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Association of dopamine serotonin and nicotinic gene polymorphisms with methylphenidate response in ADHD.

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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 147B:527 –530 (2008)
Brief Research Communication
Association of Dopamine, Serotonin, and Nicotinic Gene
Polymorphisms With Methylphenidate Response in ADHD
Hema Tharoor,1,2*{ Elizabeth A. Lobos,1 Richard D. Todd,1,3 and Angela M. Reiersen1
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri
Department of Psychiatry, Kasturba Medical College, Manipal, India
Department of Genetics, Washington University School of Medicine, St. Louis, Missouri
Gene polymorphisms of the 30 untranslated region
(30 -UTR) of the dopamine transporter (DAT1),
Dopamine receptor exon 3 D4 variable number
tandem repeat (DRD4VNTR), nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) and
(SLC6A45HTTLPR) are under consideration as potential
risk factors for attention-deficit/hyperactivity
disorder (ADHD). A post-hoc attempt was made
to investigate the association between the allelic
variations of these candidate genes and retrospective parental report of response to methylphenidate in an ADHD-enriched, populationbased twin sample. Subjects (N ¼ 243) were
selected from the twin sample based on parent
report that the child had been treated with
methylphenidate for ADHD symptoms. The functional polymorphisms screened were the VNTR
located in the 30 -UTR of the dopamine transporter,
DRD4 VNTR, CHRNA4 (rs1044396 and rs6090384)
and the long (LA and LG) and short (S) forms of the
serotonin transporter promoter region. Logistic
regression did not demonstrate a significant
association between methylphenidate treatment
response and the relevant polymorphisms. The
sample size had high power to detect effect sizes
similar to those reported in some prior methylphenidate pharmacogenetic studies; however, the
categorical (yes/no) measure of parent-reported
treatment response may not have been sensitive
enough to pick up statistically significant differences in treatment response based on genotype.
Further studies including quantitative measures
of treatment response are warranted.
ß 2007 Wiley-Liss, Inc.
nomics; ADHD
Assistant Professor.
Grant sponsor: NIMH; Grant numbers: 52813, 17104; Grant
sponsor: International Research Training in Clinical Sciences
(Fogarty); Grant number: NIH 05811.
*Correspondence to: Hema Tharoor, D.P.M., D.N.B.,
M.N.A.M.S., Post Doctoral Research Fellow, Department of
Psychiatry, Campus Box 8134, 660 South Euclid Avenue, St.
Louis, MO 63110. E-mail:,
Received 4 May 2007; Accepted 29 August 2007
DOI 10.1002/ajmg.b.30637
ß 2007 Wiley-Liss, Inc.
Please cite this article as follows: Tharoor H, Lobos EA,
Todd RD, Reiersen AM. 2008. Association of Dopamine,
Serotonin, and Nicotinic Gene Polymorphisms With
Methylphenidate Response in ADHD. Am J Med Genet
Part B 147B:527–530.
Pharmacogenetic investigations of attention-deficit/hyperactivity disorder (ADHD) are an extension of our understanding of the genetic basis of the disorder [McGough, 2005].
It is well established that dopamine dysregulation is a
significant contributor to the pathophysiology of ADHD. This
is based mainly, but not solely, on the observation that agents
increasing synaptic dopamine, such as methylphenidate
(MPH), a drug that acts primarily by blocking the dopamine
transporter, are effective in controlling ADHD symptoms
[Biederman and Faraone, 2005].
