Journal of Child Psychology and Psychiatry 55:8 (2014), pp 914–923 doi:10.1111/jcpp.

12212

Genetics of preparation and response control in

ADHD: the role of DRD4 and DAT1
€ rn Albrecht,1,2,a Daniel Brandeis,2,3,4,5,a Henrik Uebel- von Sandersleben,1
Bjo
Lilian Valko,3 Hartmut Heinrich,6,7 Xiaohui Xu,8 Renate Drechsler,3 Alexander Heise,1
Jonna Kuntsi,8 Ueli C. Mu € ller,3,9 Philip Asherson,8 Hans-Christoph Steinhausen,3,10,11
Aribert Rothenberger,1 and Tobias Banaschewski2
1
Child and Adolescent Psychiatry, University Medical Center G€ ottingen, Germany; 2Department of Child
ottingen, G€
and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim/
Heidelberg University, Mannheim, Germany; 3Department of Child and Adolescent Psychiatry, University of Z€ urich,
urich, Switzerland; 4Center for Integrative Human Physiology, University of Z€
Z€ urich, Z€
urich, Switzerland;
5
Neuroscience Center Zurich, University of Zurich and ETH Zurich, Z€ urich, Switzerland; 6Department of Child and
Adolescent Mental Health, University of Erlangen, Erlangen, Germany; 7Heckscher-Klinik, M€ unchen, Germany;
8
King’s College London, MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, London,
UK; 9Interkantonale Hochschule f€ ur Heilp€
adagogik, Z€urich, Switzerland; 10Research Unit of Child and Adolescent
Psychiatry, Aalborg University Hospital, Aalborg, Denmark; 11Clinical Psychology and Epidemiology, University of
Basel, Basel, Switzerland

Background: Difficulties with performance and brain activity related to attentional orienting (Cue-P3), cognitive or
response preparation (Cue-CNV) and inhibitory response control (Nogo-P3) during tasks tapping executive functions
are familial in ADHD and may represent endophenotypes. The aim of this study was to clarify the impact of dopamine
receptor D4 (DRD4) and dopamine transporter (DAT1) gene polymorphisms on these processes in ADHD and control
children. Methods: Behavioural and electrophysiological parameters from cued continuous performance tests with
low and high attentional load were assessed in boys with ADHD combined type (N = 94) and controls without family
history of ADHD (N = 31). Both groups were split for the presence of at least one DRD4 7-repeat allele and the DAT1
10-6 haplotype. Results: Children with ADHD showed diminished performance and lower Cue-P3, CNV and Nogo-P3
amplitudes. Children with DRD4 7R showed similar performance problems and lower Cue-P3 and CNV, but Nogo-P3
was not reduced. Children with the DAT1 10-6 haplotype had no difficulties with performance or Cue-P3 and CNV,
but contrary to expectations increased Nogo-P3. There were no Genotype by ADHD interactions. Conclusions: This
study detected specific effects of DRD4 7R on performance and brain activity related to attentional orienting and
response preparation, while DAT1 10-6 was associated with elevated brain activity related to inhibitory response
control, which potentially compensates increased impulsivity. As these genotype effects were additive to the impact of
ADHD, the current results indicate that DRD4 and DAT1 polymorphisms are functionally relevant risk factors for
ADHD and presumably other disorders sharing these endophenotypes. Keywords: Attention deficit hyperactivity
disorder, ERP, endophenotypes, CPT, CNV, Nogo, P3.

notypes, which are characterized by more fundamen-

Introduction
tal quantitative biological properties in between
Attention deficit hyperactivity disorders (ADHD),
genetic or environmental risk factors and the pheno-
characterized by high and age-inappropriate levels
type, may help to clarify these associations through
of hyperactivity, inattention and impulsivity, is asso-
potentially larger and/or more specific genetic effects
ciated with dysfunctions in neuronal networks
than found for the ADHD diagnosis. Endophenotypes
responsible for attention and response control
may thus offer advantages for molecular genetic
(Castellanos, Sonuga-Barke, Milham, & Tannock,
studies (Doyle et al., 2005) and explain the hetero-
2006; Durston, van Belle, & de Zeeuw, 2011). Her-
geneity of the ADHD phenotype (Buitelaar, 2005).
itability estimates of more than 70% favour a model of
Recently, we found that several performance and
strong genetic impact on the expression of the
electrophysiological parameters of response prepa-
disorder (Faraone & Mick, 2010). However, there is
ration and response control are driven by familial
a gap between the large heritability estimates from
factors shared with childhood ADHD (Albrecht et al.,
twin and adoption studies and the rather small
2013). Children with ADHD and to a lesser extent
effects found between ADHD and individual risk
also their nonaffected siblings showed impairments
alleles. So far, developmental pathways from genetics
when compared to controls without a family history
and environmental factors are not well understood
of the disorder. Thus, deficits on these parameters
(Banaschewski et al., 2005). Intermediate endophe-
may be a consequence of genes or environmental
factors shared within families.
a
These authors contributed equally to this work. Preparation and response control was assessed
Conflict of interest statement: See disclosures in during visual Continuous Performance Tests [CPT
Acknowledgements (Rosvold, Mirsky, Sarason, Bransome, & Beck,

