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Association of the dopamine transporter gene and ADHD symptoms in a Canadian population-based sample of same-age twins.

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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 147B:1442 –1449 (2008)
Association of the Dopamine Transporter Gene and
ADHD Symptoms in a Canadian Population-Based
Sample of Same-Age Twins
Isabelle Ouellet-Morin,1,2 Karen G. Wigg,1 Yu Feng,1 Ginette Dionne,2 Philippe Robaey,3
Mara Brendgen,4 Frank Vitaro,5 Louise Simard,6 Russell Schachar,7 Richard E. Tremblay,8
Daniel Pérusse,9 Michel Boivin,2 and Cathy L. Barr1,7*
1
Genetics and Development Division, Toronto Western Research Institute, University Health Network, Toronto, Canada
School of Psychology, Universite´ Laval, Que´bec, Canada
3
Department of Psychiatry, Universite´ de Montréal, Montréal, Canada
4
Department of Psychology, Universite´ du Que´bec à Montréal, Montréal, Canada
5
School of Psychoeducation, Universite´ de Montre´al, Montre´al, Canada
6
Faculty of Medicine, University of Manitoba, Winnipeg, Canada
7
Department of Psychiatry, Brain and Behaviour Program, The Hospital for Sick Children, Toronto, Canada
8
Department of Psychology, Universite´ de Montre´al, Montre´al, Canada
9
Departments of Anthropology and Psychiatry, Universite´ de Montréal, Montréal, Canada
2
Attention deficit hyperactivity disorder (ADHD)
is the most prevalent psychiatric disorder emerging during childhood. Psychostimulant medications (e.g., methylphenidate) noticeably reduce
ADHD symptoms in most children. Since methylphenidate inhibits dopamine transporter activity,
the dopamine transporter gene (DAT1) was considered to be the prime candidate risk gene in
ADHD. Several studies found evidence for an
association between the 10-repeat allele of the
variable number of tandem repeat (VNTR) located
in the 30 untranslated region and ADHD and/or
ADHD symptoms in clinical and population-based
samples. However, this finding was not replicated
in all samples. In this study, we investigated the
association between the DAT1 gene and ADHD
symptoms in a population-based twin sample from
Québec (Canada). We used two polymorphisms,
the VNTR and rs27072, the last providing the most
significant results in a clinical sample from
Toronto (Ontario, Canada). No association was
noted between the VNTR and ADHD symptoms
in children at 6 and 7 years of age, as reported
by teachers. However, a significant association
was found for the rs27072 polymorphism and
symptoms of inattention and hyperactivity/
impulsivity. These findings indicate that the
DAT1 gene contributes to ADHD symptoms in this
sample and further suggest that the VNTR may
not be the optimal polymorphism for study in all
populations.
ß 2007 Wiley-Liss, Inc.
KEY WORDS: ADHD; genetics; dopamine transporter gene; association; twins
Grant sponsor: Canadian Institutes of Health Research; Grant
number: NET-54016.
*Correspondence to: Cathy L. Barr, Ph.D., The Toronto Hospital
Western Division, 399 Bathurst Street, MP14-302, Toronto,
Ontario, Canada M5T 1S8. E-mail: cbarr@uhnres.utoronto.ca
Received 25 October 2006; Accepted 23 October 2007
DOI 10.1002/ajmg.b.30677
Published online 28 December 2007 in Wiley InterScience
(www.interscience.wiley.com)
ß 2007 Wiley-Liss, Inc.
Please cite this article as follows: Ouellet-Morin I, Wigg
KG, Feng Y, Dionne G, Robaey P, Brendgen M, Vitaro F,
Simard L, Schachar R, Tremblay RE, Pérusse D, Boivin
M, Barr CL. 2008. Association of the Dopamine Transporter Gene and ADHD Symptoms in a Canadian
Population-Based Sample of Same-Age Twins. Am J
Med Genet Part B 147B:1442–1449.
