SPECIAL ISSUE: ORIGINAL ARTICLE
THE COGNITIVE GENETICS OF ATTENTION DEFICIT HYPERACTIVITY
DISORDER (ADHD): SUSTAINED ATTENTION AS A CANDIDATE PHENOTYPE
Mark A. Bellgrove1,2,3, Ziarih Hawi2, Michael Gill2 and Ian H. Robertson1
(1Department of Psychology and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland;
2Departments of Psychiatry and Genetics and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin,
Ireland; 3Cognitive Neuroscience Laboratory, University of Melbourne, Victoria, Australia)
ABSTRACT
Here we describe the application of cognitive genetics to the study of attention deficit hyperactivity disorder (ADHD).
Cognitive genetics owes much to the pioneering work of cognitive neuropsychologists such as John Marshall, whose
careful observations of cognitive dissociations between brain-lesioned patients greatly advanced the theoretical
understanding of normal cognitive function. These theories have in turn helped to constrain linkages between candidate
genes and cognitive processes and thus help to drive the relatively new field of cognitive genetics in a hypothesis-driven
fashion. We examined the relationship between sustained attention deficits in ADHD and genetic variation in a
catecholamine-related gene, dopamine beta hydroxylase (DβH). DBH encodes the enzyme that converts dopamine to
noradrenaline and is crucial to catecholamine regulation. A polymorphism with the DBH gene has been associated with
ADHD. In fifty-two children with ADHD, we examined whether variation in the Taq I DBH gene polymorphism was
related to sustained attention performance. Participants performed the Sustained Attention to Response Test (SART).
Performance on the SART discriminates ADHD from control children, and in imaging work, is associated with right frontoparietal activation. A significant effect of DBH genotype was found on SART performance measures. Children possessing
two copies of the ADHD-associated risk allele (A2) had significantly poorer sustained attention than those ADHD children
who did not possess this allele or a non-genotyped control group. The DBH gene may contribute to the susceptibility for
ADHD, in part because of its varying effects on the development of brain mechanisms mediating sustained attention.
Key words: genetics, attention, sustained attention, dopamine, ADHD
INTRODUCTION
In recent times there has been increased interest
within cognitive neuroscience in the role played by
genetics in cognitive processes. This paper does not
seek to explicitly review the application of
molecular genetics to cognitive neuroscience- for
this the reader may refer to a number of recent and
excellent summaries (Goldberg and Weinberger,
2004; Parasuraman and Greenwood, 2004). Our
purpose is, however, to provide an example of this
approach from our own recent work on attention
deficit hyperactivity disorder (ADHD).
In our view the application of molecular
genetics to studies of cognition – cognitive genetics
– follows strongly in the tradition of cognitive
neuropsychology. In the latter, the effects of
localised cerebral lesions on specific cognitive
functions have thrown considerable light on the
cognitive architecture of the normally functioning
human brain (e.g., Broca, 1824-1880; Wernicke,
1848-1905). For example, the syndrome of
unilateral spatial neglect, in which patients display
deficits in detecting and acting upon contralesional
stimuli is most frequent and severe following
lesions centred on the posterior parietal lobe of the
right cerebral hemisphere (Robertson and Marshall,
1993). The central role played by this region in
human spatial attention has been confirmed by
Cortex, (2006) 42, 838-845
numerous neuroimaging studies with healthy
participants that have shown activity in the right
temporo-parietal junction, particularly when an
observer must shift their attention from an invalidly
cued location to detect a target at a contralateral
location (Corbetta et al., 2000; Corbetta and
Shulman, 2002).
In the case of cognitive genetics, specific allelic
variants of candidate genes (see Table I) take the
place of specific cerebral lesions, and so a linkage
is made between high level cognitive functions on
the one hand, and molecular genetics on the other.
Such linkages are essential to test contemporary
models of attention (Corbetta and Shulman, 2002;
Posner and Peterson, 1990) which include variables
across very different levels of analysis – cognitive,
anatomical, neurochemical and now genetic. For
example, Parasuraman et al. (2005) have recently
shown that visuospatial attention is substantially
influenced by allelic variation in a polymorphism
of the gene, CHRNA4, encoding a nicotinic
acetylcholine receptor subunit (alpha-4 subunit).