Numerous candidate genes are associated with increased
risk of ADHD, and many of these genes are related to
dopaminergic function [Faraone et al., 2005]. This includes
variable number tandem repeat polymorphisms in the 30
untranslated region of the dopamine transporter gene (DAT1
30 -UTR VNTR), and within the dopamine D4 receptor gene
Though less studied, there are several lines of evidence
suggesting that the nicotinic system may also be functionally
significant in ADHD. Kent et al. [2001] conducted the first
study to test for linkage and association between the Cfol
polymorphism within the nicotinic acetylcholine alpha 4receptor gene (CHRNA4) and ADHD and found no evidence
for association or linkage with ADHD using the TDT (w2 ¼ 0.89,
P ¼ 0.35). Todd et al. [2003a] conducted a TDT study using
multiple CHRNA4 markers in a sample of 172 children with
DSM-IV ADHD and reported significant evidence of overtransmission of the three SNPs identified in the exon/intron 2
region in ADHD (w2 ¼ 9.12, corrected P ¼ 0.011), but they did
not observe evidence of linkage between ADHD and haplotypes
constructed from the exon 5 region polymorphisms.
Many of the ADHD candidate genes have been investigated
due to presumed mechanisms of action of psychostimulants
and it has been hypothesized that polymorphic variants in
theses same genes may also influence medication responses in
individual patients [McGough et al., 2006]. The majority of
published studies in ADHD pharmacogenetics have examined
relationships between methylphenidate response and polymorphisms at the dopamine transporter gene (DAT1),
although results are inconclusive [McGough, 2005; Levy,
2007]. Four published studies have investigated the relation
between the DAT1 30 -UTR VNTR alleles/genotypes and
therapeutic response to MPH [Winsberg and Comings, 1999;
Roman et al., 2002; Kirley et al., 2003; Stein et al., 2005].
Although each of these studies reported positive findings, there
was no consistency with regard to the effect of each allele/
genotype on therapeutic response. Briefly, while Winsberg and
Tharoor et al.
Comings [1999] and Roman et al. [2002] reported a better
therapeutic response in children with the 9/10 genotype
compared to children with the 10/10 genotype, two other
studies [Kirley et al., 2003; Stein et al., 2005] found better
treatment response in patients homozygous for the 10-repeat
allele. Kirley et al. [2003] reported that transmission of the 10repeat allele was significantly greater (P ¼ 0.005) in children
retrospectively judged as very good responders to MPH. Stein
et al. [2005] was the only group that analyzed the 9/9 genotype
group separately from the two other genotype groups and
found that the homozygous 9-repeat allele had decreased
response to MPH. Several studies found no effect of DAT1
[Hamarman et al., 2004; Langley et al., 2005; Van der Meulen
et al., 2005; McGough et al., 2006]. Recently, Joober et al.
[2007] sought to test the hypothesis that the VNTR polymorphism in the 30 -UTR of the DAT1 gene modulates behavior
in children with ADHD and /or behavioral response to MPH in
a 2-week prospective within-subject (crossover) trial. They
demonstrated that individuals having the 9/10 and 10/10
genotypes displayed a significant positive response to MPH as
opposed to those homozygous for the 9-repeat allele.
The role of dopamine receptor genes (DRD4 and DRD5) in
treatment response has also been examined in ADHD.
Consistent with in vitro studies showing that the 7-repeat
(48-base pair) VNTR polymorphism in the coding region of
DRD4 produces blunted response to dopamine [Van Tol et al.,
1992; Asghari et al., 1995], Hamarman et al. [2004] found that
one or two copies of the 7-repeat allele necessitated higher
methylphenidate doses for optimal symptom reduction.
McGough et al. [2006] explored in preschoolers with ADHD
whether genetic polymorphisms likely to be involved in stimulant
mechanisms and ADHD risk may also underlie variability in
medication response. Results indicated a significant association
(P ¼ 0.05) between symptom response and variants at DRD4.
Seeger et al. [2001] examined interactive effects of the
DRD4*7-repeat allele and the long (L allele) polymorphism of
the transcriptional promoter region (5HTTLPR) of the serotonin transporter gene (SLC6A4) on treatment outcome by
estimating the CGAS (Children’s Global Assessment Scale)
improvement by genotype. Paired comparisons between the
different genotypes through post-hoc testing revealed that
subjects homozygous for the DRD4 7-repeat allele and the L
form of the 5HTTLPR showed a significantly lower improvement in the CGAS compared to each of all other polymorphic
combinations, with the exception of the combination nonDRD4*7/SS. The promoter region of the serotonin transporter
has subsequently been shown to have a second SNP near or in
the repeat region, which confers lower activity [Hu et al., 2004].
