
5-HTT genotype, including 5-HTTLPR and rs25531, on IGT
performance and somatic markers during IGT. On the
basis of the previous literature related to somatic marker
hypothesis, we specifically expected that anticipatory SCR
would mediate the effect of genotype on IGT performance.
Material and methods
Experimental subjects
N = 135 participants (118 women) volunteered for this study,
following in-class presentations. Prior to study participation, written
informed consent was obtained from all the volunteers. They were
all Caucasians of Romanian descent, and came from the same
well-circumscribed geographical area. Age ranged from 16 to 42
(M = 21.6 years). All the participants were compensated for their
time. The study followed the recommendations of AMA’s Declaration
of Helsinki, and it was approved by the Babeş-Bolyai University
Research Council.
Genotyping
DNA was extracted from leukocytes [ethylenediaminetetraacetic
acid (EDTA)-anticoagulated blood] using Genomic DNA Extraction
Kit (Fermentas, Vilnius, Lithuania) and kept at −20◦ C. Both biallelic
and triallelic (i.e. including rs25531) 5-HTTLPR genotyping were per-
formed using a protocol adapted after Lonsdorf et al . (2009) and
Kosek et al . (2009). The polymerase chain reaction (PCR) assay con-
ditions were optimized as follows: each reaction was carried out
in a 25 μl volume [50 ng of genomic template, 12.5 μl PCR mas-
termix (2x)]; the forward primer (5 -GGCGTTGCCGCTCTGAATGC-3 )
and reverse primer (5 -GAGGGACTGAGCTGGACAACCAC-3 ), from
Generi-Biotech (Hradec Kralove, Czech Republic), were used to
amplify a region encompassing 5-HTTLPR. These primers yield
amplicons of 529 (for L allele) or 486 bp (for S allele). Thermal
cycling consisted of 3 min of initial denaturation at 94◦ C followed
by 31 cycles of 94◦ C (40 seconds), 57◦ C (40 seconds) and 72◦ C (40
seconds), each with a final extension step of 4 min at 72◦ C. The LG
and LA alleles were subsequently studied by enzymatic digestion of
10 μl of PCR products that were digested by HpaII (an isoschizomer
of MspI ) type FastDigest (Fermentas) in a 30 μl reaction assay at
37◦ C for 5 min. The restriction enzyme MspI recognizes and cuts
a 5 -C/CGG-3 sequence resulting in the following fragments: 340,
127 and 62 bp for the LA allele; 174, 166, 127 and 62 bp for the LG
allele; 297, 127 and 62 bp for the SA allele; and 166, 131, 127 and
62 bp for the SG allele. Finally, 10 μl of remaining PCR product and
15 μl of restriction enzyme assay solution were loaded onto a 2.5%
agarose gel, run for 2 h at 160 V in 0.5 × TBE running buffer and
visualized by ethidium bromide for size estimation. The 5-HTTLPR
allele frequencies were 0.45 for SA allele, 0.48 for LA allele and 0.05
for LG allele, similar to the ones reported by Hu et al . (2006) for Cau-
casians. One of the participants carried an ultralong (>16 repeats)
allele (XL) (Ehli et al . 2012). The genotypes were categorized into low-
functioning (i.e. carriers of two low-expressing alleles: SS, LG LG , SLG :
N = 32), intermediate-functioning (i.e carriers of one low-expressing
allele: SLA , LG LA : N = 66), and high-functioning (i.e. carriers of two
399
Miu et al.
high-expressing alleles: LA LA , LA XL: N = 30). These genotypes were
in Hardy–Weinberg equilibrium (χ 2 = 0.13, not significant).
Iowa Gambling Task
The computerized version of IGT was used (Bechara et al . 1994).
Briefly, IGT involves four decks of cards (A–D), from which partici-
pants are allowed to choose 100 cards. Each card from decks A and B
is associated with a high gain ($100), whereas each card from C and D
comes with a lower gain ($50). However, choosing a card is followed
by unpredictable losses in all decks: for every 10 cards from A and B,
there is a $1000 gain and $1250 loss; for every 10 cards from C and
D, there is a $500 gain and $250 loss. Therefore, decks A and B are
disadvantageous because of the net $250/10 cards loss, and decks C
and D are advantageous due to the net $250/10 cards gain. The IGT
score is obtained by subtracting the total number of disadvantageous
choices from the total number of advantageous choices: [(C + D) – (A
+ B)]. Participants are allowed to choose 100 cards. Learning in IGT is
operationalized as the improvement of the [(C + D) – (A + B)] scores
from one block of 20 successive selections to another.
Psychophysiology
SCR was recorded during IGT, using a Biopac MP150 system
(Biopac Systems, Goleta, CA, USA). Area under the curve (μS/s)