Focus on this candidate gene was warranted since
pharmacological studies of primates show that
visuospatial attention can be modulated by
acetylcholine (Witte et al., 1997) and impairments
in visuospatial attention are prominent in
neurodegenerative diseases affecting basal forebrain
cholinergic pathways (e.g., Alzheimer’s disease).
Sustained attention, genetics and ADHD
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TABLE I
Glossary of terms
Term
Allele
Candidate gene
Intron
Single nucleotide polymorphism (SNP)
Linkage disequilibrium (LD)
Definition
An alternative form of a gene that can occur at a given locus on a gene. Alleles differ in their
nucleotide sequence. A single allele for each locus of a gene is inherited from each parent.
A gene located on a chromosomal region that is thought to be involved in a trait (e.g.,
cognitive process) or a disorder (e.g., ADHD). Candidate genes are normally chosen based
upon prior physiological, genetic or biochemical characterisation that leads one to suspect
that this gene is involved in the trait.
A nucleotide sequence in a gene that does not code for the gene product. Introns can be
compared to exons which are the protein coding portion of a gene.
Different versions of a gene, due to differences in nucleotides on DNA, are called
polymorphisms. The most common form of genetic variation, the SNP, reflects a change in a
single base in the DNA that differs from the usual base at that position.
LD occurs when alleles at different loci occur together within an individual at a greater than
chance frequency.
Specifically, Parasuraman et al. (2005) found that
allelic variation in CHRNA4 affected both the
pattern of benefits and costs elicited by an
endogenous cuing manipulation. The study by
Parasuraman et al. (2005) provides important first
insights that individual differences in visuospatial
attention may be at least partially explained by
underlying genetic influences.
Before turning our attention to the cognitive
genetics of ADHD, it is necessary to review the
empirical work that bears directly upon the
neuroanatomical models that guide our selection of
both candidate genes and candidate cognitive
processes in ADHD.
A Neuroanatomical Model of Sustained Attention
Our own neuropsychological and rehabilitation
research on the attentional sequelae of traumatic
brain injury (TBI), stroke, and more recently
ADHD, has been heavily influenced by
neuroanatomical models of attention that propose
distinct attentional systems for the control of
spatial attention and non-spatial alertness (Posner
and Peterson, 1990; Pardo et al., 1991; Wilkins et
al., 1987). We have defined non-spatial alertness or
sustained attention, as the internal control of
alertness in the absence of exogenous support.
Spatial selectivity, on the other hand, serves to
enhance perception at certain locations in space.
A number of sources of information converge to
suggest a predominant role of the right prefrontal
cortex in human sustained attention. First, it is well
established that right frontal lesions lead to an
increase in reaction time when an imperative
stimulus is not preceded by a warning signal
(Posner et al., 1987). Frontal patients do
nevertheless benefit from a warning signal
indicating that it is the intrinsic and not phasic
aspects of alertness that are impaired with right
frontal lesions (Posner et al., 1987; Sturm et al.,
1999). Wilkins et al. (1987) demonstrated that
patients with right frontal lobe lesions were
specifically impaired when required to perform a
simple tone counting task of a slow event rate.
These authors concluded that a monotonous task
demand impaired the right frontal patient’s ability to
sustain attention. A right frontal focus for sustained
attention is also consistent with the cortical
distribution of noradrenergic neurons arising
predominantly from the locus coeruleus (Marrocco
et al., 1994). These neurons contain DβH which is
the enzyme responsible for the conversion of
dopamine to noradrenaline. Accordingly, drugs that
suppress NA function also impair sustained
attention in humans (Smith and Nutt, 1996) but
these deficits can be reversed by the provision of
phasic alerts that extrinsically release NA from the
locus coeruleus.
Functional imaging studies have generally
confirmed this model by showing that sustained
attention is achieved through the reciprocal
interaction between cortical and sub-cortical areas.
