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Dopaminergic candidate genes in Tourette syndrome Association between tic severity and 3 UTR polymorphism of the dopamine transporter gene.

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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 144B:900 –905 (2007)
Dopaminergic Candidate Genes in Tourette Syndrome:
Association Between Tic Severity and 30 UTR Polymorphism of the
Dopamine Transporter Gene
Zsanett Tarnok,1 Zsolt Ronai,2 Judit Gervai,3 Eva Kereszturi,2 Julia Gadoros,1
Maria Sasvari-Szekely,2 and Zsofia Nemoda2*
1
Vadaskert Child and Adolescent Psychiatric Clinic, Budapest, Hungary
Institute of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary
3
Institute for Psychology of the Hungarian Academy of Sciences, Budapest, Hungary
2
Multiple evidence suggests an involvement
of the dopamine neurotransmitter system in
Tourette syndrome (TS). Therefore, dopaminergic
candidate genes are in the center of genetic
association analyses of TS. In this study, 103 TS
patients and their parents have been characterized for different dopamine-related polymorphisms including the 48 bp variable number of
tandem repeats (VNTR) of the dopamine D4
receptor (DRD4) gene, the 40 bp VNTR of the
dopamine transporter (DAT1, SLC6A3) gene
and the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene. In addition, the 120 bp duplication and three single
nucleotide polymorphisms (SNPs) were assessed
in the promoter region of the DRD4 gene. The
616G allele and the 2-G-A-C haplotype (i.e., the
2-repeat form of the 120 bp sequence 616G 615A 521C combination) were preferentially
transmitted, however, these results did not
remain significant after correction for multiple
testing. Case-control analyses have also been
carried out, resulting in negative findings. On
the other hand, using a dimensional approach, the
DAT1 40 bp VNTR showed an association with the
peak tic-severity as measured by the Yale Global
Tic Severity Scale. Patients with at least one copy
of the 9-repeat allele had significantly more severe
symptoms than individuals with the homozygous
10/10 genotype (P ¼ 0.002). In summary, allele
frequencies did not differ between cases
and controls, but DAT1 genotype accounted for
variations of tic severity within the TS group.
ß 2007 Wiley-Liss, Inc.
KEY WORDS: variable number of tandem
repeats (VNTR); dopamine D4
receptor (DRD4); promoter; polymorphism; haplotype
Grant sponsor: Hungarian Fund OTKA; Grant number:
F042730.
*Correspondence to: Zsofia Nemoda, Institute of Medical
Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, POB 260, H-1444, Hungary.
E-mail: nemzso@puskin.sote.hu
Received 21 August 2006; Accepted 29 January 2007
DOI 10.1002/ajmg.b.30517
ß 2007 Wiley-Liss, Inc.
Please cite this article as follows: Tarnok Z, Ronai Z,
Gervai J, Kereszturi E, Gadoros J, Sasvari-Szekely M,
Nemoda Z. 2007. Dopaminergic Candidate Genes in
Tourette Syndrome: Association Between Tic Severity
and 30 UTR Polymorphism of the Dopamine Transporter
Gene. Am J Med Genet Part B 144B:900–905.
INTRODUCTION
Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder characterized by multiple chronic tics, that is,
involuntary, rapid, non-rhythmic skeletal movements and
vocalizations. The prevalence of TS varies in different agegroups, and is presently estimated as 1% among school-age
children [Robertson, 2003]. TS is often accompanied by
obsessive-compulsive disorder (OCD) or attention deficit
hyperactivity disorder (ADHD). A common neurobiological
origin is hypothesized suggesting a dysfunction of the basal
ganglia—thalamico-cortical loops in these neurodevelopmental disorders [Sheppard et al., 1999]. Tic severity shows great
individual variation ranging from mild to severe. In addition, it
is characteristic for the disorder that the symptoms are waxing
and waning; their number, frequency, and complexity change
during development [Leckman, 2002]. Family and twin studies
demonstrated a significant contribution of genetic factors in
the etiology of TS. Searching for the susceptible genetic
regions, chromosomal mapping and analyses of candidate
genes have been employed in this polygenic disorder [Pauls,
2003]. Based on pharmacological evidence, candidate genes
investigated to date in TS belong primarily to the dopaminergic
system. Dopamine D2 receptor antagonists can effectively
suppress tics; while dopaminergic agonist stimulants can
occasionally exacerbate the symptoms [McCracken, 2000].