INTRODUCTION
Attention deficit hyperactivity disorder (ADHD) is the most
prevalent psychiatric disorder in childhood, affecting 8–12% of
children worldwide [Faraone et al., 2005]. ADHD is defined as
developmentally inappropriate levels of inattention, hyperactivity, and impulsivity emerging before 7 years of age and
associated with a variety of negative outcomes, including
academic impairments (e.g., poor performance or underachievement) and socio-emotional problems. Twin studies have
repeatedly shown a strong genetic component to ADHD
symptoms [Biederman and Faraone, 2005]. Willcutt [Willcutt,
2005] estimated the genetic contribution to be 0.73, based on
twelve independent twin studies, while the remaining phenotypic variance (0.27) was attributed to non-shared environmental factors. Genetic and environmental contributions have
been shown to be similar in continuous and dichotomized
ADHD measures [Levy et al., 1997]. As a result, ADHD is
considered to represent the extreme phenotypic manifestation
of naturally occurring variation in inattentive and hyperactive/impulsive behaviors in the population. Furthermore,
twin studies of DSM-IV symptom dimensions identified
common genetic factors contributing to both the inattention
and hyperactive/impulsive dimensions and specific genetic
contributions, indicating that risk genes may contribute to
both or either of the dimensions [Levy et al., 2001].
Psychostimulant medications (e.g., methylphenidate and
dexamphetamine) have been shown to generate symptomatic
improvement in up to 70% of ADHD children [Elia et al., 1999;
Wigal et al., 1999; James et al., 2001]. The exact mechanism by
which symptoms are improved is not clear; however, it is
known from functional neuroimaging studies that methylphenidate reduces dopamine transporter availability and binding
sites [Dresel et al., 2000; Krause et al., 2000], thereby
increasing dopamine availability in synaptic areas [Cragg
and Rice, 2004; Levy et al., 2006]. Since psychostimulant
Association Between DAT1 and ADHD Symptoms
medications have been shown to alter dopamine transporter
regulation and contribute to ADHD symptom relief, the
dopamine transporter gene (DAT1) was considered to be
the primary candidate risk gene in ADHD [Cook et al., 1995].
The hypothesized role for DAT1 in ADHD also came from
studies of DAT1 knock-out mice who displayed, in comparison
to normal littermates, a wide range of phenotypic differences,
including hyperactivity, cognitive and motor deficits, and
calming responses to psychostimulant medication [Gainetdinov et al., 1999; Miller et al., 1999; Madras et al., 2005].
The DAT1 gene (SLC6A3), located on chromosome 5p15.3,
contains an 40 bp variable number of tandem repeats (VNTR)
polymorphism in the 30 -untranslated region (UTR) [Vandenbergh et al., 1992] that has been indicated to contribute to
dopamine transporter transcription in some studies but not all
[Fuke et al., 2001; Miller and Madras, 2002]. Cook et al. [1995]
first reported an association between the 10-repeat allele of the
VNTR and ADHD and DSM-III-R attention deficit disorder.
Subsequent studies have replicated this association [Gill et al.,
1997; Waldman et al., 1998; Daly et al., 1999; Curran et al.,
2001; Chen et al., 2003; Hawi et al., 2003; Galili-Weisstub
et al., 2005; Todd et al., 2005; Mill et al., 2005b; Brookes et al.,
2006; Lim et al., 2006], whereas others have not [Barr et al.,
2001; Curran et al., 2001; Payton et al., 2001; Todd et al., 2001a;
Muglia et al., 2002; Feng et al., 2005; Kim et al., 2005; Langley
et al., 2005; Cheuk et al., 2006]. A meta-analysis conducted by
Purper-Ouakil et al. [2005] aggregated the data from 11
studies and found a non-significant association between the 10repeat allele of the VNTR and ADHD when the substantial
sample heterogeneity was accounted for. The estimate of the
contribution of this gene to ADHD (odds ratio of 1.13; 95%
confidence interval, 0.94–1.30) is based on transmission of
VNTR alleles and may be underestimated if this particular
polymorphism is not the functional risk allele. Inconsistent
results are also noted in studies investigating the role of the 10repeat allele of the VNTR to ADHD symptom improvement in
children treated with psychostimulant medications. Some
support of this role was observed in samples predominantly
composed of American [Stein et al., 2005] and Irish Caucasian
children [Kirley et al., 2003], whereas conflicting findings were
reported in Brazilian [Roman et al., 2001], African-American
[Winsberg and Comings, 1999] and Korean [Cheon et al., 2005]
samples.
Few studies have examined the association between the
10-repeat allele of the DAT1 VNTR and ADHD symptoms in
population-based samples [Payton et al., 2001; Todd et al.,
2001b; Mill et al., 2005b]. Conflicting results are again noted;
one study reported a significant contribution of the VNTR
when ADHD symptoms were measured as a continuum [Mill
et al., 2005b]. A second study found a significantly higher
frequency of the 10-repeat allele in 58 children selected from
the population with ADHD scores in the 90th percentile as
measured by the SWAN scale compared to 68 children who
scored below the 10th percentile [Cornish et al., 2005]. Two
other studies did not find evidence for biased transmission in
dichotomized ADHD-related phenotypes with the 10-repeat
allele [Payton et al., 2001; Todd et al., 2001a].
