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Catechol-O-methyltransferase Val158Met polymorphism is associated with methylphenidate response in ADHD children.

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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 147B:1431– 1435 (2008)
Brief Research Communication
Catechol-O-Methyltransferase Val158Met Polymorphism
Is Associated With Methylphenidate Response in
ADHD Children
Eva Kereszturi,1 Zsanett Tarnok,2 Emese Bognar,2 Krisztina Lakatos,3 Luca Farkas,2 Julia Gadoros,2
Maria Sasvari-Szekely,1 and Zsofia Nemoda1*
Institute of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary
Vadaskert Child and Adolescent Psychiatric Clinic, Budapest, Hungary
Institute for Psychology, Hungarian Academy of Sciences, Budapest, Hungary
Methylphenidate is the most frequently prescribed drug in the treatment of attention deficit
hyperactivity disorder (ADHD) but it is not effective in every case. Therefore, identifying genetic
and/or biological markers predicting drugresponse is increasingly important. Here we present a case-control study and pharmacogenetic
association analyses in ADHD investigating three
dopaminergic polymorphisms. Previous studies
suggested variable number of tandem repeats
(VNTR) in the dopamine D4 receptor (DRD4) and
the dopamine transporter (DAT1) genes as genetic
risk factors for ADHD and as possible markers of
methylphenidate response. Our results did not
indicate substantial involvement of these two
VNTRs in ADHD, however, both the case-control
and the pharmacogenetic analyses showed significant role of the high activity Val-allele of cathecolO-methyltransferase (COMT) Val158Met polymorphism in our ADHD population. The Val-allele
was more frequent in the ADHD group (n ¼ 173)
compared to the healthy population (P ¼ 0.016).
The categorical analysis of 90 responders versus
32 non-responders showed an association between
the Val-allele or Val/Val genotype and good methylphenidate response (P ¼ 0.009 and P ¼ 0.034, respectively). Analyzing symptom severity as a
continuous trait, significant interaction of COMT
genotype and methylphenidate was found on the
Hyperactivity-Impulsivity scale (P ¼ 0.044). Symptom severity scores of all three genotype groups
decreased following methylphenidate administration (P < 0.001), however Val/Val homozygote
children had significantly less severe symptoms
than those with Met/Met genotype after treatment
(P ¼ 0.015). This interaction might reflect the
regulatory effect of COMT dominated prefrontal
None of the authors reported biomedical financial interests or
potential conflicts of interest.
Grant sponsor: NKFP; Grant number: 1A/008/2002; Grant
sponsor: OTKA; Grant number: T 048576.
*Correspondence to: Dr. Zsofia Nemoda, Institute of Medical
Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis
University, POB 260, Budapest H-1444, Hungary.
Received 26 July 2007; Accepted 29 November 2007
DOI 10.1002/ajmg.b.30704
Published online 23 January 2008 in Wiley InterScience
ß 2008 Wiley-Liss, Inc.
dopamine transmission on subcortical dopamine
systems, which are the actual site of methylphenidate action.
ß 2008 Wiley-Liss, Inc.
KEY WORDS: attention deficit hyperactivity
disorder; dopaminergic polymorphism; DRD4; DAT1; pharmacogenetics
Please cite this article as follows: Kereszturi E, Tarnok Z,
Bognar E, Lakatos K, Farkas L, Gadoros J, Sasvari-Szekely
M, Nemoda Z. 2008. Catechol-O-Methyltransferase Val158Met Polymorphism Is Associated With Methylphenidate
Response in ADHD Children. Am J Med Genet Part B 147B:
Attention deficit hyperactivity disorder (ADHD) is one of the
most prevalent childhood-onset psychiatric disorders, affecting 5% of school-age children worldwide [Polanczyk et al.,
2007]. The strong genetic component of ADHD has been
demonstrated by family- and twin-studies; based on neurobiological theories, most of the candidates genes belonging to
the dopaminergic system [Faraone et al., 2005]. Early
diagnosis of ADHD and its well-chosen treatment plan are
especially important, as later illicit substance abuse could be
reduced among appropriately treated ADHD adolescents
[Faraone and Wilens, 2003]. The psychostimulant drugs
methylphenidate (MPH) and dextroamphetamine are the
most commonly used medications; and over the last decades,
pharmacogenetic analyses tried to determine the genetic
background of stimulant drug responsiveness [McGough,
Pharmacokinetic and pharmacodynamic variability exists
between ADHD children, possibly reflecting the underlying
biological and genetic influences on drug response [Masellis et
al., 2002]. However, the factors affecting drug response are not
yet clearly understood. Most of the pharmacogenetic studies
addressed the possible involvement of the dopamine transporter gene (DAT1, SLC6A3), since dopamine transporter is
the main target of MPH. The most frequently investigated
polymorphism of the DAT1 gene is the 40 bp VNTR (Variable
Number of Tandem Repeats) located in the 30 untranslated
region. Three groups found association between homozygosity
of the 10-repeat allele and poor response to methylphenidate
[Winsberg and Comings, 1999; Roman et al., 2002; Cheon et al.,
2005], although several negative findings have also been
published [Langley et al., 2005; van der Meulen et al., 2005;
Kereszturi et al.