© 2014 The Authors. Journal of Child Psychology and Psychiatry. © 2014 Association for Child and Adolescent Mental Health.
Published by John Wiley & Sons Ltd, 9600 Garsington Road, Oxford OX4 2DQ, UK and 350 Main St, Malden, MA 02148, USA
doi:10.1111/jcpp.12212
1956)] combining vigilance and cued Go-Nogo tasks
where rare cues require preparation for a Go-Nogo
task: if followed by a target, a simple response
should be executed, but if followed by a distractor,
the prepared response must be withheld through
inhibitory response control.
Processing cues requires mainly attentional orient-
ing and resource allocation reflected in the Cue-P3, a
parietally broad positive deflection in the event-re-
lated potential (ERP) starting about 300 ms after cue
onset. Source localizations revealed predominantly
posterior sources; moreover, children with ADHD
consistently show impairments (Albrecht et al.,
2013; Brandeis et al., 2002; van Leeuwen et al.,
1998). In a recent longitudinal study, the Cue-P3
showed a persistent deficit in children with ADHD
that was particularly prominent at a mean age of
12 years (Doehnert, Brandeis, Imhof, Drechsler, &
Steinhausen, 2010), and deficits were also present in
adults with ADHD (McLoughlin et al., 2010).
Following the Cue-P3, cues (but not irrelevant
distractors) evoke a centrally negative slow cortical
potential terminated by the next stimulus (contingent
negative variation, CNV), which reflects preparation
(Walter, Cooper, Aldridge, McCallum, & Winter, 1964)
or time estimation (Macar & Vidal, 2003). Neurophys-
iological and fMRI studies demonstrated dopaminer-
gic control (Kratz et al., 2012; Linssen et al., 2011)
and activity of an ensemble of thalamo-cortical
structures including the dorsal anterior cingulate,
frontal cortex, thalamus and midbrain dopaminergic
nuclei involved in CNV generation (Lutcke, Gevensle-
ben, Albrecht, & Frahm, 2009). Moreover, recent
studies showed an impact of dopaminergic genes on
visual and motor postprocessing during CNV gener-
ation (Bender et al., 2012a,b). The CNV amplitude is
consistently reduced in ADHD (Banaschewski et al.,
2003; Perchet, Revol, Fourneret, Mauguiere, & Garcia-
Larrea, 2001) and may also represent a persistent
deficit throughout life (Doehnert, Brandeis, Schneider,
Drechsler, & Steinhausen, 2013; Doehnert et al.,
2010; McLoughlin et al., 2010; Valko et al., 2009).
Following Cues, response control is required, and
the difference in task demand between Go and Nogo
trials – executing versus suppressing a prepared
response – is paralleled in the ERP. In Nogo trials,
enhanced N2 amplitudes indexing conflict monitor-
ing (Albrecht et al., 2008; Banaschewski et al., 2003)
are followed by the Nogo-P3, which is maximal at
fronto-central sites (Fallgatter & Strik, 1999). The
Nogo-P3 may be generated by several processes of
inhibitory response control in medial or anterior
cingulate cortex (ACC) and premotor and frontal
areas (Verleger, Paehge, Kolev, Yordanova, &
Jaskowski, 2006). Clinical studies have shown that
the Nogo-P3 amplitude or anteriorization is altered in
patients with ADHD and seems to represent a persis-
tent neurophysiological deficit in children and adults
with ADHD (Doehnert et al., 2010; Fallgatter et al.,
2004; McLoughlin et al., 2010; Valko et al., 2009).
© 2014 The Authors. Journal of Child Psychology and Psychiatry. © 2014 Association for Child and Adolescent Mental Health.
Genetics of preparation and response control in ADHD 915
Two genes related to dopaminergic functioning and
associated with ADHD and related difficulties may
have an impact on preparation and response control.
The dopamine D4 receptor (DRD4) gene modulates a
receptor, which is mostly present in the frontal lobe,
orbitofrontal and anterior cingulate cortex (Gizer &
Waldman, 2012; Noain et al., 2006). DRD4 has a
variable number of tandem repeats (VNTR) between 2
and 10, with the 7-repeat (7R) polymorphism thought
to be less sensitive to dopaminergic stimulation
(Asghari et al., 1995). Several studies indicate that
the DRD4 7R polymorphism is related to sustained
attention and cognitive control performance (Gizer &
Waldman, 2012; Johnson et al., 2008; Kieling,
Roman, Doyle, Hutz, & Rohde, 2006), probably in
epistatic interaction with a gene coding cate-
chol-O-methyltransferase (COMT) (Heinzel et al.,
2012). Recent metaanalyses suggest that DRD4 7R
is also moderately associated with ADHD (Faraone &
Mick, 2010; Li, Sham, Owen, & He, 2006).
The second gene to be tested here is the dopamine
transporter gene (DAT1, SLC6A3) which codes for the
carrier protein that accomplishes the reuptake of
dopamine from the synaptic cleft. It is present espe-
cially in the striatum and nucleus accumbens, with
projections to the dorsolateral prefrontal cortex
(DLPF) (Ciliax et al., 1999). Methylphenidate, the
most frequently prescribed stimulant used for ADHD
treatment, blocks the dopamine transporter which
results in higher levels of available dopamine in the
synaptic cleft (Spencer, Biederman, & Wilens, 2000).
The DAT1 gene has two commonly studied VNTR
polymorphisms of 9 or 10 repeats of a 40-basepair
sequence in the 3′ untranslated region (UTR). The
10R polymorphism may be related to some kind of
response control problem, as recent studies reported
performance problems in a verbal inhibition task
(Cornish et al., 2005) and higher number of impulsive
errors in a CPT paradigm (Gizer & Waldman, 2012),
as well as diminished brain activity related to perfor-
mance monitoring (Althaus et al., 2010) and reduced
anteriorization of the Nogo-P3 (Dresler et al., 2010).
However, the effect of these polymorphisms on the
dopamine transporter functioning may change with
development. The 10-repeat allele might be a risk
factor for childhood ADHD, while the 9-repeat poly-
morphism was associated with ADHD in adults
(Franke et al., 2010). Moreover, the 10-repeat allele
may lead to functional deficits only if other func-
tional sites within DAT1 are present that form a
specific haplotype of the 10-repeat allele in the 3′UTR
in conjunction with the 6-repeat allele of a 30-base
pair VNTR located within intron 8 (the 10-6 haplo-
type) (Asherson et al., 2007).
Taken together, cognitive behavioural performance
in the CPT and the brain activity parameters related
to attentional orienting (Cue-P3), preparation (CNV)
and inhibitory response control (Nogo-P3) show
functional impairments in ADHD that are driven by
familial factors and probably relate to dopaminergic
916 Bj€
orn Albrecht et al. J Child Psychol Psychiatr 2014; 55(8): 914–23