Specifically, the right dorsolateral prefrontal cortex,
anterior cingulate and inferior parietal lobe act to
exert top-down (endogenous) control, via thalamic
nuclei, over the locus coeruleus to promote NA
release (Manly et al., 2003; Pardo et al., 1991;
Sturm et al., 1999; Sturm and Willmes, 2001;
Sturm et al., 2004; Coull et al., 1999). It follows
that the sustained attention deficits of right frontal
patients may stem from a failure to endogenously
regulate alertness in a top-down fashion, and that
activating intact phasic alertness systems may
therefore ameliorate these deficits. In support of
this relationship we have argued that the sustained
attention deficits in TBI arise from a failure to
endogenously maintain alertness (Robertson et al.,
1997a; Manly et al., 2003) and have shown that
phasic alerting cues can improve the ability of TBI
patients to effectively maintain task goals (Manly
et al., 2002). More recently, we have also
demonstrated that sustained attention deficits in
children with ADHD (O’Connell et al., 2004) can
be ameliorated by the provision of random phasic
alerts designed to heighten activity within RH
networks (O’Connell et al., in press).
Posner and Peterson (1990) argued that the
alertness, or sustained attention system, could coactivate the spatial attentional system of the parietal
lobe, either directly or via brainstem nuclei. Clinical
support for this notion comes from the existence of
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Mark A. Bellgrove and Others
deficits in non-spatial alertness in patients with right
parietal lesions and the neglect syndrome. Working
with 44 RH patients, Robertson et al. (1997b)
demonstrated that impairments on a simple tone
counting task were a significant predictor of spatial
bias, as assessed using a range of measures of
unilateral spatial neglect. While deficits in sustained
and spatial attention could both be a consequence of
RH damage and co-exist independently, additional
evidence from both clinical and non-clinical groups
suggests a more dynamic interplay.
First, Robertson et al. (1995, 1998)
demonstrated that the extent of chronic left
unilateral neglect can be substantially reduced by
sustained attention training or by the provision of
random phasic alerts. Second, taking an individual
differences approach, we have demonstrated that
variation in the capacity for sustained attention is
accompanied by variation in the attentional bias
seen on clinical tests of neglect, in both healthy
children (Dobler et al., 2005) and adults (Bellgrove
et al., 2004). For example, Bellgrove et al. (2004)
asked healthy undergraduates to perform both the
Sustained Attention to Response Task (SART), in
which participants must withhold their response to
infrequent no-go events, and the Greyscales Task, a
perceptual measure of attentional bias. Performance
on the SART correlates highly with everyday lapses
of attention and distinguishes TBI patients
(Robertson et al., 1997a; Manly et al., 2003) and
ADHD children from controls (O’Connell et al.,
2004). Much research with the Greyscales Task has
shown a reliable leftward bias that is consistent with
the phenomenon of pseudoneglect (Nicholls et al.,
1999; Mattingley et al., 1994). In Bellgrove et al.
we found that participants who performed poorly on
the SART also had a significantly attenuated
leftward bias (i.e., as in neglect, the orienting bias
of the RH was weakened), relative to those who
performed well on the SART. We suggested that the
attenuated leftward bias on the part of the poor
sustained attenders, relative to the good sustained
attenders, arose from individual differences in the
efficiency with which fronto-parietal networks of
the RH control visual attention.
Finally, Dobler et al. (2003) have also
documented a case of developmental unilateral
neglect in a boy referred to clinical services for
attentional problems. Objective testing confirmed
the existence of both a profound sustained attention
deficit and a left-sided inattention. Strikingly, the
extent of left-sided inattention was markedly
reduced by the same phasic alerting procedures
used in adult patients with RH lesions and neglect
(Robertson et al., 1997a).
The Cognitive Genetics of ADHD
ADHD is a childhood disorder that is defined
by age-inappropriate levels of inattention,
hyperactivity and/or impulsivity (American
Psychiatric Association, 1995). Family, twin and
adoption studies all suggest that the disorder is
strongly heritable (see Kirley et al., 2002 for
review). Stimulant medications, such as
methylphenidate have efficacy in treating the
cognitive and behavioural features of the disorder.
Stimulants act by inhibiting the re-uptake and
promoting the release of catecholamines (including
dopamine and noradrenaline) (Krause et al., 2003).
In support of catecholamine hypotheses, candidate
gene studies have found associations with variants
at a number of genetic loci including the dopamine
transporter gene (Gill et al., 1997; Daly et al.,
1999; Cook et al., 1995; Waldman et al., 1998),
dopamine receptor genes (e.g., DRD4 and DRD5)
(Daly et al., 1999; Faraone et al., 2001) and the
gene (DBH) encoding DßH (Daly et al., 1999).
