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DRD4 and DAT1 in ADHD: Phenotype to pharmacogenetics.
Darko Turic1, James Swanson2 & Edmund Sonuga-Barke 1,3*
1. Institute for Disorder of Impulse & Attention, School of Psychology,
University of Southampton.
2. Child Development Centre, University of California, Irvine.
3. Department of Experimental Clinical & Health Psychology, Ghent
University.
* Correspondence to Edmund Sonuga-Barke, Institute for Disorder of
Impulse & Attention, School of Psychology, University of Southampton,
Southampton, SO17 1BJ. UK. [email protected].
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Abstract
Attention deficit/hyperactivity disorder (ADHD) is a common and potentially
very impairing
neuropsychiatric disorder of childhood that is associated with numerous
behavioural problems. Statistical genetic studies of twins have shown ADHD
to be highly heritable, with the combination of genes and gene by
unmeasured environment interactions accounting for 80% of phenotypic
variance". The initial molecular genetic molecular studies based on candidate
genes were remarkably success. For these studies DRD4 and DAT1 genetic
variants were initially identified as good candidate genes because of the
efficacy of dopaminergic compounds in the treatment of ADHD. Case-control
and family-based association studies provide strong evidence for the role of
variants of DRD4 and DAT1 in the pathogenesis of ADHD, although effect
sizes for both genes are small. Evidence relating DRD4 and DAT1
genotypes to ADHD endophenotypes, or implicating them in gene x
environment interactions, is so far weak and inconsistent. DRD4 and
DAT1 polymorphisms are interesting candidates for phamacogenetic
studies because of the primary dopaminergic mechanism of action of
stimulant drugs
that are considered to be DA agonists. The recent application of non-
candidate gene strategies (e.g. genome wide association scans) has failed to
identify additional genes with substantial genetic main effects. This is the
usual pattern observed for most other physical and mental disorders
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evaluated with current state-of-the-art methods, and the significance and
possible reasons for this are discussed.
INTRODUCTION
Attention deficit/hyperactivity disorder (ADHD) is a common psychiatric
disorder of childhood affecting around five percent of the population
(Polanczyk, de Lima et al. 2007). It is characterised by an early onset and
persistent pattern of inattention, impulsivity, and hyperactivity symptoms. The
condition is associated with several co-morbid conditions (e.g., disrupted peer
and family relationship) and adverse outcomes that emerge with age (e.g.,
educational failure and antisocial behaviour). It has an early onset and is
most frequently recognized in middle childhood (Taylor & Sonuga-BarkeLasky
Su, Anney et al, 2008). There is an overrepresentation of boys over girls by
approximately 3:1 (Reiff and Stein 2003). ADHD can persist into adulthood
and increases the risk for anti-social personality disorder (Mannuzza, Klein et
al. 1989), later criminality (Satterfield, Hoppe et al. 1982; Satterfield, Faller et
al. 2007) as well as drug and alcohol misuse (Barkley 1998; Barkley, Fischer
et al. 2004).
Pharmacological, neurobiological and genetic studies support the notion that
ADHD has a neuro-developmental basis with a strong genetic and non-
genetic components components (see Swanson, Kinsbourne, et al, 2008),
implicating neurotransmission dysregulation within brain circuits underpinning
cognition and motivation (Swanson, Kinsbourne et al. 2007; Sonuga-Barke,
2005). Disruption of multiple neurotransmitters systems has been proposed.,
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but However, the primary focus has been on the catecholamines dopamine
(DA) and norepinephrine. While oOthers have focused on norepinephrine
(see Plitska and McCracken, 1996 or Arnstein and Li, 2005), but our focus
here here we will focus hereis on evidence that variation and disruption of the
dopamine DA system contributes to the aetiology and response to treatment
of ADHD.
1. DOPAMINE DYSREGULATION IN ADHD
Dopamine neurotransmission: The catecholamine dopamine (DA)DA is a
key
neurotransmitter in the biology of a wide range of brain processes (Seeman
and Madras 1998; Schultz 2002; Schultz 2007;). It is central to the control of
movement Lees, Hardy et al. 2009), cognition (Aultman and Moghaddam
2001; Floresco and Phillips 2001), reward (Volkow, Wang et al. 2009),
emotional and motivational responses (Wender 1975; Pezze and Feldon
2004; Hranilovic, Bucan et al. 2008) including the experience of pleasure and
pain in response to positive and negative environmental events (e.g., Giuliano
and Allard 2001; Pecina and Berridge 2005; Hyman, Malenka et al. 2006).
DA is synthesized from the amino acid tyrosine, which is first converted to L-
dihydroxyphenylalanine (L-DOPA), and then to DA by the enzyme DOPA
decarboxylase. DA neurons are clustered in several mid brain regions,
including substantia nigra and the ventral tegmentum (Bjorklund and Dunnett
2007). (There are both parallel (Alexander et al., 1990; Middleton and Strick,
2002) and converging pathways in cortico-basal ganglia loops (Takada et al.,
1998; Bar-Gad and Bergman, 2001; Haber, 2003). It appears that the parallel
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organization is not completely maintained through trans-thalamic circuits
(Kolomiets et al., 2001; McFarland and Haber, 2002) and that thalamic nuclei
may modulate information processing between segregated circuits (Castro-
Alamancos and Connors, 1997). These project to large parts of the brain via
three major pathways: The nigro-striatal pathway extends from substantia
nigra to caudate nucleusputamen. It plays an essential role in voluntary
movement (Barbeau 1974). The meso-cortico-limbic pathway projects from
ventral tegmentum to mesolimbic and meso-cortical regions. It is associated
with cognition, reward and emotion processing (Mogenson, Jones et al. 1980;
Wise 2004; Wise 2004). DA within these pathways have been shown to
modulate functionally and structurally segregated cortico-basal ganglia loops
(Alexander et al., 1990; Middleton and Strick, 2002; Takada et al., 1998; Bar-
Gad and Bergman, 2001; Haber, 2003). These circuits are involved in well-
defined brain networks involved in the processes of attention as well as
motivation, and disruption of either or both contribute to the aetiology of
ADHD (see Sonuga-Barke, 2002; Volkow, Wang et al, 2009).
