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Molecular Psychiatry (2002) 7, 903–907
2002 Nature Publishing Group All rights reserved 1359-4184/02 $25.00
www.nature.com/mp
ORIGINAL RESEARCH ARTICLE
Association between the dopamine transporter gene and
posttraumatic stress disorder
RH Segman
1
, R Cooper-Kazaz
1
, F Macciardi
2
, T Goltser
1
, Y Halfon
1
, T Dobroborski
1
and AY Shalev
1
1
Department of Psychiatry, Hadassah – Hebrew University Medical Center, Jerusalem, Israel;
2
Center for Addiction and
Mental Health, University of Toronto, Canada
Keywords: posttraumatic stress disorder; dopamine trans-
porter; genetic association
Posttraumatic stress disorder (PTSD) is a chronic
anxiety disorder that follows exposure to extreme
events. A large twin study of Vietnam veterans had dem-
onstrated a significant genetic contribution to chronic
PTSD upon exposure to combat.
1,2
The underlying
genes, however, have not been described. Given pre-
vious findings of abnormal dopamine (DA) function in
PTSD, and given the putative effect of dopamine neuro-
transmission in shaping the responses to stress in ani-
mals, this study examined the association of the dopa-
mine transporter (DAT) SLC6A3 3⬘ variable number
tandem repeat (VNTR) polymorphism with PTSD. The
study evaluated 102 chronic PTSD patients and 104
carefully-documented trauma survivors (TS) who did
not develop PTSD. Significant excess of 9 repeat allele
was observed among PTSD patients (43% vs 30.5% in
TS controls;
2
= 6.3, df = 1, P = 0.012). An excess of 9
repeat homozygous genotype was also observed in
PTSD (20.43% in PTSD vs 9.47% in TS controls;
2
=
6.11, df = 2, P ⬍ 0.047). These findings suggest that gen-
etically determined changes in dopaminergic reactivity
may contribute to the occurrence of PTSD among
trauma survivors.
Molecular Psychiatry (2002) 7, 903–907. doi:10.1038/
sj.mp.4001085
Post-traumatic stress disorder (PTSD) is an extreme
and sustained maladaptive response to stressful events.
The disorder consists of symptoms of intrusive recall,
avoidance of cues reminding of the traumatic event and
hyper-arousal. These symptoms may persist for years,
and are often associated with significant disability and
distress. The etiology of PTSD is complex and multi-
factorial.
3
Importantly, exposure to a traumatic event
does not fully explain the occurrence of the disorder.
4
Exposure, in fact, triggers a cascade of biological events
that ultimately lead to the occurrence of chronic
PTSD.
5
Individuals with prior vulnerability are at
higher risk for developing PTSD upon exposure to a
traumatic event. Inherited vulnerability is among the
better researched vulnerability factors, as follows:
True et al,
1
studied 4042 twin pairs from the Vietnam
Twin Registry and found that inherited factors
accounted for up to 32% of the variance of PTSD symp-
toms, above and beyond the contribution of trauma
intensity. Xiang et al,
2
examined 3304 twin pairs of the
Vietnam Twin Registry and similarly found 35.3%,
inherited liability to develop PTSD upon combat
exposure, 20% of which pertained specifically to PTSD
and an additional 15.3% were common to both PTSD
and substance dependence. Other studies
6
have shown
an aggregation of anxiety disorders in families of
PTSD patients.
The molecular basis of the above-mentioned vulner-
ability is hardly known at this point. Two association
studies evaluated the Taq-I RFLP site near the D2 dopa-
mine receptor (DRD2) gene in PTSD. The first study
7
compared 37 drug and alcohol addicts with PTSD with
19 addicts without PTSD and found higher frequency
of the A1 allele among the former. The second study
8
failed to replicate this finding in a sample of 52 PTSD
patients and 82 normal controls.
Beyond their conflicting results, these studies are
limited by their small sample sizes, by the salient pres-
ence of co-morbid substance abuse and by fact that the
occurrence of a traumatic event was not evaluated
among control subjects of the second and larger study.
In such case, some control subjects may have under-
gone a traumatic event whereas others have not been
exposed to a trauma. Importantly, those not exposed
could not have expressed the clinical phenotype of
PTSD, despite a possible underlying vulnerability.
