Journal of Traumatic Stress, Vol. 22, No. 6, December 2009, pp.

534–539 (
C 2009)

The Role of the Dopamine Transporter (DAT) in the

Development of PTSD in Preschool Children
Stacy S. Drury
Tulane University Health Sciences Center, New Orleans, LA

Katherine P. Theall and Bronya J.B. Keats

Louisiana State University Health Sciences Center, New Orleans, LA

Michael Scheeringa
Tulane University Health Sciences Center, New Orleans, LA

Population-based association studies have supported the heritability of posttraumatic stress disorder (PTSD).
This study explored the influence of genetic variation in the dopamine transporter (DAT) 3 untranslated region
variable number tandem repeat on the development of PTSD in preschool children exposed to Hurricane Katrina,
diagnosed using a developmentally appropriate semistructured interview. A diagnosis according to the Diagnostic
and Statistical Manual of Mental Disorders, Fourth Edition ( DSM-IV; American Psychiatric Association,
1994), total symptoms, and specifically Criterion D symptoms were significantly more likely to be found in children
with the 9 allele. This study replicates a previous finding in adults with PTSD. The specificity of this finding to
the increased arousal symptoms of Criterion D suggests that dopamine and the DAT allele may contribute to one
heritable path in a multifinality model of the development of PTSD.

Posttraumatic stress disorder (PTSD) is a complex disorder that Halligan, & Beirer, 2001). Twin studies provide additional sup-
develops in a significant proportion of individuals after exposure port for a genetic component to the development of PTSD and
to one or multiple traumatic events. In addition to the criteria have consistently found that 20–30% of the variance in the devel-
for exposure to a traumatic event, PTSD is also characterized by opment of PTSD after trauma exposure is due to genetic factors
three distinct symptom clusters in the Diagnostic and Statistical (Stein, Jang, Taylor, Vernon, & Livesley, 2002; True et al., 1993;
Manual of Mental Disorders, Fourth Edition (DSM-IV ; American Xian et al., 2000). Similar to many psychiatric disorders the ge-
Psychiatric Association, 1994). Criterion B includes symptoms netic contribution is most likely polygenic. Using case control and
of reexperiencing of the traumatic experience, Criterion C in- candidate gene studies, molecular genetic studies are beginning to
cludes symptoms related to avoidance of reminders about the trau- identify associations between the development of PTSD and genes
matic experience, and Criterion D includes symptoms of increased implicated in the stress response as well as genes involved in the ac-
arousal such as sleep disturbances, irritability, hypervigilance, dif- tivity and metabolism of dopamine, and other neurotransmitters.
ficulty concentrating, and exaggerated startle response. Although These genes include the dopamine transporter (DAT), dopamine
trauma exposure is necessary for the development of PTSD, not receptor 2 (DRD2), dopamine beta-hydroxylase (DBH), the sero-
all individuals exposed to traumatic events develop PTSD. There tonin transporter (5HTT), Forkhead binding protein 5 (FKBP5),
is increasing evidence that genetic vulnerability may play a role in catechol-o-methyltransferase (COMT), and brain-derived neu-
the susceptibility to PTSD after trauma exposure. rotrophic factor (BDNF; Binder et al., 2008; Broekman, Olff,
Evidence supporting the role of genetic factors in the develop- & Boer, 2007; Kilpatrick et al., 2007; Koenen, 2007; Lee et al.,
ment of PTSD comes from several sources. Family studies exam- 2005). Few, if any of the studies have been replicated, and for genes
ining the rates of PTSD in children of parents with and without such as DRD2, where more than one study has evaluated its asso-
PTSD indicate that the rates of PTSD are higher in children whose ciation with PTSD, there have been inconsistent results (Gelernter
parents had PTSD than in similar-trauma-exposed children whose et al., 1999). Therefore, although there is clear evidence for a ge-
parents did not have PTSD (Sack, Clarke, & Seeley, 1995; Yehuda, netic component to PTSD, specific genes and/or specific genetic

This research was supported by a R01 MH65884-01 from the NIMH, awarded to Dr. Scheeringa, as well as an APIRE research award from the American Psychiatric Association awarded to Stacy
S. Drury, M.D, Ph.D.
Correspondence concerning this article should be addressed to: Stacy S. Drury, Department of Psychiatry and Neurology, Tulane University Health Sciences Center, 1440 Canal Street, TB 52 10th
floor, New Orleans, LA 70112. E-mail: [email protected].