Altogether, conflicting findings have been reported between
the DAT1 VNTR polymorphism and ADHD-related phenotypes. Some inconsistencies may have arisen because ADHD
and/or ADHD symptoms were assessed differently across
studies. ADHD has been evaluated using either DSM symptoms-based presence/absence of the diagnosis [Gill et al., 1997;
Barr et al., 2001], continuous measures [Payton et al., 2001;
Mill et al., 2005b], or dimensional approaches (e.g., latent class
analyses, symptom severity, subtypes) [Waldman et al., 1998;
Todd et al., 2005]. The inconsistent findings and large sample
heterogeneity reported by Purper-Ouakil et al. [2005] may also
be due to the important variability regarding the age of
1443
participants both within and between the samples. Twin
studies have shown that latent genetic factors contribute to
both age-specific and stability of ADHD symptoms during
childhood [Hay et al., 2004]. Data from postmortem studies in
humans indicates age-related changes in expression of the
dopamine transporter with peak expression occurring at
9–10 years of age [Meng et al., 1999; Haycock et al., 2003];
thus, the contribution of this gene to symptoms may also
change over time. Furthermore, changes in DAT1 gene
expression may also be involved in the observed decrease in
ADHD symptoms during young adulthood. Investigating the
association between the DAT1 VNTR polymorphisms and
ADHD symptoms prospectively in an age-homogeneous sample could help to clarify the role of this gene during different
periods of development.
Finally, it is noteworthy that the majority of studies have
focused on this single 30 -UTR VNTR because it was the first
polymorphism identified for this gene and later because there
was evidence that it was functional. However, other DAT1
polymorphisms or haplotypes have also shown evidence for
association [Barr et al., 2001; Hawi et al., 2003; Galili-Weisstub
et al., 2005]. Feng et al. [2005] have shown that the rs27072
polymorphism, recognized by a MspI restriction site located
422 base pairs upstream of the VNTR, was significantly
associated with ADHD in a clinical sample from Toronto while
the VNTR itself was not. This study raised the possibility that
conflicting results could arise if the VNTR is not the functional
variant but, rather, in linkage disequilibrium (LD) with it.
Inconsistent findings would occur if the degree of LD between
the VNTR and the as yet unidentified functional variant
differed across populations, resulting in significant associations in some samples and not in others. Consequently, the
DAT1 VNTR may not be the optimal polymorphism in all
samples.
In this study, we sought to determine the relationship of the
DAT1 gene to inattention and hyperactive/impulsive symptoms in a population-based sample of twins evaluated at 6 and
again at 7 years of age. Investigating the association between
the DAT1 gene and ADHD symptoms in this sample offered
several advantages. First, ADHD symptoms were evaluated
when children were 6 and 7 years of age. Second, teachers
assessed ADHD symptoms independently when the twins were
attending kindergarten and the first grade of primary school.
Twin studies have shown that teachers are less prone than
mothers to have contrast effect types of rater bias [Sherman
et al., 1997; Simonoff et al., 1998], possibly because they may
base their judgments on a larger reference group of children.
Moreover, the propensity for teachers to confuse the twins was
greatly diminished in this study since most twins were
attending separate classes in kindergarten (70%) and first
grade (76%). Finally, the age homogenous sample allows us to
investigate the contribution of this gene to symptoms at a
distinct developmental stage, and thus remove one of the
potential confounds of previous studies.
MATERIALS AND METHODS
Participants
Participants of this study were part of the Quebec Newborn
Twin Study (QNTS), a longitudinal population-based study of
twins born in the greater Montreal area. Families were
recruited between April 1995 and December 1998. Twins were
first seen at 5 months of age and then prospectively assessed at
18, 30, 48, 60, 72, 84, and 100 months to gather data on a variety
of child- and family-related characteristics. This study focuses
on data collected at 72 and 84 months when children were 6 and
7 years old. Zygosity was assessed at 5 and 18 months using a
shortened version the Zygosity Questionnaire for Young Twins
[Goldsmith, 1991]. This questionnaire allows independent
1444
Ouellet-Morin et al.
raters to aggregate their evaluation of the zygosity status
through the assessment of the twins’ physical similarity. DNA
was extracted for 31.3% of same-sex twin pairs selected
randomly. Zygosity status was determined using 8–10 highly
polymorphic micro-satellite markers. Both methods showed a
high concordance rate at 5 months (91.9%) and at 18 months
(93.8%) (reaching about 97%, when chorionicity was taken into
account, as shown in Forget-Dubois et al. [2003]). Genotypes
generated in this study were in complete agreement with the
zygosity status determined previously. The institutional review
board at Sainte-Justine Hospital Research Centre approved the
protocol. Written informed consent and assent from parents and
children was obtained for DNA and data collections.