Therefore, the first association studies targeted the D2 family
dopamine receptors (D2, D3, and D4 receptors).
The dopamine D4 receptor (DRD4) gene, which contains a
48 base pair variable number of tandem repeats (48 bp VNTR)
in the third exon, has been in the center of genetic association
studies of TS. The first association study of the 48 bp VNTR
with TS showed preferential transmission of the 7-repeat allele
[Grice et al., 1996], but the subsequent family-based study did
not confirm this finding [Hebebrand et al., 1997]. Two other
case-control studies also led to contradictory results [Cruz
et al., 1997; Comings et al., 1999]. Recently, Diaz-Anzaldua
et al. [2004] demonstrated excessive transmission of the
7-repeat allele in a French Canadian TS population. The
controversial results might be clarified by studying further
DRD4 polymorphisms. A 120 bp duplication (120 bp dup)
located 1.2 kb upstream of the transcription start site was
identified by Seaman et al. [1999]. In addition to this
duplication, there are several single nucleotide polymorphisms
(SNPs) in the 50 region of the DRD4 gene, of which the 616C/G
The P-values are presented for the allele (df ¼ 1) and genotype (df ¼ 2) distributions. DRD4 48 bp VNTR genotypes were grouped according to the presence of the 7-repeat allele, resulting in the 7-present (7þ)
and 7-absent (7) groups.
a
df ¼ 3 for the four most frequent genotype (2/4, 4/4, 4/7, 7/7) categories.
0.624
0.419a
177
62.3
107
37.7
90
31.7
139
48.9
0.875
0.707
55
19.4
4
1.4
62
21.8
0.800
0.827
218
76.8
72
25.4
131
46.1
0.744
0.255
81
28.5
74
26.1
0.473
0.740
9
3.2
201
70.8
67
65.0
36
35.0
31
30.1
55
53.4
17
16.5
2
1.9
20
19.4
81
78.6
20
19.4
57
55.3
26
25.2
77
74.8
23
22.3
3
2.9
Tourette syndrome
n (total 103)
Frequency (%)
Control
n (total 284)
Frequency (%)
P (df ¼ 1)
P (df ¼ 2)
7
7þ
TT
CT
Genotype
1/1
1/2
2/2
CC
CG
GG
AA
AG
GG
CC
521
615
616
120 bp dup
A group of 103 TS patients (mean age: 13 4.5 years; 87.4%
male and 12.6% female) from the Vadaskert Child and
Adolescent Psychiatric Clinic participated in this study.
Diagnosis was based on DSM-IV criteria [American Psychiatric Association, 1994], and was conducted by two independent
psychiatrists (inter-rater reliability reached 0.95). Comorbid
conditions were assessed by the Hungarian child version of the
Mini-International Neuropsychiatric Interview [MINI-Kid;
Balazs et al., 2004]. The following conditions were found in
the sample: ADHD 38.8%; OCD 29.1%; anxiety or mood
disorder 23.3%; learning disorder: 15.5%; conduct or oppositional defiant disorder 10.7%. Children with IQ < 80 (estimated from the Raven progressive matrices test; Raven, 1965),
as well as those who had severe medical or neurological
conditions, or pervasive psychiatric disorder were excluded.
In the analysis, peak tic severity (most severe condition in tic
symptoms) was measured by the YGTSS score. The Yale Global
Tic Severity Scale is a clinician-completed rating scale used to
assess the variety, frequency, duration, intensity, and complexity of motor and vocal tics. In addition, it measures the
degree of overall impairment. These scales produce a total
severity score that ranges from 0 to 100; in normative clinical
samples, the mean total severity score of the YGTSS is
44.8 17.7. The YGTSS has demonstrated acceptable internal
consistency, good inter-rater reliability and acceptable convergent and divergent validity [Leckman et al., 1998].
