Emotion © 2013 American Psychological Association

2013, Vol. 13, No. 6, 1012–1022 1528-3542/13/$12.00 DOI: 10.1037/a0033383

Reappraisal as a Mediator in the Link Between 5-HTTLPR and Social

Anxiety Symptoms

Andrei C. Miu Romana Vulturar, Adina Chiş, and

Babeş-Bolyai University Loredana Ungureanu
Iuliu Hat᝺ieganu University of Medicine and Pharmacy

James J. Gross
Stanford University
This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.
This document is copyrighted by the American Psychological Association or one of its allied publishers.

Social anxiety symptoms have been related to (a) polymorphisms in the serotonin-transporter gene-
promoter region (also, serotonin-transporter-linked polymorphic region; 5-HTTLPR) and (b) reduced use
of adaptive forms of emotion regulation such as reappraisal. It is not known, however, whether
reappraisal functions as a mediator in the link between 5-HTTLPR and social anxiety. To address this
issue, 182 unselected community volunteers were tested for 5-HTTLPR status, and self-report measures
of social anxiety symptoms and reappraisal use were obtained. Relative to other participants, those with
two low-expressing alleles displayed increased social anxiety and decreased reappraisal. As predicted,
the influence of 5-HTTLPR on social anxiety symptoms was transmitted via reappraisal, and this effect
of 5-HTTLPR was observed using two different measures of reappraisal. These findings suggest that
cognitive reappraisal may be an intermediate phenotype of the social anxiety spectrum, and that
individuals with low-expressing 5-HTTLPR genotypes may benefit the most from cognitive– behavioral
psychotherapy because they do not appear to engage as frequently as others in reappraisal.

Keywords: 5-HTTLPR, emotion regulation, social anxiety, cognitive reappraisal, serotonin