Each of these variants may confer a small part of
the genetic susceptibility to ADHD.
A limited number of studies have examined
whether genetic variants that are thought to confer
susceptibility to ADHD are also associated with
cognitive impairment (Langley et al., 2004;
Swanson et al., 2000; Manor et al., 2002; Bellgrove
et al., 2005a, 2005b, 2005c, 2005d). The approach
of linking a genetic risk factor to an alternative, or
intermediate, cognitive phenotype has much
intuitive appeal. Rather than seeking associations
between a gene and a subjective diagnostic
category, here association is sought between a gene
and a well-operationalised, objectively measured
cognitive process. In the pursuit of such linkages it
is worth bearing in mind that “a poorly-defined
phenotype is unlikely to facilitate identification of
the underlying genotype” (Baddeley, 1996, p.186).
When, however, the cognitive process itself is well
understood in cognitive-neuroanatomical terms,
then progress may be made in determining how the
gene contributes to variation in the development of
brain mechanisms modulating that cognitive
process. Associations of this type will prove
powerful in elucidating the brain-behaviour basis of
conditions, such as ADHD.
In our own genotype/phenotype studies of
ADHD, we have employed a sustained attention
phenotype. As reviewed above, sustained attention
is thought to be achieved throughout a frontoparietal network and to be modulated by
catecholamines. A large body of evidence supports
the existence of sustained attention deficits in
children, adolescents and adults with ADHD
(Seidman et al., 1998; Epstein et al., 2001; Shallice
et al., 2002; O’Connell et al., 2004). Further, such
deficits are ameliorated by methylphenidate
(Solanto, 1998).
Groot et al. (2004) recently examined familial
influences on sustained attention in preschoolers
using the Amsterdam Neuropsychological Tasks.
Correlations of performance measures were
generally higher in monozygotic than dizygotic
twin pairs suggesting genetic influence. Heritability
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Sustained attention, genetics and ADHD
estimates for sustained attention measures were,
however, generally moderate (.46-.72) and modelfitting suggested the influence of both genetic and
unique environmental effects. Using an affectedsibling pair design within an ADHD cohort, SlaatsWillemse et al. (2005) recently showed significant
sib-pair correlations for aspects of sustained
attention. These studies provide preliminary
evidence for genetic influences on sustained
attention in ADHD and non-ADHD samples.
Although the heritability of sustained attention may
be less than for the ADHD diagnosis itself,
sustained attention measures may still be
informative for molecular genetic studies if the
magnitude of the association between the gene and
cognitive phenotype is larger than between the gene
and the clinical phenotype (Doyle et al., 2005).
In our work we have used the SART to
examine sustained attention in ADHD. The SART
is a short (5 minute) go/no-go test in which
participants are presented, for example, with a
fixed sequence of 1-9 digits and are required to
respond to the presentation of digits (go-trials),
except when the digit “3” (no-go trial) is presented.
Withholding to a rare target, as opposed to
responding to a rare target in the case of CPT-like
tasks, shifts the automatic response set to the nontargets and thus successful withholding places
greater demands on the sustained attention system
in order to overcome the pre-potent non-target
response (Robertson et al., 1997a). This is
particularly true in a fixed sequence version of the
SART, where the no-go target (‘3’) occurs
predictably in the 1, 2, 3… 9 cycle. This version is
sensitive to frontal lobe dysfunction (Manly et al.,
2003) and minimizes the inhibitory components of
the task that may be apparent in, for example, a
random sequence (Fassbender et al., 2004) (see
also Bellgrove et al., 2005d). The specificity of the
SART for indexing a sustained attention deficit in
children and adolescents with ADHD, relative to
matched controls has been demonstrated (Shallice
et al., 2002; O’Connell et al., 2004).
Here we examined the performance of children
and adolescents with ADHD on the SART, in
relation to DBH genotype. DßH is the enzyme
catalysing the conversion of dopamine to
noradrenaline and is critical to catecholamine
regulation in the brain. An association between
ADHD and the A2 allele of a Taq I polymorphism
(maps to intron 5) of the DBH gene has been
reported (Daly et al., 1999; Roman et al., 2002).