PTSD, in fact, required a triggering trauma in order to
be expressed. Thus, the control group could have
included both genetically vulnerable and non-vulner-
able individuals. Yet, the rationale for implying dopa-
minergic neurotransmission in the etiology of PTSD is
sound. Several human studies have shown increased
urinary excretion of dopamine (DA) in PTSD.
9–12
Uri-
nary excretion of DA correlated with the severity of
PTSD symptoms. Higher levels of plasma dopamine
were also found in PTSD.
13
In animal studies, dopami-
nergic innervation of the basolateral nucleus of the
amygdala, the medial prefrontal cortex, and other lim-
bic regions is highly responsive to stress and may be
altered by stress.
14,15
Additionally, genetically deter-
mined strain-dependent alterations in DA release and
DA receptor expression in relevant brain regions of C57
and DBA mice strains have been implicated in differ-
ential strain-specific behavioral abnormalities induced
by chronic stress.
16
This finding was interpreted as sug-
gesting that stress-induced alterations of central dopa-
DAT and PTSD
RH Segman
et al
904
Molecular Psychiatry
minergic neurotransmission may be genotype-depen-
dent and expressed in behavior.
17
Finally, exposure to
stress augments the locomotor responses to cocaine
challenge, partly through altering DA release. Such
sensitization was seen as relevant to the pathogenesis
of PTSD.
18
The dopamine transporter (DAT) is located pre-syn-
aptically on dopaminergic neurons. Reuptake of dopa-
mine released into the synaptic cleft limits the extent
and duration of dopamine receptor activation. A poly-
morphic VNTR region has been described in the
SLC6A3 3⬘ untranslated region cDNA sequence,
19
and
has been previously associated with several behavioral
phenotypes including attention deficit, hyperactivity
disorder
20
and tobacco addiction.
21
Functional rel-
evance for the SLC6A3 for in vivo DAT availability has
been reported, based on striatal [I–123]

-CIT binding,
taken to reflect DAT binding availability based on dis-
placement studies of dopamine and serotonin trans-
porter inhibitors.
22,23
A single positron emission tom-
ography (SPECT) study reported reduced [I-123]

-CIT
striatal binding in 10 repeat homozygotes compared
with 9 repeat carriers in normals,
22
whereas another
study reported reduced [I-123]

-CIT putamen binding
in 9 repeat–10 repeat heterozygotes compared with 10
repeat homozygotes in a mixed sample of normals and
abstinent alcoholics.
23
Although unassociated with
amino acid substitution, the 3⬘ VNTR site may affect
DAT expression through mRNA transcription and stab-
ility, or through linkage disequilibrium with another
functional site.
Given this rationale we investigated DAT gene poly-
morphism in PTSD and trauma-exposed healthy sub-
jects. We compared a group of 102 patients with
chronic PTSD (PTSD group) with 104 trauma survivors
who did not develop PTSD (TS control group). The TS
group consisted of survivors seen in previous prospec-
tive studies of PTSD,
24
whose exposure to traumatic
events and whose initial responses to those events had
been comprehensively documented, as well as the fact
that none of them developed PTSD. Traumatic events
among controls included road traffic accidents (75%),
war events and terrorist acts (18%) and other traumatic
events, such as work accidents, street- and domestic
violence (7%). Traumatic events among PTSD patients
included road traffic accidents (69%), terrorist acts
(25%) and other events (6%). The difference between
the groups in not significant statistically.
As shown in Table 1, there was a significant excess
of 9 repeat alleles in chronic PTSD patients (43% vs
30.5% in non-PTSD;
2
= 6.3, df = 1, P = 0.012). The 9
repeat allele was associated with increased risk for
PTSD (OR = 1.72, 95% CI = 1.12–2.62). Genotype distri-
bution among the two groups was also significantly dif-
ferent (
2
= 6.11, df = 2, P = 0.047). There was an excess
of 9 repeat homozygotes among the chronic PTSD
patients (20.43%) compared to TS (9.47%). Compared
to the other genotypes, homozygosity for the 9 repeat
allele was associated with an increased risk for chronic
PTSD (OR = 2.45, 95% CI = 0.98–6.52).