Social anxiety is defined as a spectrum that ranges from ordi-
nary shyness and mild social anxiety symptoms at one end of the
continuum to generalized social anxiety disorder (SAD) at the
other end (McNeil, 2001). Social anxiety symptoms are known to
emerge early in life (Stein & Stein, 2008), and often remain stable
into adulthood (Wittchen, Stein, & Kessler, 1999), increasing the
risk for depression (Kessler, Stang, Wittchen, Stein, & Walters,
1999; Stein et al., 2001), suicide attempts (Sareen et al., 2005),
alcohol abuse (Grant et al., 2004; Schneier, Martin, Liebowitz,
Gorman, & Fyer, 1989), incomplete educational attainment (Kes-
sler, Foster, Saunders, & Stang, 1995), and severe social restric-
tions (Pine, Cohen, Gurley, Brook, & Ma, 1998).
This article was published Online First June 24, 2013.
Andrei C. Miu, Department of Psychology, Babeş-Bolyai University,
Cluj-Napoca, Romania; Romana Vulturar and Adina Chiş, Department of
Cell and Molecular Biology, Iuliu Hat᝺eganu University of Medicine and
Pharmacy, Cluj-Napoca, Romania; Loredana Ungureanu, Department of
Dermatology, Iuliu Hat᝺eganu University of Medicine and Pharmacy; James
J. Gross, Department of Psychology, Stanford University.
This work was supported by a grant from the Romanian National
Authority for Scientific Research, Executive Agency for Higher Education,
Research, Development and Innovation Funding (CNCS–UEFISCDI),
project number PNII-ID-PCCE-2011–2-0045. The authors thank Ihno Lee
for statistical advice.
Correspondence concerning this article should be addressed to Andrei C.
Miu, Cognitive Neuroscience Laboratory, Department of Psychology,
Babeş-Bolyai University, 37 Republicii, 400015 Cluj-Napoca, Cluj, Ro-
mania. E-mail: andreimiu@psychology.ro
1012
Serotonin Transporter Polymorphisms and Social
Anxiety Symptoms
In light of the therapeutic efficacy of selective serotonin
reuptake inhibitors (SSRIs) in SAD (van der Linden, Stein, &
van Balkom, 2000), and the impact of psychopharmacological
manipulations of serotonin availability (e.g., tryptophan deple-
tion) on social anxiety symptoms (Argyropoulos et al., 2004),
many genetic association studies have focused on the serotonin-
transporter gene (5-HTT). Several functional polymorphisms
have been described in the promoter region of this gene (5-
HTTLPR), including an insertion/deletion (indel) polymor-
phism (Lesch et al., 1996) and a single-nucleotide polymor-
phism (SNP rs25531; Hu et al., 2006; Wendland, Martin, Kruse,
Lesch, & Murphy, 2006).
The 5-HTTLPR indel polymorphism consists of 14 (the S al-
lele), 16 (the L allele) or more copies (the XL alleles) of a 20 –23,
base-pair, imperfect repeat sequence (Ehli, Hu, Lengyel-Nelson,
Hudziak, & Davies, 2012; Lesch et al., 1996). The SNP rs25531
involves the substitution of an adenine (A) to a guanine (G) in the
6th nucleotide within the first of two extra 20 –23 base-pair repeats
in the L allele of the indel polymorphism (Hu et al., 2006; Kraft,
Slager, McGrath, & Hamilton, 2005; Nakamura, Ueno, Sano, &
Tanabe, 2000; Wendland et al., 2006). Therefore, the two resulting
L alleles, LA and LG, together with the S allele, comprise a
triallelic locus (Hu et al., 2006; Nakamura et al., 2000). The A¡G
substitution creates a binding site for the transcription factor AP2
(from Activating Protein 2), which suppresses the 5-HTT gene
expression in the presence of the LG and S alleles in dorsal raphe
 5-HTTLPR, REAPPRAISAL, AND SOCIAL ANXIETY
neurons (Hu et al., 2006; Mortensen, Thomassen, Larsen, Whitte-
more, & Wiborg, 1999). Consequently, the LG and S alleles are
usually grouped together (i.e., carriers of one [S’L’] or two low-
expressing alleles [S’S’]) because they reduce the 5-HTT expres-
sion with equal magnitude, and then compared with the LA allele
(i.e., LA homozygotes [L’L’]). Recent studies have shown that the
triallelic approach to 5-HTTLPR (i.e., genotyping both polymor-
phisms, not only the indel) is essential for correctly categorizing
genotypes and identifying more reliable associations with pheno-
types such as obsessive– compulsive disorder (Hu et al., 2006),
therapeutic response to SSRI (Kraft et al., 2005), anterior cingulate
volume (Selvaraj et al., 2011), and trait-behavioral inhibition
(Whisman, Richardson, & Smolen, 2011).
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The S allele has been consistently associated with anxiety-
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related personality traits (Sen, Burmeister, & Ghosh, 2004), in-
creased attention to negative emotional stimuli (Pergamin-Hight,
Bakermans-Kranenburg, van Ijzendoorn, & Bar-Haim, 2012), in-
creased amygdala reactivity to stress (Drabant et al., 2012; Mu-
nafò, Brown, & Hariri, 2008), and emotional disorders such as
obsessive– compulsive disorder (Lin, 2007) and depression (Caspi,
Hariri, Holmes, Uher, & Moffitt, 2010; Uher & McGuffin, 2010).
Recent genetic association studies have also explored the influence
of 5-HTTLPR on social anxiety. The low-expressing alleles of
5-HTTLPR polymorphisms (e.g., S or LG) have been significantly
associated with symptoms such as state-anxiety escalation and
amygdala hyperactivity during public speaking (Furmark et al.,
2004), increased shyness and reduced discrimination of angry and
neutral faces (Battaglia et al., 2005), and blushing propensity
(Domschke et al., 2009) in SAD patients. In addition, these low-
expressing alleles also predicted reduced responses to SSRI (Stein,
Seedat, & Gelernter, 2006) and placebo treatments that reduce
amygdala hyperactivity during public speaking in SAD (Furmark
et al., 2008). These converging results seem to support the influ-
ence of 5-HTTLPR on key dimensions of SAD, although another
recent study found no association between 5-HTT promoter poly-
morphisms and the SAD diagnosis (Strug et al., 2010). This
underscores the possibility that intermediate phenotypes, rather
than the global diagnosis of SAD, are associated with 5-HTT
promoter polymorphisms.
Emotion Regulation and Social Anxiety Symptoms
Psychological theories have drawn attention to the important
role that emotion regulation plays in the onset and maintenance
of social anxiety symptoms (Clark & Wells, 1995; Hofmann,
2007). Individuals with social anxiety engage in maladaptive
regulatory strategies, such as avoidance and safety behaviors
and rumination after the social situation has passed, which leads
to maintenance and further exacerbation of social anxiety symp-
toms (Hofmann, 2007). In addition to making greater use of
maladaptive regulation strategies, individuals with social anx-
iety make lesser use of adaptive forms of emotion regulation,
such as reappraisal, an emotion-regulation strategy that in-
volves changing the meaning of a situation to change the
emotional response to that situation (Giuliani & Gross, 2009;
Sheppes & Gross, 2011; Szasz, Szentagotai, & Hofmann,
2011). Several studies have recently suggested that emotion-