Mick et al., 2006; Zeni et al., 2007]. Making the picture more
complex, an Irish group reported association between the 10repeat allele and better response to MPH in a family-based
study [Kirley et al., 2003]. In line with these results, a
Canadian group observed poor response in children with
homozygous 9/9 genotype [Joober et al., 2007]. Two other
studies described association between poor response and the
rare 9/9 genotype in ADHD children and healthy adults [Lott et
al., 2005; Stein et al., 2005].
Another frequently studied polymorphism is the 48 bp VNTR
located in exon III of the dopamine D4 receptor (DRD4) gene.
The published results are controversial: Hamarman et al.
[2004] found that patients carrying the 7-repeat allele required
higher dose of MPH for symptom improvement, but opposite
findings were described by van der Meulen et al. [2005]. In a
Korean ADHD population the 4-repeat allele was associated
with good response to MPH [Cheon et al., 2007]. In addition,
two studies resulted in negative findings [Winsberg and
Comings, 1999; Zeni et al., 2007].
Although dopamine transporter is the key regulator of
dopamine neurotransmission, the main determinant of extracellular dopamine level in the prefrontal cortex is the
cathecol-O-methyltransferase (COMT) metabolizing enzyme.
A human-specific single nucleotide polymorphism (SNP) has
been described in the COMT gene, altering valine 158 to
methionine in the membrane-bound form and reducing the
enzyme activity threefold [reviewed by Tunbridge et al., 2006].
The present study aimed to evaluate the association between
methylphenidate response and polymorphisms of three
dopaminergic genes: DAT1, DRD4, and COMT.
Previously published cohorts of 173 ADHD patients and
284 sex-matched Hungarian control subjects participated in
this study [Kereszturi et al., 2007]. Both the clinical and control
samples were ethnically homogenous and of Caucasian origin.
The study was approved by the Local Ethics Committee
(TUKEB), patients and their parents provided written
informed consent for their participation. DNA sampling and
genotyping methods of the three dopaminergic polymorphisms
have been described earlier [Tarnok et al., 2007]. No significant
deviations from Hardy–Weinberg equilibrium were detected
for any of the polymorphisms either in the case or in the control
population. Transmission Disequilibrium Test (TDT) was
calculated using 272 parental data, since genetic data were
available only in 104 trios and 64 duos. Chi-square analyses
were carried out, and P-value threshold for multiple comparison was calculated by the False Discovery Rate adjustment
[Benjamini and Hochberg, 1995].
A prospective methylphenidate-response analysis was conducted in 122 inpatients (45 children were not given any drug
treatment, and 6 patients received antipsychotic or antidepressant treatment because of their comorbid disorders). The
initial psychiatric evaluation of these 122 children (mean age:
9.6 2.6; 88.5% male, and 11.5% female) was carried out in a
drug-free period. ADHD-subtypes were evaluated based on
DSM-IV criteria [American Psychiatric Association, 1994] by
two independent child psychiatrists both specialists in the
assessment and treatment in ADHD. The Attention-Deficit
Hyperactivity Disorder Rating Scale [ADHD-RS; DuPaul,
1998] was used for dimensional measurement. Comorbid
conditions were assessed by the Hungarian child version of
the Mini-International Neuropsychiatric Interview [MINIKid; Balazs et al., 2004]. Socioeconomic status (SES) assessment was based on family composition and the parents’
education level, occupation, and income (1 ¼ far below average,
2 ¼ below average, 3 ¼ average, 4 ¼ above average, 5 ¼ far
above average).
Patients participating in the drug response study were given
10–30 mg methylphenidate according to their body weight, in
two doses (morning and noon). The daily dose thereby ranged
from 0.22 to 0.95 mg/kg/day, in average 0.55 0.15 mg/kg/day.