A linkage disequilibrium (LD) model for phase
unknown data
25
also supported association/LD
between the DAT VNTR site and PTSD (
2
= 6.34,
df = 2, P = 0.011). SLC6A3 allele distribution was in
accordance with Hardy–Weinberg equilibrium (P ⬎
0.1) in both PTSD and TS groups.
Breakdown of the non-Ashkenazi group into respect-
ive countries of origin including North Afrika, Yemen,
Iraq, Iran, and other Asian, showed the following
results: North Africa (n = 44; 22 with PTSD), Yemen (n
= 8; three with PTSD), Iran (n = 8; five with PTSD), Iraq
(n = 11; eight with PTSD) and other Asian (n = 11; nine
with PTSD;
2
(4,80) = 7.68, P = 0.11). Additionally
there was no statistically significant difference in geno-
type distribution (99, 910, 1010) between the above
mentioned non-Ashkenazi ethnic groups (
2
(8,71) =
13.2, P = 0.11), nor a statistically significant difference
in allele (9, 10) distribution (
2
(4,79) = 5.4, P = 0.25).
Logistic regression analysis was applied to evaluate the
effect of population origin and diagnosis (ie PTSD or
non PTSD) as predictors of the DAT alleles and geno-
types frequency; the likelihood ratio (LR) test of the
two models (model 1: population + diagnosis and
model 2: population alone) determines the significance
of diagnosis, controlled for the potential confounding
effect of population. The LR test for DAT alleles shows
a significant association between DAT and PTSD after
controlling for the confounding effect of population
stratification (
2
= 6.42, df 1, P = 0.011), and remains
significant when restricting the analysis to the larger
Non-Ashkenazi group only (
2
= 3.93, df = 1, P =
0.0475). The LR test for association between DAT geno-
types and PTSD controlling for population, shows
again a positive association of DAT with PTSD (
2
=
6.43, df = 2, P = 0.04). Both analyses confirm that the
increased risk to develop PTSD is associated with the
DAT locus and cannot be attributed to population
based genetic biases.
Fourteen (13.5%) of 104 TS subjects and ten (9.8%)
out of 102 PTSD subjects suffered from anxiety dis-
orders (
2
(4,213) = 1.25, P = 0.87). Eighteen (17.3%) of
104 non PTSD subjects and 62 (60.8%) out of 102 PTSD
subjects suffered from depressive disorders (
2
(4,213)
= 43.1, P ⬍ 0.0001). The distribution of DAT genotypes
between PTSD subjects with (n = 38) and without (n =
55) depression was statistically similar (
2
= 0.61, P =
0.73) with 21.8% of those with depression and 18.4%
of those without depression showing the 99 genotype;
41.8% and 50% showing the 910 genotype and 36.4%
and 31.5% showing a 1010 genotype. DAT allele fre-
quency (9 and 10 repeats) did not differ between PTSD
patients with and without depressive disorders (
2
=
0.00, P = 0.97). DAT genotypes were similarly distrib-
uted among PTSD patients with (n = 8) and without (n
= 85) anxiety disorders (
2
= 1.58, P = 0.45) with 18.8%
of those with and 37.5% of those without anxiety dis-
orders showing the 99 genotype; 45.9% and 37.5%
showing the 910 genotype and 35.3% and 25% show-
ing the 1010 genotype. DAT allele frequency was equ-
ally distributed among PTSD patients with and without
anxiety (
2
= 1.42, P = 0.23.)
Our results point to a significant association between
DAT and PTSD
RH Segman
et al
905
Table 1 SLC6A3 9 and 10 repeat allele and genotype frequencies in patients with chronic PTSD and trauma survivors without
PTSD, and
2
analyses for the two groups
Group n Allele frequency Genotype distribution
% (n) % (n)
9 repeat 10 repeat 9–9 9–10 10–10
No PTSD (TS) 95 30.5 (58) 69.5 (132) 9.5 (9) 42.1 (40) 48.4 (46)
PTSD 93 43.0 (80) 57.0 (106) 20.4 (19) 45.7 (42) 34.4 (32)
2
(df) P 6.31 (1) P = 0.012 6.1 (2) P = 0.047
the SLC6A3 9 repeat allele and 9 repeat homozygous
genotype and susceptibility for chronic PTSD. The
above-mentioned twin studies,
1,2
suggest a polygenic
contribution to susceptibility to develop PTSD among
twins exposed to combat. In accordance with this
model, our findings indicate that the 9 repeat allele and
genotype may contribute to such vulnerability.