regulation difficulties are more specific to SAD than general
anxiety disorder (Mennin, McLaughlin, & Flanagan, 2009; Sa-
1013
lovey, Stroud, Woolery, & Epel, 2002; Turk, Heimberg,
Luterek, Mennin, & Fresco, 2005), in contrast to general symp-
toms, such as increased negative affect and reduced positive
affect, which are shared by most anxiety disorders (Bradley et
al., 2011; Kashdan, 2007; Watson, Clark, & Carey, 1988).
Therefore, disease-specific interventions have started to target
emotion regulation as a key mechanism of change in SAD
(Kley, Heinrichs, Bender, & Tuschen-Caffier, 2012; Mosco-
vitch et al., 2012).
Recent studies have identified atypical patterns of emotion
regulation in SAD. More specifically, these studies have identified
a link between difficulties with reappraisal and social anxiety
symptoms (Goldin, Manber-Ball, Werner, Heimberg, & Gross,
2009; Goldin, Manber, Hakimi, Canli, & Gross, 2009). Both
children and adults with SAD use reappraisal less frequently in
daily life; they are less able to generate reappraisals of potentially
threatening situations; and their self-efficacy concerning reap-
praisal is reduced, compared with healthy controls (Carthy,
Horesh, Apter, Edge, & Gross, 2010; Goldin, Manber-Ball, et al.,
2009; Werner, Goldin, Ball, Heimberg, & Gross, 2011). In addi-
tion, the lesser down-regulation of negative affect through reap-
praisal in SAD is related to the severity of social anxiety symp-
toms, which suggests that the intensity of SAD contributes to
emotion dysregulation (Carthy et al., 2010; Goldin, Manber-Ball,
et al., 2009). Two functional neuroimaging studies found that SAD
patients displayed decreased early recruitment of the brain systems
(e.g., dorsolateral prefrontal cortex) implicated in reappraisal of
harsh faces or negative self-beliefs (Goldin, Manber-Ball, et al.,
2009; Goldin, Manber, et al., 2009). These studies support the
view that SAD patients may need more time or more external cues
to access and implement reappraisal during social threat. Reap-
praisal thus appears to be an important predictor of social anxiety
symptoms.
5-HTTLPR, Emotion Regulation, and Social Anxiety
Symptoms
One crucial question that has not yet been empirically addressed
is whether emotion regulation is a mediator in the link between the
5-HTTLPR polymorphisms and social anxiety symptoms. This
idea is consistent with the widely discussed hypothesis that emo-
tion regulation may be a candidate intermediate phenotype of
emotional disorders (Canli, Ferri, & Duman, 2009; Canli & Lesch,
2007; Hariri & Holmes, 2006; Meyer-Lindenberg & Weinberger,
2006). The main support for this idea came from a functional
neuroimaging study that reported reduced functioning of an
amygdala-cingulate neural circuit, which is critical for the extinc-
tion of negative emotions, in carriers of the S allele of 5-HTTLPR
(Pezawas et al., 2005).
Although these findings were replicated and extended by sub-
sequent neuroimaging studies in which emotion regulation was
manipulated (Gillihan et al., 2010; Lemogne et al., 2011; but see
Firk, Siep, & Markus, 2013; Heinz et al., 2005; Schardt et al.,
2010), there are surprisingly few direct behavioral findings of an
association between 5-HTTLPR and individual differences in
emotion regulation. Carriers of the low-functioning alleles of
5-HTTLPR have been shown to display reduced emotional resil-
ience (Stein, Campbell-Sills, & Gelernter, 2009) and self-efficacy
related to coping with negative emotions (Szily, Bowen, Unoka,
 1014 MIU, VULTURAR, CHIŞ, UNGUREANU, AND GROSS
Simon, & Keri, 2008). Three other studies reported higher levels of
rumination (Canli et al., 2006; Clasen, Wells, Knopik, McGeary,
& Beevers, 2011) and lower levels of reappraisal (Schardt et al.,
2010) in S carriers, but a systematic investigation of the associa-
tion between 5-HTT promoter polymorphisms and specific
emotion-regulation strategies is still lacking. In particular, an in-
vestigation of the links among 5-HTTLPR, reappraisal, and emo-
tional symptoms is clearly needed.
The Present Study
The goal of this study was to investigate whether the effect of
5-HTTLPR polymorphisms on social anxiety symptoms is trans-
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mitted via reappraisal. The sample included a randomly selected
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set of community-dwelling participants who were screened for
social anxiety symptoms using a clinical scale. This allowed us to
generalize our findings to a broad segment of the social anxiety
spectrum. We predicted that carriers of the low-expressing alleles
(i.e., S’S’ and S’L’) of the 5-HTTLPR indel and rs25531 poly-
morphisms would be associated with increased social anxiety
symptoms and reduced use of cognitive reappraisal. Moreover, we
hypothesized that cognitive reappraisal would function as a medi-
ator in the link between triallelic 5-HTTLPR genotypes and social
anxiety symptoms.
Method
Participants
Participants for this study were 182 (139 women) volunteers.
They were all students at Babeş-Bolyai University in Cluj-Napoca,
Romania. An a priori sample size analysis had indicated that a
minimum of 164 participants were needed (small effect size; ␣ ⫽
.05; power ⱖ 0.8). 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 ⫽
21.3 years). None of the participants reported cardiovascular or
neurological conditions, and they were not on medication (e.g.,
anxiolytics, beta-adrenergic antagonists, psychotropics). Since our
sample was not balanced for sex, all the statistical analyses in-
cluded sex as covariate in order to control for the effect of this
potential confound. All the participants were compensated for their
time. The study followed the recommendations of the American
Medical Association’s Declaration of Helsinki (World Medical
Association, 1964/2008), and it was approved by the Babeş-Bolyai
University Research Council. No experimental manipulations were
made and all the measures that were administered are described in
this section.
Assessment
Social anxiety symptoms were assessed by the total score of the
self-report version of the Liebowitz Social Anxiety Scale (LSAS-
SR; Fresco et al., 2001; Liebowitz, 1987), which quantifies fear
and avoidance in social and performance situations. The partici-
pants had to rate the degree to which she or he feared or avoided
social situations (e.g., speaking in front of an audience, talking to
someone in authority), using a scale from 0 (none/never) to 4
(severe/usually). The internal consistency of LSAS-SR in our
sample was excellent (Cronbach’s ␣ ⫽ .9). LSAS-SR shows good
sensitivity and specificity to clinical American Psychiatric Asso-
ciation’s DSM–IV criteria for SAD; a cut-off score of 30 on
LSAS-SR correctly identifies over 93% of SAD patients (Mennin
et al., 2002), but studies on student samples emphasize that scores
above 55 more reliably indicate moderate and severe social anxiety