The primary outcome measures of MPH-treatment were the
ADHD-RS Inattention and Hyperactivity-Impulsivity severity
scores (0–3 points for 9–9 items), and the seven-point Severity
of Illness subscale of the Clinical Global Impression scale [CGIS; Guy, 1976]. ADHD-RS and CGI-S were collected at the
beginning of the treatment (baseline levels) and every month in
the first 6 months when the children and their parents came
back for control examinations and drug-prescription. Drug
response was assessed by both categorical and dimensional
approaches. The categorical definition of drug-response was
obtained according to previous studies [Buitelaar et al., 2004;
Kemner et al., 2005]: children were evaluated as responders
after 6 months of treatment if they had at least 25% decrease in
ADHD-RS total score, and their CGI-S score was two points or
less (corresponding to no or minimal symptoms) in the last two
consecutive months. Categorization of the non-responder
children was done during the first 3 months, as they had less
than 10% decrease in their ADHD-RS total score and
discontinued the treatment. According to these criteria, 90
children were categorized as responder, whereas 32 children as
non-responder. There were no significant differences in the
demographic variables, comorbid conditions, frequencies of
ADHD type or severity between the responder and nonresponder groups (Supplementary Table I), neither showed a
multivariate analysis of variance significant effect of group
membership on ADHD-scales [F(2,119) ¼ 2.25, P ¼ 0.110].
CGI-S baseline scores differed between the two groups
[responder: 5.94 0.88, non-responder: 5.53 0.92, t(1,120) ¼
2.26, P ¼ 0.026], although the extent of the difference of the
means was small. Therefore, responder and non-responder
status was ignored for further analyses of variance investigating the effect of MPH on ADHD-RS and CGI-S scores in a
repeated measures design including genotype as a betweensubject factor.
The case-control analyses of the three dopaminergic polymorphisms (DAT1 40 bp VNTR, DRD4 48 bp VNTR, and COMT
Val158Met) were carried out on 173 ADHD children and 284
sex-matched (but not age-matched) control subjects. There
were no significant differences in the allele- or genotypefrequencies of the investigated VNTRs between the ADHD and
control groups (Table I). However, significant differences
were detected both in allele- and genotype-distributions of
the COMT Val158Met polymorphism: the Val-allele and the
Val/Val genotype were more frequent in the ADHD group
compared to healthy population [w2 (df ¼ 1) ¼ 5.82, P ¼ 0.016,
and w2 (df ¼ 2) ¼ 6.60, P ¼ 0.037, respectively]. After the False
Discovery Rate adjustment for multiple testing, the allele-wise
P-value of the COMT Val158Met remained significant
(P < 0.0167). TDT analyses gave similar results: in the
available heterozygote parental data we could not detect any
preferable transmission of the DRD4 7-repeat allele (passed:
34 times, not-passed: 33 times, TDT w2 ¼ 0.01, P ¼ 0.903) or the
DAT1 10-repeat allele (53 vs. 40 transmission from the 9/10
parents, TDT w2 ¼ 1.82, P ¼ 0.178; and 56 vs. 43 transmission
from any kind of heterozygote parents, TDT w2 ¼ 1.71,
P ¼ 0.191). On the other hand, there was a tendency for the
over-transmission of the COMT Val-allele (71 vs. 52 times,
TDT w2 ¼ 2.93, P ¼ 0.087).
In the second set of analyses the methylphenidate response
was assessed in 122 ADHD children. Using the categorical
grouping system, 90 patients (73.8%) were described as
responder, while 32 (26.2%) were non-responder. The allele
COMT Val158Met and Methylphenidate Response in ADHD
TABLE I. Genotype Frequencies of the DAT1, COMT, and DRD4 Polymorphisms in ADHD Patients and Controls
DAT1 40 bp VNTRa
Polymorphic sites
n (total 173)
Frequency (%)
n (total 284)
Frequency (%)
Allele-wise P (df ¼ 1)
Genotype-wise P (df ¼ 2)
DRD4 48 bp VNTRb
COMT Val158Met
0.325 (df ¼ 3)
0.235 (df ¼ 5)
The rare DAT1 40 bp VNTR genotypes were grouped as ‘‘others’’ and left out from the analyses (four 10/11, one 6/10, one 9/11 genotype in the ADHD group,
and single 6/10, 7/9, 9/15, 10/11, 10/13, 10/14 genotype in the control group).
In the Chi-square analyses of the DRD4 48 bp VNTR only the most frequent alleles (2, 3, 4, and 7) were used. In the genotype-wise analyses the following
genotype groups were used: 2/4, 2/7, 3/4, 4/4, 4/7, and 7/7. For more detailed genotype distribution see Supplementary Table II.
and genotype frequencies of the dopaminergic polymorphisms
were compared by Chi-square analyses between the two
patient groups. We could not detect any biased distribution
in the allele- and genotype-frequencies of either the DRD4
48 bp VNTR or the DAT1 40 bp VNTR (Table II). The Val-allele
of the COMT polymorphism, however, showed a significant
association with good methylphenidate response [w2 (df ¼ 1) ¼
6.87, P ¼ 0.009]. The Val/Val genotype was twice as frequent
in the responder group compared to the non-responders [w2
(df ¼ 2) ¼ 6.78, P ¼ 0.034]. The ratio of Val/Met heterozygotes
was similar in the two groups.