The study was approved by the Local Ethics Committee
(TUKEB). All children and their parents provided written
informed consent for their participation. The sex-matched
Polymorphic sites
METHODS
Subjects and Measures
TABLE I. Genotype Frequencies of the DRD4 Polymorphisms in TS Patients and Controls
and 521C/T SNPs have been extensively studied in ADHD
[Mill et al., 2003; Lowe et al., 2004].
The dopamine transporter is another key element in the
dopamine neurotransmission, as it removes dopamine from the
synaptic cleft thus influencing the magnitude and duration of
the post-synaptic receptor-mediated signaling. A common
40 bp VNTR in the 30 untranslated region has been widely
studied in relation to ADHD; the 10-repeat allele has been
suggested as a genetic risk factor for this disorder [Faraone
et al., 2005]. The 10/10 genotype was also more frequent in a TS
group [Comings et al., 1996]; and tendency for preferential
transmission of the 10-repeat allele was observed in a familybased study [Diaz-Anzaldua et al., 2004]. The 10-repeat allele
has been associated with internalizing disorders [Rowe et al.,
1998], whereas externalizing behavior problems were linked to
the 9-repeat allele [Young et al., 2002].
The dopamine catabolizing enzyme, catechol-O-methyltransferase (COMT) has been also studied in child psychiatric
disorders. A G-to-A transition in the 158th codon of the
membrane-bound enzyme form causes a valine–methionine
substitution (Val158Met). In the soluble COMT form this
polymorphism is located in the 108th codon. The Met form (A
allele) has 20–25% reduced enzyme activity compared to the
Val variant coded by the G allele [Lachman et al., 1996]. Since
COMT catabolizes dopamine, this variation might cause
significant differences in the brain dopamine level. Assessing
the complexity of dopamine homeostasis, association studies
started to use allele-combinations reflecting high and low
dopamine levels [Fossella et al., 2002].
In the present study, we performed an association analysis
between TS and seven dopaminergic polymorphisms located in
the DRD4, DAT1, and COMT genes using both case-control
and family-based approaches. Beside the diagnostic categories,
we used a dimensional measure of tic-severity assessed by the
Yale Global Tic Severity Scale [YGTSS; Leckman et al., 1998].
48 bp VNTR
DAT1 Polymorphism and Tic Severity
901
902
Tarnok et al.
control group was selected from the previously described
healthy Hungarian population [Szantai et al., 2005]. Both the
clinical and the control samples were ethnically homogenous
and of Caucasian origin.
Genotyping
Non-invasive DNA sampling was applied as described
elsewhere [Boor et al., 2002]. DNA was isolated from buccal
cells using phenol-extraction and alcohol precipitation [Sambrook et al., 1989] or by the DNA-purification kit obtained from
Gentra (Minneapolis, MN). Genotyping procedures for the
DRD4 48 bp VNTR and the DAT1 30 VNTR were carried out
using published protocols [Vandenbergh et al., 1992; Ronai
et al., 2000]. Genotyping and haplotyping of the four DRD4
promoter polymorphisms were performed as described previously [Szantai et al., 2005].
The COMT Val158Met polymorphism was genotyped by a
single-step allele-specific amplification using two allele-specific
and two outer primers (comt-a: TGG TGG ATT TCG CTG GCA,
comt-g: CAC ACC TTG TCC TTC AC; comt-k2: ACA CCC ATA
CAA GCA TTC ATC, comt-k1: TGC TCA CCT CTC CTC CGT).
The HotStarTaq DNA-polymerase kit (Qiagen, Valencia, CA)
was used applying 0.125 U enzyme in a total volume of 10 ml, in
the presence of 1x buffer and 1x Q solution supplied, 1 mM
primers, 200 mM of dATP, dCTP, dTTP, and 100 mM of dGTP and
dITP. The thermocycling was initiated by 15 min 958C
denaturation step; it was followed by 40 cycles of 948C 1 min,
568C 30 sec, 728C 1 min; and 10 min 728C final extension.
Data Analysis
SPSS 10.0 for Windows was used for all statistical analyses.