(Russell & Shaw, 2009). Although these clinical cut-offs were
informative regarding possible SAD diagnoses in our participants,
a clinical LSAS-SR score was not an inclusion criterion.
One of the measures of individual differences in emotion reg-
ulation was the cognitive reappraisal score from the Emotion
Regulation Questionnaire (ERQ; Gross & John, 2003). Using a
scale from 1 (strongly disagree) to 7 (strongly agree), the partic-
ipants rated their habitual use of reappraisal (e.g., when I want to
feel less negative emotion, I change what I’m thinking about) and
suppression (e.g., I keep my emotions to myself). The internal
consistency of ERQ reappraisal in our sample was very good
(Cronbach’s ␣ ⫽ .84). Because individual differences in cognitive
reappraisal were the focus of this study, we used a second, con-
vergent measure of reappraisal from the Cognitive Emotion Reg-
ulation Questionnaire (CERQ; Garnefski, Kraaij, & Spinhoven,
2001). In this questionnaire, the participants rated on a scale from
1 (almost never) to 5 (almost always) the frequency of using
reappraisal when confronted with negative events (e.g., I look for
the positive sides to the matter). The internal consistency of CERQ
reappraisal in our sample was good (Cronbach’s ␣ ⫽ .72). The
significant correlation between ERQ reappraisal and CERQ reap-
praisal scores (Pearson r ⫽ .33, p ⫽ .005) in the present sample
confirmed that we could use these scales as parallel measures of
the frequency with which cognitive reappraisal is used. ERQ
expressive suppression scores (Cronbach’s ␣ ⫽ .76) were used in
additional analyses designed to explore the specificity of cognitive
reappraisal as a mediator.
Genotyping
DNA was extracted from leukocytes (ethylenediaminetet-
raacetic acid; EDTA-anticoagulated blood) using the Genomic
DNA Extraction Kit (Fermentas, Vilnius, Lithuania) and kept at
⫺20 °C. Both 5-HTTLPR indel and rs25531 genotyping were
performed using published protocols (Miu et al., 2012; Vultu-
rar, Chis, Ungureanu, & Miu, 2012). Briefly, the polymerase
chain reaction (PCR) assay conditions were optimized as fol-
lows: Each reaction was carried out in a 25-␮l volume: 50 ng of
genomic template, 12.5-␮l PCR mastermix (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 the L allele) or 486 base pairs (for
the S allele). Thermal cycling consisted of 3 min of initial
denaturation at 94 °C followed by 31 cycles of 94 °C (40 s), 57
°C (40 s) and 72 °C (40 s), each with a final extension step of
4 min at 72 °C. The LG and LA alleles of rs25531 were
subsequently studied by enzymatic digestion of 10 ␮l of PCR
products that were digested by HpaII. This restriction enzyme
recognizes and cuts a 5=-C/CGG-3= sequence resulting in the
following fragments: 340 base pairs, 127 base pairs and 62 base
 5-HTTLPR, REAPPRAISAL, AND SOCIAL ANXIETY
pairs for the LA allele; 174, 166, 127 and 62 base pairs for the
LG allele; 297 base pairs, 127 base pairs and 62 base pair for the
SA allele; and 166, 131, 127 and 62 base pairs for the SG allele.
Finally, 10 ␮l of remaining PCR product and 15 ␮l of
restriction-enzyme assay solution were loaded onto a 2.5%
agarose gel and visualized by ethidium bromide for size esti-
mation. The 5-HTTLPR allele frequencies were 0.44 for th SA
allele, 0.48 for the LA allele and 0.07 for the LG allele, similar
to the ones that were reported for oCaucasians by Hu et al.
(2006). One of the participants carried an XL (⬎ 16 repeats)
allele (Ehli et al., 2012). The genotypes were categorized into
S’S’ (i.e., carriers of two low-expressing alleles, SS, LGLG,
SLG: N ⫽ 50); S’L’ (i.e., carriers of one low-expressing allele,
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SLA, LGLA: N ⫽ 81); and L’L’ (i.e., carriers of two high-
This document is copyrighted by the American Psychological Association or one of its allied publishers.
expressing alleles, LALA, LAXL: N ⫽ 51). These genotypes
were in Hardy-Weinberg equilibrium (␹2 ⫽ 2.2, n.s.; Rodri-
guez, Gaunt, & Day, 2009). There were no age differences
between the genotypes.
Data Analysis
There were no missing data. Analyses of covariance (AN-
COVA), with sex as covariate, were used to test for differences
between genotypes in reappraisal, suppression, and in social
anxiety symptoms. There were no sex differences in ERQ
reappraisal, CERQ reappraisal, ERQ suppression, or LSAS-SR
scores (all p ⬎ .05). Mediation was tested using multiple
regression (Baron & Kenny, 1986; Frazier, Tix, & Barron,
2004; Hoyt, Imel, & Chan, 2008), following the steps suggested
by Baron and Kenny (1986); see Figure 1: (1) the initial
variable (genotype group) was significantly related to the out-
come variable (LSAS-SR score; Path c); (2) the initial variable
was related to the mediator (emotion-regulation score; 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 (Path c) in the first
regression. Because there is no general consensus on the addi-
tive or dominant status of the low-expressing alleles of
5-HTTLPR, the genotype was coded according to the number of
S’ alleles present (instead of dummy coding comparing low-
expressing alleles carriers with L’ homozygotes: 0 ⫽ L’L’; 1 ⫽
S’L’; and 2 ⫽ S’S.’ (For similar approaches, see Conway et al.,
2012; Heinz et al., 2005). We tested the significance of the
indirect effect of 5-HTTLPR on social anxiety through emotion
regulation using the bootstrapping method (bias corrected, with
1,000 iterations; Preacher & Hayes, 2004; Shrout & Bolger,
2002). The indirect effect was significant if the CI from boot-
strapping did not include zero (Frazier et al., 2004; Shrout &
Bolger, 2002). Two sets of analyses were conducted, one for
each of the two reappraisal measures (i.e., ERQ, CERQ). In
addition, we tested an alternative model in which ERQ-
suppression was specified as a mediator in the relation between
5-HTTLPR and social anxiety symptoms. This allowed us to
explore the specificity of cognitive reappraisal as a mediator.
All the analyses, including the bootstrapping tests, were run in
SPSS.
1015
Results
5-HTTLPR and Social Anxiety Symptoms
Table 1 presents the scores of participants from each genotype
group on anxiety symptoms (LSAS-SR). Participants with
LSAS-SR scores over 55 represented 49% (N ⫽ 89), categorized
using Russell and Shaw’s (2009) cut-off scores as follows: Mod-
erate social anxiety (Scores 55– 64: 20%); marked social anxiety
(Scores 65–79: 14%); severe social anxiety (Scores 80 –95: 10%);
and very severe social anxiety (Scores 96⫹: 4%). An ANCOVA,
with 5-HTTLPR genotype group as between-subjects factor and
sex as covariate, indicated a significant effect of 5-HTTLPR on
LSAS-SR scores, F(2, 179) ⫽ 20.32, p ⬍ .01, ␩P2 ⫽ 0.281. The
S’S’ group showed significantly higher LSAS-SR scores than the
S’L’ and L’L’ groups.
5-HTTLPR and Emotion Regulation
Table 1 also shows reappraisal scores from ERQ and CERQ by
genotype group. An ANCOVA, with the 5-HTTLPR genotype
