Genes, Brain and Behavior (2011) 10: 536–541 doi: 10.1111/j.1601-183X.2011.00690.x
Serotonin transporter gene variants and prediction
of stress-induced risk for psychological distress
N. C. Stefanis∗,†,‡,§, L. Mandelli¶,
A. Hatzimanolis†, L. Zaninotto¶, N. Smyrnis†,
D. Avramopoulos∗∗, I. Evdokimidis†
and A. Serretti¶
†University Mental Health Research Institute, Athens, Greece,
‡School of Psychiatry and Clinical Neurosciences, University of
Western Australia,§Department of Psychosis Studies, Institute
of Psychiatry, London, UK,¶Department of Psychiatry,
University of Bologna, Italy, and**Department of Psychiatry
and Institute of Genetic Medicine, Johns Hopkins University,
*Corresponding author: Prof. N. C. Stefanis, Centre for Clinical
Research in Neuropsychiatry, School of Psychiatry and Clinical
Neurosciences, University of Western Australia, John XXIII
Avenue, Mt Claremont, Perth, WA 6010, Australia. E-mail:
The response to psychosocial stress is influenced by
both psychosocial factors and genetic vulnerability. The
most investigated gene in gene × environment stud-
ies in abnormal response to environmental stressors is
the one coding for the serotonin transporter (SLC6A4).
Variability within this gene has been associated with
functional brain differences, personality dimensions,
reactivity to stress and risk for various psychopatho-
logical conditions. In the present study, we set out to
investigate the association of common genetic variants
within SLC6A4 with state psychopathology in a com-
munity sample homogeneously exposed to stress, thus
inquiring about potential genetic differences in stress
sensitivity. One thousand eight hundred seventy-five
young conscripts were evaluated for psychopathological
distress with the 90-item Symptoms Checklist Revised
in their first 2 weeks of admission to obligatory military
service. Of these, 1594 were genotyped for the bial-
lelic ins/del polymorphism (5-HTTLPR S/L) within the
promoter region of SLC6A4, as well as the variation
within the ‘long’ 5-HTTLPR allele (rs25531A/G). Homozy-
gous for the 5-HTTLPR S allele reported significantly
higher scores for paranoid ideation as compared with
L-allele carriers. Slight effects on other subscales were
observed, but were not significant after correction for
multiple testing. Despite limitations linked to the evalu-
ation of psychopathology by a single general scale and
multiple comparisons, the present study support a role
of SLC6A4 in modulating abnormal responses to envi-
ronmental stress. In particular, variation within this gene
may confer risk for paranoid/defensive reactions under
conditions of environmental stress associated with mil-
Received 17 November 2010, revised 2 February 2011 and
14 March 2011, accepted for publication 16 March 2011
Response to stress largely vary among individuals depending
on a complex interaction among personal attitudes, percep-
tion of life events, coping strategies, life experience and
learning and cultural influences. Among these, heritable fac-
tors may have an important role, affecting the functional
activity of central brain structures involved in the process-
ing of stimuli and emotional response. The serotonin (5-HT)
system has been consistently implicated in both response
and adaptation to stress. There is extensive evidence for the
presence of 5-HT nerve terminals and/or receptors in key
stress-related neuroendocrine (e.g. hippocampus, hypothala-
mus, brainstem and medulla.) and behavioral (e.g. amygdala,
striatum, hippocampus and cortex) regions (Chaouloff et al.
1999). Animal models have consistently reported the acti-
vation of the 5-HT system in response to social stress
(Blanchard et al. 2001). In this context, the serotonin trans-
porter (5-HTT), responsible for the reuptake of 5-HT from the
synaptic cleft, may have an important role in determining
the magnitude and duration of stress-induced 5-HT activa-
tion. Indeed, altered 5-HT reuptake may affect the ability of
the system to adapt to the stress-induced 5-HT activation
This is borne out at the genetic level by a growing
body of data from mouse and human studies. In response
to exposure to a variety of stressors, 5-HTT knockout or
5-HTT-deficient mice display an exaggerated glucocorticoid
catecholamine response, a reduction of aggressive behav-
iors and an enhancement of defensiveness (Blanchard et al.