was estimated from reward or punishment intervals (i.e. 5 seconds
after the result of each selection was displayed), and anticipatory
intervals (i.e. 5-second intervals before the result of each selection
was displayed). The difference between anticipatory SCR before
disadvantageous and advantageous cards was computed.
Statistical analyses
Analysis of covariance (ANCOVA) was used to test for differences in
IGT performance and SCR by 5-HTTLPR group. Pearson correlations
were computed to determine associations between IGT performance
and SCR. Mediation was tested using multiple regression analyses
(Baron & Kenny 1986; Frazier et al . 2004; Hoyt et al . 2008). According
to Baron and Kenny (1986), the model had to satisfy three conditions
in order to be confirmed (Fig. 1): (1) the initial variable (5-HTTLPR
group) was significantly related to the outcome variable (CD–AB
score) (Path c ); (2) the initial variable was related to the mediator
(anticipatory SCR difference between CD and AB cards) (Path a)
and (3) the mediator was significantly associated with the outcome
variable when regressed on both the mediator and the initial variable
(Path b), and the effect of the initial variable (Path c ) was reduced
compared with that in the first regression (Path c ). The Aroian version
A
B indicated a consistently smaller indirect effect (18% of the
Figure 1: Links between genotype, somatic markers and
gambling performance. Mediation model describing the direct
effect of genotype on IGT performance (a) and the indirect effect
of genotype on IGT performance through anticipatory SCR (b).
400
of the Sobel test was used to test whether the indirect effect was
significant (Aroian 1947; Baron & Kenny 1986). All the analyses were
run in SPSS V.13.0.
Results
Iowa Gambling Task performance and somatic
markers by 5-HTTLPR group
A 3 (genotype: low- vs. intermediate- vs. high-functioning) ×
5 (block of trials) ANCOVA, with sex as covariate, indicated sig-
nificant main effects of genotype (F2,132 = 4.61, P = 0.01,
Cohen’s d = 0.96) and block (F4,130 = 5.79, P = 0.003,
Cohen’s d = 1.56) on CD–AB scores, as well as a significant
interaction of genotype and block (F7,127 = 4.1, P = 0.01,
ohen’s d = 0.87). In comparisons with the high-functioning
group, the low- and intermediate-functioning groups had sig-
nificantly higher CD–AB scores in blocks 2–4 (i.e. trials
21–80) (Fig. 2a). A similar ANCOVA analysis found a sig-
nificant effect of genotype on CD–AB anticipatory SCR
(F2,132 = 3.09, P = 0.04, Cohen’s d = 0.45), with higher SCR
in low- and intermediate-functioning genotypes compared
with high-functioning genotype (Fig. 2b). There was a sta-
tistically significant correlation between CD–AB anticipatory
SCR and CD–AB scores (r = 0.29, P = 0.04). There were
no statistically significant effects on SCR during reward or
punishment intervals.
Somatic markers mediating the association between
5-HTTLPR and Iowa Gambling Task performance
Table 1 describes the results of the analyses that examined
the mediation hypothesis (see also Fig. 1). As predicted,
genotype was significantly related to IGT performance (Path
c ) and to anticipatory SCR (Path a). When regressing IGT
performance on both genotype and anticipatory SCR, the
coefficient associated with the relation between anticipatory
SCR and IGT performance, while controlling for genotype
(Path b), was significant. The coefficient associated with
the relation between genotype and IGT performance, while
controlling for anticipatory SCR (Path c ), remained significant.
However, Path’s c coefficient was smaller than Path’s c
and anticipatory SCR was a significant mediator (Aroian’s
z = 5.33, P = 0.00). The ratio a × b/c indicated that about
42% of the total effect of genotype on IGT performance was
mediated by anticipatory SCR. A reverse-causality analysis
that tested a path from IGT performance to anticipatory SCR
total effect). The mediation model was also tested after
excluding the fewer men from the sample, and the results
were closely similar (i.e. 41% mediation by anticipatory SCR).
Discussion
As hypothesized, we found that anticipatory SCR during
IGT partially mediated the relation between 5-HTTLPR
genotype and IGT performance. In terms of causation,
genotype preceded both SCR development (the mediator)
and learning IGT (the outcome). In addition, we tested
Genes, Brain and Behavior (2012) 11: 398–403
 5-HTTLPR, somatic markers and decision making