ADHD symptoms were available for 789 twins at 6 years of
age and 838 twins at 7 years of age (665 were assessed at
both time collection). DNA was collected, genotyped, and
analyzed for the DAT1 VNTR in 458 and 514 twins (at 6 and
7 years old, respectively) and rs27072 polymorphisms in 461
and 579 twins (at 6 and 7 years old, respectively). Note that
only families for whom at least one parent and one child were
genotyped were retained for the analyses. No phenotypic mean
differences were noted between twins genotyped for the DAT1
VNTR [t(787) ¼ 0.71, P ¼ 0.48 and, t(836) ¼ 1.03, P ¼ .30 at 6
and 7 years old, respectively] and rs27072 polymorphisms
[t(787) ¼ 0.54, P ¼ 0.59 and, t(836) ¼ 1.17, P ¼ .24 at 6 and
7 years old, respectively] and twins who were not. The total
number of genotyped families and their distribution according
to parent-child composition, zygosity status, and gender are
summarized in Table I for each polymorphism and time of data
collection. Of the twins that were genotyped for at least one
marker, 88.3% were Caucasian, 1.9% were Asian, 1.1% were
Black, 0.6% were of mixed ethnicity [Caucasian-Native North
American (1 twin pair) and Caucasian-Black (1 twin pair)] and
2.2% were grouped in the ‘‘other ethnicity’’ category. The
remaining families (5.9%) did not provide ethnicity information. Most of the participants (76.8%) had French-Canadian
ancestors.
grade teachers rated the children’s level of inattention and
hyperactivity/impulsivity using eight items adapted from the
Child Social Behavior Questionnaire (CBSQ) [Tremblay et al.,
1987], itself derived from the Preschool Behavior Questionnaire (PSD) [Behar and Stringfield, 1974]. These items chosen
to quantify ADHD symptoms in this population-based sample
were not intended for use for a clinical diagnosis of ADHD. For
instance, teachers reported to what extent a child ‘‘is easily
distracted, has difficulty to pursue an activity,’’ ‘‘is impulsive,
acts before thinking,’’ ‘‘has difficulty awaiting turn in games.’’
The same items were used at both collection times. All items
were assessed on a three point Likert-type scale (0 ¼ never,
1 ¼ sometimes, and 2 ¼ often). This instrument has good
criterion validity and high interrater and test–retest reliabilities in both population-based and clinical samples [Behar and
Stringfield, 1974]. This scale yields high internal consistency
in 6 and 7 year olds (a ¼ 0.85 and 0.91, respectively). ADHD
symptoms were reasonably normally distributed at 6 (kurtosis ¼
0.48, skewness ¼ 0.74) and 7 years of age (kurtosis ¼ 0.17,
skewness ¼ 0.79) [Tabachnick and Fidell, 2001].
Isolation of DNA and Markers Typing
Standard high salt extraction methods were used to isolate
DNA from blood lymphocytes [Miller et al., 1988]. The DAT1
VNTR was genotyped as previously described [Vandenbergh
et al., 1992]. The DAT1 rs27072 marker was genotyped
according to Ueno et al. [1999]. Briefly, the 217-bp fragment
was amplified at an annealing temperature of 608C using the
primers 30 MspF: 50 -ccg tgt ctt
gtg ttg ctg ta-30 and 30 MspR: 50 0
acg ggg att ctc agc agg tg 3 and PCR products subsequently
digested with Msp1 for 2 hr. Restriction fragments (MspI
polymorphism) and PCR products (VNTR) were electrophoresed on 3% agarose gels. Two investigators, blind to the
zygosity status of the twins, scored the genotypes independently. Ambiguous results were reamplified. Samples that
continued to amplify poorly were eliminated from the study,
resulting in different numbers of twins genotyped for the
VNTR and rs27072 polymorphisms.