In the dimensional approach repeated measures analyses
of variance were carried out to test the effect of MPH on
ADHD-RS and CGI-S scores, and its potential interaction with
COMT genotype. Severity scores after the first month of MPH
treatment were used (for the baseline and after-treatment
scores see Supplementary Table III). The Inattention and
Hyperactivity-Impulsivity scales of the ADHD-RS were
entered into the same analysis, while the CGI-S scores were
analyzed separately. Methylphenidate significantly reduced
ADHD-RS scores after 1 month of treatment [F(2,118) ¼ 104.73,
P < 0.001, Z2 ¼ 0.640], for both Inattention [F(1,119) ¼ 201.52,
P < 0.001, Z2 ¼ 0.629] and Hyperactivity-Impulsivity [F(1,119) ¼
169.45, P < 0.001, Z2 ¼ 0.587]. The marginal multivariate
interaction of MPH-effect and COMT genotype [F(4,234) ¼ 1.99,
P ¼ 0.097, Z2 ¼ 0.033] remained a tendency for Inattention
[F(2,119) ¼ 2.44, P ¼ 0.091, Z2 ¼ 0.039], however was significant
for Hyperactivity-Impulsivity [F(2,119) ¼ 3.42, P ¼ 0.036,
Z2 ¼ 0.054]. The Hyperactivity-Impulsivity severity score was
significantly reduced in all genotype groups (P < 0.001); and
significant genotype difference was detected only in the post-
MPH scores [F(2,119) ¼ 4.11, P ¼ 0.019, Z2 ¼ 0.065], with
Val/Val children scoring lower than Met/Met ones (Bonferroni
test, P ¼ 0.015). The extent of decrease was also related to
COMT genotype: using the difference of baseline minus aftertreatment scores, the univariate analysis of variance revealed
significant genotype effect [F(2,119) ¼ 3.42, P ¼ 0.036, Z2 ¼
0.054], with the decrease in the Val/Val group being significantly larger, than that in the Met/Met group (Bonferroni test,
P ¼ 0.031). Methylphenidate also significantly decreased the
CGI-S scores [F(1,119) ¼ 154.75, P < 0.001, Z2 ¼ 0.57], but this
reduction was not modified by COMT genotypes [F(2,119) ¼
0.89, P ¼ 0.41, Z2 ¼ 0.015].
In contrast to previous studies, we found no association
between ADHD and the common 48 bp VNTR of the DRD4 gene
using a case-control approach. The frequency of the 7-repeat
allele in our Hungarian population was comparable to that of
other European populations [Li et al., 2006], however, the
frequency of this risk allele was slightly decreased (but not
reaching significance) in our ADHD population compared to
the controls (18.2% vs. 21.3%). Similarly, the TDT did not
reveal any biased transmission of the 7-repeat allele (Supplementary Table II). We found no biased distribution or transmission of the DAT1 40 bp VNTR alleles either. This negative
result, however, is not so surprising, as the most recent
meta-analysis has found no significant evidence for this
polymorphism in the etiology of ADHD neither in European
nor in Asian populations [Li et al., 2006]. Concerning the
COMT polymorphism, the first association analysis by
TABLE II. Genotype Frequencies of the DAT1, COMT, and DRD4 Polymorphisms in Methylphenidate-Treated ADHD Patients
DAT1 40 bp VNTRa
Polymorphic sites
n (total 90)
Frequency (%)
n (total 32)
Frequency (%)
Allele-wise P (df ¼ 1)
Genotype-wise P (df ¼ 2)
DRD4 48 bp VNTRb
COMT Val158Met
0.903 (df ¼ 2)
0.868 (df ¼ 3)
The rare DAT1 40 bp VNTR genotypes were grouped as ‘‘others’’ and left out from the analyses (one 6/10 and one 10/11 genotype in the responder group, and
two 10/11 genotype in the non-responder group).
In the Chi-square analyses of the DRD4 48 bp VNTR only the most frequent alleles (2, 4, and 7) were used. In the genotype-wise analyses the following
genotype groups were used: 2/4, 4/4, 4/7, and 7/7. For more detailed genotype distribution see Supplementary Table II.