A B

Figure 2: Gambling performance

and somatic markers by geno-
type. The effects of 5-HTTLPR
genotype (low- vs. intermediate-
vs. high-functioning) on IGT perfor-
mance (a) and difference in antici-
patory SCR between advantageous
and disadvantageous decks (T
scores) (b). Error bars represent
one standard error of the mean.
∗
P < 0.05; ∗∗ P < 0.01.

Table 1: Path coefficients for the mediation by anticipatory SCR of the relation between genotype and IGT performance

Testing steps in mediation model B SE B 95% CI β

Testing step 1 (Path c )

Outcome: [(C + D) – (A + B)] score
Predictor: genotype (low- vs. intermediate- vs. high-functioning)∗ 1.70 0.32 1.30–1.98 0.21∗∗
Testing step 2 (Path a)
Outcome: anticipatory SCR level
Predictor: genotype 0.72 0.09 0.34–1.21 0.22∗∗
Testing step 3 (Paths b and c  )
Outcome: [(C + D) – (A + B)] score
Mediator: anticipatory SCR level (Path b) 1.01 0.14 0.87–1.12 0.36∗∗
Predictor: genotype (Path c  ) 0.93 0.19 0.59–1.17 0.19∗

B, unstandardized regression coefficient; β, standardized regression coefficient; CI, confidence interval; SE, standard error.
∗
0 = high-functioning genotype (i.e. LA /LA and LA /XL genotypes); 1 = intermediate-functioning genotype (i.e. S /LA and LG /LA
genotypes); 2 = low-functioning genotype (i.e. S /S , LG /LG and S /LG genotypes).
∗
P < 0.05; ∗∗ P < 0.01.

an alternative model in which IGT performance mediated
anticipatory SCR and found that the indirect effect dropped
significantly. Therefore, these results support the view that
low-functioning 5-HTTLPR genotypes are associated with
increased IGT performance (partially) because they lead to
higher anticipatory SCR during IGT.
The present finding that low-functioning alleles of
5-HTTLPR facilitate IGT performance is in line with previ-
ous genetic association studies in humans (Stoltenberg et al .
2011; Stoltenberg & Vandever 2010). This effect is similar to
that of SSRI, which may facilitate IGT performance and par-
ticularly decision making under risk (Bechara et al . 2001), as
well as to observations from psychopharmacological manip-
ulations of tryptophan (Koot et al . 2012; Murphy et al . 2009).
Our results are also supported by the previous observation
that 5-HTT knockout in rats increased performance in the
second half of a murine IGT analog (Homberg et al . 2008).
Overall, these studies indicate that the reduced function
of 5-HTT, which probably leads to an increased synaptic
availability of serotonin, is beneficial to decision making in
IGT. 5-HTTLPR may thus illustrate differential susceptibility
(Belsky & Pluess 2009; Homberg & Lesch 2010) to IGT learn-
ing environment, particularly in the second part of the task.
From this perspective, carriers of low-functioning alleles of
5-HTTLPR may be particularly susceptible to learning from
environments that include risk, in which the decision maker
has complete information regarding the stochastic relation-
ship between actions and outcomes (Rangel et al . 2008).
We found that anticipatory SCR mediated 42% of the
total effect of genotype on IGT performance. This partial,
yet consistent mediation provides a new type of support
for the somatic marker hypothesis (Bechara et al . 2000).
To our knowledge, this is the first study showing that a
genetic-driven difference in somatic markers has impact on
IGT performance. These results contribute to the recent lit-
erature on how genes contribute to individual differences in
decision making (Ebstein et al . 2010), and may open a new
and important line of research related to somatic marker
hypothesis and the contribution of emotions to IGT. In light of
debates surrounding the somatic marker hypothesis, future
studies might test a complementary model in which declar-
ative knowledge acquired during IGT might mediate another
portion of the effect of 5-HTTLPR on IGT performance.
Somatic markers and declarative knowledge independently
contribute to IGT performance (Guillaume et al . 2009), and it
is thus possible that they are influenced by different genetic
polymorphisms or perhaps gene × environment interactions.
To date, twin studies have not approached the genetic
and environmental influences on IGT and its underlying
mechanisms. An intriguing possibility, although entirely spec-
ulative, is that heritability contributes to IGT through somatic
markers, and individual environment influences IGT through