2001). In humans, there has been enormous interest in a
common variable number tandem repeat polymorphism in
the promoter region of human 5-HTT gene (5-HTTLPR). The
short (S) allelic version of the 5-HTTLPR polymorphism is
associated with reduced serotonin transporter brain expres-
sion and lesser serotonin reuptake in vitro (Lesch et al. 1996).
Moreover, because of a single nucleotide polymorphism
(rs25531), the long (L) allele can be divided into two variants
LA or LG. The LG allele has been reported as functionally
equivalent to the S allele (Hu et al. 2006).
The S allele has been associated with a moderately
increased risk for depressive disorders, as well as to a wide
range of human variations including structural and functional
brain abnormalities, temperamental traits and risk for other
psychiatric conditions (Serretti et al. 2006). Interestingly, the
5-HTTLPR has been hypothesized to influence the individual
© 2011 The Authors
Genes, Brain and Behavior © 2011 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society
Serotonin transporter gene and stress-induced psychopathology
have found that the S allele was associated with a greater
risk of adult depression in the presence of a history of either
childhood maltreatment or multiple life events (Caspi et al.
2003; Eley et al. 2004; Mandelli et al. 2007). The S allele
has also been associated to a greater extent with amygdale
neuronal reactivity to negative social stimuli, when compared
with L/L homozygous (Hariri et al. 2002, 2005).
In the present study, we aimed to further investigate the
role of 5-HTTLPR polymorphism in the response to envi-
ronmental stress. Here, we investigated a large sample of
young healthy men who were uniformly exposed to stressful
conditions of military induction, as assessed within their first
2 weeks of obligatory service. Indeed, conscription in the
army may be considered an exposure to some moderate
stressors (e.g. family detachment, contact with arms, severe
discipline demands), which may trigger psychopathological
symptoms in some predisposed individuals (Hageman et al.
2008). Here, we also considered the single nucleotide poly-
morphism within the L allele (rs25531) and evaluated general
psychopathological symptoms by the 90-item Symptoms
Check List revised (SCL90-R).
Sample and evaluations
All 2243 young healthy male conscripts aged 18–24 who were
admitted in eight consecutive waves between January 1999 and
March 2000 to the National Basic Air Force Training Center in
Tripolis, Greece, were eligible to participate in the Athens Study
of Psychosis Proneness and Incidence of Schizophrenia (Stefanis
et al. 2004). Of the 2243 conscripts, 1955 participated by filling in
a psychometric battery of self-administered questionnaires (Smyrnis
et al. 2007) from which 1875 had valid responses to the SCL90-R
(Derogatis et al. 1973). The SCL90-R is a 90-item multidimensional
self-reported questionnaire designed to screen for a broad range of
psychological problems within the last week prior to assessment.
Each of the 90 items is rated on a 5-point Likert scale of dis-
tress, ranging from 0 ‘not at all’ to 4 ‘extremely’. The answers are
then combined in nine symptomatological dimensions: somatization,
obsessive–compulsive, interpersonal sensitivity, depression, anxi-
ety, anger–hostility, phobic anxiety, paranoid ideation and psychoti-
cism. In addition, three global indices provide measures of overall
psychological distress: the Global Severity Index (GSI), the Posi-
tive Symptom Total (PST) and the Positive Symptom Distress Index
(PSDI). GSI is the mean score for all 90 items, the PST is the number
of items that scored higher than 0 and the PSDI is the average score
of the items scored above 0. SCL90-R subscales with more than
10% of missing values were excluded from analysis. Scores for each
subscale were calculated as the sum of item scores, weighted for
missingvalues. The maximumscore is4for each ofthe nineSCL90-R
subscales, GSI and PSDI, while the maximum score for PST is 90.
