Genetics and personality traits in patients with social
anxiety disorder: A case-control study in South Africa
Christine Lochnera,*, Sian Hemmingsb, Soraya Seedata, Craig Kinnearb,
Renata Schoemanc, Kristina Annerbrinkd, Marie Olssone, Elias Erikssond,
Johanna Moolman-Smookb, Christer Allgulanderf, Dan J. Steina,g
aMRC Unit on Anxiety and Stress Disorders, Department of Psychiatry. University of Stellenbosch, South Africa
bMRC/US Centre on Molecular and Cellular Biology, University of Stellenbosch, South Africa
cDepartment of Psychiatry, University of Stellenbosch, South Africa
dDepartment of Pharmacology, Go ´ ´teborg University, Sweden
eDepartment of Pharmacy, Apoteket AB, Sahlgrenska University Hospital, Go ´ ´teborg, Sweden
fKarolinska Institutet, Sweden
gDepartment of Psychiatry, University of Cape Town, South Africa
Received 16 February 2006; received in revised form 5 June 2006; accepted 27 June 2006
Background: Social anxiety disorder (SAD) is among the most common of all psychiatric disorders
with lifetime prevalence estimates ranging from 7% to 13%. Although there is evidence that SAD
has a strong familial basis, there are few studies of potential candidate genes. In addition to a
genetic association, there is also the possibility that temperamental risk factors for the disorder
may be genetically transmitted. Against this background, our aims were threefold: i.) to
compare patients and controls with respect to personality traits, ii.) to genotype a subgroup of
these participants to investigate the role of genes encoding components of serotonergic (5-HT)
and dopaminergic (DA) pathways in patients with SAD and iii.) to compare differences in
temperament dimensions between carriers of different (dominant vs. recessive) alleles for
selected polymorphisms in SAD patients.
Methods:Sixty-three patients (n=63; 35 male, 28 female) with a DSM-IV diagnosis of generalized
SAD and SPIN-scores N18, and age-matched control participants (n=150; 31 male, 119 female)
were included in the study. The Temperament and Character Inventory (TCI) was used to
measure behaviours associated with specific personality dimensions (i.e. temperament/
character). DNA was extracted and genotyped to investigate the role of select candidate genes
0924-977X/$ - see front matter D 2006 Elsevier B.V. and ECNP. All rights reserved.
* Corresponding author. PO Box 19063, Tygerberg, 7505, South Africa. Tel.: +27 21 938 9179; fax: +27 21 933 5790.
E-mail address: email@example.com (C. Lochner).
European Neuropsychopharmacology (2007) 17, 321—327
encoding components in serotonergic and dopaminergic pathways in mediating the development
of SAD. To achieve this, the frequency of variants in 5-HTand DA genes was compared between a
Caucasian subset of SAD patients (n=41) and a convenience sample of Caucasian controls
(n=88), using case-control association analyses. We also investigated the frequency of variants
in 5-HT and DA-related genes across temperament characteristics in SAD patients, using
analyses of variance (ANOVA).
Results: Patients scored significantly higher on harm avoidance (pb0.001) but lower on novelty
seeking (p=0.04) and self-directedness (p=0.004) compared to controls. In the Caucasian
subset, there was a difference between patients and controls in distribution of the 5-HT2A
T102C polymorphism, with significantly more patients harboring T-containing genotypes (T-
containing genotypes: [T/T+T/C] vs. [C/C]) (v2=7.55; p=0.012). Temperament dimensions
did not, however, differ significantly between carriers of different (dominant vs. recessive)
alleles for the 5-HT2AT102C polymorphism in SAD patients.
Conclusions: The results suggest a possible role for the 5-HT2AT102C polymorphism in the
development of SAD. To date genetic findings in SAD have been inconsistent; nevertheless,
serotonergic variants, and their associations with temperaments (e.g. reward dependence)
deserve further exploration, in the hope that endophenotypes relevant to SAD can ultimately be
D 2006 Elsevier B.V. and ECNP. All rights reserved.
Social anxiety disorder (SAD) is a common, disabling
condition, characterized by fears that a person will become
embarrassed or humiliated in situations where he/she is
exposed to perceived public scrutiny in social or perfor-
mance situations. These fears can either be specific to
certain situations, i.e. specific/discrete SAD, or SSAD, for
instance, public speaking, or eating/drinking in front of
others; or they can be generalized across a wide range of
situations (i.e. generalized SAD or GSAD), with the latter
subtype being associated with more severe disability
(Brunello et al., 2000). SAD is a very common anxiety
disorder with current prevalence estimates in the range
from 4% to 6% and a lifetime risk from 7% to 13% (Wittchen
and Fehm, 2001).