Genes, Brain and Behavior (2012) 11: 398–403 401

Miu et al.
declarative knowledge. Therefore, subsequent research may
investigate whether 5-HTTLPR interacts with other genetic
polymorphisms (Ha et al . 2009; da Rocha et al . 2011) and
environmental factors (e.g. socioeconomic status) in influ-
encing the susceptibility to learning IGT. Somatic markers
and IGT performance may qualify for endophenotypes of neu-
ropsychiatric conditions (e.g. obsessive-compulsive disorder,
bipolar disorder, pathological gambling, addiction), and shed
light on the pathogenesis of these conditions (Verdejo-Garcia
& Bechara 2009).
This design was based on a priori predictions, which
were derived from an empirically supported theory. Our
hypotheses were also in line with previous experimental
results from psychopharmacological studies in humans and
genetic engineering in animals. As expected, the results
supported our model. However, it is noteworthy that the
association of low-functioning 5-HTTLPR alleles with higher
IGT performance is not in line with several previous studies
(He et al . 2010; Homberg et al . 2008; van den Bos et al .
2009). Most of these studies did not genotype rs25531,
and the failure in categorizing L alleles into low-functioning
LG and high-functioning LA may explain the divergence of
their results from the theoretically and empirically supported
view. Future studies might thus try to replicate these results
by genotyping both 5-HTTLPR polymorphisms (Ehli et al .
2012; Hu et al . 2006; Lesch et al . 1996), and measuring IGT,
somatic markers and declarative knowledge.
In conclusion, this study showed that anticipatory SCR
during IGT mediate part of the effect of 5-HTTLPR on
IGT performance, with low-functioning alleles conferring an
advantage in learning IGT by their association with increased
somatic markers.
References
Aroian, L.A. (1947) The probability function of the product of two
normally distributed variables. Ann Math Stat 18, 265–271.
Baron, R.M. & Kenny, D.A. (1986) The moderator-mediator variable
distinction in social psychological research: conceptual, strategic,
and statistical considerations. J Pers Soc Psychol 51, 1173–1182.
Bechara, A. (2004) The role of emotion in decision-making: evidence
from neurological patients with orbitofrontal damage. Brain Cogn
55, 30–40.
Bechara, A. & Damasio, A.R. (2005) The somatic marker hypothesis:
a neural theory of economic decision. Games Econ Behav 52,
336–372.
Bechara, A., Damasio, A.R., Damasio, H. & Anderson, S.W. (1994)
Insensitivity to future consequences following damage to human
prefrontal cortex. Cognition 50, 7–15.
Bechara, A., Damasio, H., Tranel, D. & Damasio, A.R. (1997) Deciding
advantageously before knowing the advantageous strategy.
Science 275, 1293–1295.
Bechara, A., Damasio, H., Damasio, A.R. & Lee, G.P. (1999) Different
contributions of the human amygdala and ventromedial prefrontal
cortex to decision-making. J Neurosci 19, 5473–5481.
Bechara, A., Damasio, H. & Damasio, A.R. (2000) Emotion, decision
making and the orbitofrontal cortex. Cereb Cortex 10, 295–307.
Bechara, A., Damasio, H. & Damasio, A.R. (2001) Manipulation of
Dopamine and Serotonin Causes Different Effects on Covert and
Overt Decision-Making. Society for Neuroscience Annual Meeting,
San Diego, CA, (abstract 456.5).
Bechara, A., Damasio, H., Tranel, D. & Damasio, A.R. (2005) The
Iowa Gambling Task and the somatic marker hypothesis: some
402
questions and answers. Trends Cogn Sci 9, 159–162. discussion
162-154.
Belsky, J. & Pluess, M. (2009) Beyond diathesis stress: differential
susceptibility to environmental influences. Psychol Bull 135,
885–908.
van den Bos, R., Homberg, J., Gijsbers, E., den Heijer, E. &