Using retrospective data on methylphenidate treatment
response from an epidemiological and clinically relevant
naturalistic study of ADHD, the current report describes a
post-hoc analysis of the association between methylphenidate
treatment response and several gene polymorphisms that
have previously shown association with ADHD diagnoses or
methylphenidate treatment response. The Missouri Twin
study is a large birth records based sample of twins born in
the state of Missouri, which was enriched for the presence of
ADHD symptoms. The study design and features of the sample
are detailed in Neuman et al. [2005]. Twin pairs were selected
for the study if parent response to a brief screening interview
indicated endorsement of three or more present or past
inattentive symptoms in at least one twin of the pair. The
MAGIC (Missouri Assessment for Genetics Interview for
children) interview was used to collect parental report on child
psychopathology in 1,647 twins selected for the study. This
interview has demonstrated excellent reliability for all DSM1V diagnoses including ADHD (kappa 0.79–1.0 for both
diagnosis and individual symptom endorsement) [Todd et al.,
For the current analysis, subjects (N ¼ 243) treated with
methylphenidate for ADHD symptoms were selected from the
larger sample of 1,647 twins. The twins (N ¼ 243) were
predominantly male (83.5%), with an average age of 12.8 3.3 years (range 7–19 years) and mean WISC-III vocabulary
scaled score of 8.31 3.1. One hundred and eight of the 243
subjects (44.4%) had a DSM-1V diagnosis of ADHD by the
interview. The remaining 135 subjects (55.6%) did not meet
criteria for ADHD, but according to parent report were treated
with methylphenidate for ADHD symptoms. Among those
without DSM-IV ADHD, the mean DSM-IV ADHD symptom
count SD was 9.45 4.2 (range 1–18), indicating that on
average these children had a high number of ADHD symptoms
even though they did not meet formal diagnostic criteria
(usually due to late age of onset, lack of significant impairment,
and/or absence of six symptoms in either the inattentive or
hyperactive-impulsive category). As described in a previous
publication [Reich et al., 2006], 85% of methylphenidatetreated children from this sample had improvement of ADHD
symptoms after treatment. Response to treatment was based
on parent report (yes/no) in the MAGIC-regarding improvement in ADHD symptoms after medication treatment. The
Queries related to treatment response in the MAGIC included
the following: ‘‘Did you ever take her/him to a doctor, a
counselor, or some other professional person because of (ADHD)
problems?’’, ‘‘Did {whom child saw} give her/him any medication to help her/him with these (ADHD) problems?’’, ‘‘Do you
remember the name of the medication?’’, ‘‘After (s)he started
taking the medication, did these (ADHD) problems get any
better?’’. The dose of MPH and treatment related side effects
were not included in the MAGIC interview.
Samples of DNA were obtained from families in which at
least one twin had DSM-IV ADHD and complete diagnostic
information was obtained on both twins. Therefore, genotyping
data was not available for all the methylphenidate treated
subjects. In the methylphenidate-treated group, 156 subjects
were genotyped for DAT1, 159 subjects were genotyped for
DRD4, 104 subjects were genotyped for the 5HTTLPR, and 109
subjects were genotyped for CHRNA4 markers.
Written informed consent (and assent for youth under age
18 years) was obtained from participants and legal guardians
prior to participation. The Washington University School of
Medicine Human Studies Committee approved the study
Genotyping of the DAT1 and DRD4 polymorphisms was
performed as described by Cook et al. [1995] for the 30 VNTR
DAT polymorphism and as described by La Hoste et al. [1996]
for the exon 3 48-base pair repeat of the DRD4 receptor gene,
with minor modifications. Full details can be found in Todd
et al. [2001a, b]. The polymorphisms of the CHRNA4 (exon 5
SNP rs1044396, CHRNA4 intron 2 SNP rs6090384) described
by Todd et al. [2003a] and the 5 HTT allelic variants (LA: long
allele with ‘A’ nucleotide at the SNP in/near the insertion, LG:
long allele with G nucleotide at the SNP, and S: short allele)
described by Chorbov et al. [2007] were also genotyped.