Since activity within fronto-parietal networks
subserving sustained attention is modulated by
input from DβH-containing noradrenergic neurons,
we predicted that DBH genotype would relate to
sustained attention deficits in ADHD. No studies
have examined the relationship between DBH
genotype and a quantitative sustained attention
phenotype either in normality or in pathological
conditions, such as ADHD. We predicted that
sustained attention would be affected by DBH
genotype, with ADHD children possessing two
copies of the A2 allele of the Taq I polymorphism
displaying greater impairment than those not
possessing this allele.
MATERIALS AND METHODS
Subjects
Fifty-two children and adolescents with ADHD
(45 male, 48 right-handed) were recruited as part
of ongoing genotype/phenotype studies within our
laboratory. The mean age of this sample was 12.2
years (SD = 2.3) and the mean IQ, as assessed by
the WISC-III, was 97 (SD = 11.2)1. Exclusion
criteria included known neurological conditions
including pervasive developmental disorders and
epilepsy. All children met DSM-IV criteria for
ADHD. Diagnostic details can be found in Kirley
et al. (2002). 75% of these participants met
diagnostic criteria for ADHD-Combined Type
(ADHD-CT), 15% for ADHD-Predominantly
Inattentive Type (ADHD-In) and 10% for ADHDPredominantly
Hyperactive-Impulsive
Type
(ADHD-H/I). 73% of the ADHD probands met
diagnostic criteria for other disorders such as
Oppositional Defiant Disorder (ODD) and Conduct
Disorder (CD). Stimulant medication was
withdrawn at least 24 hours prior to the
neuropsychological testing.
These 52 participants were divided according to
the presence of the A2 allele of the Taq I DBH
gene polymorphism, yielding three DBH genotype
groups, henceforth referred to as “No High-Risk”
(n = 15), “One High-Risk” (n = 17) and “Two
High-Risk” (n = 20), respectively. These groups
did not differ in terms of Age [F (2, 49) = .72, p =
.49], IQ [F (2, 48) = 1.29, p = .28], frequency of
the three ADHD Sub-types (ADHD-CT: χ22 = 3.9,
p = .14; ADHD-In: χ22 = .55, p = .76; ADHD-H/I:
χ22 = 4.35, p = .11) or in terms of parental ratings
of symptomatology as assessed by the Conners
rating scale (Conners, 1998).
A comparable group of 21 healthy control
children (18 = male, 20 = right-handed) was also
recruited from schools in and around Dublin.
Control children had a mean age of 12 years (SD =
1.29) and a mean IQ of 103 (SD = 11.5). There
were no significant differences between the control
children and the ADHD DBH-genotype groups in
terms of age [F (3, 69) = .63, p = .60] or IQ [F (3,
68) = 2.13, p = .10].
DBH Genotyping
DNA was extracted from blood samples or buccal
cells from the ADHD proband in each family. Primer
1Note
that IQs were not available for 1 of the ADHD participants.
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Mark A. Bellgrove and Others
sequence and amplification conditions can be found
elsewhere (Daly et al., 1999).
The Sustained Attention to Response Task (SART)
Briefly, the SART is a short (5 minute) test in
which participants are presented, for example, with
a fixed sequence of 1-9 digits and are required to
respond to the presentation of digits (go-trials),
except when the digit “3” (no-go trial) is presented.
In order not to disadvantage ADHD children with
an impulsive response style, participants were
required to respond upon the presentation of a
predictably timed response cue. Participants
performed 225 trials, incorporating 25 no-go trials.
Dependent measures included: a) Commission
errors (i.e., failure to withhold to the no-go ‘3’); b)
Omission errors (i.e., failures to respond to the go
digits); c) Total errors (a composite of commission
and omission errors); d) Mean RT (msec) to the go
digits (GoRT) and e) Response variability (defined
as the SDGoRT/MeanGoRT). The latter measure
adjusts for differences in RT making it suitable for
comparing intra-individual variability between
patient and control groups (Manly et al., 2000;
Stuss et al., 2003).
RESULTS
Performance of the ADHD participants was
standardized relative to that of the control group.
Z-scores for each of the DBH-genotype groups for
each of the dependent variables are presented in
Table II.
Z-scores were compared across the four groups
(Control vs. No High-Risk vs. One High-Risk vs.