Kereszturi et al.
Eisenberg et al. [1999] found an over-transmission of the Valallele in ADHD trios, but the subsequent family-based
studies have not confirmed this finding [for a meta-analysis
see Cheuk and Wong, 2006]. Our results partly support the
original finding: while the TDT analysis showed a tendency
(Val-allele was transmitted 71 vs. 52 times, P ¼ 0.087), the
case-control analysis gave a significant association between
ADHD and the high activity Val-allele of the COMT SNP
(P ¼ 0.016 for allele, and P ¼ 0.037 for genotype distribution).
This finding raises the possibility that the COMT polymorphism might be important in the development of certain
ADHD-symptoms connected with prefrontal cortex dopamine neurotransmission.
The COMT Val158Met polymorphism has been widely
studied in relation to cognitive functions: Egan et al. [2001]
found that the low activity Met-allele associated with better
performance on Wisconsin Card Sorting Test in healthy
subjects as well as in schizophrenic patients. In accordance
with this, Mattay et al. [2003] showed that healthy people with
the Val/Val genotype perform worse in working memory tasks,
but after amphetamine administration the efficiency of PFCfunctions increases in this group. Therefore, we aimed to study
the methylphenidate response in ADHD children treated with
stimulant drug. Children with at least one Val-allele were
indeed more likely to benefit from the MPH-treatment (while
58.3% of the Met/Met genotype group was classified as
responder, the percentages were 71.2 for the Val/Met and
87.2 for the Val/Val groups). For the ADHD combined type
only, these ratios were slightly different (58.3% responder of
the Met/Met genotype group, 68.2% of the Val/Met group, and
88.9% of the Val/Val group).
It is important to note that the demographic and clinical
variables did not differ significantly among the three COMT
genotype groups (see Supplementary Table III) except for the
ADHD-type frequencies: in the Met/Met group there were only
combined-type ADHD children. Therefore, we repeated the
pharmacogenetic analyses for the combined-ADHD-type
patients only. In this sub-sample the difference in COMT
allele- and genotype-frequencies of the responder versus nonresponder groups was significant [w2 (df ¼ 1) ¼ 6.39, P ¼ 0.011;
w2 (df ¼ 2) ¼ 6.30, P ¼ 0.043, respectively], similarly to the total
group’s results (Table II). The dimensional analyses also
gave similar findings in the combined-type-only sub-sample:
after 1 month of treatment MPH significantly reduced ADHDRS scores [F(2,91) ¼ 90.86, P < 0.001]. The multivariate interaction of MPH-effect and COMT genotype [F(4,180) ¼ 2.69,
P ¼ 0.033] was a tendency for Inattention [F(2,92) ¼ 2.75,
P ¼ 0.069], and was significant for Hyperactivity-Impulsivity
[F(2,92) ¼ 5.02, P ¼ 0.009], with the decrease in the Val/Val
group being significantly larger, than that in the Met/Met
group (Bonferroni test, P ¼ 0.006). Methylphenidate treatment also significantly decreased the CGI-S scores [F(1,92) ¼
116.76, P < 0.001], and this reduction was not modified by the
COMT genotype in this sub-sample either [F(2,92) ¼ 0.81,
P ¼ 0.45].
We propose that the COMT interaction effect reflects an
attenuated prefrontal dopaminergic negative control on subcortical dopaminergic systems, with the high activity Val/Val
group having lower cortical dopamine level, hence a more
active striatal dopamine neurotransmission [Tunbridge et al.,
2006]. MPH increases dopamine level predominantly in the
striatum acting on dopamine transporter, and presumably
improving the signal-to-noise in target neurons [Swanson and
Volkow, 2002]. In patients with COMT Val/Val genotype this
beneficial MPH-effect could be more pronounced with a lower
inhibitory tone from the prefrontal cortex. Since Hyperactivity-Impulsivity phenotype is more closely linked to basal
ganglia function, MPH-effect might be better observed on this
ADHD-RS scale.
To date, only Tahir et al. [2000] reported a genetic
association analysis between methylphenidate response and
the COMT polymorphism with a non-significant result, but
they tested only 72 children, which might be an inadequate
group-size for this type of analysis. Since our study is the first
reporting positive association between the Val-allele of the
COMT polymorphism and methylphenidate response, independent investigations are needed to clarify the role of the
COMT polymorphism in ADHD treatment.
This work was supported by Hungarian funds NKFP 1A/008/
2002 and OTKA T 048576. The authors thank Gabriella
Kolmann for her technical assistance.
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catechol, associates, val158met, response, polymorphism, methyltransferases, children, adhd, methylphenidate
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