DRD4 48 bp VNTR genotypes were grouped according to the
presence of the 7-repeat allele, resulting in 7-present (7þ) and
7-absent (7) groups. In the case of the DAT1 30 VNTR, the rare
10/11 genotype was grouped together with the 10/10 genotype,
because a study investigating the effect of this repeat sequence
on gene expression did not find significant difference between
the 11-repeat and 10-repeat alleles [Inoue-Murayama et al.,
2002]. Since no functional data existed for the 8-repeat allele, a
single subject with 8/10 genotype was omitted from the
association analyses. For the family-based approach the
extended Transmission Disequilibrium Test [ETDT, Sham
and Curtis, 1995] was used.
RESULTS
In the case-control analysis, 103 TS patients and 284 sexmatched control individuals were included. In addition to the
DRD4 48 bp VNTR, the 120 bp duplication, the 616C/G SNP
(rs74302), the 521C/T SNP (rs1800955), and the recently
identified 615A/G SNP (rs936462) were included to evaluate
potential effects of the DRD4 promoter variants. Neither allele
nor the genotype frequencies of the DRD4 polymorphisms
differed significantly between the case and the control groups
(Table I). Haplotypes of the DRD4 promoter polymorphisms
were also assessed, but there was no significant difference
detected in the case-control study (Table II).
Family genotype data were available for 71 trios and 23 duos.
The TDT analysis showed a bias for the DRD4 promoter
haplotypes (Table II). The 2-repeat allele of the 120 bp
sequence 616G 615A 521C (2-G-A-C) combination
was preferentially transmitted to TS patients (26 vs. 7 times;
TDT w2 ¼ 10.939, df ¼ 1, P ¼ 0.0009). However, the P-value of
the overall allele-wise TDT was only marginally significant
(TDT w2 ¼ 18.064, df ¼ 10, P ¼ 0.054). A tendency of overtransmission of the 616G allele was also detected (39 vs.
24 times; TDT w2 ¼ 3.606, df ¼ 1, P ¼ 0.058). No preferential
allele transmission has been observed for the other DRD4
polymorphisms (allele-wise TDT P values were the followings:
48 bp VNTR: 0.173; 120 bp dup: 0.516; 616A/G: 0.724; 521C/
T: 0.257). The same approach was used for the DAT1 3’ VNTR
and the COMT Val158Met polymorphisms. Neither the casecontrol (Table III), nor the TDT analysis yielded significant
association (the allele-wise TDT P values were 0.188 and 0.541,
for the DAT1 and COMT polymorphisms, respectively).
Finally, we tested the potential effects of the dopaminergic
polymorphisms on the Yale Global Tic Severity Scale scores.
Since TS symptoms are waxing and waning in time, we used
the peak tic severity scores to obtain an overall measurement of
tics. Preliminary analyses showed that the sex of subjects did
not affect tic severity (females: 52.46 20.47, males:
51.73 18.58, F ¼ 0.02 (df ¼ 1,100) P ¼ 0.888), but the age of
subjects had a nearly significant effect (F ¼ 3.72 (df ¼ 1,100)
P ¼ 0.057). Therefore, age was entered as a covariant in all
subsequent ANOVAs testing genetic effects. Table IV summarizes the results for the individual polymorphisms. Only the
DAT1 3’ VNTR showed a significant association with the total
tic severity score (F ¼ 4.784 (df ¼ 2,98) P ¼ 0.010). Since the
YGTSS mean score of the 9/9 group was similar to that of the 9/
10 group, we grouped the genotypes according to the presence
or absence of the 9-repeat allele (9/9 þ 9/10 vs. 10/10). Patients
carrying at least one copy of the 9-repeat allele had more severe
tic symptoms on average than individuals with the 10/10
genotype (9-present: n ¼ 49, 57.80 16.83; 9-absent: n ¼ 53,
46.51 19.01; F ¼ 9.664 (df ¼ 1,99) P ¼ 0.002, effect size: etasquare ¼ 0.089). After the stringent Bonferroni correction for
multiple testing the DAT1 VNTR—YGTSS association was
still significant (P < 0.0073).