The lifetime prevalence of PTSD in the general popu-
lation is estimated to be of 10%, and the incidence of
new cases of PTSD among survivors of traumatic
events varies between 2% and 49%.
26
This suggests
that among samples not selected for trauma exposure,
some proportion of subjects may carry a genetic vulner-
ability for PTSD, which remains unexpressed for lack
of exposure. Assuming multifactorial polygenic
inheritance for PTSD,
1
common allelic variation which
may possess a small pathogenic effect given a context
of adequate trauma exposure, would be expected to be
found in different frequencies among differentially
selected samples. A frequency gradation should be
observed with highest pathogenic allele frequency
expected among susceptible samples, intermediate fre-
quency among subjects not selected for trauma
exposure (ie ‘reference population controls’, a pro-
portion of whom may be expected to carry unexpressed
genetic vulnerability for PTSD), and lowest frequency
among a less susceptible sample of trauma survivors
not expressing PTSD. Alternatively an allele pos-
sessing protective effect would be expected to show the
reverse gradation. A previous study of SLC6A3 allele
frequencies in normal Jewish population non selected
for trauma exposure, has shown 15% and 35% for 9
repeat homozygotes and allele carrier frequencies
respectively.
27
Compared with our finding, this fre-
quency is indeed between that found for PTSD and that
found in trauma-exposed non-PTSD subjects (ie,
between 20.4% and 9.5% 9-repeat homozygotes,
respectively for PTSD and TS, and between 43% and
30.5% 9 allele carrier frequency for the same groups;
see Table 1). The group difference (PTSD, Trauma sur-
vivors without PTSD, normal Jewish population) is
statistically significant (
2
(df = 2) = 6.5; P ⬍ 0.05)
Differences in allele frequencies for the SCL6A3
polymorphic site
28
have been reported among different
ethnic populations. Ethnic stratification, however, is
unlikely to explain our results, as both our data and
the above-mentioned study of non-traumatized Jewish
Molecular Psychiatry
controls
27
show similar allele frequencies among Ash-
kenazi and non-Ashkenazi Jews. Moreover, our study
groups had a similar ethnic distribution. Independent
replication, preferably through transmission disequi-
librium design is required to confirm our results. Such
design would be immune to both ethnic confounds and
false-negative diagnoses which may occur in case-
control studies of trauma survivors.
These results provide direct evidence for the
involvement of SLC6A3 allelic status in the etiology of
PTSD. If replicated, they imply that variations in dopa-
minergic neurotransmission may mediate the patho-
logical response to trauma, and, in general, the vulner-
ability to the effect of stress. They also suggest that
trauma-exposure should be monitored in case control
studies of PTSD.
Materials and methods
Subjects
All subject candidates for this study signed a written
informed consent, as sanctioned by the Human Use
Committee of Hadassah University Hospital. Subjects
were considered for inclusion in this study if they were
between 18 and 65 years old, had experienced an event
meeting DSM-IV PTSD criterion A (an operational
definition of a traumatic event) and were Jewish of
definite Ashkenazi or non-Ashkenazi origin (both par-
ents being of Ashkenazi or non-Ashkenazi origin). Sub-
jects were not included in this study if they suffered
from head injury, burn injury or serious physical
injury. Additionally, subjects with current or lifetime
use of alcohol or illicit drugs, those with past or
present psychosis, and those suffering from medical or
neurological illness that could confound the assess-
ments, were not included.
PTSD subjects (n = 102) were recruited among parti-
cipants of follow-up studies of this disorder
24
and
among subjects presenting for treatment in outpatient
clinics in Jerusalem. All PTSD subjects met DSM-IV
diagnostic criteria for current PTSD as obtained by the
Clinician Administered PTSD Scale (CAPS)
29
—a struc-
tured clinical interview for PTSD. The co-occurrence
of other mental disorders was ascertained by the Struc-
tured Clinical Interview for DSM-IV Mental Disorders
(SCID).