Procedure and Measures
Teacher ratings of ADHD scores. To ensure that the
teacher had sufficient time to know the children, data
collections took place in the spring. Kindergarten and first
Statistical Analyses
The associations between DAT1 markers and the ADHD
scores were tested using the quantitative transmission
TABLE I. Characteristics of Children Rated for ADHD Symptoms and Genotyped for the DAT1 VNTR and rs27072 Polymorphisms
Zygosity status (%)
Gender (%)
Data collection
DAT1
polymorphisms
Family
composition
Number of
families
MZ
DZ
Male
Female
6 years of age
VNTR
2 parents–2 children
2 parents–1 child
1 parent–2 children
1 parent–1 child
Total
2 parents–2 children
2 parents–1 child
1 parent–2 children
1 parent–1 child
Total
2 parents–2 children
2 parents–1 child
1 parent–2 children
1 parent–1 child
Total
2 parents–2 children
2 parents–1 child
1 parent–2 children
1 parent–1 child
Total
163
31
44
13
251
168
29
40
16
253
174
31
61
13
279
180
29
57
16
282
41
39
27
46
39
40
46
28
44
39
43
43
30
61
41
42
50
30
56
40
59
61
73
54
61
60
54
72
56
61
57
57
70
39
59
58
50
70
44
60
52
39
61
46
51
51
41
65
44
52
51
32
64
61
52
51
35
65
56
52
48
61
39
54
49
49
59
35
56
48
49
68
36
39
48
49
65
35
44
48
rs27072
7 years of age
VNTR
rs27072
Association Between DAT1 and ADHD Symptoms
1445
TABLE II. Frequencies of the DAT1 VNTR and rs27072 Alleles
disequilibrium test (QTDT) [Abecasis et al., 2000]. This
extended version of the transmission disequilibrium test
(TDT) allows conducting family-based association tests of
quantitative phenotypes in nuclear families of any size,
including monozygotic (MZ) and dizygotic (DZ) twin pairs.
The variance-components approach allows for simultaneously
modeling of the mean and variances enhancing the information gathered by the test [Abecasis et al., 2000]. The presence of
spurious association due to population stratification, essentially relegated to the between familial component, could also
be estimated (AP model). In the presence of population
stratification, the association could be reliably tested by
partitioning the genotype and phenotype scores into orthogonal within- and between-familial variance components (AO
model). While exerting an adequate control for population
stratification, the AO model constitutes a conservative test of
allelic association. In the absence of population stratification,
testing the total evidence for association (AT model) should
otherwise be pursued [Fulker et al., 1999; Chen and Abecasis,
2007]. LD between markers was estimated using ldmax
[Abecasis and Cookson, 2000]. We used one-sided tests because
there was an a priori hypothesis for the biased transmission of
the 10-repeat allele and the G allele of rs27072 in previous
studies. Corrections for multiple testing were performed in the
main analyses considering four tests [two markers and the
two time points (6 and 7 years of age)] using the Bonferroni
method with a critical level of a ¼ 0.05 (critical corrected value
P ¼ 0.0125). This method is nevertheless known to be an overly
conservative test because it does not account for the dependence structure existing between the DAT1 polymorphisms and
phenotypes over time. Finally, because identical results are
obtained for diallelic markers, only the G allele’s statistics of
the rs27072 are presented.
DAT1
polymorphisms
VNTR
rs27072
Alleles
Allele
frequencies
11
10
9
7
8
6
G
A
0.011
0.700
0.279
0.002
0.004
0.004
0.834
0.166
sample of twins. Based on previous findings, we used two
polymorphisms located in the 30 -UTR of the DAT1 gene: the
VNTR and the rs27072 polymorphism positioned 422 bp
upstream of the VNTR. High LD was observed between these
polymorphisms (D0 ¼ 0.965, w2(2) ¼ 71.36, P ¼ 0.000). Table II
shows the allelic distribution in this sample. The distribution of
VNTR alleles is similar to those noted in mixed European and
US populations [Vandenbergh et al., 1992; Kang et al., 1999].
In addition, VNTR and rs27072 allele frequencies were
comparable to those observed for the parental chromosomes
of a clinical sample composed of Canadian children with a
diagnosis of DSM-IV ADHD [Feng et al., 2005].