TSuchhe parallel organization is now thought to not completely
maintainedcomplete (Kolomiets et al., 2001; McFarland and Haber, 2002) with
thalamic nuclei allowing the passage of signals across different circuits (Haber
& Calzavra, 2009). .
In addition there is aThe tubero-infundibular pathway that plays a role in
neuronal control of the hypothalmic-pituatory endocrine system (Ben-
Jonathan et al., 2002). These pathways are involved in well-defined brain
networks involved in the processes of attention as well as motivation, and
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disruption of either or both contribute to the aetiology of ADHD (see Sonuga-
Barke, 2002; Volkow, Wang et al, 2009).
DA is released into the synaptic cleft by action potentials via a calcium
dependent mechanism. Calcium influx triggers fusion of the neurotransmitter
vesicles with the pre-synaptic membrane. DA is then released into the
synaptic cleft from where it disperses and binds to postsynaptic receptors.
Receptors bind neurotransmitter molecules and open nearby ion channels in
the postsynaptic cell membrane. This alters the local trans-membrane
potential of the cell. DA exerts its effects by binding to DA receptors which
are functionally categorised into two families: D1-like (stimulatory) and D2-like
(inhibitory). Members of the D1 family (D1/D5) couple to Gs class of G
proteins and activate adenylyl cyclise. D2 type receptors (D2/D3/D4) couple to
Gi protein which inhibits the production of cAMP (Callier, Snapyan et al.
2003). Pre-synaptic receptors (auto-receptors) monitor extracellular DA levels
and modulate the impulse dependant release and synthesis of DA (Altar,
Boyar et al. 1987). Blockade of these receptors leads to an increased
production, and pre-synaptic release, of DA, . Swhile their stimulation causes
the opposite effect (Marinelli, Rudick et al. 2006; see below for a discussion of
the role of pre-synaptic receptors in the action of methylphenidate). DA
clearance from the synaptic cleft is regulated by the products of three genes:
DA transporter (SLC6A3/DAT1), Mono-amine Oxidase-A (MAO-A) and
Catechol-O-Methyl Transferase (COMT). DAT1 is responsible for the rapid
uptake of DA from the synaptic cleft while MAO-A and COMT are involved in
DA catabolism (Longstaff, 2000).
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Non-genetic evidence for DA dysregulation in ADHD
Neuro-chemical studies support a role for neurotransmitter dysregulation in
ADHD pathophysiology (Zametkin and Liotta 1998). Serotonergic,
noradrenergic and glutamatergic pathways have all also been implicated
(Gizer, Ficks et al. 2009). Initial interest in DA in ADHD came from the long
standing observation that psycho-stimulant medication such as
methylphenidate, assumed to alter the activity of this neuro-transmitter,
provided an effective treatment for many ADHD patients (Wender 1975).
Since then methylphenidate has been shown to inhibit the activity of the DA
transporter and increase extra-synaptic levels of DA (Volkow, Wang et al.
2004; Volkow, Wang et al. 2005). There is evidence that it has little effect on
pre-synaptic
DA release (Patrick, Caldwell et al. 1987) but this is has been questioned by
(Seeman and Madras 2002). Another psychostimulant amfetamine, has
been shown to increase DA levels by extenuating (affectingmodifying) its
release (Fan, Xu et al. 2009). It interacts with DA transporters to promote DA
efflux from the presynaptic neuron into the synaptic cleft (Kuczenski and
Segal 1975;
Kuczenski and Segal, 1997).
Other evidence in support of the DA dysregulation hypothesis of ADHD
comes from two main sources (other than the genetic evidence described
later). First, ADHD animal models display dysregulation of DA function.
(Giros, Jaber et al. 1996; Xu, Moratalla et al.1994; Granon, Passetti et al.
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2000; Accili, Fishburn et al. 1996; Leo, Sorrentino et al. 2003). The earliest
animal model was developed by administration of 6-hydroxydopamine to
neonatal rats that results in depletion of DA (Shaywitz, Yager, Klopper, 1976).
After treatment with 6-OHDA the activity of animals is initially greater than that
of controls. This but then declines , as a result of profound depletion of brain
dopamineDA. Genetic models also provide evidence. The ADHD type
characteristics of the spontaneously hypertensive rat (SHR; Mook, Jeffrey et
al. 1993; Sagvolden 2000; Wong, Buckle et al. 2000; Wyss, Fisk et al. 1992)
is reduced by DA agents (Boix, Qiao et al. 1998; Myers, Musty et al. 1982),
while those of the . The hyperactivity of the Naples high-excitability/low
excitability (NHE/NLE) strain is associated with larger DA neurons and altered
DA functioning in limbic and cortical areas of forebrain (Gonzalez-Lima and
Sadile 2000; Papa, Sellitti et al. 2000; Sadile, Lamberti et al. 1993; Sadile,
Pellicano et al. 1996). In the case of the The ADHD features of the coloboma
mouse, these are associated with altered activity within specific surface
proteins that mediate the process of docking and fusion of DA synaptic
vesicles to the pre-synaptic plasma membrane (Hess, Collins et al. 1996).
This results from a 2-cM deletion of mouse chromosome 2 containing several
genes including SNAP-25. These effects can be reversed by either transgenic
insertion or stimulant medication (Steffensen, Henriksen et al. 1999).
Second, neuro-chemical imaging studies using Positron Emission
Tomography (PET) and Single Photon Emission Computed Tomography
(SPECT) suggest altered regulation of striatal DAT DA transporter levels.