C 2009 International Society for Traumatic Stress Studies. Published online in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/jts.20475

534
 DAT and PTSD in Preschool Children 535

variations that influence the development of PTSD have yet to be preschool children who experienced Hurricane Katrina and were
convincingly and consistently reported. subsequently assessed for PTSD using a developmentally specific
Several lines of evidence support the role of dopamine in the semistructured interview.
etiology of PTSD including increased urinary and plasma levels
of dopamine in individuals with PTSD, and a significant posi-
tive correlation between dopamine levels and severity of PTSD
METHOD
(Hammer & Diamond, 1993; Yehuda, Southwick, Giller, Ma,
& Mason, 1992). Preclinical studies have indicated that of the
Participants
three known major dopaminergic neuronal systems, the mesocor- Participants were recruited primarily from weekly newspaper ad-
tical/mesoprefrontal system (from midbrain to prefrontal cortex) vertisements. A minority were recruited from flyers in a pedia-
is preferentially activated by stress compared to the other two sys- trician’s office and contacts at community events. One hundred
tems. This is thought to have the effect of increasing the “gain” on thirty-nine children were enrolled and their caregivers attended
the information processing system and increasing vigilance related the first laboratory visit alone. Of these, 109 returned for the
to PTSD (see Vermetten & Bremner, 2002 for a review). Several second visit with their children during which buccal swabs were
genes involved in dopamine neurotransmission and metabolism obtained. This study was approved by the Tulane University School
including DAT, COMT, and DRD2 have been associated with the of Medicine Institutional Review Board.
development of PTSD (Goldstein, Rasmusson, Bunney, & Roth, Inclusion criteria included children who were (a) 3–6 years of
1996; Rauch et al., 2000). Exploring the association between poly- age, (b) English-speaking, and (c) an inhabitant of the New Orleans
morphic variations in genes integral to dopamine metabolism and metropolitan area at the time of Hurricane Katrina. Children could
neurotransmission is therefore an appropriate approach to identify not participate if they had moderate mental retardation, autistic
genetic factors contributing to the development of PTSD. disorder, deafness, blindness, or were non-English speaking. These
The DAT gene, also known as SLC6A3, is located on chro- conditions were screened with questions for the caregiver over the
mosome 5p15 and functions as the main regulator of dopamine phone during intake and a second level review of videotape of
levels in the synaptic cleft via reuptake through the transporter. the children by an experienced child psychiatrist (M.S.). Moderate
DAT is expressed in a small number of neurons in the brain, mental retardation was screened as a Peabody Picture Vocabulary
particularly in the striatum, nucleus accumbens, and the ventral Test score below 50. No children met these exclusion criteria.