dysfunctions. We aim to clarify the role of DRD4 and

DAT1 genes and their impact on preparation and
response control in addition to the diagnostic phe-
notype further in this study.

Method
Participants
Children or adolescents with ADHD were recruited from
specialist clinics or child and adolescent psychiatrists in
private practice in Z€ urich, Switzerland and G€ ottingen, Ger-
many. Controls were recruited from local schools or sports
clubs. All children participated on the basis of informed
consent from child and parents. Ethical approval for this
study was obtained from the local ethical review boards.
One hundred and twenty-five boys aged 8–16 years with an
estimated IQ above 80, genotyped and with good EEG quality
fulfilled either a research diagnosis of ADHD combined type
(N = 94) or were healthy controls without a known family
history of ADHD (N = 31). The sample overlap with a previous
familiality study (Albrecht et al., 2013) was 90% (disregarding
unaffected siblings). More details of the sample, diagnostics,
comorbidities and the genotyping are given in the supplemen-
tary Appendix S1. The ADHD and Control groups were further
subdivided according to DRD4 7R (presence of at least one
7-repeat allele, 10/31 controls & 24/94 ADHD) and DAT1 10-6
haplotype (homozygotic for the 10-repeat allele of the VNTR in
the 3UTR and homozygotic for the 6-repeat allele of the intron
8 VNTR, 17/31 controls & 38/94 ADHD) polymorphisms.
Children taking stimulant treatment were off medication for at
least 48 hr before testing.
Stimuli and task
To assess attentional alerting, orienting and preparation and
response control, a Standard- and a Flanker-CPT (augmenting
attentional and response control load) was used (Doehnert
et al., 2010, 2013; Valko et al., 2009). In both CPTs, the
children had to respond with the index finger of their dominant
hand only if a central Cue ‘O’ (presented 80 times, see Figure 1)
was followed by a central Target ‘X’ (N = 40), but to withhold
responding if the cue was followed by a nontarget (Nogo trials,
N = 40) and on all other trials. The total of 400 stimuli
presented pseudorandomized every 1650 ms.
Both CPTs included 25 practice trials, lasted 11 min each,
and were run counterbalanced after 5 min of resting EEG and
with a 13 min action monitoring task in between.
Data analysis
The recording and processing of performance and electrophys-
iological data is similar to the methods used in a previous
publication (Albrecht et al., 2013); details are given in the
Appendix S1.
Performance and electrophysiological parameters were
tested parametrically with a repeated measure analysis of
variance (ANOVA) with within-subject factor ‘Task’ (Flanker-
vs. Standard-CPT) and between-subject factors ‘Diagnosis’
(ADHD vs. Controls) and genotype status of either ‘DRD4’
(presence of 7R) or ‘DAT1’ (presence of the 10-6 haplotype). Age
was entered as a covariate in analyses of performance and ERP
data to control for small differences in the genotype splits.
Entering IQ as an additional covariate retained all effects
except for the Nogo-P3 (see below) and revealed no further
significant main effects or interactions.
ERP waveforms, topographic mapping and sLORETA analy-
ses (Fuchs, Kastner, Wagner, Hawes, & Ebersole, 2002; Pasc-
ual-Marqui, 2002) of the control group’s grand average explored
Figure 1 Task description. Standard- and Flanker-CPT in compar-
ison. Both tasks require responding if the central Cue letter ‘O’ is
followed by the Target ‘X’, the additional flankers augment
additional attentional load
the time course and source localizations of Cue-P3, -CNV and
Nogo-P3 (see Figure 2). Topographic exploration by genotype
and group is given in the supplementary Figures S2 and S3.
Results
Group description
Children with ADHD and controls did not differ in
age in both genotype splits (Diagnosis: both
F(1,121)<1.4, p > .24, part. g2<.02). Frequencies of
DRD4 7R polymorphisms and the DAT1 10-6 hap-
lotype were similar in both diagnostic groups
(v2(1) = .5, p = .47 and v2(1) = 2.0, p = .16 respec-
tively). In the DRD4 split, nonsignificant trends for
higher prorated IQ in Controls (F(1,121) = 3.7, p = .06,
part. g2 = .03) and for age a marginal trend Diagno-
sis*DRD4 (F(1,121) = 2.8, p = .10, part. g2 = .02) were
detected. No effects were found for DAT1 (all
F(1,121)<1.9, p > .17). The SDQ teacher ratings (Fig-
ure 3, missing for 5 controls and 1 boy with ADHD)
showed consistently higher behavioural problems in
ADHD compared to controls (Diagnosis: all
F(1,115)>9.9, p < .01, part. g2>.08) without main
effects for either DRD4 nor DAT1 (all F(1,115)<1.6,
p > .22, part. g2<.02) nor interactions between Diag-
nosis and Genetics (all F(1,115)<1.9, p > .16, part.
g2<.02) except for Hyperactivity (Diagnosis*DRD4:
F(1,115) = 3.5, p = .06, part. g2 = .03).
Performance data
Mean reaction time (MRT). Responses were faster
in older participants (Age: both genotype splits
F(1,120)>25.2, p < .01, part. g2>.17) and slower in
the more difficult Flanker-CPT (Task: both
F(1,120)>6.0, p < .02, part. g2>.05).
The split by DRD4 status revealed slower MRT on
the one hand in ADHD (Diagnosis: F(1,120) = 4.6,
p = .04, part. g2 = .04) and in children with DRD4
7R polymorphism (DRD4: F(1,120) = 5.9, p = .02,
part. g2 = .05) without a significant interaction
Diagnosis*DRD4 (F(1,120)<1, p = .81, part. g2<.01).