30
Both instruments had been extensively used
in previous studies of PTSD and other mental disorders
DAT and PTSD
RH Segman
et al
906
Molecular Psychiatry
and were administered by clinicians with extensive
experience in research, diagnosis and treatment of
PTSD (RK, RS).
Control subjects (n = 104) were equally recruited
among participants of prospective longitudinal studies
of PTSD.
24
Participants in these studies were followed,
for up to 6 months, from the time of their admission
to an emergency room, following a traumatic event.
Information regarding the traumatic event and the early
psychological responses was obtained within 10 days
of admission to the emergency room. The presence of
PTSD was detected, via clinical interviews using the
CAPS, at 1 and 4 months following trauma. Control
subjects did not have PTSD at both 1 and 4 months.
The study groups had similar gender distribution
(55.8% vs 47.1% males among PTSD and non-PTSD
respectively;
2
= 1.58, df = 1, P ⬎ 0.20). The mean age
at the time of the traumatic event was somewhat higher
among PTSD subjects (39.7 ± 11.7 vs 33.9 ± 10.2 years,
P ⬍ 0.05). Lifetime history of mental disorders was
higher among PTSD subjects (12.6% vs 1.1% in TS;
2
= 9.07, df = 1, P ⬍ 0.005).
The study groups were of similar ethnic origins
(Ashkenazi 37.6% vs 39.7%, among PTSD and non-
PTSD respectively; P ⬎ 0.1). Further breakdown of the
non-Ashkenazi group into respective countries of ori-
gin including North Africa, Yemen, Iraq, Iran, and
other Asian, showed no significant differences between
PTSD and controls (
2
(df = 4,80) = 7.6; P = 0.11), and
there was no significant difference in DAT allele (
2
(df
= 4,79) = 5.4; P = 0.25) or genotype (
2
(df = 8,71) =
13.2; P = 0.11) distribution among subjects from the
different countries of origin within the two groups.
Genotyping
Genotyping of the SCL6A3 DAT 3⬘ VNTR polymor-
phism was performed by PCR based restriction analy-
sis, as previously described.
19
Statistical analyses
The Stata-6 program and Statistica for Windows were
used for statistical analyses. There were no differences
in allele frequency for the SCL6A3 alleles between sub-
jects of Ashkenazi and non-Ashkenazi origin among
the control and patient groups; therefore, the groups
were combined for statistical analysis. Maximum
likelihood chi-square statistics were used for categ-
orical analyses. Differences between groups on con-
tinuous variables were evaluated by t-test. Significance
levels are for two-tailed tests; P values ⬍0.05 (two-
tailed) were regarded as significant.
A linkage disequilibrium (LD) model for phase
unknown data was employed as previously described
by Mander & Clayton (2000).
25
This method calculates
allele/haplotype frequencies using log-linear modeling
embedded within an EM algorithm. The EM algorithm
handles the phase uncertainty and the log-linear mode-
ling allows testing for linkage disequilibrium and dis-
ease association. The log-linear model is fitted using
iterative proportional fitting which is implemented in
a specific routine of the Stata 6.0 program which can
handle very large contingency tables and converges to
maximum likelihood estimates. The data to be entered
consist of paired variables representing the alleles at
each locus. If phase is known then the pairs are the
genotypes. When phase is unknown the algorithm
assumes Hardy–Weinberg equilibrium so that models
are based on chromosomal data and not genotypic data.
To evaluate the relationship of more than one inde-
pendent variable to DAT alleles and/or genotypes, a
logistic regression procedure was implemented. The
outcome variable of the logistic regression was the
presence of the DAT alleles or genotypes, employing a
multinomial logistic regression test. The covariates of
the model were the clinical phenotype of interest (ie
presence/absence of PTSD) and the ethnicity, given a
possible population effect on the frequency of DAT
alleles and genotypes. In this case, the phenotype of
interest is regarded as a predictor of the outcome, and
ethnicity as a potential confounder. To increase the res-
olution for detecting a possible ethnic stratification
effect, in addition to the traditional dichotomous
division of subjects to ‘Ashkenazi’ or ‘Non Ashkenazi’
groups, we further evaluated their specific country of
birth, as well as their father’s and mother’s country of
birth. Results from the model are presented as Likeli-
hood Ratio Tests. P values of ⬍0.05 (two-tailed) were
regarded as significant in all analyses. With this
approach, we checked for the homogeneity of the Odds
Ratios (OR) across possible population differences and
tested whether the observed association between DAT
(alleles and genotypes) and PTSD is due to a ‘true’
association or is an effect of a population-specific
variability. This method has been previously success-
fully applied in other studies where there was the need
to assess for a potential effect of population varia-
bility.