Although the etiology of SAD is not yet fully estab-
lished, twin and family studies suggest that SAD is
heritable (Kendler et al., 1992; Lieb et al., 2000; Mancini
et al., 1996; Mannuzza et al., 1995; Nelson et al., 2000;
Stein et al., 2002). In addition, there is evidence from
various studies, including imaging and treatment studies
(Furmark et al., 2005, 2004; Rowe et al., 1998; Schneier
et al., 2000; Tiihonen et al., 1997) that the serotonin (5-
HT), and dopamine (DA) neurotransmitter systems mediate
the symptoms of SAD. Specific variants of 5-HT and DA
have been investigated in patients with SAD (e.g. Kennedy
et al., 2001; Mathew et al., 2001; Schneier et al., 2000;
Stein et al., 1998; Tiihonen et al., 1997; van der Linden et
al., 2000), but to date findings have been inconsistent.
The inconsistency across studies may be addressed in
part by examining heritable personality dimensions
thought to contribute to susceptibility for SAD. In a
familial aggregation study of anxiety-related quantitative
traits (e.g. behavioral inhibition and related temperamen-
tal features) in GSAD, Stein et al. (2001) suggested that
these traits were heritable, and proposed that future
family and genetic studies of SAD may benefit from
including a focus on these quantitative traits (Stein et
al., 2001). Certainly, there are several candidate genes
encoding proteins that may have a role in subserving brain
functions that underlie specific personality traits. A
number of studies in both psychiatric and non-psychiatric
populations have proposed associations between candidate
genes and human personality (Munafo et al., 2003).
However, this has not yet been investigated within the
context of SAD.
Therefore, the aims of this study were threefold: i.)
to compare patients and controls with respect to
personality traits, ii.) to genotype a subgroup of these
participants to investigate the role of genes encoding
components of serotonergic (5-HT) and dopaminergic (DA)
pathways in patients with SAD and iii) to compare
differences in temperament dimensions between carriers
of different (dominant vs. recessive) alleles for the
The present study was conducted on outpatients assessed at an
anxiety disorders research unit. Patients were referred from
specialist psychiatrists, primary care practitioners, and advocacy
groups. Seventy-five patients (n=75: 40 male; 35 female) with
generalized SAD were recruited for participation. All patients met
DSM-IV criteria for a primary diagnosis of SAD on the Structured
Clinical Interview for the Diagnosis of Axis I Disorders-Patient
Version (SCID-I/P) (First et al., 1998) as assessed by an experienced
clinician. However, a cut-off value of N18 on the Social Phobia
Inventory (SPIN) was used to confirm SAD diagnoses. In other words,
only patients with SPIN-scores higher than 18, i.e. with clinically
significant social phobic symptoms (Connor et al., 2000), were
included (n=63; 35 male, 28 female). The presence of another
mood or anxiety disorder did not mean exclusion from the study,
provided that it was not the principal diagnosis. The decision to
include patients with a primary diagnosis of SAD with/out comor-
bidity was based upon the fact that secondary depressive episodes
are very frequent among patients with anxiety disorders presenting
to clinical and research settings (Brawman-Mintzer et al., 1993;
C. Lochner et al.322
Massion et al., 1993; Sanderson et al., 1990), and SAD in particular
(e.g. Kessler et al., 1996; Kessler et al., 1999). A history of
psychosis, inadequate understanding of the aims and practical
implications of participation, and unwillingness to provide consent
after reading the information and consent forms, were exclusion
criteria. (The subgroup of patients that were genotyped (n=41) was
recruited from this group of 63 patients.) A convenience sample of
controls was recruited from the community. These controls (n=150;
31 male, 119 female; mean age: 35.8 years, SD: 8.7) were not
screened and were included irrespective of their possible diagnostic
status or family history of psychiatric illness. The study was
approved by the Institutional Review Board of the University of
2.2. Interview and self-reports
Demographic data from patients (including age, age of onset of
SAD, gender, population group and education level) were collated.