Studies vary greatly
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in their methodological rigour and, perhaps because of this there are
inconsistencies between them (Gonon 2009; Volkow et al., 2009). On the
one hand, upregulation of striatal DA transporter densities, consistent with
lower levels of extracellular DA, have been reported in studies with small
samples of mostly methylphenidate treated cases (Dougherty, Bonab et al.
1999; Krause, Dresel et al. 2000; Larisch, Sitte et al. 2006; Cheon, Ryu et al.
2003). Other studies with larger sample sizes found no evidence of altered
DA transpoter activity (van Dyck, Quinlan et al. 2002). While the largest and
methodologically most robust study with a large sample of treatment naïve
adults with ADHD but without a history of comorbid SUD (Volkow, Wang et al.
2009) reported down-regulation of striatal DAT consistent with higher levels of
extra-cellular DA. This has been confirmed in recent study in drug naïve
ADHD patients (Hesse, Ballaschke et al. 2009) finiding decreased striatal DA
transporter availability in the basal ganglia. Given the methodological
strength of these most recent findings studies with drug naïve patients it
seems likely
that initial reports suggesting DAT upregulation were due to the
methodological
limitations of the study. Leaving aside their directionThe altered levels of DA
transporters are
difficult to interpret given the reciprocal and adaptive nature of the relationship
between DA transporter densities and DA synthesis and release (Madras,
Miller et al. 2002; Volkow, Wang et al. 2009). Likewise the DAT DA
transporter blocking effect
of psycho-stimulants could be differently interpreted as either; i) a
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compensation for the deficit of DA (Swanson and Volkow 2002) or; ii) by the
modulation of synaptic activity through dopamine (D2) auto-receptors
(Seeman and Madras 1998).
2. GENETICS OF ADHD: BACKGROUND
Research has consistently shown a strong genetic component in ADHD
etiology. Twin studies suggest a heritability between 0.7 and 0.8 (Stevenson
1992; Swanson, Sergeant et al. 1998; Biederman and Faraone, 2005). These
effects are similar for boys and girls (Nadder, Silberg et al. 1998; Saudino,
Ronald et al. 2005). The non-heritable component appears to be attributable
almost exclusively to non-shared environmental influences (Thapar,
Harrington et al. 2001; Larsson, Larsson et al. 2004; but also see Poderman
et al, 2009 for a discussion of “contrast” effects in twin studies). Although,
heritability estimates themselves do encompass the influence of the
environment through gene-environment interaction and correlation (Rutter,
2007; see below for discussion in relation to DAT1 and DRD4).
There are two commonly used approaches in molecular genetic
studies: candidate gene approaches based on theoretical involvement of
neuron-biological pathways leading to specific hypotheses; and non-
hypothesis driven genome-wide approaches that consider all genes as
equally plausible candidates. Candidate gene approaches use either case-
control or family based (e.g., linkage) association designs. In case-control
studies the frequency of candidate alleles or genotypes are compared in
ADHD cases and controls. Family based approaches look for patterns of
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genetic transmission disequilibrium (Spielman et al, 1993) across generations
within affected families to examine whether the probability of transmission of
an allele from parents to an affected offspring differs from the expected
Mendelian pattern of inheritance. There are pros and cons to these
approaches. Family based studies have an advantage over case-control
studies as they are designed to be immune to population stratification
(Spielman and Ewens, 1996). , Hhowever the use of transmission
disequilibrium test (TDT) employed in family based studies is subject to
selection effects due to missing parents and genotyping errors (Clayton, 1999;
Weinberg, 1999). Morton and Collins (1998) argue that stratification, which
reduces the accuracy and power of the case-control design, is a problem only
under rare circumstances while the impact of
genotyping errors in family based approaches may have been underestimated
(Mitchell AA, Cutler DJ, & Chakravarti A, 2003). Genome wide non-
hypothesis based approaches (see Risch and Merikangas, 1996) have also
employed association (GWAS) and linkage designs models. In genome wide
linkage studies related individuals, either siblings or those in extended
pedigrees, are studied in an attempt to localize chromosomal regions which
may harbour genes influencing a trait by examining the familial co-segregation
of the phenotype and genetic markers (Lander and Schork 1994). It is
assumed that GWAS designs are more powerful in detecting common alleles
with small effects than linkage approaches (Risch and Merikangas 1996).
GWAS
studies require very large numbers of markers, (i.e., perhaps even millions;
see
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Clark and Li, 2007), in order to cover whole genome.
In both candidate gene and genome wide approaches the ADHD
phenotype can be characterized as a diagnostic category or a quantitative
trait (Fisher RA, 1918). The identification of a quantitative trait loci (QTL)s has
been interpreted as the operation of multiple genes of varying effect so that,
broadly speaking, a continuous trait (rather than a diagnostic category) can be
influenced by a few oligogenes with a moderate effect on the phenotype, or by
many polygenes each with very small effect, or by a combination of the two.
While most studies have defined the ADHD phenotype in terms of diagnostic
categories categories, measures of activity, impulsivity and attention are
continuously distributed in the general population (Mill, Xu et al. 2005Pinto
and Tryon 1996; Burns, Walsh et al , 1997) and researchers have argued for
the use of dimensional approaches could in the ADHD field (Hudziak,
Achenbach et al. 2007). Although statistically powerful (Curran, Mill et al,
2001Asherson, ) and despite the fact that they have been successfully applied
both in human and animal behavioural studies (e.g Spence, Liang et al.