31
Hardy–Weinberg equilibrium (P ⬎ 0.1) in both PTSD
and TS groups was calculated with the utility program
of J Ott (http://linkage.rockefeller.edu/ott/linkutil.
htm).
Acknowledgements
This work was supported in part by grants from the
Ministry of Health (Chief Scientist), and the Milton
Rosenbaum Foundation (Hebrew University), to RHS
and AYS.
References
1 True WR, Rice J, Eisen SA, Heath AC, Goldberg J, Lyons MJ, Nowak
J. A twin study of genetic and environmental contributions to liab-
ility for posttraumatic stress symptoms. Arch Gen Psychiatry 1993;
50:257–264.
2 Xian H, Chantarujikapong SI, Scherrer JF, Eisen SA, Lyons MJ,
Goldberg J et al. Genetic and environmental influences on PTSD,
alcohol and drug dependence in twin pairs. Drug Alc Depend 2000;
61:95–102.
3 Brewin CR, Andrews B, Valentine JD. Meta analysis of risk factors
for posttraumatic stress disorder. J Consult Clin Psychol 2000; 68:
784–766.
4 Yehuda R, McFarlane AC. Conflict between current knowledge
about posttraumatic stress disorder and its original conceptual
basis. Am J Psychiatry 1995; 152: 1705–1713.
DAT and PTSD
RH Segman
et al
907
5 Shalev AY, Pitman RK, Orr SP, Peri T, Brandes D. Auditory startle
in trauma survivors with PTSD: a prospective study. Am J Psy-
chiatry 2000; 157:255–261.
6 Connor KM, Davidson JRT. Familial risk factors in PTSD. Ann NY
Acad Sci 1997; 821:35–51.
7 Comings DE, Muhleman D, Gysin R. Dopamine D2 receptor (DRD2)
gene and susceptibility to posttraumatic stress disorder: a study
and replication. Biol Psychiatry 1996; 40:368–372.
8 Gelernter J, Southwick S, Goodson S, Morgan A, Nagy L, Charney
DS. No association between D2 dopamine receptor (DRD2) ‘A’ sys-
tem alleles, or DRD2 haplotypes, and posttraumatic stress disorder.
Biol Psychiatry 1999; 45:620–625.
9 Yehuda R, Southwick S, Giller EL, Ma X, Mason JW. Urinary cat-
echolamine excretion and severity of PTSD symptoms in Vietnam
combat veterans. J Nerv Ment Dis 1992; 180: 321–325.
10 Lemieux AM, Coe CL. Abuse related PTSD: evidence for chronic
neuroendocrine activation in women. Psychosom Med 1995; 57:
105–115.
11 Spivak B, Vered Y, Graff E, Blum I, Mester R, Weizman A. Low
platelet–poor plasma concentrations of serotonin in patients with
combat related PTSD. Biol Psychiatry 1999; 45:840–845.
12 De Bellis MD, Baum AS, Birmaher B, Keshavan MS, Eccard CH,
Boring AM et al. Bennett Research Award. Developmental trauma-
tology. Part I: Biological stress systems. Biol Psychiatry 1999; 45:
1259–1270.
13 Hamner MB, Diamond BI. Elevated plasma dopamine in posttrau-
matic stress disorder: a preliminary report. Biol Psychiatry 1993;
33:304–306.
14 Inglis FM, Moghaddam B. Dopaminergic innervation of the amyg-
dala is highly responsive to stress. J Neurochem 1999; 72: 1088–
1094.