tegmental area (VTA; Ciliax et al., 1995; Garris & Wightman, The primary female caregiver of each child participated with the
1994). Located within the gene is a variable number tandem re- children.
peat (VNTR) element of 40 base pairs in the 3 UTR noncoding Of the 109 children enrolled in the study with exposure to Hur-
region of the gene. Individuals can have alleles of this VNTR rang- ricane Katrina, the final analysis was conducted on 88 children.
ing from 3 to 12 copies (Min Kang, Palmatier, & Kidd, 1999), but DNA samples that did not amplify consistently (8), individuals
the majority of individuals have alleles with either 9 or 10 copies. who refused to participate in genetic aspect of the study (2), or
Functional differences appear to exist specifically between the 9 individuals with alleles different from the 9 or 10 alleles (11) were
and 10 alleles. In vitro studies have found that the 9 repeat allele not included in the final analysis. Individuals who did not partic-
has an elevated transcription rate when compared to the 10 repeat ipate in the genetic aspect of the study or whose DNA did not
allele (Michelhaugh, Fiskerstrand, Lovejoy, Bannon, & Quinn, amplify consistently did not differ in number of PTSD symptoms
2001). In vivo studies examining the influence of genotype on or number of criterion specific symptoms from those included in
DAT binding have been inconsistent: Some find increased DAT the final analysis. The genotype distribution of the three genotypes
binding with the 10/10 allele, another study found decreased stri- included in analysis did not differ from the Hardy-Weinberg equi-
atal binding with the 10/10 genotype, and a third study found no librium, χ 2 (1, N = 88) = 3.31, ns (Table 1). Our allele frequency
difference (Heinz et al., 2000; Jacobsen et al., 2000; Marinez et al., is 0.70 for 10 allele and 0.60 for the frequency of 10/10 genotype
2001). One previous study has examined the relation between this and is consistent with a range of studies of the DAT transporter
polymorphism and PTSD. In this study, Segman et al. (2002) (Min Kang et al., 1999).
identified an association between the 9 allele of the VNTR and
the development of PTSD in a case control study of 102 chronic
PTSD patients and 104 control individuals matched for combat
Measures
and trauma exposure without PTSD. Posttraumatic stress disorder (PTSD) diagnosis and symptoms
Due to the significant evidence supporting the role of dopamine counts were assessed using the Preschool Age Psychiatric Assess-
neurotransmission in PTSD and the previous finding of an asso- ment. Test–retest reliability of the Preschool Age Psychiatric As-
ciation between the 9 allele of the DAT VNTR and PTSD we sessment is comparable to structured psychiatric interviews used
sought to replicate this finding. We examined the association of to assess older children and adults, with an intraclass correlation
this polymorphism with the development of PTSD in a group of coefficient of .56 and a kappa of .73 for the PTSD module. (Egger