group as between-subjects factor and sex as covariate, indicated
that genotype had a significant effect on the ERQ-reappraisal
scores, F(2, 179) ⫽ 15.8, p ⬍ .01, ␩p2 ⫽ 0.32. The S’S’ group
displayed significantly lower ERQ-reappraisal scores than both the
S’L’ (p ⬍ .01) and the L’L’ groups (p ⬍ .01). The difference
between the S’L’ and L’L’ genotypes on ERQ-reappraisal scores
was not significant (p ⫽ .99). The significant effect of the
5-HTTLPR genotype was also evident on reappraisal scores from
CERQ, F(2, 179) ⫽ 8, p ⬍ .01, ␩p2 ⫽ 0.192. The S’S’ group had
significantly lower CERQ-reappraisal scores than the L’L’ group
(p ⬍ .01), and the S’L’ group had significantly lower scores than
the the L’L’ group (p ⬍ .01). The difference between the S’S’ and
S’L’ groups was not significant (p ⬍ .5). ERQ-suppression scores
were not significantly different between genotype groups (see
Table 1).
5-HTTLPR, Reappraisal, and Social Anxiety
Symptoms
Table 2 presents the regression coefficients from the analyses of
the mediation model, in which the 5-HTTLPR genotype was the
initial variable, LSAS-SR was the outcome variable, and the
ERQ-reappraisal was the potential mediator (see also Figure 1A).
To test the direct effect (Path c in Figure 1A), LSAS-SR scores
were first regressed on the genotype. As hypothesized, the geno-
type was significantly associated with social anxiety. By regress-
ing ERQ-reappraisal scores on 5-HTTLPR, we also confirmed that
this genotype was significantly related to individual differences in
cognitive reappraisal (Path a in Figure 1A). In the third step, social
1
The effect of genotype remained significant and the effect size was
comparable even after excluding the covariate (i.e., sex) from the analysis,
F(2, 179) ⫽ 13.18, p ⬍ .01, ␩2p ⫽ 0.28. The effects of age and Age ⫻
5-HTTLPR on LSAS-SR scores were not significant.
2
Excluding the covariate from the analyses did not change the effects of
genotype on ERQ reappraisal, F(2, 179) ⫽ 15.73, p ⬍ .01, ␩2p ⫽ 0.31 and
CERQ reappraisal, F(2, 179) ⫽ 7.46, p ⬍ .01, ␩2p ⫽ 0.18. Similarly,
excluding the covariate from the analyses on ERQ-suppression scores did
not change the null result, F(2, 179) ⫽ 0.41, p ⬎ .05.
 1016 MIU, VULTURAR, CHIŞ, UNGUREANU, AND GROSS
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Figure 1. Standardized regression coefficients for the relationship be-
tween the 5-HTTLPR genotype and social anxiety symptoms as carried by
ERQ reappraisal (A), CERQ reappraisal (B) and ERQ suppression (C).
anxiety was regressed on both the genotype and the reappraisal
scores. Reappraisal and social anxiety were significantly related
when controlling for the genotype (Path b in Figure 1). The
coefficient associated with the relation between the genotype and
social anxiety decreased, but remained significant when control-
ling for reappraisal in the equation (Path c’ in Figure 1). Using
bias-corrected bootstrapping (with 1,000 iterations), we tested the
significance of the indirect effect of the genotype on social anxiety
through ERQ reappraisal. The 95% CI [0.01, 14.28] for the indi-
rect effect did not include zero, indicating that ERQ reappraisal
was a significant mediator.3 When we restricted the analyses to the
participants who scored above the clinical cut-off (i.e., ⬎ 55) on
LSAS-SR (n ⫽ 89), the indirect effect remained significant (CI for
the indirect effect: [0.74, 13.66]). A reverse-causality analysis that
tested a model in which the effect of the genotype on ERQ
reappraisal was transmitted via social anxiety found a nonsignifi-
cant indirect effect (CI from bias-corrected bootstrapping: [⫺2.5,
0.23]).
We tested a similar model in which CERQ reappraisal was the
mediator between the genotype and social anxiety symptoms (Ta-
ble 3 and Figure 1B).
We confirmed that the genotype was significantly related to
individual differences in CERQ reappraisal (Path a in Figure 1B),
and CERQ reappraisal and social anxiety were significantly related
while controlling for the genotype (Path b in Figure 1B). The CI
[5.63, 19.8] from bootstrapping did not include zero, which con-
firmed that CERQ reappraisal was a significant mediator between
the genotype and social anxiety.4 The indirect effect was also
significant when we restricted the analyses to the participants who
scored above 55 on LSAS: the CI from bias-corrected bootstrap-
ping was [2.26; 14.41]. The reverse causality analysis that tested
the indirect effect of the genotype on CERQ reappraisal through
social anxiety revealed no significant mediation, CI [⫺1.19, 0.04]
from bias-corrected bootstrapping.
To examine the specificity of reappraisal as a mediator, we
tested whether ERQ-suppression mediated the relation between
5-HTTLPR and social anxiety symptoms (see Table 4). The
5-HTTLPR was not related to ERQ suppression (Path a in Figure
1C), and suppression and social anxiety were not significantly
related while controlling for the genotype (Path b in Figure 1C).
The indirect effect was not significant, as indicated by the CI
[⫺3.35; 4.93] from bootstrapping.
Discussion
Low-expressing 5-HTTLPR genotypes were associated with
decreased reappraisal and increased social anxiety. Using two
measures of cognitive reappraisal, we found converging evidence
that individual differences in this emotion-regulation strategy carry
the influence of 5-HTTLPR genotype on anxiety symptoms. By
contrast, expressive suppression was not linked to 5-HTTLPR and
social anxiety. These findings support the hypothesis that
5-HTTLPR contributes to social anxiety symptoms via decreased
reappraisal.
Cognitive Reappraisal Is an Intermediate Phenotype
Individual differences in reappraisal are known to influence
levels of positive and negative affect, as well as social support and
well-being in the general population (Gross & John, 2003; Sheppes
& Gross, 2011). In contrast, decreased use of such adaptive
emotion-regulation strategies in daily life significantly contributes
to the development of psychopathology (Aldao, Nolen-Hoeksema,
& Schweizer, 2010; Bradley et al., 2011; Szasz et al., 2011),
including social anxiety symptoms (Rusch, Westermann, & Lin-
coln, 2011). In a diathesis-stress framework, is has been hypoth-
esized that the risk of social anxiety problems, associated with the
decreased use of cognitive reappraisal, is related to a certain
genetic background. However, until now, there were no studies
that traced the pathway from genetic susceptibilities to social
anxiety, through emotion regulation. The present study found that
the habitual use of cognitive reappraisal significantly mediated the
link between the 5-HTTLPR genotype and social anxiety symp-
toms.
3
Based on Preacher and Kelley (2011), we estimated the effect size as
the ratio of the obtained indirect effect to the maximum possible indirect
effect: k2 ⫽ 0.27.
4
The effect-size index (Preacher & Kelley, 2011) for this indirect effect
is k2 ⫽ 0.09.
 5-HTTLPR, REAPPRAISAL, AND SOCIAL ANXIETY 1017