© 2014 The Authors. Journal of Child Psychology and Psychiatry. © 2014 Association for Child and Adolescent Mental Health.
doi:10.1111/jcpp.12212
Figure 2 Event-related Potentials during Preparation and Response Control. This figure gives Control subjects ERP waveforms from Cues
(above) and Cued Distractors (below) of the Standard-CPT
This was more pronounced in the Flanker-CPT
(Diagnosis*Task: F(1,120) = 5.6, p = .02, part.
g2 = .04 and DRD4*Task: F(1,120) = 3.3, p = .07,
part. g2 = .03, see Figure 4).
The split by DAT1 10-6 haplotype revealed non-
significant trends for slower RT in ADHD particularly
in the Flanker-CPT (Diagnosis: F(1,120) = 3.5, p = .07,
part. g2 = .03 and Diagnosis*Task: F(1,120) = 3.4,
p = .07, part. g2 = .03). No main effects or interac-
tions including DAT1 10-6 haplotype were found (all
F(1,120)<1.0, p > .33, part. g2<.01).
Reaction time variability (RT-SD). RT-SD was
lower in older participants (Age: both F(1,120)>11.1,
p < .01, part. g2>.85) and in controls (Diagnosis:
both F(1,120)>10.6, p < .01, part. g2>.08). It did not
differ between tasks (Task, both F(1,120)<2.3, p > .13,
part. g2<.02 and Task*Diagnosis: both F(1,120)<1,
p > .54, part. g2<.01)).
RT-SD was nonsignificantly increased in DRD4 7R
(DRD4: F(1,120) = 3.7, p = .06, part. g2 = .03), and
clearly unaffected from DAT1 10-6 haplotype
(F(1,120) = .7, p = .40, part. g2<.01), without any
higher order interactions including Diagnosis or
DRD4 nor DAT1 status (all F(1,120)<2.0, p > .15, part.
g2<.02).
ERP data
Cue-P3. The mean Cue-P3 was maximal over pari-
etal areas with sources in the superior parietal
© 2014 The Authors. Journal of Child Psychology and Psychiatry. © 2014 Association for Child and Adolescent Mental Health.
Genetics of preparation and response control in ADHD 917
cortex (Figures 2 and S2a). Controls showed higher
amplitude than children with ADHD (Diagnosis:
both F(1,120)>10.0, p < .01, part. g2>.08). Moreover,
children with DRD4 7R had a diminished Cue-P3
amplitude (DRD4: F(1,120) = 5.1, p = .03, part.
g2 = .04; DRD4*Task: F(1,120) = 2.7, p = .10, part.
g2 = .02), independently of ADHD (Diagnosis*DRD4:
F(1,120)<1, p = .93, part. g2<.01, see Figure S2b). The
DAT1 10-6 haplotype yielded no effect on Cue-P3 (all
F(1,120)<1.6, p > .21, part. g2<.02, see Figure S2c).
Contingent negative variation (CNV). The CNV
mean amplitude has a centro-parietal maximum
with sources in medial and orbitofrontal cortex, as
well as dorsal ACC (see Figures 2 and S2a for further
details). It was generally lower in ADHD than
controls (Diagnosis: both genotype splits
F(1,120)>17.2, p < .01, part. g2>.13). The Flanker-CPT
evoked a smaller CNV in children with ADHD, but
not in controls (Task: both F(1,120)>7.0, p < .01, part.
g2>.05 and Task*Group: both F(1,120)>5.0, p < .03,
part. g2>.04). In addition, this CNV reduction under
increased attentional load was smaller in older
children (Age: both F(1,120)<1, p > .90, part. g2<.01,
but Task*Age: both F(1,120)>5.6, p < .02, part.
g2>.04). Children with DRD4 7R showed a lower
CNV (DRD4: F(1,120) = 4.3, p = .04, part. g2 = .04,
see Figure S2d). Moreover, the CNV reduction in the
Flanker-CPT in DRD4 7R carriers was particularly
present in ADHD, but not in control children