DISCUSSION
The aim of the present study was to identify specific
dopaminergic gene variants as genetic risk factors for TS. In
our TS group neither the case-control analysis nor the TDT
supported an association between the DRD4 48 bp VNTR and
TABLE II. Genotype Frequencies and Transmission Disequilibrium Test of the DRD4 Promoter Haplotypes
Haplotype
Tourette syndrome
n (total 103)
Frequency (%)
Control
n (total 284)
Frequency (%)
TDT
Passed
Not passed
1CAC
1CAT
1GAC
1GAT
1GGC
1GGT
2CAC
2CAT
2GAC
2GAT
2GGC
2GGT
7
3.4
10
4.9
2
1.0
8
3.9
—
—
2
1.0
32
15.5
60
29.1
37
18.0
26
12.6
11
5.3
11
5.3
22
3.9
23
4.0
17
3.0
24
4.2
3
0.5
3
0.5
86
15.1
162
28.5
76
13.4
88
15.5
46
8.1
18
3.2
2
4
7
2
—
—
2
2
18
25
26
7
14
19
8
10
9
5
4
5
5
10
27
33
The overall P-value in the case-control study was P ¼ 0.402 (df ¼ 9). In the family-based analysis the overall allele-wise TDT (df ¼ 10) yielded P ¼ 0.054.
DAT1 Polymorphism and Tic Severity
903
TABLE III. Genotype Frequencies of the DAT1 and COMT Polymorphisms in TS Patients and Controls
DAT1 30 VNTR
Polymorphic sites
Genotype
Tourette syndrome
n (total 103)
Frequency (%)
Control
n (total 284)
Frequency (%)
P (df ¼ 1)
P (df ¼ 2)
COMT
9/9
9/10
10/10
Othersa
Met/Met
10
9.7
39
37.9
51
49.5
3
2.9
28
27.2
51
49.5
24
23.3
28
9.9
100
35.2
150
52.8
6
2.1
80
28.2
151
53.2
0.488
0.595
53
18.7
0.797
0.859
Met/Val
Val/Val
The P-values are presented for the allele (df ¼ 1) and genotype (df ¼ 2) distributions.
a
Rare genotypes included one 8/10 and two 10/11 genotypes in the TS group; 10/11, 10/13, 10/14, 9/15, 6/10, and 7/9 genotypes in the control group.
TS. To analyze the possible interactive effect of promoter
polymorphisms, we also assessed the 120 bp duplication and
three SNPs in the 50 non-coding region of the DRD4 gene. The
616G allele and the 2-G-A-C haplotype (i.e., the 2-repeat
form of the 120 bp sequence 616G 615A 521C
combination) was preferentially transmitted to TS patients.
However, after correcting for multiple testing these results did
not remain significant. In addition to the DRD4 polymorphisms, two other dopaminergic polymorphisms were tested.
Although both case-control and TDT analyses have been
carried out, neither the DAT1 30 VNTR, nor the COMT
Val158Met polymorphisms were associated with TS using
the diagnostic categories. Regarding the COMT polymorphism, our findings are consistent with previous studies [Barr
et al., 1999; Cavallini et al., 2000]. In the case of the DAT1
VNTR, we cannot confirm the possible role of the 10-repeat
allele as a risk allele.
A different picture emerged when we analyzed tic severity of
the TS patients. The 40 bp VNTR located in the 30 non-coding
region of the dopamine transporter gene was associated with
peak tic severity measured by the Yale Global Tic Severity
Scale. Assessing the total tic severity score, subjects with a 9repeat variant had 25% higher scores than those possessing the
long allele only. There was no difference in the mean tic
severity scores between the 9/9 and 9/10 genotype groups,
suggesting that the 9-repeat allele might act as a dominant
allele in this neurobiological correlation.