2009), QTL approaches have so far attracted relatively little interest in the
ADHD field. This is probably because the quantification of ADHD when
measured using common rating scales focuses only on the severity of
psychopathology, rather than fully dimensional and does not capture the
entire range of the underlying dimensions of attention/inattention and
reflectivity/impulsivity (see Cornish, Manly et al. 2005; Polderman, de Geus et
al. 2009; Swanson, Wigal et al. 2009)
The first ADHD genome scan identified four regions (5p13, 10q26,
12q23, and 16p13) showing some evidence of linkage with LOD scores > 1.5
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(Fisher, Francks et al. 2002). A recent meta-analysis of seven ADHD linkage
scans (Bakker, van der Meulen et al. 2003; Ogdie, Macphie et al. 2003;
Arcos-Burgos, Castellanos et al. 2004; Hebebrand, Dempfle et al. 2006;
Asherson, Zhou et al. 2008; Faraone, Doyle et al. 2008; Romanos, Freitag et
al. 2008) identified the genomic region on chromosome 16, between 16q21
and 16q24 as most consistent linkage evidence across the studies (Zhou,
Dempfle et al. 2008). Ten other regions on chromosomes 5, 6, 7, 8, 9, 15, 16,
and 17 had nominal significant levels for linkage (Zhou, Dempfle et al. 2008).
Two genome wide linkage studies in humans employing QTL methods have
identified linkage to chromosomes 1p36 and 3q13 for ADHD traits (Doyle,
Ferreira et al. 2008; Zhou, Dempfle et al. 2008). Interestingly the
chromosomal region 1p36 overlaps with a dyslexia QTL raising a possibility
that pleiotropy might play role in the genetic origins of ADHD and dyslexia
(Zhou, Dempfle et al. 2008). Initial GWAS studies with hundreds of thousands
of markers and thousands of patients have so far failed to identify genome
wide significant association between ADHD and these markers (Neale et al.,
2008; Hong, Su et al. 2008; McCarthy, Abecasis et al. 2008). See Dermitzakis
and Clark (2009); Clark and Li (2007) for a more general discussion of why
GWAS approaches have not been more productive).
In contrast candidate gene approaches have been more successful.
The first two evaluated functional variants of DA genes and showed
association of ADHD with DAT1(Cook, Stein et al. 1995) and DRD4 (LaHoste,
Swanson et al. 1996). Since then other candidates within the DA system (e.g,
Payton, Holmes et al. 2001) and other neurotransmitter systems (e.g., Hawi,
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Dring et al. 2002; Turic, Langley et al. 2005) have been proposed but few of
these have produced robust and replicable effects. Several meta-analyses for
single and multiple loci have been published that review this data (e.g.
Faraone, Perlis et al. 2005; Purper-Ouakil, Wohl et al. 2005; Yang, Chan et al.
2007).
3. ADHD AND THE DOPAMINE RECEPTOR D4 GENE
DRD4, its distribution and functional polymorphisms: DA receptor D4
(DRD4) is a member of D2 class of receptors. The D2-like receptors regulate
several signalling events including inhibition of adenylate cyclase, stimulation
of arachidonic acid release and modulation of potassium channels (Jaber,
Robinson et al. 1996; Oak, Oldenhof et al. 2000; Neve, Seamans et al. 2004;
Tarazi, Zhang et al. 2004). The human D4 receptor gene maps to
chromosome 11p15.5. It consists of four exons and encodes a putative 387-
amino acid protein with seven trans-membrane domains (Van Tol, Bunzow et
al. 1991). DRD4 is highly expressed in pyramidal neurons and inter-neurons
in prefrontal cortex. There are lower concentrations in basal ganglia,
hippocampus and thalamus (Mrzljak, Bergson et al. 1996; Ariano, Wang et al.
1997; Gan, Falzone et al. 2004; Tarazi, Zhang et al. 2004; Noain, Avale et al.
2006).
Genetic variations in the DRD4 sequence have been examined in
relation to various neuro-psychiatric disorders. These have focused on a
variable number tandem repeat (VNTR) polymorphism in exon 3, consisting of
a 48-bp repeat unit. This codes for an amino-acid sequence located in the
third cytoplasmic loop of the receptor, thought to be involved in G-protein
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coupling (Van Tol, Wu et al. 1992). In the human population, this VNTR
displays a high degree of variability with multiple and nucleotide variation
within each repeat (Chang, Kidd et al. 1996; Ding, Chi et al, 2004; Lichter,
Barr et al, 1993). The most common repeat variants are the 4R, 7R and 2R
alleles respectively. The frequency of these alleles varies widely among
different ethnic groupings
(Ding, Chi et al. 2002). The 7R allele, for example, has an extremely low
prevalence in Asian populations (<2%) yet a high frequency in native
populations in the Americas (~48%;Chang, Kidd et al. 1996). As yet there is
no commonly accepted explanation of this variability at the DRD4 locus. The
common and probable ancestral allele has four repeats (4R) originating ~
300,000 years ago, whereas the 7R allele, often associated with psychiatric
disorders, is ‘younger’ by up to 10 times (Wang, Ding et al. 2004; Wang,
Kodama et al. 2006).The 7R allele may have arisen as a rare mutational
event and then become a high frequency allele through positive selection
(Ding, Chi et al. 2002) at a time (the upper Paleolithic) of the major expansion
of human population (Chen, Burton et al, 1999). In this way individuals with
novelty seeking personality traits may have driven the expansion of the 7R
variant (Ding, Chi et al. 2002) or it may have conferred a reproductive
advantage in male-competitive societies (Harpending and Cochran 2002). In
China, the loss of the 7R may have been due to selective reproduction of
males without the 7R allele (ref; 4). At the same time there appears to be
selective forces working to balance these processes as the prevalence of the
7R allele is probably near fixation point (ref; 5).