15 Goldstien LE, Rasmusson AM, Bunney BS, Roth RH. Role of the
amygdala in the coordination of behavioral neuroendocrine and
prefrontal cortical monoamine responses to psychological stress in
the rat. J Neurosci 1996; 16: 4787–4798.
16 Puglisi-Allegra S, Cabib S. Psychopharmacology of dopamine: the
contribution of comparative studies in inbred strains of mice. Prog
Neurobiol 1997; 51:637–661.
17 Cabib S, Oliverio A, Ventura R, Lucchese F, Puglisi-Allegra S. Brain
dopamine receptor plasticity: testing a diathesis-stress hypothesis
in an animal model. Psychopharmacology 1997; 132:153–160.
18 Post RM, Weiss SRB, Li H, Leverich GS, Pert A. Sensitization
components of PTSD: implications for therapeutics. Semin Clin
Neuropsychiatry 1999; 4: 282–294.
19 Vandenbergh DJ, Persico AM, Hawkins AL, Griffin CA, Li X,
Jabs EW, Uhl GR. Human dopamine transporter gene (DAT1) maps
Molecular Psychiatry
to chromosome 5p15.3 and displays a VNTR. Genomics 1992; 14:
1104–1106.
20 Cook EH, Stein MA, Krasowski MD, Cox NJ, Olkon DM, Kieffer
JE, Leventhal BL. Association of attention-deficit disorder and the
dopamine transporter gene. Am J Hum Genet 1995; 56: 993–998.
21 Sabol SZ, Nelson ML, Fisher C, Gunzerath L, Brody CL, Hu S et
al. A genetic association for cigarette smoking behavior. Health Psy-
chol 1999; 18:7–13.
22 Jacobsen LK, Staley JK, Zoghbi SS, Seibyl JP, Kosten TR, Innis RB,
Gelernter J. Prediction of dopamine transporter binding availability
by genotype: a preliminary report. Am J Psychiatry 2000; 157:
1700–1703.
23 Heinz A, Goldman D, Jones DW, Palmour R, Hommer D, Gorey JG
et al. Genotype influences in vivo dopamine availability in human
striatum. Neuropsychopharmacology 2000; 22: 133–139.
24 Freedman SA, Peri T, Brandes D, Shalev AY. Predictors of chronic
PTSD: a prospective study. Br J Psychiatry 1999; 174:353–359.
25 Mander A, Clayton D. Haplotype analysis in population-based
association studies using Stata. Stata Techn Bull 2000; 57:5–7.
26 Kessler RC, Sonega A, Bromet E, Hughes M, Nelson CB. Posttrau-
matic stress disorder in the national comorbidity survey. Arch Gen
Psychiatry 1995; 52: 1048–1060.
27 Frisch A, Postilnick D, Rockah R, Michaelovsky E, Postilnick S,
Birman E et al. Association of unipolar major depressive disorder
with genes of the serotonergic and dopaminergic pathways. Mol
Psychiatry 1999; 4:389–392.
28 Kang AM, Palmatier MA, Kidd KK. Global variation of a 40-bp
VNTR in the 3⬘ untranslated region of the dopamine transporter
gene (SLC6A3). Biol Psychiatry 1999; 46:151–160.
29 Blake DD, Weathers FW, Nagy LM, Kaloupek DG, Klaminzer G,
Charney DS, Keane TM. A clinician rating scale for assessing cur-
rent and life time PTSD. The CAPS-I. Behavior Therapist 1990; 13:
187–188.
30 Spitzer RL, Williams JBW, Gibbon M. Structured Clinical Interview
for DSM-III-R (SCID). New York State Psychiatric Institute, Bio-
metrics Research: New York, 1987.
31 Lerer B, Macciardi F, Segman RH, Adolfsson R, Blackwood D,
Blairy S et al. Variability of 5-HT2C receptor cys23ser polymor-
phism among European populations and vulnerability to affective
disorder. Mol Psychiatry 2001; 5:579–585.
Correspondence: RH Segman or AY Shalev, Department of Psychiatry,
Hadassah University Hospital, PO Box 12000, Ein Karem, Jerusalem
91120, Israel. E-mail: sronen얀md2.huji.ac.il or ashalev얀cc.huji.ac.il
Received 9 May 2001; revised 21 July 2001; accepted 24 September
2001