Cuppen, E. (2009) The effect of COMT Val158 Met genotype on
decision-making and preliminary findings on its interaction with the
5-HTTLPR in healthy females. Neuropharmacology 56, 493–498.
Damasio, A.R. (1996) The somatic marker hypothesis and the
possible functions of the prefrontal cortex. Philos Trans R Soc
Lond B Biol Sci 351, 1413–1420.
Dunn, B.D., Dalgleish, T. & Lawrence, A.D. (2006) The somatic
marker hypothesis: a critical evaluation. Neurosci Biobehav Rev
30, 239–271.
Ebstein, R.P., Israel, S., Chew, S.H., Zhong, S. & Knafo, A. (2010)
Genetics of human social behavior. Neuron 65, 831–844.
Ehli, E.A., Hu, Y., Lengyel-Nelson, T., Hudziak, J.J. & Davies, G.E.
(2012) Identification and functional characterization of three novel
alleles for the serotonin transporter-linked polymorphic region. Mol
Psychiatry 17, 185–192.
Frazier, P.A., Tix, A.P. & Barron, K.E. (2004) Testing moderator and
mediator effects in counseling psychology research. J Counsel
Psychol 51, 115–134.
Guillaume, S., Jollant, F., Jaussent, I., Lawrence, N., Malafosse, A.
& Courtet, P. (2009) Somatic markers and explicit knowledge
are both involved in decision-making. Neuropsychologia 47,
2120–2124.
Ha, R.Y., Namkoong, K., Kang, J.I., Kim, Y.T. & Kim, S.J. (2009) Inter-
action between serotonin transporter promoter and dopamine
receptor D4 polymorphisms on decision making. Prog Neuropsy-
chopharmacol Biol Psychiatry 33, 1217–1222.
He, Q., Xue, G., Chen, C., Lu, Z., Dong, Q., Lei, X., Ding, N., Li, J.,
Li, H., Chen, C., Li, J., Moyzis, R.K. & Bechara, A. (2010) Serotonin
transporter gene-linked polymorphic region (5-HTTLPR) influences
decision making under ambiguity and risk in a large Chinese
sample. Neuropharmacology 59, 518–526.
Homberg, J.R. (2012) Serotonin and decision making processes.
Neurosci Biobehav Rev 36, 218–236.
Homberg, J.R. & Lesch, K.P. (2010) Looking on the bright side of
serotonin transporter gene variation. Biol Psychiatry 69, 513–519.
Homberg, J.R., van den Bos, R., den Heijer, E., Suer, R. & Cuppen, E.
(2008) Serotonin transporter dosage modulates long-term decision-
making in rat and human. Neuropharmacology 55, 80–84.
Hoyt, W.T., Imel, Z.E. & Chan, F. (2008) Multiple regression and
correlation techniques: Recent controversies and best practices.
Rehab Psychol 53, 321–339.
Hu, X.Z., Lipsky, R.H., Zhu, G., Akhtar, L.A., Taubman, J., Green-
berg, B.D., Xu, K., Arnold, P.D., Richter, M.A., Kennedy, J.L., Mur-
phy, D.L. & Goldman, D. (2006) Serotonin transporter promoter
gain-of-function genotypes are linked to obsessive-compulsive dis-
order. Am J Hum Genet 78, 815–826.
Jollant, F., Buresi, C., Guillaume, S., Jaussent, I., Bellivier, F.,
Leboyer, M., Castelnau, D., Malafosse, A. & Courtet, P. (2007)
The influence of four serotonin-related genes on decision-making
in suicide attempters. Am J Med Genet B Neuropsychiatr Genet
144B, 615–624.
Koot, S., Zoratto, F., Cassano, T., Colangeli, R., Laviola, G., van den
Bos, R. & Adriani, W. (2012) Compromised decision-making
and increased gambling proneness following dietary serotonin
depletion in rats. Neuropharmacology 62, 1640–1650.
Kosek, E., Jensen, K.B., Lonsdorf, T.B., Schalling, M. & Ingvar, M.
(2009) Genetic variation in the serotonin transporter gene (5-
HTTLPR, rs25531) influences the analgesic response to the short
acting opioid Remifentanil in humans. Mol Pain 5, 37.
Lage, G.M., Malloy-Diniz, L.F., Matos, L.O., Bastos, M.A., Abrantes,
S.S. & Correa, H. (2011) Impulsivity and the 5-HTTLPR polymor-
phism in a non-clinical sample. PloS ONE 6, e16927.
Lesch, K.P., Bengel, D., Heils, A., Sabol, S.Z., Greenberg, B.D.,
Petri, S., Benjamin, J., Muller, C.R., Hamer, D.H. & Murphy, D.L.
Genes, Brain and Behavior (2012) 11: 398–403