Table 1
Anxiety Symptoms and Emotion-Regulation Scores by 5-HTTLPR Genotype

Cognitive reappraisal Positive reappraisal Expressive suppression

Liebowitz social (Emotion regulation (Cognitive emotion (Emotion regulation
Genotype anxiety scale questionnaire) regulation questionnaire) questionnaire)

L’L’ 44.84 ⫾ 4.07 5.41 ⫾ 0.06 16.47 ⫾ 0.66 2.77 ⫾ 0.31

S’L’ 49.78 ⫾ 3.86 5.39 ⫾ 0.07 13.6 ⫾ 0.61ⴱⴱ 3.09 ⫾ 0.21
S’S’ 76.57 ⫾ 5.02ⴱⴱ 4.9 ⫾ 0.06ⴱⴱ 12.47 ⫾ 0.76ⴱⴱ 3.05 ⫾ 0.26
Note. Values in cells are M ⫾ 1 SEM.
ⴱⴱ
p ⬍ .01.
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This finding complements previous neuroimaging reports of an imaging results, the behavioral results reported in these studies
This document is copyrighted by the American Psychological Association or one of its allied publishers.

association between 5-HTTLPR and activity in an amygdala-
cingulate circuit related to emotion regulation (Firk et al., 2013;
Heinz et al., 2005; Pezawas et al., 2005; Schardt et al., 2010). In
the largest of these studies (N ⫽ 94), S-allele carriers displayed
reduced functional connectivity between the rostral subgenual
portion of the anterior cingulate cortex and the amygdala during
perception of fearful stimuli (Pezawas et al., 2005). The reduced
correlation of activity in this cingulate-amygdala circuit predicted
almost 30% of the variance in dispositional anxiety (Pezawas et
al., 2005). However, in a similar study, Heinz et al. (2005) reported
an increased functional connectivity between the ventromedial
prefrontal cortex and the amygdala during the perception of aver-
sive images in S-allele carriers. By manipulating emotion regula-
tion, two recent studies also found that emotional detachment
(Schardt et al., 2010) or cognitive reappraisal (Firk et al., 2013)
with aversive images triggered increased activity in brain areas
associated with the top-down control of emotions (e.g., ventrolat-
eral and dorsolateral prefrontal cortex; left medial prefrontal cor-
tex; rostral anterior cingulate cortex) in S carriers.
As pointed out by Pezawas et al. (2005), the differences between
these neuroimaging results may be explained by the focus on
nonoverlapping prefrontal and cingulate regions, based on differ-
ent algorithms for the selection of the regions of interest. In
addition, differences in emotion tasks (i.e., perception vs. regula-
tion), sample size and genotyping procedures (i.e., biallelic vs.
triallelic 5-HTTLPR) may have also contributed to the heteroge-
neity of neuroimaging observations. In constrast with the neuro-
were more convergent. In line with the present results, S-allele
carriers displayed reduced ERQ reappraisal, but similar ERQ-
suppression scores (Schardt et al., 2010). Moreover, S carriers
were less succesful than L homozygotes in reducing negative
affect by cognitive reappraisal (Firk et al., 2013). This is also
supported by studies that found reduced coping potential in
S-allele carriers (Szily et al., 2008). Our present results confirmed
the association between 5-HTTLPR and habitual cognitive reap-
praisal in a larger sample, and showed for the first time that this
association is one of the mechanisms by which 5-HTTLPR influ-
ences social anxiety.
A large theoretical and empirical literature in the diathesis-stress
framework (for review see Caspi et al., 2010; Canli & Lesch,
2007) suggests that genetic differences might moderate the rela-
tionship between stress and emotional disorders. These studies
highlight the possibility that the magnitude of the effects of
5-HTTLPR on emotion regulation might differ as a function of
exposure to stressors. More specifically, it recently has been hy-
pothesized that people who are genotypically more reactive to
stress might develop emotional problems, particularly when their
emotion regulation, which developed to allow adaptation to the
type of stressor that was encountered early in life, is challenged
during adulthood by a different type of stressor (Homberg, 2012).
This stress-coping mismatch hypothesis is based on animal
studies, and it has started to be supported in 5-HTT knockout
rodents exposed to escapable or inescapable stress (van der
Doelen, Kozicz, & Homberg, 2013). Based on the recent findings

Table 2
Results of Multiple Regression Analyses on the Mediator Role of ERQ Cognitive Reappraisal in the Relationships Between 5-HTTLPR
Genotype and Social Anxiety Symptoms

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

Testing Step 1 (Path c)