A team of military medical doctors of all specialties had already
evaluated the conscripts as having a satisfactory physical and
psychological condition. This study was approved by the Bioethics
and Medical Deontology Committee of the University Mental Health
Research Institute in charge of genetic experimentation with human
After obtaining written informed consent, 2029 conscripts provided
mouthwash samples from which genomic DNA was extracted as
described previously (Avramopoulos et al. 2002). It has been proven
that for large samples there are no significant genotyping discrep-
ancies between DNA obtained from blood and mouthwash (De
Vries et al. 1996). In this study, 1911 DNA samples from the entire
conscript sample were available for analysis of the 5-HTTLPR poly-
morphism, from which 1859 (97.3%) were successfully genotyped
for the biallelic ins/del polymorphism (5-HTTLPR S/L). From the entire
sample of conscripts with valid SCL90R scores (1875), 1594 (85%)
overlapped with the 1859 successfully genotyped 5-HTTLPR sub-
sample and was used as the working database file for this study.
The 5-HTTLPR polymorphism was genotyped in Erasmus Center,
Rotterdam, Netherlands, using a TaqMan allelic discrimination assay.
Polymerase chain reaction (PCR) cycling reaction was performed in
384 wells PCR plates in an ABI 9700 PCR system (Applied Biosys-
tems, Foster City, CA, USA) and consisted of initial denaturation for
10 minat95◦C and40cycles withdenaturation of15seconds at 96◦C
and annealing and extension for 90 seconds at 62.5◦C. Results were
analyzed by the ABI Taqman 7900HT using the sequence detection
system 2.3 software (Applied Biosystems). A second TaqMan allelic
discrimination assay served to distinguish LAvs. LGalleles (rs25531)
by using the same primers and amplification conditions as for the L
vs. S allele assay, but using LAvs. LGallele-specific probes. To eval-
uate genotyping accuracy, 360 samples were genotyped a second
time using quantitative real-time PCR. No discrepancies were found.
Statistical analyses were performed with the STATISTICA 6.0 soft-
ware (StatSoft, Tulsa, OK, USA) and deviation from Hardy–Weinberg
expectations was assessed using an exact test. SCL90-R scores
were stratified for the biallelic 5-HTTLPR polymorphism and analyzed
for 5-HTTLPR alleles. Post hoc analyses were also performed to test
dominant/recessive models and to analyze SCL90-R scores stratified
Student’s t test and ANOVA. All the analyses were two-tailed and the
false discovery rate (FDR) correction was applied to control for multi-
pletesting. FDR was calculated according tothe method of Benjamini
and Hochberg (1995), by ranking the individual P-values from small-
est to largest and comparing each P-value to 0.05 × i/m, where i is
the individual rank of the P-value and m the total number of P-values.
Only P-values lower than 0.05 × i/m have been considered signifi-
cant (see also Benjamini et al. 2001). Considering nine factors plus
three global indices at the SCL-90 tested in four different genetical
models (=48 tests), the set P-value threshold was lower than 0.0010
(smallest k). In our sample, we had a sufficient statistical power
(>0.80) to detect small effect sizes (f < 0.10) in primary analyses.
Distribution of genotypes for the biallelic 5-HTTLPR poly-
morphism is as follows: 475 L/L (29.8%), 764 L/S (47.9%)
and 355 S/S (22.3%). Genotypes were in Hardy–Weinberg
equilibrium (HWE, P = 0.15). Distribution of genotypes for
the triallelic rs25531 polymorphism was 408 LA/LA(25.8%),
56 LA/LG(3.5%), 690 S/LA(43.7%), 69 S/LG(4.4%), 354 S/S
(22.4%) and 3 LG/LG(0.2%) (HWE, P = 0.12). The S and LG
alleles were grouped together, according to the evidence of
a similar functional activity (Hu et al. 2006). Using this cat-
egorization, 408 genotypes (25.8%) were in the L/L group,
746 (47.2%) were in the L/S group and 426 (27%) were in
the S/S group. The frequency of the S allele in our study
population was 46.2%, which is in line with previous reports
in Caucasian populations (Lesch et al. 1994).