Journal of Traumatic Stress DOI 10.1002/jts. Published on behalf of the International Society for Traumatic Stress Studies.
536 Drury et al.

Table 1. Frequency of DAT Alleles Distributed in the turer’s recommendations. Genotyping for the DAT VNTR was
Sample performed using the polymerase chain reaction (PCR). The PCR
products were then electrophoresed through a 2% agarose gel
Sample using standard protocols. Allele determination was made based
on the size of fragments compared to known genotypes and size
DAT Allele (N = 99) No. alleles Allele % standards (Michelhaugh et al., 2001). The PCR was performed
3 3 1.5 on a Bio-Rad C1000 thermal cycler (Bio-Rad Laboratories, Her-
5 1 .5 cules, CA) using the following conditions 5 primer (forward): 5 -
8 5 2.5 TGTGGTGTAGGGAACGGCCTGAG-3 , 3 primer (reverse):
9 48 24.5 5 -CTTCCTGGAGGTCACGGCTCAAGG-3 . The PCR was
10 139 70.0 carried out in a 50 μL reaction with 10 pmol of each primer,
11 1 .5 1.25 U of Ex TaqTM DNA Polymerase (TaKara Bio USA, Madi-
12 1 .5 son, WI), 1 × Ex TaqTM Buffer, 200μm dNTPS. Thermal cycling
conditions were an initial denaturation for 5 minutes followed by
Note. Each subject (N = 99) has two alleles; therefore, there were 198 alleles in the 40 cycles of 94 for 30 seconds, 58 for thirty seconds, and 72 for
total sample.
45 seconds. Ten microliters of final reaction was size fractionated
on a 2% agarose gel with a standard 1kb DNA ladder for size
determination. Alleles ranged from 3 copies to 12 copies; 100% of
et al., 2006). The Preschool Age Psychiatric Assessment interview the samples were reamplified and analyzed twice. All genotyping
was performed by trained research assistants who were blind to was done blind to PTSD status. Samples that failed to amplify
genotyping information. Interviewers were trained on the con- fragment size consistently or failed to amplify were eliminated
tent and scoring of the Preschool Age Psychiatric Assessment by a from further analysis.
trainer from Duke University where the Preschool Age Psychiatric
Assessment was created. Subsequent interviewers were trained on
content and scoring rules by one of the local investigators (M.S.). Data Analysis
New interviewers that joined the study observed experienced inter-
As there is evidence that there are functional differences between
viewers give three interviews and then coded two interviews while
the 9 and 10 alleles of the VNTR, and the number of individ-
observing experienced interviewers and compared codes afterward.
ual rare alleles was small, we examined the relationship between
Next, they administered their first interview while being observed
PTSD and the DAT VNTR in individuals with 9/9, 9/10, or
by a trainer and given immediate feedback. Next, the coding of
10/10 genotypes. We excluded those with the rare alleles as the
every symptom of their next three interviews was completed with
functional significance of those alleles is unknown and this is con-
the advice of an experienced interviewer. Finally, throughout the
sistent with previous studies of this polymorphism (Durston et al.,
study, the lead investigator (M.S.) met individually with inter-
2008; Karama et al., 2008). The PTSD diagnosis by genotype
viewers weekly to watch their most symptomatic interviews on
group was tested with logistic regression. Number of symptoms by
videotape to prevent drift, critique technique, and correct coding
genotype group was tested with nonparametric Wilcoxon rank sum
errors, with special attention focused on the Criterion B reexperi-
tests because symptom count data was not normally distributed.
encing symptoms and the two avoidance symptoms.
Gender, race, and age were examined for association with geno-
Because of research that has suggested that DSM-IV criteria
type. Analysis of variance examining total symptoms and symp-
need substantial modifications to be valid for young children, we
toms specific to each criterion were examined for association with
also diagnosed PTSD by the empirically validated alternative algo-
genotype. Analysis of PTSD symptoms was performed exploring
rithm for young children (Scheeringa, Zeanah, Myers, & Putnam,
10/10 homozygotes compared to children with the 9 allele (9/9
2003; Task Force on Research Diagnostic Criteria: Infancy and
and 9/10 genotypes).
Preschool, 2003). The alternative algorithm required only one
of the seven symptoms in Criterion C (avoidance and numbing
symptoms) instead of three symptoms. Severity variables for Crite-
ria B, C, and D were summed scores of the 5, 7, and 5 symptoms,
RESULTS
respectively, that constitute those criteria.
From February 2006 through April 2008, buccal swabs were
Genotype Data and Allele Frequencies
obtained from children during an ongoing study PTSD study in There was no significant association between genotype and eth-
preschool children (M.S.). DNA was extracted from MasterAmp nicity, gender, or age. Analysis of genotype by PTSD symptoms
buccal swabs from Epicentre Biotechnologies (Madison, WI) us- within race categories, White and Black, resulted in no signifi-
ing the MasterAmp DNA extraction solution following manufac- cant difference in mean total symptoms or symptom number by

Journal of Traumatic Stress DOI 10.1002/jts. Published on behalf of the International Society for Traumatic Stress Studies.
 DAT and PTSD in Preschool Children 537