Outcome: LSAS social anxiety
Predictor: Genotype (L’L’ vs. S’L’ vs. S’S’)a 15.86 3.5 9.39, 22.52 0.48ⴱⴱ
Testing Step 2 (Path a)
Outcome: ERQ-reappraisal
Predictor: Genotype ⫺1.52 0.34 ⫺2.09, ⫺0.93 ⫺0.47ⴱⴱ
Testing step 3 (Paths b and c’)
Outcome: LSAS social anxiety
Mediator: ERQ-reappraisal (Path b) ⫺5.89 1.01 ⫺7.58, ⫺4.09 ⫺0.57ⴱⴱ
Predictor: Genotype (Path c“) 6.88 3.27 0.02, 13.84 0.21ⴱ
Note. Abbreviations: B ⫽ unstandardized regression coefficient; ␤ ⫽ standardized regression coefficient; CI ⫽ confidence interval; SE ⫽ standard error.
a
0 ⫽ L’L’ (i.e., LA/LA and LA/XL genotypes); 1 ⫽ S’L’ (i.e., S/LA and LG/LA genotypes); 2 ⫽ S’S’ (S/S, LG/LG and S/LG genotypes).
ⴱ
p ⬍ .05. ⴱⴱ p ⬍ .01.
 1018 MIU, VULTURAR, CHIŞ, UNGUREANU, AND GROSS

Table 3
Results of Multiple Regression Analyses on the Mediator Role of CERQ Positive Reappraisal in the Relationships Between 5-HTTLPR
Genotype and Social Anxiety Symptoms

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

Testing step 1 (Path c)

Outcome: LSAS social anxiety
Predictor: Genotype (L’L’ vs. S’L’ vs. S’S’)a 15.86 3.5 9.39, 22.52 0.48ⴱⴱ
Testing step 2 (Path a)
Outcome: CERQ-reappraisal
Predictor: Genotype ⫺2 0.54 ⫺2.94, ⫺1.01 ⫺0.41ⴱⴱ
Testing step 3 (Paths b and c’)
Outcome: LSAS social anxiety
Mediator: CERQ-reappraisal (Path b) ⫺1.51 0.76 ⫺2.78, ⫺0.13 ⫺0.22ⴱ
Predictor: Genotype (Path c’) 12.85 3.27 5.9, 19.93 0.39ⴱⴱ
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This document is copyrighted by the American Psychological Association or one of its allied publishers.

Note. Abbreviations: B ⫽ unstandardized regression coefficient; ␤ ⫽ standardized regression coefficient; CI ⫽ confidence interval; SE ⫽ standard error.
a
0 ⫽ L’L’ (i.e., LA/LA and LA/XL genotypes); 1 ⫽ S’L’ (i.e., S/LA and LG/LA genotypes); 2 ⫽ S’S’ (S/S, LG/LG and S/LG genotypes).
ⴱ
p ⬍ .05. ⴱⴱ p ⬍ .01.

that people choose certain emotion-regulation strategies depending
on the intensity of stress (i.e., reappraisal for low-intensity stress
vs. distraction for high-intensity stress; Sheppes, Scheibe, Suri, &
Gross, 2011; Sheppes et al., 2012), and that like 5-HTT knockout
rodents, people of the SS genotype of 5-HTTLPR show increased
sensitivity to stress (Drabant et al., 2012), the following predic-
tions could be made in humans, in line with the stress-coping
mismatch hypothesis: (a) Exposure to lower or higher levels of
stress during childhood would be specifically associated with
higher habitual reappraisal and distraction, respectively; (b) emo-
tional problems in adults would be increased in habitual reapprais-
ers who were exposed to low levels of stress during childhood, but
currently experience high levels of stress, as well as in habitual
distractors who were exposed to high levels of stress during
childhood, but currently experience low levels of stress; and (c) the
latter effect would be facilitated in S homozygotes for 5-HTTLPR.
These interesting predictions remain to be tested in future studies
(ideally, longitudinal studies); they also offer an explanation for
the present finding that habitual reappraisal is a partial mediator of
the relation between 5-HTTLPR and social anxiety. In light of our
perspective on the stress-coping mismatch hypothesis, it is possi-
ble that the magnitude of this mediation is influenced by the use of
other emotion-regulation strategies (e.g., distraction) and the sim-
ilarity between the early and adult levels of stress.
Implications for Psychotherapy
The present study has important implications for psychotherapy.
Cognitive– behavioral therapy (CBT) for anxiety and depression
has focused on teaching reappraisal skills (Clark & Beck, 2010;
Mennin, Ellard, Fresco, & Gross, 2013). Recent studies have
demonstrated that the successful acquisition of these skills differ-
entiated between responders and nonresponders to CBT, and cor-
related with decreases of symptoms in SAD (Heinz et al., 2005;
Kley et al., 2012; Moscovitch et al., 2012). Moreover, 5-HTTLPR
was also found to influence the response to CBT in a large sample
of children with anxiety disorders (Eley et al., 2012). The SS
genotype was associated with increased response to therapy, in
comparison with SL and LL genotypes (Eley et al., 2012).
Based on the present finding that low-expressing 5-HTTLPR
genotypes are also associated with decreased use of cognitive
reappraisal, and in light of the observation that cognitive reap-
praisal is a key mechanism of change in CBT, we suggest that the
patients with the low-expressing 5-HTTLPR genotypes may ben-

Table 4
Results of Multiple Regression Analyses on the Mediator Role of ERQ Expressive Suppression in the Relationships Between 5-
HTTLPR Genotype and Social Anxiety Symptoms

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

Testing step 1 (Path c)