(1996) Association of anxiety-related traits with a polymorphism
in the serotonin transporter gene regulatory region. Science 274,
1527–1531.
Li, X., Lu, Z.L., D’Argembeau, A., Ng, M. & Bechara, A. (2010) The
Iowa Gambling Task in fMRI images. Hum Brain Mapp 31,
410–423.
Little, K.Y., McLaughlin, D.P., Zhang, L., Livermore, C.S., Dalack,
G.W., McFinton, P.R., DelProposto, Z.S., Hill, E., Cassin, B.J.,
Watson, S.J. & Cook, E.H. (1998) Cocaine, ethanol, and genotype
effects on human midbrain serotonin transporter binding sites and
mRNA levels. Am J Psychiatry 155, 207–213.
Lonsdorf, T.B., Weike, A.I., Nikamo, P., Schalling, M., Hamm, A.O.
& Ohman, A. (2009) Genetic gating of human fear learning and
extinction: possible implications for gene-environment interaction
in anxiety disorder. Psychol Sci 20, 198–206.
Maia, T.V. & McClelland, J.L. (2004) A reexamination of the evidence
for the somatic marker hypothesis: what participants really know
in the Iowa gambling task. Proc Natl Acad Sci U S A 101,
16075–16080.
Murphy, S.E., Longhitano, C., Ayres, R.E., Cowen, P.J., Harmer, C.J.
& Rogers, R.D. (2009) The role of serotonin in nonnormative
risky choice: the effects of tryptophan supplements on the
‘‘reflection effect’’ in healthy adult volunteers. J Cogn Neurosci
21, 1709–1719.
Rangel, A., Camerer, C. & Montague, P.R. (2008) A framework for
studying the neurobiology of value-based decision making. Nat
Rev Neurosci 9, 545–556.
Reimold, M., Smolka, M.N., Schumann, G., Zimmer, A., Wrase, J.,
Mann, K., Hu, X.Z., Goldman, D., Reischl, G., Solbach, C.,
Machulla, H.J., Bares, R. & Heinz, A. (2007) Midbrain serotonin
transporter binding potential measured with [11 C]DASB is affected
by serotonin transporter genotype. J Neural Transm 114, 635–639.
Genes, Brain and Behavior (2012) 11: 398–403
5-HTTLPR, somatic markers and decision making
da Rocha, F.F., Malloy-Diniz, L., Lage, N.V. & Correa, H. (2011) The
relationship between the Met allele of the BDNF Val66Met
polymorphism and impairments in decision making under
ambiguity in patients with obsessive-compulsive disorder. Genes
Brain Behav 10, 523–529.
da Rocha, F.F., Malloy-Diniz, L., Lage, N.V., Romano-Silva, M.A., de
Marco, L.A. & Correa, H. (2008) Decision-making impairment is
related to serotonin transporter promoter polymorphism in a
sample of patients with obsessive-compulsive disorder. Behav
Brain Res 195, 159–163.
Rogers, R.D. (2011) The roles of dopamine and serotonin in decision
making: evidence from pharmacological experiments in humans.
Neuropsychopharmacology 36, 114–132.
Stoltenberg, S.F. & Vandever, J.M. (2010) Gender moderates the
association between 5-HTTLPR and decision-making under
ambiguity but not under risk. Neuropharmacology 58, 423–428.
Stoltenberg, S.F., Lehman, M.K., Anderson, C., Nag, P. & Anagnopou-
los, C. (2011) Serotonin transporter (5-HTTLPR) genotype and
childhood trauma are associated with individual differences in
decision making. Front Genet 2, e1–e7.
Verdejo-Garcia, A. & Bechara, A. (2009) A somatic marker theory of
addiction. Neuropharmacology 56 (Suppl. 1), 48–62.
Acknowledgements
We are grateful to Simona Pană, Silviu Matu, Ioana Cocia, Bianca
Blaj and Julia Avram for help with data collection. This research
was supported by grant 411/2010 from the National Council of
Scientific Research in Higher Education (CNCSIS) to A.C.M.
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