Logistic regression was used to obtain odds ratios for
treatment outcome based on genotype. Standard errors were
adjusted to account for family clustering (non-independence of
observations within twin pairs) using the ‘cluster’ option
available in STATA 9 (College Station, TX).
For the subset of subjects who were genotyped, Table I
reflects the percentage of methylphenidate treated subjects
responding to treatment by genotype. As seen in Table I,
subjects tended to be treatment resistant if they were homozygous for the DAT1 10-repeat allele, homozygous for the
CHRNA4 intron two ‘G’ allele, or heterozygous for the DRD4
7-repeat allele. In these cases, we obtained odds ratios for
treatment failure based on homozygosity (or heterozygosity in
the case of DRD4). None of these odds ratios were statistically
Methylphenidate Response in ADHD
TABLE I. Percentage of Methylphenidate Treated Subjects Responding to Treatment by Genotype
Number of
alleles present
1 (heterozygous)
2 (homozygous)
DAT1 10 repeat,
N ¼ 156
N ¼ 104
CHRNA4 exon
5 rs1044396 ‘C’,
N ¼ 103
CHRNA4 intron
2 rs6090384 ‘G’,
N ¼ 109
100% (n ¼ 10)
90% (n ¼ 63)
86% (n ¼ 83)
85% (n ¼ 27)
85% (n ¼ 48)
90% (n ¼ 29)
84% (n ¼ 25)
87% (n ¼ 54)
92% (n ¼ 24)
100% (n ¼ 2)
100% (n ¼ 8)
86% (n ¼ 99)
DRD4 7 repeat,
N ¼ 159
89% (n ¼ 107)
88% (n ¼ 48)
100% (n ¼ 4)
TABLE II. Age, Sex, and WISC-III Vocabulary Scores by Genotype Group
Genotype as categorized for calculation of OR
for treatment outcome based on genotype
Homozygous for DAT1 10-repeat
Not homozygous for DAT1 10-repeat
Homozygous for CHRNA4 intron 2 ‘‘G’’ allele
Not homozygous for CHRNA4 intron 2 ‘‘G’’ allele
Heterozygous for DRD4 7-repeat allele
Not heterozygous for DRD4 7-repeat allele
Homozygous for five HTT-LAallele
Not homozygous for 5 HTT- LA allele
Homozygous for CHRNA4 exon 5 ‘‘C’’ allele
Not homozygous for CHRNA4 exon 5 ‘‘C’’ allele
male (n)
Mean age
Mean SD (n)
Mean WISC-III vocabulary
scaled score Mean SD (n)
78.31 (83)
86.30 (73)
82.83 (99)
90.00 (10)
77.08 (48)
86.49 (111)
89.66 (29)
81.33 (75)
70.83 (24)
88.61 (79)
13.42 3.31 (83)
12.60 3.30 (73)
12.82 3.43 (99)
12.80 2.90 (10)
12.94 3.50 (48)
13.00 3.24 (111)
12.62 3.41 (29)
12.93 3.31 (75)
12.38 3.32 (24)
12.85 3.40 (79)
8.57 3.02 (76)
8.33 3.20 (61)
8.42 3.00 (83)
5.38 2.77 (8)
8.07 3.50 (41)
8.62 2.84 (100)
7.58 3.19 (26)
8.52 3.13 (64)
7.53 2.63 (19)
8.56 3.13 (66)
Bold type indicates that there was a significant difference between the two genotype classes for the indicated gene.
significant (OR ¼ 1.89, P ¼ 0.24; OR ¼ 1.90, P ¼ 0.55; OR ¼
1.18, P ¼ 0.76, respectively). Subjects homozygous for the 5
HTT-LA or CHRNA4 exon 5 ‘C’ allele tended to improve more
often with treatment. In these cases, we obtained odds ratios
for improvement based on homozygosity, and these odds ratios
were non-significant (OR ¼ 1.48, P ¼ 0.56; OR ¼ 1.78, P ¼ 0.48).