(Task*Group*DRD4: F(1,120) = 5.1, p = .03, part.
918 Bj€
orn Albrecht et al.
Figure 3 Psychopathology. SDQ teacher ratings by ADHD and genotype; error bars indicate confidence intervals with p = .05. More
problems in ADHD, but neither DRD4 (top) nor DAT1 (bottom) main effects are evident
g2 = .04). However, we detected homogeneity of
variance in the Standard-CPT’s CNV (driven by lower
variance within the Controls samples), as well as one
potential outlier in the control sample carrying
DRD4 7R (with CNV amplitude 2.2 SD below the
group’s mean, but not detected as an outlier by
Grubbs’ procedure (Grubbs, 1969), p > .05), which
may compromise the statistics. Limiting the DRD4
analysis to the ADHD sample confirmed a significant
main effect of DRD4 (F(1,91) = 5.0, p = .03, part.
g2 = .05 and a tendency towards an interaction
Task*DRD4 (F(1,91) = 3.1, p = .08, part. g2 = .03),
indicating for ADHD that the diminished CNV ampli-
tude in children with DRD4 7R was present in both
CPTs, but as a tendency more pronounced in the
more difficult Flanker-CPT.
No such effects were found for the DAT1 10-6
haplotype (DAT1: F(1,120)<1.0, p > .48, part. g2<.01;
Group*DAT1: F(1,120)<1, p = .48, part. g2<.01; Task*-
Group*DAT1: F(1,120) = 1.6, p = .21, part. g2 = .01,
Figure S2e).
Nogo-P3. The amplitude of the Nogo-P3 had a
more anterior maximum than the Cue-P3 and
sources in superior and medial frontal cortex (Fig-
ures 2 and S3a). It was lower in the Flanker-CPT
(Task: both genotype splits F(1,120)>4.6, p < .04,
part. g2 ≥ .04), but this difference tended to
decrease with age (Age: both F(1,120)<1.6, p > .20,
© 2014 The Authors. Journal of Child Psychology and Psychiatry. © 2014 Association for Child and Adolescent Mental Health.
J Child Psychol Psychiatr 2014; 55(8): 914–23
part. g2<.02, and Task*Age: both F(1,120)>3.7,
p < .06, part. g2>.03).
It was smaller in ADHD (Diagnosis: both
F(1,120)>3.8, p < .05, part. g2>.03). No effects of
DRD4 were found (all F(1,120)<1.9, p > .17, part.
g2<.02, see Figure S3b for further details), but the
Nogo-P3 amplitude was contrary to the hypothesis
larger in children with DAT1 10-6 haplotype, following
an additive model with ADHD (DAT1: F(1,120) = 6.9,
p = .01, part. g2 = .05, and Diagnosis*DAT1:
F(1,120)<1, p > .39, part. g2<.01; see Figure S3c).
To clarify whether the elevated Nogo-P3 in children
with DAT1 10-6 may index reduced neuronal pro-
cessing efficiency, partial correlations with RT con-
trolling for age and phenotype effects were computed.
If the Nogo-P3 reflects an intact response inhibitory
process, higher Nogo-P3 amplitudes are expected in
children responding faster, resulting in negative
correlations. The interindividual correlations in
children with (r(51) = .46, p < .01) and without
(r(66) = .24, p = .05) the 10-6 haplotype were both
significantly negative, but as a tendency more
strongly in children with the 10-6 haplotype
(p = .09, one-tailed).
Controlling for IQ in the DAT1 comparison reduced
the main ‘Task’ effect on Nogo-P3 to a trend; no other
changes in the results were found. Please see
Figure 5 for a synopsis of results regarding brain
electrical activity.
doi:10.1111/jcpp.12212 Genetics of preparation and response control in ADHD 919