The neuro-functional significance of the DRD4 7R allele is not fully
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understood. In vitro studies indicate that the sensitivity to DA of the 7R allele
is half that of the 2R and 4R variants (Van Tol, Wu et al. 1992; Asghari,
Sanyal et al. 1995). Moreover, DRD4 mRNA is distributed in prefrontal cortex
(Primus, Thurkauf et al. 1997; De La Garza and Madras 2000; Noain, Avale et
al. 2006) but also to a lesser extent in parietal and temporal lobes, cingulate
cortex, cerebellum (Primus et al, 1997; Mrzljak et al, 1996). It is found in the
basal ganglia although its density relative to DRD2 is low (De La Garza and
Madras 2000). This suggests it plays a role in cognitive and also potentially
motivational processes (Dolan 2002; Durston, de Zeeuw et al. 2009) Crucially
DRD4 and DAT1 seem not to be co-localized within brain regions (unlike
DRD2 and DAT1) suggesting a different role for these two DA receptors (De
La Garza and Madras 2000). Synthesis and clearance of DA are elevated in
mice lacking the DRD4 gene (Rubinstein, Phillips et al. 1997). Also, mice
lacking a functional DRD4 receptor display cortical hyper-excitability
(Rubinstein, Cepeda et al. 2001; Avale, Falzone et al. 2004) and
hypersensitivity to single administrations of alcohol, methamphetamine, and
cocaine (Rubinstein, Phillips et al. 1997).
DRD4 in ADHD; categorical diagnoses and quantitative traits: The
developing understanding of the neuro-functional significance of DRD4 7R
has led to the investigation of its association with disorders with a putative DA
basis. In relation to ADHD, therefore most studies have focused on the 7R
polymorphism. An additional 120-bp duplication polymorphism located in the
5’ flanking region of DRD4 (Seaman, Fisher et al. 1999) has also been
studied recently (e.g., Kereszturi, Kiraly et al. 2007) as well as a SNP (-521
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C/T; rs1800955) in the same region (e.g., Yang, Jang et al. 2008). The
association between the 7R allele DRD4 polymorphism and ADHD is well
replicated. However the findings are not completely consistent and the
absolute size of the effects are small although relative to the maximum size
possible if all cases had the allele (which is limited by the allele proportion in
the population), in some ethnic groups it may be considered large (see Grady
et al, 2005). (; i.e., if the allele probability is .20 in the population, then the
maximum is 1/.2 = 5, and 1.9/5 is about 40%.). In their groundbreaking study,
LaHoste, Swanson et al. (1996) first reported the association between DRD4
7R and ADHD. Many studies have followed this lead and the first meta-
analysis of this association was published in 2001 (Faraone, Doyle et al.
2001) including both family-based (14 studies, 1665 probands) and case–
control studies (8 studies, 1266 children with ADHD and 3068 controls). This
gave an odds ratio of 1.9 for case-control studies (95% confidence interval =
1.5–2.2, p < 0.001) and 1.4 for family-based studies (95% confidence interval
= 1.1–1.6, p = 0.02). Five more meta/pooled analyses of the 7R and ADHD
have been published. All of them have demonstrated a significant n
association although the effect size has reduced in size as more studies have
been conducted and the total sample size has increased (Maher, Marazita et
al. 2002; Faraone, Perlis et al. 2005; Wohl, Purper-Ouakil et al. 2005; Li,
Sham et al. 2006; Gizer, Ficks et al. 2009). The most recent meta-analysis
showed a fixed effects significance of p<0.00001 with evidence of significant
heterogeneity between studies (Gizer, Ficks et al. 2009). In contrast to the 7R,
the 4R allele may confer a protective effect (OR = 0.9, 95% CI 0.84–0.97; Li,
Sham et al. 2006).
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Several studies have examined DRD4 in relation to ADHD as a quantitative
trait. Curran, Mill et al. (2001) first reported association between the DRD4-7R
and ADHD-trait scores. Lasky-Su, Lange et al. (2008) found evidence for
association between two SNPs in the promoter region of DRD4 and the
quantitative phenotype (mainly inattentive) generated from the ADHD
symptoms. In contrast (Mill, Xu et al. 2005) and (Todd, Neuman et al. 2001)
failed to find evidence for association between DRD4 and ADHD trait
symptoms in general population. None of these studies used a measure the
full range of attentional abilities in the population and this could account for
negative results (see Swanson et al., 2009).
DRD4 and putative ADHD endophenotypes: Endophenotypes are
conceptualised as “sitting ‘between”’ genes and the clinical expression of the
disorder (Gottesman and Gould 2003). To be of value in genetic studies they
should be heritable, co-segregate with a psychiatric illness, yet be present
even when the disease is not (i.e. state independent), and be found in non-
affected family members at a higher rate than in the population (Gottesman
and Gould 2003). Endophenotypes are postulated to be influenced by fewer
genes than the clinical phenotype and consequently the size of the effects of
genetic loci contributing to endophenotypes is postulated to be larger than to
disease susceptibility. The fewer the genes that give rise to an
endophenotype, the better the chances of revealing their genetic mode of
action (Gottesman and Gould 2003). The concept has been controversial with
the suggestion that genetic effects are no greater in those studies employing
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endophenotypes than those using standard clinical phenotypes (Flint and
Munafo 2007). There is a range of candidate endophenotypes in ADHD
(Willcutt, Doyle et al. 2005). The best evidence has been found in relation to
response inhibition (e.g. Slaats-Willemse, Swaab-Barneveld et al. 2003;
Rommelse 2008), temporal processing, (e.g. Bidwell, Willcutt et al. 2007),
verbal and visuospatial working memory , (e.g. Rommelse 2008) and delay
aversion (Bitsakou, Psychogiou et al. 2009). A number of recent studies have
found associations between DRD4 7R and performance on putative
endophenotypes of ADHD, although the effects are inconsistent (Kebir,
Tabbane et al. 2009). The first study of this sort in ADHD was conducted by
(Swanson, Oosterlaan et al. 2000) who demonstrated the then seemingly
paradoxical effect that in a small ADHD sample the cases with the 7-present
genotype showed better neuropsychological performance (faster and less
variable reaction time on 3 tasks) than those with the 7-absent genotype. This
direction of finding has been replicated (Manor, Tyano et al, 2002; Langley,
Marshall et al, 2004) although some studies have also shown DRD4 7R ed it
be as related to worse performance (Waldman 2005). The association
between DRD4 7R and neuropsychological performance is not task specific
but the strongest and most consistent effects seem to be in relation to high
reaction time variability and the absence of 7R (Kebir, Tabbane et al. 2009).