The severity of social anxiety symptoms was assessed using the
SPIN (Connor et al., 2000) and the Liebowitz Social Anxiety Scale
(LSAS) (Liebowitz, 1987). The SPIN is a self-rated scale consisting
of questions that evaluate fear, avoidance and physiological
discomfort. Each of the 17 items is rated on a scale from 0 to 4:
not at all, a little bit, somewhat, very much, and extremely; with
higher scores corresponding to greater distress. The full-scale
score ranges from 0 to 68. The SPIN demonstrates solid psycho-
metric properties, is used as a valid measure of severity of social
phobia symptoms, and is sensitive to the reduction in symptoms
over time. The LSAS, a clinician-administered social anxiety rating
scale with much support for its validity (Heimberg et al., 1999), is
used to assess anxiety or avoidance in a number of typical social
and performance situations. Comorbid disorders were assessed
using the SCID-I/P and selected parts of the Structured Clinical
Interview for the Diagnosis of Axis II Disorders (SCID-II/P) (First et
al., 1998). The self-report TCI (Cloninger et al., 1994) (240 item-
version) is an instrument with yes/no answers used to measure
behaviours associated with six personality dimensions (i.e. tem-
perament/character), namely novelty seeking, harm avoidance,
reward dependence, persistence, self-directedness, cooperative-
ness, and self-transcendence.
All controls were required to complete a questionnaire pertain-
ing to his/her personal demographic data and present state of
DNA was extracted from venous blood (30 ml) in a Caucasian subset
of the interviewed SAD patients (n=41) and a convenience age-
matched sample of controls (n=88). Samples were genotyped for
polymorphisms in genes involved in monoamine function that have
previously been hypothesized to play a role in SAD pathogenesis.
Owing to logistical considerations, not all samples were genotyped
for the selected polymorphisms. The number of samples genotyped
for each polymorphism is shown in the Results section. The
polymorphisms investigated were: a 40 bp VNTR in the 3’
untranslated region of the dopamine transporter (DAT) (Vanden-
bergh et al., 1992), a functional 44 bp insertion/deletion polymor-
phism in the promoter region of the serotonin transporter (5-HTT)
(Heils et al., 1996) and single nucleotide polymorphisms in the
serotonin receptor type 1B (5HT1B, previously referred to as 5-
HT1Db) (G861C) (Sidenberg et al., 1993), the serotonin receptor
type 2A (5-HT2A) (T102C) (Warren et al., 1993), and tyrosine
hydroxylase (TH) (Val81Met) (Ishiguro et al., 1998). Previously
described genotyping protocols were followed (Heils et al., 1996;
Hemmings et al., 2003; Ishiguro et al., 1998). Agreement with
Hardy—Weinberg equilibrium (HWE) was determined using the
Fisher exact test.
2.4. Data analysis
Statistical differences in genotype and allele frequencies between
patients with SAD and controls were ascertained using the t-test or
chi-squared (v2) test, as relevant. Using analyses of variance
(ANOVA), the differences in TCI dimensions were compared to
genotypes grouped by alternatively considering either allele of
each polymorphism as playing a dominant or recessive role. For
the multi-allelic polymorphism (i.e. the DAT 40 bp VNTR), we
decided a priori to make the most common variants our focus of
interest (i.e. for DAT: the A9/A9, A9/A10, A10/A10 repeats) and
to exclude patients with the more rare combinations) in an
attempt to increase statistical power.
P-values attained in the present study (i.e. the genetics
analyses specifically) were corrected for multiple testing using
Bonferroni’s correction, taking into account the mode of
inheritance investigated. In other words, we Bonferroni corrected
for the number of tests performed within any particular
polymorphic variant. (When considering the alleles as playing
dominant or recessive roles in each marker, two (2) tests were
Statistical tests were performed using the Software Package for
Social Sciences (SPSS) version 13.0 (SPSS Inc, Chicago).
3.1. SAD symptomatology
Data obtained from 63 patients with generalized SAD (35
male, 28 female), with ages ranging between 17 and 62
years (mean: 35.22 years, SD: 11.63) were used in the
clinical analyses. The mean age of onset of SAD was mid-
adolescence (mean: 14.58 years, SD: 7.89). A mean score of
46.89 (SD: 11.6) on the SPIN indicated that the majority of
patients had moderate to severe SAD.
Lifetime axis I and II disorders diagnosed with the highest
frequency in the study population were major depressive
disorder (MDD; 66.7%), generalized anxiety disorder (GAD;
38.1%), alcohol abuse (20.6%) (or dependence (11.1%)),
specific phobia (17.5%), avoidant personality disorder
(64.5%) and obsessive—compulsive disorder (9.7%). Current
rates of comorbidity were generally much lower than
lifetime; in particular with regards to MDD (28.6%), and
alcohol abuse (3.2%) and dependence (4.8%). For the
genetics analyses, we did not make a distinction between
those patients with a diagnosis of SAD only, and those with
SAD and one or more comorbid disorders.
in Caucasians with SAD and controls (if the T-containing
genotypes are dominant)
Genotype distribution of the 5-HT2Apolymorphism
5-HT2Avariants SAD patientsControls
* With Bonferroni correction: p=0.006?2: p=0.012.