Two High-Risk DBH groups) using univariate
analysis of variance (ANOVA). Post-hoc
comparisons were performed using the GamesHowell Test.
There was a significant effect of Group on
errors of commission [F (3, 69) = 3.16, p = .03, η2
= .12], that was driven by the significant difference
TABLE II
Fixed SART performance as a function of ADHD DBH genotype
groups. Performance of each of the ADHD DBH genotype groups
on each of the Fixed SART measures are displayed as mean (SD)
of z-scores. Performance of the control sample is not shown since
this group, by definition, had a mean of zero (SD = 1)
DBH genotype group
(Number of copies of allele 2)
0
(N = 15)
1
(N = 17)
2
(N = 19)
Fixed SART
Mean (SD) Mean (SD) Mean (SD)
Commission Errors
Omission Errors
Total Errors
Mean Go-RT
Mean Response Variability
.03 (1.06) .54 (1.53) 1.05 (1.27)
.67 (1.99) 3.59 (4.17) 3.01 (3.78)
.36 (1.53) 2.11 (2.71) 2.19 (2.40)
.71 (.88)
.44 (1.54) .62 (1.14)
.58 (1.03) 1.37 (1.95) 1.21 (1.70)
between the control group and the Two High-Risk
DBH group (p = .028). The Two High-Risk DBH
group made more errors of commission than the
No High-Risk DBH group (p = .06).
There was a significant effect of Group on
omission errors [F (3, 69) = 6.27, p = .001, η2 =
.21]. Post-hoc comparisons revealed that the
controls differed significantly from both the One
and Two High-Risk DBH groups (p = .014, p =
.012, respectively).
After controlling for Group, there was a
significant correlation between errors of
commission and omission [r2 = .28, p = .001].
There was a significant effect of Group on the
composite measure of total errors (commission plus
omission) [F (3, 69) = 6.14, p = .001, η2 = .21].
Post-hoc comparisons indicated that controls
differed significantly from both the One (p = .03)
and Two High-Risk DBH (p = .004) groups.
Additionally, the Two High-Risk DBH group made
significantly more total errors than the No HighRisk DBH group (p = .045).
There was no effect of Group for Go RT
[F (3,69) = 1.41, p = .25, η2 = .06] but there was
for response variability [F (3, 69) = 3.50, p = .02,
η2 = .13]. Post-hoc comparisons indicated that
controls differed significantly from the Two HighRisk DBH group.
Using the scores of the ADHD participants
alone, regression was performed to examine the
parametric effect of the A2 allele of the Taq I DBH
polymorphism. Significant effects were observed
for errors of commission [F (1, 50) = 5.45, p = .02,
r2 = .08] and total errors [F (1, 50) = 4.97, p = .03,
r2 = .07].
DISCUSSION
In this paper we have outlined an approach
whereby discrete cognitive processes may be linked
to specific genes. We have termed this approach
cognitive genetics and have provided one example
of its application in ADHD research. In the
example given, we investigated the relationship
between sustained attention and DBH genotype in
ADHD. We presented preliminary data that the A2
allele of the Taq 1 polymorphism of the DBH gene
is associated with sustained attention deficits in
children and adolescents with ADHD. ADHD
participants who possessed one or two copies of
this allele performed more poorly than nongenotyped control children. Comparisons within the
ADHD sample indicated that possession of two
copies of the A2 allele was associated with
significantly poorer sustained attention than nonpossession of this allele.
The observation that sustained attention in
ADHD is affected by a DBH gene variant is
significant for several reasons. First, the results
suggest a neurocognitive phenotype that is related
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Sustained attention, genetics and ADHD
to variation in the DBH gene in ADHD. A number
of studies have now demonstrated an association
between ADHD and a number of susceptibility loci
(Hawi et al., 2003a) including the Taq I DBH gene
polymorphism (Daly et al., 1999; Roman et al.,
2002). An important innovation within such studies
is to use continuously quantifiable phenotypes that
might relate more closely to dysfunction within
discrete neural systems, than do symptom-based
categories. The use of such refined phenotypes may
increase the power of genetic studies to detect
associations with genes of small effect (Castellanos
and Tannock, 2002). We have provided preliminary
evidence that the association of ADHD with the A2
allele of the Taq I DBH gene polymorphism may be
related, in part, to its effects on sustained attention.