Table 2. Race and Gender by Genotype: 10/10 Homozy- race (Table 2). When the analysis was performed within the Black
gotes Compared to 9/9 and 9/10 Homozygotes (n = 88) race category, PTSD symptoms continued to be significantly as-
sociated with allele status. Black children with the 9 allele had
10/10 n = 52 % 9/10 + 9/9 n = 36 % significantly more PTSD symptoms (M = 6.7, SD = 2.9) com-
pared to Black children with the 10 allele (M = 4.6, SD = 2.4;
Race
Wilcoxon rank sum test z(49) = 2.42, p < .05). White children
Black 33 38 16 18
with the 9 allele showed a similar pattern of more PTSD symptoms
White 17 20 18 20
(M = 5.9, SD = 3.4) compared to White children with the 10
Other/mixed 2 2 2 2
allele (M = 4.8, SD = 2.3), but it did not reach statistical sig-
Gender
nificance. For the calculated effect size of 0.39 to reach statistical
Male 29 33 23 26
significance in the White children, a sample size of 37 per group
Female 23 26 13 15
would have been needed.

criterion indicating that these results are unlikely due to population

stratification (Table 2).
DISCUSSION
The pathophysiology underlying PTSD is complex and is likely
explained by multifinality in which different pathways, includ-
Genetic Association With PTSD Diagnosis and Symptoms ing multiple genetic contributions, lead to different outcomes.
Logistic regression results revealed that there is a significant differ- Population-based association studies have supported the heritabil-
ence in PTSD diagnosis according to genotype classification, odds ity of PTSD, and several specific genes have been associated with
ratio (OR) = 2.40, 95% CI = 1.02–5.67, Wald χ 2 (1, N = 88) = the development of PTSD. No previous studies had examined the
4.00, p < .05. Pairwise analysis indicates that individuals with the genetic contribution of PTSD in preschool children, although her-
9/9 genotype are approximately 6 times as likely to develop PTSD itability for anxiety disorders may be higher in younger age groups
as individuals with the 10/10 genotype, OR = 6.00, 95% CI = (Boomsma, van Beijsterveldt, & Hudziak, 2005). To date, asso-
1.07–33.54, Wald χ 2 (1, N = 61) = 4.17, p < .05. Using the ciations of specific allele variants with PTSD had been shown in
alternative PTSD criteria there was a marginally significant associ- single studies or have had replication failures raising the possibility
ation between the three genotypes and PTSD diagnosis, OR = of false-positive findings. Our findings replicate those of Segman
1.88, 95% CI = .97–3.67, Wald χ 2 (1, N = 88) = 3.45, et al. (2002) and strengthen the hypothesis that DAT is implicated
p = .06. in the etiology of PTSD. Further, the finding that this association
Individuals with the 9 allele (9/9 or 9/10 genotypes) had signifi- appears driven, for the most part, by Criterion D symptoms sug-
cantly greater total number of PTSD symptoms than homozygous gests a relatively more specific relationship between DAT and the
10 children and further analysis revealed that this was driven by neurobiology of PTSD.
Criterion D symptoms. Children with the 9 allele had significantly Criterion D symptoms have been conceptualized as increased
more Criterion D symptoms compared to homozygous 10/10 chil- arousal phenomena including hypervigilance, concentration dif-
dren, but there was no significant differences with Criterion B or ficulty, irritability, exaggerated startle, and sleep disturbance. The
Criterion C symptom counts (Table 3). underlying disturbance of these symptoms is thought to be due to
To explore ethnic stratification we analyzed PTSD symptoms individuals’ preoccupations with trauma-related internalizations
within the two largest race categories, Black (n = 49) and White that preclude normative orienting, attention, and self-regulation.
(n = 35), as the other categories did not contain sufficient num- This model is consistent with research that has found increased
bers of individuals for meaningful analysis (n = 4). There were no attention to threat stimuli in individuals with PTSD compared
significant differences in allele frequencies or PTSD symptoms by to individuals without PTSD in samples of children 9–17 years

Table 3. Mean Number of Posttraumatic Stress Disorder Symptoms by Allele Status

Frequency Frequency Total Criterion B Criterion C Criterion D
Allele (n) (%) symptoms SD symptoms SD symptoms SD symptoms SD
9/10 or 9/9 36 40 6.2 3.1 2.0 1.1 1.6 1.3 2.5 1.1
10/10 52 60 5.1 2.5 1.8 1.0 1.1 1.1 1.9 1.0
Test statistic Z(N = 88) = 2.22∗ Z(N = 88) = 1.02 Z(N = 88) = 1.90 Z(N = 88) = 2.46∗
∗p < .05.