There has also been some evidence for altered speed of processing
(Waldman 2005). and cognitive impulsiveness on non-reaction tasks in 7R
carriers (Langley, Marshall et al. 2004). However, there is no but no effect of
genotype on response inhibition (Langley, Marshall et al. 2004)
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DRD4 and gene-environment interactions: Results of behavioural genetic
studies are consistent with a role for environmental factors in ADHD and in
personality characteristics in general (see Sheese, Voelker et al. 2007).
Gene-environment interaction (GxE)) has been an increasing focus of study.
Here specific gene variants are shown to only exert a risk effect on disorder if
they are accompanied by exposureed to a particular environmental risk factor
(Rutter and Silberg 2002; Moffitt, Caspi et al. 2005). In relation to ADHD
these studies can be divided up into two sortstypes: Those focusing on the
role for
pre- and perinatal physical environmental risk factors (e.g., maternal smoking
and alcohol consumption during pregnancy (e.g. Brookes, Mill et al. 2006) and
those focusing on the post-natal social environment (e.g., expressed emotion
and social deprivation) ; (Weindrich, Laucht et al. 1992). There have been a
small number of replicated effects for GxE with DRD4 specifically and the
results are currently unconvincing; but this may be due to insufficient
statistical power in studies. Neuman, Lobos et al. (2007) reported an
interaction between maternal smoking during pregnancy and the 7R allele but
Langley, Turic et al. (2008) failed to replicate this. Other DRD4 7R GxE
findings include effects of season of birth (Seeger, Schloss et al. 2004). DRD
7R has also been shown to moderate the effects of parenting on externalizing
behavior including ADHD (Bakermans-Kranenburg, Van Ijzendoorn et al.
2008; Sheese, Voelker et al. 2007).
4. ADHD AND THE SLC6A3/DAT1 GENE
DAT1, its distribution and functional polymorphisms: The DA transporter
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is a plasma membrane protein that belongs to the large family of the Na+/Cl-
dependent transporters. It is responsible for terminating neurotransmission by
rapid reuptake of DA into pre-synaptic terminals (Amara and Kuhar 1993). It
has been shown to control the intensity and duration of DA neurotransmission
by resetting the DA concentration in the extra-cellular space (Gainetdinov,
Jones et al. 1998; Frazer, Gerhardt et al. 1999). In situ hybridization and
immunochemistry studies have shown that DAT1 mRNA is primarily present
in DA-synthesising neurons of the substantia nigra and ventral tegmentum al
area (VTA) and that the corresponding protein coincides with DAergic
innervation of regions including ventral mesencephalon, medial forebrain
bundle and dorsal and ventral striatum (Ciliax, Heilman et al. 1995; Freed,
Revay et al. 1995). The human DAT1 gene maps to chromosome 5p15.3.
Sequence analysis of the 3’UTR of this gene revealed a variable number of
tandem repeat (VNTR) polymorphism with a 40-bp unit repeat length, ranging
from 3 to 11 repeats (Vandenbergh, Persico et al. 1992). In humans the 9R
and 10R are most common (Mitchell, Howlett et al 2000). Reporter gene
studies (Fuke, Suo et al. 2001) and studies of RNA expression in human
tissues (Mill, Asherson et al. 2002) have shown that expression is significantly
higher for the 10R than for other alleles suggesting this variant may be
functional. However Miller and Madras, (2002) found greater gene expression
for vectors containing the 9R sequence and others (Greenwood and Kelsoe
2003) demonstrating that neither the 9R or the 10R allele had an effect on
transcription. Furthermore, a brain imaging study (Heinz, Goldman et al.
2000) showed higher density of striatal DAT1 in the 10R homozygotes
compared with the 9/10 genotype, but another in vivo experiment yielded
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conflicting results showing that the 9R carriers (9/9 homozygotes and 9/10
heterozygotes) had significantly higher striatal DAT1 availability (van Dyck,
Malison et al. 2005). However, the density of DAT is not fixed. Turnover of
DA transporter protein takes about two days (Kimmel, Carroll et al. 2000), and
plasticity has been documented – e.g., the effects of drugs on DA transporter
density has been established in studies of cocaine (Xia, Goebel et al. 1992)
and methylphenidate (Volkow et al, 2009]. In as much as the brain “strives for”
biochemical equilibrium, the impact of exposure to high levels of synaptic DA
is thought to result in a compensatory increase in DAT to keep DA levels in a
narrow range (1). Thus, exposure to stimulants that block DA transporters
and increase synaptic DA are thought to increase the density of DA
transporters. However, this must be measured when the drugs are not
present in the brain, since occupancy of DA transporters would interfere with
estimates of DA transporter density.