Due to the prior report of an interaction between DRD4 and
5HTT genotypes in predicting treatment failure, we also tested
a model that included DRD4 7-repeat and 5HTT LA alleles plus
their interaction, but no significant main or interaction effects
were found.
We also looked for any differences in sex, age, or WISC-III
vocabulary score (Table II) between the genotype groups that
we used for calculation of odds ratios for treatment outcome
based on genotype. Age and sex variables were available for all
subjects, and the WISC-III vocabulary score was available for
the majority of subjects. There was no significant relationship
between genotype and sex, age, or IQ except in the case of the
CHRNA4 gene. The mean WISC-III vocabulary scaled score in
subjects homozygous for the CHRNA4 intron 2 ‘G’ allele was
significantly higher than that of subjects with other genotypes
(mean 8.42 vs. 5.38, P ¼ 0.007), but only 8 of the 10 nonhomozygous subjects had scores on this measure. The group
that was homozygous for the CHRNA4 exon 5 ‘C’ allele had a
lower proportion of male subjects than the non-homozygous
group (70.83% vs. 88.61% male, w2 ¼ 4.43, P ¼ 0.035).
We failed to replicate previously reported significant
associations between ADHD treatment response and the
studied genes. Our largest odds ratio was for the association
between treatment failure and homozygosity for the DAT1 10repeat allele. As discussed previously, there are opposing
results in the ADHD pharmacogenetics literature on association of treatment outcome with the 10-repeat allele of the DAT1
gene. Although non-significant, the direction of our DAT1
finding is in agreement with previously reported data on poor
outcome in subjects homozygous for the DAT 10-repeat allele.
Two previous studies reported response rates of 31% and 47%
for individuals with the 10/10 DAT genotype, compared to,
respectively, 86% and 75% for those with other genotypes
[Winsberg and Comings, 1999; Roman et al., 2002]. The power
of our study (with a much larger sample size: 156, compared to
30 and 50 in previous studies) to detect differences of this
magnitude is well over 90% at the 0.05 level of significance. The
percentage of responders in individuals with the 10/10
genotype found in our study (86%) is highly significantly
different from that observed in the other two studies combined
(40%; Chi-square 1 df ¼ 28.7, P < 0.0001). Post-hoc power
analyses suggest the present study would have 80% power to
detect an association with the 10/10 genotype as long as the
associated OR was 2.5–3.0 or higher, much lower than, for
example, the OR of 13.7 reported in Winsberg and Comings
[1999] study.
This study has some limitations. Our sample size was
adequate to detect a significant association assuming odds
ratios of the magnitude reported by studies such as Winsberg
and Comings [1999]; however, it may be that our simple
retrospective measure of treatment outcome resulted in high
methylphenidate response rates in children who would have
been non-responders by other outcome measures. These high
response rates may have interfered with our ability to detect
significant associations between treatment response and
genotype. Also, parent reports of treatment response could
not be corroborated by physician records, and compliance and
medication dosage were not assessed. Similar studies using
larger samples, consideration of comorbid disorders, quantitative measures of symptom improvement, and documentation
of medication compliance are needed to determine whether
true associations are present.
This study was supported by grants NIMH 52813 (RDT),
NIMH 17104 (AMR) and International Research Training in
Clinical Sciences (Fogarty) grant number NIH 05811 (HT).
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associations, response, polymorphism, dopamine, nicotinic, serotonin, genes, adhd, methylphenidate
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