Continuous SCL90-R subscale scores were stratified for
5-HTTLPR genotypes (L/L, L/S and S/S) and analyzed by
ANOVA (Table 1). In our principal analysis, no significant asso-
ciation could be observed, with the exception of small
Genes, Brain and Behavior (2011) 10: 536–541
Stefanis et al.
Table 1: Association between SLC6A4 gene variants and SCL90-R subscale scores
L/L (n = 475)
L/S (n = 764)
S/S (n = 355)
S/S vs. other
La/La, La/S, Lg/S + S/S
Lg/S + S/S vs. others
M ± SD
M ± SD
M ± SD
0.84 ± 0.70
0.82 ± 0.66
0.85 ± 0.66
1.05 ± 0.66
1.03 ± 0.64
1.13 ± 0.69
0.35 ± 0.46
0.35 ± 0.45
0.40 ± 0.53
0.89 ± 0.79
0.87 ± 0.83
0.95 ± 0.87
0.75 ± 0.61
0.78 ± 0.62
0.85 ± 0.66
1.08 ± 0.71
1.11 ± 0.71
1.19 ± 0.76
1.11 ± 0.82
1.12 ± 0.75
1.25 ± 0.81
0.62 ± 0.60
0.65 ± 0.63
0.70 ± 0.65
0.87 ± 0.69
0.85 ± 0.70
0.92 ± 0.70
Global Severity Index
0.86 ± 0.55
0.86 ± 0.54
0.93 ± 0.58
Positive Symptom Total
41.04 ± 18.02
40.96 ± 17.86
42.81 ± 18.28
1.76 ± 0.49
1.75 ± 0.50
1.83 ± 0.53
∗Required significance after correction for multiple testing.
∗∗Significant association according to FDR correction.
nonsignificant trends on depressive (P = 0.04) and paranoid
symptoms (P = 0.02), and on the Positive Symptom Total
index (P = 0.04) that did not survive FDR correction. In post
hoc analyses, we were able to detect a significant effect of
5-HTTLPR on ‘paranoid ideation’ by comparing S/S subjects
with L-allele carriers (P = 0.0005), which attained control
for multiple testing (FDR threshold = 0.001). No significant
effects were observed when analyzing the triallelic rs25531
polymorphism, neither in the codominant model nor in the
recessive model for the S allele.
According to accumulating evidence supporting a role for
5-HTTLPR asamodulator oftheeffect ofstressorsonthe risk
to develop psychological distress (Uher & McGuffin 2008),
ant and a broad spectrum of abnormal responses following
exposure to a homogeneous stress, including an increase in
depression, interpersonal sensitivity, obsessive–compulsive
symptoms and overall state psychopathology, although
consistent evidence of association was obtained only for
paranoid ideation. Therefore, we may conceptualize the
5-HTTLPR polymorphism as a modulator of risk for nonspe-
cific psychopathological responses to stress, the expression
of which would be further influenced by the overall genetic
vulnerability of the individual, together with other psychoso-
cialandenvironmental influences, depending alsoonthespe-
cific nature of the stressor. In this context, we propose that
5-HTTLPR S-allele carriers, exposed to a social environment
such as obligatory military induction, characterized by strong
hierarchy, subordination and discipline, may be more likely to
react defensively, with marked suspiciousness and paranoia.
It is noteworthy that previous studies investigating the
moderating effect of 5-HTTLPR of stressors have mainly
focused on depressive responses (Brown & Harris 2008).
Unlike these studies, we intentionally employed a gen-
eral state scale for psychopathology. However, the use of
SCL90-R may have both advantages and disadvantages. The
SCL90-R scale may be practical when evaluating large cohort
samples, but it is quite nonspecific for clinical purposes.