DAT1 in ADHD; Categorical diagnoses and quantitative traits: The DAT1
gene was the first DA candidate gene examined in candidate gene
association studies (Cook, Stein et al. 1995). Using a family based
association study the authors reported an association between the 10R allele
and ADHD. Since the first publication a number of studies have also reported
the association between the DAT1 10R and ADHD (e.g. Gill, Daly et al. 1997;
Chen, Chen et al. 2003) however this has not always been replicated (e.g.,
Roman, Schmitz et al. 2001; Todd, Jong et al. 2001). Overall the evidence
from meta-analyses is less supportive than for DRD4. For instance, Curran
and colleagues reported a small positive but non-significant OR of 1.16
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(Curran, Mill et al. 2001), while Maher and colleagues reported a non-
significant OR (Maher, Marazita et al. 2002). The most recent study (Gizer,
Ficks and Waldman 2009) found significant association (OR=1.12; p=0.028),
but also significant heterogeneity between studies It has been suggested that
specific haplotypes rather than single markers are associatied with ADHD
(Asherson, Brookes et al 2007) . Muglia, Jain et al. (2002) tested for an
association between DAT1 and ADHD considering the disorder as categorical
as well as a QTL, finding no association for either measure. Unlike Muglia et
al (2002), Cornish, Manly et al. (2005), who evaluated ADHD as a continuous
trait not as severity of psychopathology, and Mill, Xu et al. (2005) found an
association between DAT1 10R-allele and ADHD symptom score measure.
Most recently Cornish, Wilding et al. (2008) used a QTL approach to assess
the association between the DAT1 high-risk genotype, visual search and
vigilance, and ADHD symptoms in a community sample of boys 6-11 years of
age. DAT1 genotypes were only related to ADHD symptoms. In contrast,
Todd, Huang et al. (2005) found that the lower frequency allele (9R), along
with the DRD4 7R allele was over transmitted in ADHD families.
DAT1 and putative ADHD endophenotypes: The data linking DAT1 to
putative endophenotypes of ADHD is probably less compelling than that found
for DRD4, given the dynamic properties of DA transporter densities.
However,
once again high reaction time variability seems to be the most replicated
cognitive marker associated with the 10-repeat homozygosity (e.g. Loo,
Specter et al 2003). It is far from clear what causes such inconsistent results,
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but it has been suggested that endophenotypes like delay aversion (Sonuga-
Barke et al., 2008) may be better suited when studying DAT1 and ventral
striatum-
related functions. It is also possible that any association between DAT1 and
neuropsychological performance may be age specific (Rommelse, Altink et al.
2008). This is in line with the idea that the over-transmission of an already
high frequency allele (i.e., DAT1 10R) is possible only if this is in linkage
disequilibrium with a causative allele.
DAT1 and gene environment interactions: DAT1 has been implicated in a
broader range of GxE effects than DRD4. In the first study of its kind in ADHD
Kahn and colleagues (Kahn, Khoury et al. 2003) reported that
hyperactivityimpulsivity symptom scores in young children were associated
with 10/10 genotype, but only in children exposed to prenatal smoking. It
should be noted that the number of cases of children affected by both genetic
and environmental risks was small. This was recently replicated in males
(Becker, El-Faddagh et al. 2008). In contrast, Neuman, Lobos et al. (2007)
reported an association between the DAT1 9R and prenatal smoking while
other have found no effect at all (Langley, Turic et al. 2008). Brookes, Mill et
al. (20006) examined alcohol consumption during pregnancy and found
interaction with a DAT1 haplotype. In terms of psychosocial factors it has
been reported that family adversity moderates the impact of the DAT1
genotype on the expression of ADHD symptoms (Laucht, Skowronek et al.
2007). SonugaBarke, Oades et al. (2009) reported that DAT1 moderated the
effect of parenting expressed emotion on the development of conduct
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problems in ADHD. Stevens et al. (2009) showed that the risk of ADHD was
increased only in those children who had experienced severe early
institutional deprivation and were either homozygote for the 10R or carried a
DAT1 haplotypes combining a 40-bp VNTR in 3'UTR and a 30-bp VNTR in
intron 8.
5. CLINICAL IMPLICATIONS
Pharmacogenetics of DRD4 and DAT1 in ADHD: Individual differences in
drug response are well documented throughout medicine, including
psychiatry. A specific drug can be highly beneficial to some patients while in
others it can produce little or no effect, for still others they can have serious
side-effects. The therapeutic value of medication (stimulants) in ADHD
patients were first reported more than 70 years ago (Bradley, 1937). Since
then multiple randomised controlled trials have been published confirming
without doubt the therapeutic effects of stimulants (e.g., methylphenidate &
damphetamines; e.g Malone and Swanson 1993; Wilens, Biederman et al.
1996; Chavez, Sopko et al. 2009; Patrick, Straughn et al. 2009). More
recently non-stimulants (e.g., atomoxetine) have also been licensed (ref). , but
the optimal clinical dose appears to vary 6-fold or more across individuals.
(This is another source of variance that may a better target for
pharmacogenetic studies, since the "response rate" seems to be so high --
85% to 90% -- when titration includes a range of doses for each stimulant and
multiple stimulants).
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More recently non-stimulants such as atomoxetine have also been licensed
for the treatment of ADHD (Garnock-Jones and Keating 2009). While these
treatments are, at least in the short term, very efficacious (e.g., "response rate
of -- 85% to 90% -- when titration includes a range of doses for each
stimulant and multiple stimulants), and generally well
tolerated there is still a range in the degree of responses (Sonuga-Barke, Van
Lier
et al. 2008). The ; reduction of levels of ADHD to levels of healthy controls is
relatively uncommon in clinical trials or in normal clinical practice (ref). ).
Furthermore, there is likely to be much greater variability in the long term
effect of stimulants and the optimal clinical dose appears to vary 6-fold or
more across individuals. These two dimensions of treatment response will be
important sources of variance that may be interesting targets for future
pharmacogenetic studies (especially given the high “response rates”).