Figure 4 Performance Data. Mean RT and RT-SD with confidence intervals (adjusted to the mean age of 138.6 months, p = .05) for the
main effects from both Standard- and Flanker-CPT (Mean: (CPTS+ CPTF)/2, left side in each plot) as well as the interaction difference [D:
(CPTF-CPTS], right side) of Controls and children with ADHD and DRD4 and DAT1 comparisons. Mean was slower (left column) and more
variable (right column) in both CPTs for children with ADHD and for those with DRD4 7R (above), but not with the DAT1 10-6 haplotype
(below)

Discussion given the small risks associated with polymorphisms

The first research question addressed in the study
was whether functional polymorphisms of the DRD4
and DAT1 genes have an impact on symptom sever-
ity in ADHD. As groups were matched for age, we
would not expect that the findings were confounded
with effects of typical development. Moreover, gen-
eral cognitive ability was similar in ADHD and
controls, and did not differ between DRD4 and
DAT1 polymorphisms.
As expected, children with ADHD showed increased
hyperactivity, but also less social behaviour and
increased emotional, conduct and peer problems. As
outlined in the supplement, children with ADHD also
frequently showed comorbidities, particularly
oppositional defiant and conduct disorders, as well
as mood disorders, which are common, particularly in
boys (Biederman, 2005). Taken together, these
results suggest that the patient sample investigated
shows very typical behavioural problems of children
with ADHD (Becker et al., 2006). There were no
relations either of DRD4 or DAT1 polymorphisms
with symptom severity, although this was expected
in previous studies of ADHD. Thus, the functional
relationship between these polymorphisms and brain
activity parameters in ADHD discussed below may not
be the consequence of increased symptom severity
per se.
In a previous report with an overlapping sample,
we found that the performance parameters response
speed and variability, as well as the electrophysio-
logical brain activity parameters Cue-P3, CNV and
Nogo-P3 were driven by familial factors in ADHD,
and may thus be linked to shared genetic or
environmental factors (Albrecht et al., 2013). This
leads to the second question addressed here,
whether the DRD4 and DAT1 polymorphisms have
an impact on performance and electrophysiological
brain activity parameters associated with prepara-
tion and response control.
Here, we observed that performance (mean
response speed) decrements were also present in
children with the DRD4 7R polymorphism. As DRD4
7R is also associated with ADHD, such an effect
might be expected if the DRD4 7R polymorphism

© 2014 The Authors. Journal of Child Psychology and Psychiatry. © 2014 Association for Child and Adolescent Mental Health.
920 Bj€
orn Albrecht et al. J Child Psychol Psychiatr 2014; 55(8): 914–23