Moreover, although there is evidence for the usefulness of
the SCL90-R in the identification and discrimination of psy-
chiatric patients (Schmitz et al. 2000), its validity is someway
controversial. Indeed, the factorial structure of the SCL90-R
has proven to be variable with different patient populations
(Bonynge 1993; Holi et al. 1998) and the intercorrelations
among the different factors are high in many studies. In
our sample, SCL90-R subscales were highly intercorrelated
as well, suggesting a potential nonspecific effect of stress
on psychopathology, at least as measured by the SCL90-R
scale. Accordingly, a study on a sample of university stu-
dents employing the SCL90-R scale found small interactive
effects between 5-HTTLPR and stressful events on almost all
subscales, including paranoid ideation (Veletza et al. 2009).
Other studies, not considering gene–environment interac-
tions, reported small associations between 5-HTTLPR and
almost all subscales of the SCL90-R as well (Kirtak et al.
Genes, Brain and Behavior (2011) 10: 536–541
Serotonin transporter gene and stress-induced psychopathology
2008; Offenbaecher et al. 1999). Nevertheless, intheir study,
Aguilera et al. (Aguilera et al. 2009) were able to detect a
strong interactive effect between 5-HTTLPR and childhood
sexual abuse on the depressive subscale of the SCL90-R
(P < 0.0001) in a sample of healthy controls, although other
subscales of the SCL90-R scale were not considered in that
study. At the opposite end, Gillespie et al. (2005) failed to
find an interactive effect between genotype and stressful life
events on the depressive subscale in a sample of twins, but
other subscales of the SCL90-R were not considered.
The small effect on the depressive subscale may further
rely on sex-specific effects. An early study of Brummett
et al. found an effect of 5-HTTLPR on moderating the effect
of stress on the risk to depression in females only (Brummett
et al. 2008). Others suggested that, among S-allele carriers,
males seem to be protected from depression whereas
females tend to develop depressive symptoms (Eley et al.
2004; Sjoberg et al. 2006). In line with this hypothesis, in a
recent study on a large sample of male prisoners we found
L-allele carriers, instead of the expected S-allele carriers,
to be more severely affected by depressive symptoms if
exposed to early adversities (Carli et al. unpublished). Sex-
specific effects may be relevant in the present study also, as
the sample was composed only of male conscripts.
However, less consistent or negative findings regarding
the role of SLC6A4 as a moderator of the risk for psy-
chopathology and depression in particular have also been
reported (Araya et al. 2009; Gillespie et al. 2005; Power et al.
2010; Scheid et al. 2007; Wray et al. 2008; ) and recent meta-
analyses suggested caution in the interpretation of findings
(Munafo et al. 2009; Risch et al. 2009). Nevertheless, the
small, nonsignificant effect on depression in our study may
be considered consistent, with previous body of work view-
ing 5-HTTLPR variability as a modulator of emotional distress.
Regarding the effect of SLC6A4 on paranoia there is only
scarce evidence. An early study reported an inverse associ-
ation between the S/S genotype and paranoia as measured
by the Minnesota multiphasic personality inventory in both
psychiatric and healthy controls (Golimbet et al. 2003). No
effect was instead observed in a sample of bulimic patients
evaluated by the SCL90-R (Ribases et al. 2008). Three other
above-mentioned studies found small associations between
although small effects were observed also on other sub-
scales (Kirtak et al. 2008; Offenbaecher et al. 1999; Veletza
et al. 2009). To our knowledge, only Veletza et al. found a
gene × environment interaction on paranoid ideation.
In this regard, there is some evidence suggesting that
psychosocial stress may increase the risk for psychosis,
especially in the case of cumulative exposure (van Winkel
et al. 2008). Zigler and Glick (1988) have proposed that para-
noid symptoms seem much more to reflect a psychological
motivation, serving a protective role against threats to the
individual’s sense of self. Moreover, people with anxiety or
depression have commonly elevated scores on measures
of persecutory ideation (Van Os et al., 1999). Under this
perspective, paranoia can be viewed within the affective
spectrum of responses under stressful conditions in a mili-
tary setting. As mentioned above, it is indeed likely that in
such an environment, where underperformance is publically
criticized and punished, depressive symptoms would be fre-
quently accompanied by symptoms of fear and mistrust of
novel social contacts. It is therefore plausible to assume that
a more refined stress-induced ‘depressive–paranoid’ pheno-
type may be closely related to genetic variations of 5-HTTLPR
in this cohort.