ADHD scores for inattention and hyperactivity/impulsivity
gathered prospectively from teachers when twins were attending kindergarten (6 year olds) and the first grade of primary
school (7 year olds) were examined separately. The MZ and DZ
intraclass correlations for the ADHD symptoms were high at
both time points (6 year olds: MZ ¼ .65 and DZ ¼ .31; 7 year
olds: MZ ¼ 0.63 and DZ ¼ 0.33), yielding to heritability estimates (95% confidence intervals) of similar amplitude to what
is reported in other twin studies [h2 ¼ 0.651 (0.559–0.723) and
h2 ¼ 0.647 (0.558–0.718) at 6 and 7 years of age, respectively].
Using QTDT, we did not observe any evidence of population
stratification for the VNTR or rs27072 polymorphisms, as
reported in Table III (AP model). Therefore, the total evidence
for the association test (AT model) should be prioritized
because it constitutes a reliable but less conservative test of
allelic association when population stratification is unlikely
[Abecasis et al., 2000]. No significant association was observed
between the VNTR and teachers’ report of ADHD symptoms.
However, we did observe a significant allelic association
between the rs27072 polymorphism and ADHD scores when
children were attending kindergarten [w2(1) ¼ 7.26, P ¼ 0.007]
and a trend for a significant association when children were in
the first grade of primary school [w2(1) ¼ 3.74, P ¼ 0.053]. To
explore the possibility that the different findings between 6 and
7 years of age may have resulted from chance variation in the
Power of the Sample
The power of the sample to identify QTL associations with
two-sided tests of significance was estimated using the Genetic
Power Calculator for variance-component QTL association
for sibships (http://pngu.mgh.harvard.edu/purcell/gpc/qtlassoc.html). For 266 twin pairs (averaged number of pairs
included in statistical analyses) assuming the allele frequencies of the VNTR 10-repeat allele and that the risk alleles are
in complete LD with a QTL for ADHD symptoms, this
sample could detect QTLs contributing at least to 1.6% to trait
variance (a ¼ 0.05 and 80% power). The power of the present
sample is therefore slightly less powerful than the one
investigated in Mills et al. [2005b] (1.6% vs. 1.3%).
RESULTS
The aim of this study was to examine the relationship
between DAT1 and ADHD symptoms in a population-based
TABLE III. QTDT Tests of Association for ADHD Symptoms Evaluated at 6 and 7 Years of Age by Teachers
DAT1
polymorphisms
VNTR
9
10
rs27072
G
6 years of age
7 years of age
w2 fit statistic of the modelsa
w2 fit statistic of the models
AP
AT
AO
AP
AT
AO
0.36 (P ¼ 0.551)
0.26 (P ¼ 0.614)
0.02 (P ¼ 0.897)
0.05 (P ¼ 0.822)
0.15 (P ¼ 0.694)
0.06 (P ¼ 0.801)
0.60 (P ¼ 0.437)
0.62 (P ¼ 0.431)
1.07 (P ¼ 0.300)
0.89 (P ¼ 0.345)
1.56 (P ¼ 0.221)
1.45 (P ¼ 0.228)
0.25 (P ¼ 0.616)
7.26 (P ¼ 0.007)
4.27 (P ¼ 0.039)
0.06 (P ¼ 0.808)
3.74 (P ¼ 0.053)
0.89 (P ¼ 0.345)
The AP models showed no indication of population stratification. Thus, AT models could be prioritized over AO models.
AP models, test for Population stratification; AT models, test for Total Association; AO model, test for Orthogonal Association.
a
TDT tests were only conducted for alleles with a frequency higher than 10%.
1446
Ouellet-Morin et al.
TABLE IV. QTDT Tests of Association Between the rs27072 Polymorphism and ADHD Symptoms for Twins Evaluated at Both 6 and
7 Years Olds
6 years of age
7 years of age
2
a
2
w fit statistic of the models
rs27072
G
w fit statistic of the models
AP
AT
AO
AP
AT
AO
0.13 (P ¼ 0.714)
5.33 (P ¼ 0.021)
3.04 (P ¼ 0.081)
0.03 (P ¼ 0.861)
5.62 (P ¼ 0.018)
1.86 (P ¼ 0.172)
The AP models showed no indication of population stratification. Thus, AT models could be prioritized over AO models.