Figure 5 Electrophysiology of preparation and response control. Brain electrical mean amplitudes and confidence intervals (adjusted to
the mean age of 138.6 months, p = .05) of brain electrical activity. The Cue-P3 (left) and CNV (middle) showed an additive effect of ADHD
phenotype and DRD4 7R genotype. The Nogo-P3 (right) was lower in ADHD, but contrary to expectations increased in children with the
DAT1 10-6 haplotype

play a functional role in ADHD. But furthermore, the
effect of the DRD4 7R was present in both children
with ADHD and Controls, i.e. the effect appears to be
additive and of similar small to medium effect size as
the response speed problems of children with ADHD.
However, the DAT1 polymorphisms revealed no such
impact on CPT performance.
The analysis of performance errors was limited
by the generally high accuracy reached, and the
expected ADHD and genotype effects may be hid-
den by ceiling effects. This is in contrast to a
recent study by Gizer and Waldman with a similar
CPT that found an association of DRD4 with
inattention errors (commission errors to uncued
targets) and of DAT1 with impulsivity (commission
errors to cued nontargets) (Gizer & Waldman,
2012). It remains open whether this discrepancy
could be explained by differences in speed accu-
racy trade-off; but response speed was not
assessed in there. The slower mean response speed
associated with DRD4 7R in this study may thus
similarly be driven by inattention, but the role of
DAT1 on impulsivity cannot be confirmed at the
performance level.
Specifically, the DRD4 polymorphism had a gen-
eral impact on brain activity during cue processing:
the Cue-P3 associated with attentional orienting
appears to be diminished in children with the 7R
variant. In line with other studies, we found source
localizations of Cue P3 in superior parietal brain
areas. However, as the posterior attention system is
particularly associated with Acetylcholine and Nor-
epinephrine (Posner & Rothbart, 2007), the influ-
ence of DRD4 may be due to processes that trigger
the Cue-P3. The preparatory Cue-CNV shows a very
similar pattern of results, as it is diminished in
ADHD and children with the DRD4 7R allele. In
previous work, we found sources of the CNV
located in dorsal anterior cingulate and frontal
cortex (Albrecht et al., 2013; Lutcke et al., 2009).
These brain regions have strong dopaminergic
innervation potentially following input from dopa-
minergic midbrain nuclei, and correspond well to
the DRD4 expression in frontal areas as the
orbitofrontal cortex and anterior cingulate. Impor-
tantly, these DRD4 genotype and ADHD phenotype
effects on Cue-P3 and CNV follow and additive
model, so the DRD4 7R polymorphism led to