Of note, no significant effects, neither on paranoid ideation
nor on other factors, were observed analyzing the triallelic
rs25531 polymorphism. The LGvariant has been reported as
functionally equivalent totheSallele(Huet al.2006), thus we
expected strongest findings when taking into account this
further polymorphism. On one hand, the negative findings
obtained may definitively disconfirm the effect of SCL6A4
variants on psychopathological dimensions. On the other,
the actual effect of the LGallele on the expression level of
SLC6A4 is uncertain and no difference has been reported
in serotonin transporter binding potential after triallelic geno-
type reclassification in healthy volunteers or in subjects with
major depressive disorder (Parsey et al. 2006).
The magnitude and homogeneity of the sample (young
nonpsychiatric subjects) and the homogeneous exposure of
subjects to stress represent major strengths of the present
study as the level of environmental exposure to stress was
datable, similar forallrecruits andnot associatedwithgenetic
variation (i.e. no confounding by gene–environment correla-
tion). Similarly, all participants were of Greek family back-
ground, although a clear limitation of this study has been the
lack of adjustment for genetically inferred ancestry. Together
with ‘case-only’ designs, the ‘exposed-only’ methodology
shares the advantage to not require a control group (or ‘unex-
posed’) group, resulting in a high power to detect genetic dif-
ferences in stress sensitivity as compared with case–control
designs. Furthermore, in this study we had a high statistical
power, allowing to detect small effect sizes. Another advan-
tage has been the ability to measure the SLC6A4 polymor-
army recruits at the end of their military service, with overall
reduced SCL90-R scores ranging from 14% to 53% for indi-
vidual subscales (nonstress condition) (Stefanis et al. 2007).
Assuming the same recessive model of analysis as above, no
association of 5-HTTLPR was found on SCL90-R subscales
(data upon request), indicating that the original 5-HTTLPR
association we report here on SCL90-R paranoid ideation
subscale is indeed conditioned on the presence of stress.
On the other hand, it should be noted that military train-
ing may be a generic and not otherwise specified form of
moderate stress exposure and potentially independent from
the outcome measures. Indeed, no information was avail-
able about psychological status before exposure to stress
and no other variables, such as past traumatic life events
and personality dimensions, have been taken into account.
We only presumed an overall premorbid psychological well-
being because all conscripts had been already evaluated for
physical and psychological condition and no conscript was
excluded because of psychiatric conditions, as this exclusion
process took place prior to conscription. Another major prob-
lem was represented by the high number of comparisons
that we performed to test two polymorphisms on the nine
subscales of the SCL90-R plus the three global indices, and
in different genetic models. This obliged a correction for
Genes, Brain and Behavior (2011) 10: 536–541
Stefanis et al.
multiple testing and thus the interactive effects observed on
the subscales of depression, interpersonal sensitivity, obses-
sive–compulsive and on the indices of global severity and
positive symptoms’ total lost of significance. Nevertheless,
the significance of those associations was too small to be
considered as consistent in any case.
In conclusion, present results suggest an effect of SLC6A4
on the risk for paranoid ideation in response to social stress
deriving from obligatory admission to a military environment.
However, further studies focussing on more defined mea-
sures of psychopathological domains and accounting for
variables potentially influencing the individual response to
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This work was supported by the grant ‘EKBAN 97’ from the
General Secretariat of Research and Technology of the Greek
Ministry of Development. Authors would also like to thank Pascal
P. Arp, ErasmusMC Rotterdam, for his help in the genotyping
Genes, Brain and Behavior (2011) 10: 536–541