AP models, test for Population stratification; AT models, test for Total Association; AO model, test for Orthogonal Association.
a
TDT tests were only conducted for alleles with a frequency higher than 10%.
twin families included in the analyses, we conducted an
exploratory analysis on a subsample of twins that were rated
for ADHD symptoms at both time points, as presented in
Table IV. We found evidence for association between the
rs27072 polymorphism and ADHD symptoms at 6 years of age
[w2(1) ¼ 5.33, P ¼ 0.021] and at 7 years of age [w2(1) ¼ 5.62,
P ¼ 0.018], indicating that random sample variation may
explain, to some extent, divergent findings in the primary
analyses. Including the sex of the twins as a covariate in the
analyses did not alter the results (not shown). Because
variance components models can be sensitive to the nonnormality of the phenotypic distribution [Iles, 2002], we
recalculated the AP models using 10,000 Monte Carlo
permutations to make sure that the results were not influenced
by non-normality. Similar results were obtained for the VNTR
[9 allele (w2(1) ¼ 0.36, P ¼ 0.58 and w2(1) ¼ 0.60, P ¼ 0.43 at 6
and 7 years of age, respectively) and 10 allele (w2(1) ¼ 0.26,
P ¼ 0.60 and w2(1) ¼ 0.62, P ¼ 0.44 at 6 and 7 years of age,
respectively)] and the rs27072 polymorphisms [w2(1) ¼ 0.25,
P ¼ 0.65 and w2(1) ¼ 0.06, P ¼ 0.79 at 6 and 7 years of age,
respectively]. These results suggest that the phenotypic
distributions did not affect the test of population stratification.
Finally, based on results from twin studies that indicate that
there are shared as well as unique genetic influences
contributing to symptom dimensions [Levy et al., 2001], we
performed a secondary analysis, examining separately the
relationship of the rs27072 marker and symptom dimensions of
ADHD (inattention, and hyperactivity/impulsivity) using
teacher-reported symptoms at 6 years of age. We found
evidence for association with both dimensions and this marker
(Table V).
DISCUSSION
The main objective of this study was to investigate the
association between the DAT1 gene and ADHD symptoms in a
TABLE V. QTDT Tests of Association Between the rs27072
Polymorphism and ADHD Dimensions at 6 Years of Age
w2 fit statistic of the models
ADHD dimensions
AP
Hyperactivity/impulsivity
G
0.41
(P ¼ 0.52)
Inattention
G
0.04
(P ¼ 0.84)
AT
AO
6.78
(P ¼ 0.009)
4.48
(P ¼ 0.03)
5.43
(P ¼ 0.02)
2.59
(P ¼ 0.107)
AP models, test for Population stratification; AT models, test for Total
Association; AO model, test for Orthogonal Association.
population-based sample. The polymorphism that has been
examined most often in relation to ADHD symptoms is the
30 -UTR VNTR; however, inconsistent findings have been
noted, suggesting that other DAT1 polymorphisms in LD with
the VNTR could be involved. Accordingly, the rs27072 polymorphism, located 422 bp upstream of and in strong LD with
the VNTR, was shown to be significantly associated with
ADHD in a clinical sample of children aged between 6 and
16 years old [Feng et al., 2005]. In this study, we did not find a
significant association between the DAT1 VNTR and ADHD
symptoms in a population-based sample; however, a significant association was observed with the rs27072 polymorphism.
Few studies have examined the DAT1 contribution to ADHD
symptoms in population-based studies. Our DAT1 VNTR
results contrasts with the conclusions of Cornish et al. [2005]
that found an association with the DAT1 VNTR in selected
children with high ADHD scores. Our findings are in contrast
to the main analyses reported by Mill et al. [2005a] that
indicated an association between ADHD and the 10-repeat
VNTR allele in a sample of 329 DZ male twins followed
prospectively when a composite measure of symptoms was
averaged across parental reports obtained at ages 2, 3, 4, and
7 years and the teacher assessment collected at 7 years of age.
However, the results agree with the single point analysis of the
measures reported by teachers at 7 years of age that were not
significant. Nevertheless, our results are consistent with other
population-based twin studies [Payton et al., 2001; Todd et al.,
2001a] that did not find an association. Those two studies differ
in the age of participants (5–17 years olds and 7–19 years olds,
respectively) and phenotype analyzed. Payton et al. [2001]
compared selected MZ twins with extremely high and low
symptoms whereas Todd et al. [2001a] targeted DSM-IV
subtypes and latent classes. Because of the different phenotypes chosen for analyses (instruments, informant, age,
selection criteria), conclusions based on the results of the
different population based samples are difficult to interpret
and potential age or informant related differences could be
obscured.
The present study provided evidence that the rs27072
polymorphism was significantly associated with ADHD symptoms even though it was in strong, but not complete, LD with
the VNTR. This finding, based on a distinct sample with a more
homogeneous ethnic background (mostly French ancestors),
converges with results obtained by Feng et al. [2005] using a
clinical sample of Canadian school age children (ages 6–16)
drawn from a much more heterogeneous ethnic background.