© 2014 The Authors. Journal of Child Psychology and Psychiatry. © 2014 Association for Child and Adolescent Mental Health.
doi:10.1111/jcpp.12212
similar impairments in children with ADHD and
healthy Controls.
No effects of DRD4 were found for the Nogo-P3, an
electrophysiological parameter of executive attention
during inhibitory response control. As it is generated
in prefrontal brain regions where the D4 receptor is
most abundant (Meador-Woodruff et al., 1996), an
impact would be expected. However, this specificity
of DRD4 for attention and preparation rather than
response inhibitory control is also reported in per-
formance data studies (Gizer & Waldman, 2012) and
is thus paralleled by brain activity parameters.
Effects of the dopamine transporter (DAT1) 10-6
haplotype polymorphism were almost a reverse
image of the DRD4 7R findings. Performance data
and brain activity during Cue processing were not
affected, but children carrying the 10-6 haplotype
(moderately associated with ADHD) showed
increased instead of reduced Nogo-P3 amplitude,
linked to neuronal sources in cingulate cortex and
premotor and frontal areas (Verleger et al., 2006). As
the Nogo-P3 analysed here was recorded in trials
with successful inhibition or termination of the
prepared response, one may speculate that this
larger brain activity does in fact reflect lower neuro-
nal efficiency (as the same performance could be
achieved with higher ‘effort’ in children with the
DAT1 10-6). However, this may be not the case, as
interindividually faster responding was associated
with enhanced Nogo-P3 which may reflect higher
need for response inhibition and consequently more
resource allocation in individuals responding faster.
Similarly, a recent study using transcranial mag-
netic stimulation in healthy adults shows that
increased Nogo-P3 may compensate deficient inhib-
itory processes within the motor system (Hoegl et al.,
2011). Albeit this study gives no evidence for
increased impulsivity from performance data or
psychopathology, the increased Nogo-P3 in children
with the DAT1 10-6 haplotype may reflect a com-
pensatory neuronal response inhibition process.
There are a number of limitations that need to be
considered in the evaluation of the study. The 24
scalp electrodes available for this study are suffi-
cient to capture the basic scalp topography of the
evoked potentials, but the precision of the brain
electrical neuroimaging is limited (Michel & Bran-
deis, 2009), and source localization is used here as
an exploratory tool that may help to integrate the
findings into theories of ADHD. As simple genotype
effects are expected to be rather small, this study
is limited by a relatively small sample, particularly
of Controls. Albeit the data suggest that the
genotype effects of DRD4 and DAT1 polymor-
phisms may be additive to the impact of the ADHD
phenotype and occur similarly in patients and
controls, we think that the results need to be
replicated. It remains open whether DRD4 and
DAT1 polymorphisms are specifically associated
with comorbid disorders, and whether these may
© 2014 The Authors. Journal of Child Psychology and Psychiatry. © 2014 Association for Child and Adolescent Mental Health.
Genetics of preparation and response control in ADHD 921
further explain preparation and response control
deficits in ADHD.
Conclusion
In this study, we found evidence that preparation and
response control, both impaired in ADHD, are related
to polymorphisms of genes related to the dopaminer-
gic system. The DRD4 7R effect on performance and
brain activity in the superior parietal and medial
frontal cortex and the dorsal anterior cingulate is
related to attentional orienting and response prepa-
ration. The impact of the DAT1 10-6 haplotype,
potentially leading to increased impulsivity, may be
compensated by increased inhibitory response con-
trol generated in the superior and medial frontal
cortex and the anterior cingulate. The medium to
large effects of the diagnostic phenotype and the
small to medium effects of the genetic DRD4 and
DAT1 polymorphisms were additive, indicating sim-
ilar genetic mechanisms in patients with ADHD and
healthy controls, supporting a dimensional view of
ADHD. If replicated, these results highlight the func-
tional role of dopaminergic gene variants among the
risk factors for ADHD and probably other disorders
with attentional orienting, preparation and response
control as endophenotypes.
Supporting information
Additional Supporting Information may be found in the
online version of this article:
Figure S1. Supplement to Response preparation follow-
ing Cues.
Figure S2. Supplement to Inhibitory Response Control
following Cued Nontargets.
Appendix S1. Supplementary Methods and Materials.
Acknowledgements
In this study, recruitment of ADHD sibling pairs was
supported by National Institute of Mental Health Grant
R01MH062873 to Steve Faraone and Swiss National
Science Foundation grant 32-109591 to H.-C. S.
H.U.S received conference attendance support or was
paid for public speaking by Eli Lilly and Company,
Janssen-Cilag, Medice, Novartis and Shire. P.A. has
received funding for educational and research activities
from Janssen-Cilag and Shire, and consultancy and
speaker fees from Eli Lilly and Company, Flynn
Pharma, and Shire that have been used for educational
and research activities. In the last 36 months, H.-C. S.
has been a member of the advisory board and/or
received payment for lectures including service on
speakers’ bureaus by Shire and Medice (pharmaceuti-
cal companies). A. R. is on the advisory board and
speakers’ bureau of Eli Lilly and Company, Medice,
Novartis and Shire; has received educational grants
from Medice and Shire; and has received research
support from Schwabe and Shire. T. B. served in an
advisory or consultancy role for Hexal Pharma, Lilly,
Medice, Novartis, PCM scientific, Shire and Viforphar-
922 Bj€
orn Albrecht et al. J Child Psychol Psychiatr 2014; 55(8): 914–23

ma. He received conference attendance support and
speaker’s fee by Lilly, Janssen McNeil, Medice, Novartis
and Shire. He is/has been involved in clinical trials
conducted by Lilly, Shire & Viforpharma. The authors
declare that the present work is unrelated to the above
grants and relationships. Rest of the authors declare
they have no potential or competing conflicts of interest.
The authors acknowledge: Christa Dahlmann, Re-
nate Kolle and Antonia Bak conducted ERP-recordings;
Anke Fillmer-Otte, Anne Reiners, Gudrun Schneider
and Nicola W€ostmann performed IQ- and further neu-
ropsychological testings. The authors also thank all
children and their families for participation.
Correspondence
Bj€
orn Albrecht, University Medical Center of G€
ottingen,
Child and Adolescent Psychiatry, von Siebold-Str. 5,
37075 G€ ottingen, Germany; Email:balbrec@gwdg.de

Key points
• Attention, Preparation and Response Control problems that are familially driven in ADHD may reflect the
impact of genetic or environmental factors shared with the disorder.
• In this study, we tested the impact of ADHD and candidate gene polymorphisms regulating the Dopamine D4
receptor (DRD4) and Dopamine Transporter (DAT1).
• Children with the DRD4 7R polymorphism showed reduced attentional orienting and response preparation,
while the DAT1 10-6 haplotype led to increased need for response preparation.
• Genetic effects were similar in children with ADHD and healthy controls.
• Polymorphisms of genes regulating dopaminergic brain networks may increase the risk for ADHD by
diminishing attention and preparation or requiring compensatory response control.

Strengths and difficulties questionnaire in a pan-european

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Accepted for publication: 28 December 2013
Published online: 13 February 2014