Second, while noradrenaline has been proposed
as the dominant neuromodulator of the sustained
attention network, it seems likely that other
catecholamines may also play an important role. In
the context of ADHD research, genetic variants
within the dopamine system have also been found
to be associated with sustained attention deficits
(Bellgrove et al., 2005c, 2005d; Loo et al., 2003;
Manor et al., 2002). Given the central role of DBH
in the regulation of catecholamines in the brain, it
seems unlikely that changes within the
noradrenergic system would not be associated with
concomitant changes within the dopaminergic
system. Since the prefrontal cortex is exquisitely
sensitive to fluctuations in both noradrenaline or
dopamine (Arnsten, 1998), dysfunction within
either system may impair the reciprocal relationship
between top-down and bottom-up influences that
seems necessary for sustained attention.
There are several limitations to the preliminary
study described herein. A critique of these
limitations may prove instructive in highlighting
methodological issues in cognitive genetics. While
we have demonstrated in this study that the Taq I
DBH polymorphism is relevant to sustained
attention in ADHD, we have not demonstrated that
it is relevant to sustained attention in healthy
populations. We have, however, recently examined
the effect of this polymorphism on sustained
attention in healthy undergraduate students and
have observed an association between the A2 allele
of the Taq I polymorphism and relatively poorer
sustained attention (Bellgrove et al., in
preparation). Given the small sample size of the
current study and the moderate heritability of
sustained attention, our results should nevertheless
be viewed as preliminary until replicated in an
independent sample.
While the Taq I DBH polymorphism has been
associated with ADHD within our Irish studies, it
is unlikely to be a functional variant given its
intronic location. A number of other markers exist
within the DBH gene that are thought to be
functional; that is allelic variation within a
polymorphism located within the DBH gene leads
to variation in the expression of the gene’s protein
product in the brain. In the case of DBH, genetic
variation may lead to an alteration in the
expression of DβH, the enzyme converting
dopamine to noradrenaline. DβH occurs in the
plasma as a heritable trait and is strongly related to
variation in the DBH gene (Cubells and Zabetian,
2004). Linking plasma DβH levels to a DBH gene
variant therefore helps to establish that variant’s
functional candidacy.
Parasuraman et al. (2005) recently reported that
a single nucleotide polymorphism (SNP), a G to A
substitution at 444 within exon 2 of the DBH gene,
associated with spatial working memory in
controls. The A allele of this variant is associated
with lower plasma and cerebrospinal fluid (CSF)
levels of DβH, relative to the G allele. The G444A
polymorphism is in linkage disequilibrium with the
ADHD-associated Taq I polymorphism within the
Irish population (D’ = .85; Hawi et al., 2003b).
Linkage disequilibrium refers to two markers in
close physical proximity such that a specific allele
at one locus predicts the existence of specific
alleles at other loci (Cubells and Zabetian, 2004).
Given that sustained attention may be a separable
factor in maintaining the integrity of behavioural
goals in working memory (Robertson, 2004), the
results of Parasuraman et al. (2005) therefore
overlap somewhat with those reported herein. A
plausible biological hypothesis for ADHD might
therefore be that polymorphisms within the DBH
gene lower the expression of DβH by diminishing
DBH gene transcription. This scenario would lead
to a relative elevation in the dopamine to
noradrenaline ratio and thus contribute to sustained
attention deficits. Future work in ADHD should
therefore examine multiple functional markers
within the DBH gene in order to elucidate its role
in the sustained attention deficits in ADHD. In this
endeavour a polymorphism within the promoter
region of the gene (– 1021C-T) has recently been
identified as the main variant controlling plasma
DβH levels (Cubells and Zabetian, 2004).
In summary, we have provided an example of a
cognitive genetic approach to ADHD by showing
that sustained attention deficits can be predicted by
DBH genotype. This preliminary work indicates
that the DBH gene may contribute to the
susceptibility for ADHD, in part because of its
varying effects on the development of brain
mechanisms mediating sustained attention.
Acknowledgments. The authors would like to
acknowledge the support of the Irish Health Research
Board (HRB) and Science Foundation Ireland (SFI). The
authors thank Redmond O’Connell for his helpful
comments on this manuscript.
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[email protected]