Furthermore, this association was observed for both the
inattention and hyperactive/impulsive symptom dimensions
at 6 years of age, consistent with results from the abovementioned clinical sample (Crosbie et al., in preparation).
Replication of these data is especially noteworthy not only
because it further supports the previous report [Feng et al.,
2005], but also because this convergent finding was obtained
Association Between DAT1 and ADHD Symptoms
from a population-based sample that was evaluated at the
same age for all twins. It is currently unknown if the DAT1
gene influences ADHD risk differently across age groups.
However, evidence from postmortem studies indicating temporal changes in DAT1 expression during development [Meng
et al., 1999; Haycock et al., 2003] suggests this possibility.
Continued study of the twins over additional time points will
allow us to determine if there is in fact a developmental change.
Prospective molecular studies conducted with age-homogenous participants are now needed to replicate the rs27072
polymorphism association with ADHD symptoms and to
determine if this association is specific to a given period of
development or is stable over time.
As stated previously, the 30 VNTR polymorphism has been
the focus of the majority of molecular genetic studies involving
the DAT1 gene because there is some evidence suggesting that
the VNTR alleles may influence transcription [Fuke et al.,
2001; Miller and Madras, 2002]. Using in vitro expression
assays, several groups have provided experimental evidence
that variability in the repeat number of the VNTR and the 30 UTR sequence may influence dopamine transporter protein
levels. The first study of this polymorphism found that
luciferase expression was significantly higher when the 30 UTR containing the 10-repeat allele was transfected in the
COS7 (African Green Monkey kidney) cell line compared to
constructs harboring either the 7- or 9-repeat alleles [Fuke
et al., 2001]. However, another study found the opposite result
as greater expression was observed when constructs containing the 9-repeat were transfected into a human embryonic
kidney (HEK-293) cells [Miller and Madras, 2002]. These
authors also identified a DNA variant (T/C), located 134 bp
downstream of the VNTR recognized by the restriction enzyme
DraI. This DNA variant was reported to influence levels of
protein expression but in a promoter-dependent manner. This
DNA variant was not observed in 102 individuals with ADHD,
which suggests that this DNA change is unlikely to be relevant
to ADHD symptoms [Feng et al., 2005]. Two additional studies,
using either a mouse dopaminergic cell line [Greenwood and
Kelsoe, 2003] or human neuroblastoma and human embryonic
kidney cell lines [Mill et al., 2005a], found no effect on
transcription by the 10- or 9-repeat alleles. The varying results
from the in vitro studies may be a function of the different
constructs used including the specificity of the promoter,
different cell types used for transfection studies or possibly
from the sequence around the VNTR included in the construct.
Evidence in support of the latter can be gleamed from a study
that found that the inclusion of the 800 bp sequence from the
stop codon to just 50 of the VNTR influences DAT1 transcription, mRNA stability or translation as evident from the
lower DAT1 protein density in an in vitro assay [VanNess et al.,
2005]. Notably, the 800 bp sequence includes the rs27072
polymorphism but excluded the VNTR. The position of rs27072
within a functional region may thus explain the significant
result for this marker in our sample.
In conclusion, this study gives some support to the idea that
the DAT1 VNTR may not be the best polymorphism to
investigate the association between DAT1 and ADHD related
phenotypes in all samples. While the role of the VNTR
sequence on gene expression remains unclear, other polymorphisms have now been identified that also appear to be
functional. These include a VNTR located in intron 8 [Brookes
et al., 2006; Guindalini et al., 2006], several variants that
change DAT1 amino acid sequence [Dar et al., 2006], and
several promoter polymorphisms [Kelada et al., 2005]. Further
molecular studies are now needed to ascertain the relationship
between these as well as the rs27072 polymorphism and
ADHD symptoms, particularly in the studies that previously
reported no association between the DAT1-VNTR and ADHD
symptoms.
1447
ACKNOWLEDGMENTS
This work was supported by a New Emerging Teams Grant
from the Canadian Institutes of Health Research (NET-54016),
and by NHRDP and FQRSC grants. Isabelle Ouellet-Morin is
supported by fellowships from the Canadian Institutes of
Health Research (CIHR) and the Behavioral, Gene and
Environment Training Grant Program (CIHR). We thank all
families that have generously accepted to participate in this
study.
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