Several lines of evidence suggest that the DAT1 30 VNTR
affect gene expression, however, results obtained from the
in vitro experiments as well as from the in vivo neuroimaging
studies are controversial. Using luciferase reporter gene
expression system, Fuke et al. [2001] showed that the 10repeat allele had higher transcriptional activity compared to
the 9-repeat form, but other studies resulted in contradictory
TABLE IV. Effect of the Dopaminergic Gene Polymorphisms on the YGTSS Total Tic Severity
Score
Polymorphism
DRD4
120 bp dup
616C/G SNP
615A/G SNP
521C/T SNP
48 bp VNTR
COMT
Val158Met
DAT
30 VNTR
Genotype
YGTSS score SD
1/2
2/2
CC
CG
GG
AA
AG
CC
CT
TT
7
7þ
54.17 20.75
50.51 18.12
55.38 19.92
50.42 17.20
51.20 21.53
50.63 19.12
53.90 15.82
52.29 13.25
53.82 21.33
48.03 16.01
51.57 19.45
52.31 17.53
Met/Met
Met/Val
Val/Val
51.50 20.41
53.06 17.37
49.58 20.02
9/9
9/10
10/10
9/9þ9/10
10/10
57.00 16.01
58.00 17.23
46.51 19.00
57.80 16.83
46.51 19.00
F
df
P
1.198
1,97
0.276
0.326
2,99
0.722
0.750
1,98
0.388
1.020
2,99
0.364
0.009
1,100
0.926
0.570
2,99
0.568
4.784
2,98
0.010
9.664
1,99
0.002
Due to n < 5 group sizes, the 120 bp 1/1 and 615 GG genotypes were omitted from these analyses. In case of the
DAT1 30 VNTR the 10/11 genotype was grouped together with the 10/10 genotype; the single 8/10 genotype was left
out (see Methods Section).
904
Tarnok et al.
findings [Miller and Madras, 2002; Mill et al., 2005]. Regarding
the SPECT studies, one group showed significant differences in
the protein density between various genotype groups of a
healthy population: those with at least one copy of the 9-repeat
allele (9/9 and 9/10 genotype) had higher transporter density
compared to the 10/10 genotype group [van Dyck et al., 2005].
Two other studies did not find any significant difference
between the genotype groups [Heinz et al., 2000; Martinez
et al., 2001].
SPECT analyses of TS patients have produced more
consistent results. Most studies showed increased dopamine
transporter density in the striatum of TS patients compared to
controls [Muller-Vahl et al., 2000; Cheon et al., 2004; SerraMestres et al., 2004]. When tic severity was assessed, there was
no significant association between the dopamine transporter
binding ratios and YGTSS scores (Serra-Mestres et al., 2004;
Cheon et al., 2004). However, these analyses were carried out
on very small samples (n 15), therefore, they might be unable
to detect moderate effects of complex interactions. Based on the
results of the largest SPECT study [n ¼ 96; van Dyck et al.,
2005], where the 9-repeat allele was linked to higher dopamine
transporter density, we may speculate about this allele as a
risk factor for TS and/or for tic severity. Still, we need to be
cautious in interpreting our result of the association between
the DAT1 40 bp VNTR and tic severity until independent
replication. In addition, functional studies clarifying the effect
of the 40 bp VNTR in the 30 non-coding region of the dopamine
transporter gene are still needed.
It is important to note that using the dichotomous DSM-IV
diagnostic variable, we did not find association between the
DAT1 30 VNTR and TS. However, when we used the continuous
YGTSS variable, the 9-repeat allele was associated with more
severe tic symptoms. We propose that this dopamine transporter polymorphism is a genetic risk factor for tic severity in
TS, but it contributes to the overall syndrome in a minor,
sometimes undetectable way. The dopamine transporter—
being a key component in the ‘‘uptake-dominated’’ dopamine
transmission of basal ganglia—might contribute to the development of tics on a larger scale. In addition, our data support
the recent guidelines in psychiatric genetics, which suggest
that dimensional models, such as severity-scales, might better
describe a disorder than the categorical ones. Using quantitative dimensions could also facilitate the detection of small
genetic effects. Showing the same association between tic
severity and DAT1 30 VNTR in a larger sample (including
patients with less severe symptoms) would support the notion
that YGTSS peak tic severity can be used as a reliable
diagnostic variable of TS.
ACKNOWLEDGMENTS
This work was supported by Hungarian fund OTKA
F042730. The authors thank Gabriella Kolmann for her
valuable technical assistance.
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associations, tic, polymorphism, syndrome, dopaminergic, dopamine, severity, transport, tourettes, utr, genes, candidatus
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