Genetics and personality traits in patients with social anxiety disorder: A case-control study in South Africa323
3.3. Genetic polymorphisms: SAD patients versus
Both SAD-affected and control groups were in Hardy—
Weinberg equilibrium at each locus investigated. In the
Caucasian subset, there was a difference between patients
and controls in terms of 5-HT2AT102C, with significantly
more patients characterized by T-containing genotypes
([T/T+T/C] vs. [C/C]) (v2=7.55; p=0.012) (Tables 1
and 2). No statistically significant results were obtained
for the genetic variants investigated in 5-HTT LPR, TH, DAT,
3.4. Genetic Polymorphisms and TCI dimensions
Patients (of all populations) with SAD scored significantly
higher on harm avoidance (pb0.001) but significantly lower
on novelty seeking ( p =0.04) and self-directedness
(p=0.004) compared to controls (Table 3). Findings were
similar for the Caucasian subset, i.e. Caucasian patients
scored significantly higher on harm avoidance (pb0.001)
but lower on self-directedness (p=0.006) compared to
In the Caucasian group of patients, we focused the
analyses of genes vs. TCI dimensions on the 5-HT2AT102C
polymorphism, given i.) the significant finding with 5-
HT2A in the categorical analysis (above), and ii.) the low
sample size. Before statistically correcting for multiple
testing, comparison of the associations between T-con-
taining genotypes, with the C/C genotype of 5-HT2A
T102C, and the different temperament dimensions in 21
patients suggested a significant association between
decreased reward dependence and the T-containing
genotypes ([T/T +T/C] vs. [C/C]) (n =17; F =4.49;
p=0.048). However, after correcting for multiple testing,
the significance disappeared (Table 4).
In summary, our findings suggested increased harm avoid-
ance and decreased novelty seeking and self-directedness in
SAD patients compared to controls. In a Caucasian subset, a
possible role for the T-containing genotypes of the 5-HT2A
T102C polymorphism in the development of SAD was
suggested. Temperament dimensions did not, however,
differ between carriers of different (dominant vs. recessive)
alleles for the 5-HT2AT102C polymorphism in Caucasian SAD
The TCI findings here are consistent with several previous
studies comparing temperament of SAD patients with that of
controls (e.g. Chatterjee et al., 1997; Kim and Hoover, 1996;
Marteinsdottir et al., 2003; Pelissolo et al., 2002), and
showing significantly higher scores on harm avoidance, and
significantly lower scores on novelty seeking and self-
directedness in SAD. It is possible that temperament is a
useful endophenotype in studying vulnerability to the
development of SAD, and its underlying genetic basis
(Gladstone et al., 2005). On the other hand, it is also
possible that abnormal scores on the TCI in SAD primarily
reflect the effects of the core symptoms of this condition.
The genetic vulnerability hypothesis is supported by our
finding of a link between the 5-HT2AT102C polymorphism
and SAD; the function of T102C, a silent polymorphism
occurring in exon 1 of 5-HT2A(Warren et al., 1993) has been
under debate recently. Two studies have indicated that the
T102 allele and T102T genotype may result in increased
expression of 5-HT2A (Khait et al., 2005; Polesskaya and
Sokolov, 2002), but Bray et al. (2004) observed no difference
in the expression of the alleles. If T-alleles (T/T-genotype)
lead to increased expression of 5-HT2A, this would be
consistent with other evidence of serotonergic involvement
We cannot, however, rule out the possibility that the
TCI merely reflects SAD symptoms, and that the 5-HT2A
finding here is a false positive. We were unable to find a
relationship between abnormal temperament in SAD and 5-
HT2A. Although Stein et al. (1998) studied only a small
sample of SAD, they did not find evidence of linkage
between SAD and 5-HT2A. Furthermore, the risk of
depression and anxiety has been reported to increase in
the presence of the C/C genotype of the T102C polymor-
phism (Arias et al., 2001; Du et al., 2000; Fehr et al.,
2001). There are several reasons for inconsistency across
genetic studies, including epistatic effects that could
in Caucasians with SAD and controls (if the T-containing
genotypes are recessive)
Genotype distribution of the 5-HT2Apolymorphism
Temperament and Character Inventory: SAD patients vs. controls (all population groups)
Temperament/character trait*SAD patients (n=33) Controls (n=76)FP
* NS = novelty seeking total score, SD = self-directedness total score.