Journal of Traumatic Stress DOI 10.1002/jts. Published on behalf of the International Society for Traumatic Stress Studies.
538 Drury et al.

old (Dalgleish, Moradi, Taghavi, Neshat-Doost, & Yule, 2001) as a result of this polymorphism and alterations in dopamine
and adults (Bryant & Harvey, 1997). The association of the DAT levels support our hypothesis. The association with Criterion D
9 allele, heightened attention, and PTSD appears to converge with symptoms is intriguing, as no previous studies have examined
evidence from healthy populations that the DAT 9 allele is asso- the association of genetic factors with specific PTSD symptom
ciated with increased attention capacities. In a general population criterion. It may be that part of the complexity of PTSD comes
study of healthy 6- to 11-year-olds, children with the 9/10 geno- from differential genetic risk factors for particular criterion. If
type performed better on tests of selective attention and inhibitory so, future genetic studies of PTSD ought to consider specifically
capacity than children with the 10/10 genotype (Cornish et al., exploring associations with the Criteria B, C, and D symptoms to
2005). In another study of normal children aged 9–16, heterozy- delineate further the neurobiology of PTSD.
gous children with the 9/10 genotype performed better on tests Clinical applications of genetic findings in this early stage of
of reorienting attention compared to children homozygous for the research are somewhat remote. However, genetic studies may ul-
10 allele (Bellgrove et al., 2007). These studies when taken together timately identify vulnerable individuals and guide interventions
indicate that the DAT 9 allele may confer heightened capacity for or preventive approaches for those at risk for trauma exposure.
attention. As PTSD is associated with heightened attentional bias With increasing numbers of studies finding associations between
to threat, it appears logical that the DAT 9 allele would confer allele variants and psychiatric disorders, traction is building in the
increased risk, relative to the DAT 10 allele, for the development field for genetics to help define the underlying mechanisms leading
of PTSD. to the development of psychopathology, relations between genet-
Several caveats to this study exist. Genotype was statistically as- ically determined neurobiology and disorders, and personalized
sociated with PTSD using the DSM-IV criteria, but was marginally approaches to interventions.
statistically significant with the alternative criteria diagnosis. The Future genetic studies may benefit from restricted data sets that
fact that the genotype was significantly associated with continuous focus on single trauma types, limited age ranges, and evaluation of
measures of the number of PTSD symptoms and the number of specific criterion. Genetic studies of PTSD have the potential to
Criterion D symptoms may indicate that genotype status is more delineate further the underlying neurocircuitry altered with trau-
predictive of severity of PTSD rather than categorical diagnoses. matic exposure that results in the development of this complex,
A potential limitation is that we did not correct for ethnic common, and impairing disorder. Given the role of the DAT in
stratification in this study. Statistical analysis to adjust for ethnic attention and the known role of attention to trauma reminders and
stratification is done to prevent false-positive findings in studies PTSD, future studies ought to evaluate attention and orientation
when allele frequencies differ normatively between ethnic groups. tasks as a function of DAT genotype in children with and without
However, ethnic stratification was not corrected for in this study, PTSD. These studies may further define the relation between varia-
as analysis of mean total symptoms and criterion symptoms were tion in the DAT and the neurobiology underlying PTSD. Through
not statistically different between Black and White race categories. an enhanced understanding of the neurobiological underpinnings
For population stratification to present a statistical difficulty for of PTSD novel treatment modalities may be developed.
association studies both differences in allele frequencies between
racial groups and differences in rates of psychopathology have to
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Journal of Traumatic Stress DOI 10.1002/jts. Published on behalf of the International Society for Traumatic Stress Studies.