Outcome: LSAS social anxiety
Predictor: Genotype (L’L’ vs. S’L’ vs. S’S’)a 15.86 3.5 9.39, 22.52 0.48ⴱⴱ
Testing step 2 (Path a)
Outcome: ERQ-suppression
Predictor: Genotype 0.13 0.2 ⫺0.26, 0.53 0.08
Testing step 3 (Paths b and c”)
Outcome: LSAS social anxiety
Mediator: ERQ-suppression (Path b) 0.96 2.11 ⫺3.25, 5.19 0.04
Predictor: Genotype (Path c“) 15.73 3.53 8.67, 22.79 0.47ⴱⴱ
Note. Abbreviations: B ⫽ unstandardized regression coefficient; ␤ ⫽ standardized regression coefficient; CI ⫽ confidence interval; SE ⫽ standard error.
a
0 ⫽ L’L’ (i.e., LA/LA and LA/XL genotypes); 1 ⫽ S’L’ (i.e., S/LA and LG/LA genotypes); 2 ⫽ S’S’ (S/S, LG/LG and S/LG genotypes).
ⴱⴱ
p ⬍ .01.
 5-HTTLPR, REAPPRAISAL, AND SOCIAL ANXIETY
efit the most from CBT because their cognitive reappraisal skills
are markedly deficient. Therefore, our findings may have timely
implications for the new field of “therapygenetics” (Beevers &
McGeary, 2012; Eley et al., 2012), by highlighting the role of
cognitive reappraisal in the link between 5-HTTLPR and response
to CBT.
Limitations and Future Directions
Although promising, the present study has several limitations.
One is the relatively modest sample size. Recent meta-analyses
have failed to replicate Gene ⫻ Environment interaction effects
(e.g., 5-HTTLPR ⫻ Child Abuse on depression), which have been
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reported in samples too underpowered to detect small genetic
This document is copyrighted by the American Psychological Association or one of its allied publishers.
effects (Duncan & Keller, 2011; Risch et al., 2009). These results
highlight the importance of the sample size in reducing the prob-
ability of Type I errors, which would require over a thousand
participants to be recruited for detection of a genetic influence with
small effect size (Duncan & Keller, 2011). However, similar, more
inclusive meta-analyses (Karg, Burmeister, Shedden, & Sen, 2011;
Uher & McGuffin, 2010), i.e., studies with alternative measures or
statistical models were considered, replicated the original effects.
Although there is general agreement that results from genetic
association studies with underpowered samples should be taken
with caution until they are replicated in large-scale studies or
meta-analyses (Caspi et al., 2010), it has also been acknowledged
that the rate of false positive findings may not be that high in these
studies (Lohmueller, Pearce, Pike, Lander, & Hirschhorn, 2003).
Large-scale genetic association studies may offer a sample-size
standard that has seldom been achieved in psychological research,
and the solution of organizing multicentric studies may be prob-
lematic because of ethnic stratification and increased variability of
the 5-HTTLPR allele distribution in different populations, for
instance (Murdoch, Speed, Pakstis, Heffelfinger, & Kidd, 2013).
Even though they do not offer definitive results, hypothesis-driven
genetic association studies such as this one, i.e., those with explic-
itly defined phenotypes, precise localization of polymorphisms,
low genotyping error rate, availability of genotype counts and
analyses, that avoid overlap with previous studies (Buckland,
2001; Conneally & Sparkes, 1998; Lohmueller et al., 2003), may
guide the discovery of true genetic influences on psychological
phenotypes. Notwithstanding these favoring perspectives, we ac-
knowledge that our promising results should be independently
replicated before they begin to influence mainstream research on
social anxiety.
A second limitation of the present study is the lack of clinical
diagnosis of the participants. Previous genetic studies failed to find
an association between 5-HTTLPR and the SAD diagnosis (Strug
et al., 2010), but identified significant influences of this genotype
on particular phenotypes that characterize the social anxiety spec-
trum. This motivated our decision to focus on social anxiety
symptoms in nonpatient volunteers, which allows us to generalize
our findings to a broad segment of the social anxiety spectrum.
However, it must be acknowledged that the generalization of the
present findings might be limited by the underrepresentation of
men in this sample.
A third important limitation of this study is that we focused on
just one form of emotion regulation and just one genetic suscep-
tibility factor. Our decision to focus on one form of emotion
1019
regulation—reappraisal— using two different measures allowed us
to show that our core findings were robust in that they were
evidenced using two different measures of reappraisal. However,
we explored the specificity of reappraisal by showing that sup-
pression was not a mediator. Our decision to focus on just one
genetic susceptibility factor was motivated by the fact that prior
research strongly pointed to this risk factor as a promising candi-
date susceptibility factor. One important direction for future re-
search might be to investigate the additive effects of 5-HTTLPR
and Tryptophan Hydroxylase 2 gene polymorphisms (i.e.,
rs4570625), which were both related to emotion appraisal (this
study; Szily et al., 2008; Szily & Keri, 2012) and are known to
interactively affect other emotion phenotypes (Herrmann et al.,
2007). In the present study, the frequency of using reappraisal or
suppression was assessed using self-report instruments (i.e., ERQ
and CERQ), which, however reliable, are subject to demand char-
acteristics and limited to emotion regulation processes to which
participants have introspective access. Therefore, future studies
could also measure other aspects (e.g., ability rather than fre-
quency) and processes of emotion regulation (e.g., automatic
rather than voluntary), using performance-based and neural assess-
ments (Firk et al., 2013; Schardt et al., 2010). Moreover, other
clinically relevant forms of emotion regulation (e.g., reappraisal
vs. distraction) that may be adaptive or maladaptive depending on
the level of stress during development and adulthood (Clasen et al.,
2011; Homberg, 2012), could also be investigated in the future.
The present study supported the hypothesis that reappraisal is a
potential intermediate phenotype on the pathway from 5-HTTLPR
to social anxiety symptoms. These results have important impli-
cations for diathesis-stress theories of SAD, by identifying
5-HTTLPR as a genetic candidate that influences social anxiety
symptoms through cognitive reappraisal, and for clinical interven-
tions that include an emphasis on cognitive reappraisal training,
such as CBT.
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Received November 29, 2012
Revision received May 2, 2013
Accepted May 10, 2013 䡲