HA = harm avoidance total score, C = cooperativeness total score.
RD = reward dependence total score, ST = self-transcendence total score.
C. Lochner et al. 324
underplay the impact that a single locus may have in
contributing to the development of SAD. Also, in the
current study focusing on single candidate genes in
isolation may have lacked power and reproducibility.
We noted that SAD patients carrying at least one T-
allele (of the 5-HT2A T102C polymorphism) exhibited
significantly decreased reward dependence scores com-
pared to those homozygous for the C-allele (p=0.048).
However, after correcting for multiple testing, only a trend
towards significance was observed. Reward dependence is
a temperament trait described as the tendency for a
positive response to signals of reward to maintain or resist
behavioral extinction (Cloninger et al., 1994). Decreased
reward dependence in SAD — relevant to patients carrying
at least one T-allele of the 5-HT2AT102C polymorphism —
may suggest that these patients are less dependent on
external stimuli for pleasure or reward or gave a greater
tendency to form pessimistic (rather than optimistic)
attributions and expectations of socially-related events
compared to those homozygous for the C-alleles. The link
found between reward dependence and 5-HT2Ain our SAD
sample is also consistent with literature describing dys-
functional reward processing in affective disorders such as
depression and SAD.
At present there is debate about which test constitutes
the most appropriate for correcting for multiple tests in
genetic analyses. Applying the Bonferroni correction may
produce a p-value that is too conservative (Macciardi, 2003;
Pernerger, 1998) and so lead to false negative (Type II error)
results, especially where data is not independent. On the
other hand, multiple testing does increase the risk of
obtaining a false positive result. While we did not Bonferroni
correct for the multiple genes investigated, we did Bonfer-
roni correct for the number of tests performed within any
particular polymorphic variant.
The limitations of the study include the relatively small
sample size, and the potential influence of comorbid
psychiatric conditions (such as mood disorders) on gene
expression. Insufficient DNA of good quality resulted in the
inclusion of smaller sample numbers for particular analy-
ses, even though the number of patients initially enrolled
was greater. In terms of the frequency of comorbid
depression, our group of patients was representative of
other individuals with a primary diagnosis of SAD included
in other studies. For example, data from epidemiological
studies indicate that approximately 25—31% of adolescents
and young adults with SAD have a comorbid depressive
disorder (Essau et al., 1999; Wittchen et al., 1999) while
rates from clinical studies may be higher, ranging from 17%
to 52% (Albano et al., 1996; Chavira and Stein, 2002; Last
et al., 1992). Similar rates have been shown in adult SAD
samples, both in terms of current and lifetime comorbid
depression (e.g. Kessler et al., 1996, 1999; Schneier et al.,
1992; Van Ameringen et al., 1991). It may be argued that
some conclusions can be drawn from these data about SAD
and its associated temperament dimensions as well as its
genetic underpinnings, given the fact that this was a
representative group of SAD patients. In future research,
larger sample sizes (with a renewable source of DNA such
as cell lines) will increase power to detect the role that
(even minor) susceptibility genes may play in SAD. A larger
sample may also allow subdivision by social phobia type
(i.e. generalized vs. discrete), comorbidity, and tempera-
ment dimensions, and linking these subtypes with gene
In conclusion, our results suggest a possible role for the 5-
HT2AT102C polymorphism in the development of SAD. The
mechanism of 5-HT2A is not clearly understood, but it is
possible that various inherited temperaments increase
susceptibility to SAD. Findings in the literature have been
inconsistent, and deserve further exploration, in the hope
that endophenotypes relevant to SAD can ultimately be
This work is supported by the Medical Research Council of
South Africa, the National Research Fund of South Africa,
and the Swedish International Development Agency and
Associations between dominant and recessive carriers of 5-HT2AT102C and temperament in 21 Caucasian patients with
Temperament/character trait*5-HT2AT102C variantMean (SD)FP
RD 4.49 NSw
ST 2.08 NS
* NS = novelty seeking total score, SD = self-directedness total score.
HA = harm avoidance total score, C = cooperativeness total score.
RD = reward dependence total score, ST = self-transcendence total score.
wAfter Bonferroni correction.
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