There
have been a number of attempts to identify predictors of response with the
aim of improving the tailoring of treatments to patient characteristics and
needs. Factors such as age, gender, comorbidity and clinical have been
considered, although evidence of significant effects is limited (Sonuga-Barke,
Coghill et al. 2007; Cornforth et al., in press). In general Ppharmacogenetic
research in
psychiatry focuses on studies of gene x drug interactions can help in the
validation of therapeutic targets, the detection of factors determining response
and the identification of genetically induced side-effects. The long term goal is
to develop more effectively tailored treatment and integrated personalised
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therapeutics. The therapeutic effects of stimulants on the neuronal level will
depend on their ability to alter the release, uptake and/or enzymatic
inactivation of neuro-transmitters (see discussion of the effects of
methylphenidate and amfetamine above; Giros, Jaber et al. 1996; Seeman
and Madras 1998). Given that, as we have reviewed, these functions effects
appear
to vary as a function of DRD4 and DAT1 variants, polymorphisms in these
genes are important candidate genes for pharmacogenetic investigation. The
working hypothesis is then that such polymorphisms alter the impact of
stimulant
medication on brain systems as well as treatment efficacy (Stein and
McGough 2008). However, DAT1 is not co-localized with DRD4 as shown by
Madras, Miller et al. (2002) and methylphenidate is only an “indirect agonist”
of DA, via DA transporter blockade, so the hypothesis is stronger for DAT1
than DRD4.
A number of pharmacogenetic studies have examined relationship
between methylphenidate response and DA gene polymorphisms in ADHD.
The majority of studies have focused on DAT1. The results, so far, are
inconclusive for both genes (Levy 2007; Stein and McGough 2008). The first
study (Winsberg and Comings 1999) reported a better therapeutic response
to methylphenidate in ADHD children with the 9/10 genotype compared to
children with the 10/10 genotype. While (Roman, Szobot et al. 2002) and
(Cheon, Ryu et al. 2005) replicated this finding, others (Kirley, Lowe et al.
2003; Stein, Waldman et al. 2005), found better treatment response in
patients homozygous for the 10R. A further two studies demonstrated that
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9/9 genotype was associated with a decreased response to methylphenidate
(Stein, Waldman et al. 2005; Joober, Grizenko et al. 2007). In addition,
several studies found no effect of DAT1 in relation to a medication response
(Langley, Turic et al. 2005; van der Meulen, Bakker et al. 2005; McGough,
McCracken et al. 2006; Zeni, Guimaraes et al. 2007; Tharoor, Lobos et al.
2008). For DRD4 Hamarman, Fossella et al. (2004) found that patients with
7R allele required higher doses for symptom improvement while Cheon, Kim
et al. (2007) reported that children homozygous for the 4R allele presented a
better response to MPH. Other studies did not report a significant association
between the DRD4 7R (van der Meulen, Bakker et al. 2005; Zeni, Guimaraes
et al. 2007; Tharoor, Lobos et al. 2008) . In trying to understand this
conflicting and inconsistent set of results it must be acknowledged that studies
to date have
been on very small samples and therefore papers may be reporting chance
findings.
6. SUMMARY OF KEY FINDINGS
ADHD is highly heritable (among the highest of all psychiatric disorders
and nearly as high as the physical traits such as height) and at the
advent of molecular genetic studies of ADHD it was assumed that the
discovery of specific genes would be relatively easy.
The initial discoveries of associations with candidate genes was
remarkably successful (in the context of general psychiatric genetics),
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with significant association with first DAT1 and then DRD4 genetic
variants that were chosen as candidate genes because of their pattern
of distribution and neurofunctionality with regard DA activity and a
presumed role in the response to the common pharmacological
treatments for ADHD with stimulant drugs.
The subsequent genome wide scans (GWA) approaches have not
discovered additional genes and have not even detected the replicated
associations with ADHD from the candidate gene studies of DAT and
DRD4 (see Neale et al, 2008).
Association studies provide stronger evidence for DRD4 (i.e., 7R allele)
than DAT1 (i.e. 10/10 genotype) in the pathogenesis of ADHD
probably because of greater between-study heterogeneity in DAT1
findings. Absolute effect sizes for either gene individually are very
small but due to high allele proportions in the population, the relative
magnitude is much larger in term of percentage of the maximum effect.
Evidence relating DRD4 and DAT genotypes to endophenotypes of
ADHD is so far weak and inconsistent, but somewhat stronger for
DRD4, especially with regard to response time variability.
There are also inconsistencies in evidence implicating these genes in
gene-environment interactions, with the strongest findings for DAT1
especially with regard to the impact of maternal smoking during
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pregnancy, although the role of gene-environment correlations cannot
be ruled out.
DRD4 and DAT1 polymorphisms are interesting candidates for
phamaco-genetic studies. DAT1 has the best evidence but the specific
genotype associated with greater efficacy is yet to be determined
definitively. This finding has to be treated cautiously given the
inconsistency of findings and the small samples.
7. FUTURE DIRECTIONS
Future studies relating to the role of DRD4 and DAT1 should:
Examine more fully the interactions between genetic factors.
Examining DRD4 x DAT1 interactions as well interactions between
these and variants in other genes perhaps in the context of genome
wide association studies. A few studies have examined gene x gene
interactions but initial results are encouraging (Gabriela, John et al.
2009; Carrasco, Rothhammer et al. 2006)
Explore a wider range of endophenotypes especially moving away from
the focus on executive functions and basic cognitive processes and
towards markers of motivational dysfunction which one might expect to
be more closely linked to DAT1 alterations within sub-corticol regions.
Furthermore, studies of neuro-biological endophenotypes in clinical
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samples should be encouraged. Preliminary results are promising;
DAT1 genotype interacting with familial risk of ADHD in stiatum
(Durston, Fossell et al, 2008).
Test for GxE interaction with a wider range of environmental risk
factors especially where these are neuro-biological plausible. As far as
the social environment is concerned it might be especially valuable to
examine genetic moderation of outcomes in non-pharmacological
interventions such as parent training.
To combine GxE and endophenotype designs to explore the role of the
environment in moderating genetic effects at multiple levels of analysis
within the child (neuro-biology, neuro-chemistry and neuropsychology).
To include measues of the environment and endophenotypes in
pharmaco-genetic studies in an attempt to account for the current
heterogeneity in published studies.
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