ADVANCING THE NEUROSCIENCE OF ADHD
Molecular Genetics of Attention-Deficit/Hyperactivity
Stephen V. Faraone, Roy H. Perlis, Alysa E. Doyle, Jordan W. Smoller, Jennifer J. Goralnick,
Meredith A. Holmgren, and Pamela Sklar
Results of behavioral genetic and molecular genetic studies have converged to suggest that both genetic and nongenetic factors
contribute to the development of attention-deficit/hyperactivity disorder (ADHD). We review this literature, with a particular emphasis
on molecular genetic studies. Family, twin, and adoption studies provide compelling evidence that genes play a strong role in
mediating susceptibility to ADHD. This fact is most clearly seen in the 20 extant twin studies, which estimate the heritability of ADHD
to be .76. Molecular genetic studies suggest that the genetic architecture of ADHD is complex. The few genome-wide scans conducted
thus far are not conclusive. In contrast, the many candidate gene studies of ADHD have produced substantial evidence implicating
several genes in the etiology of the disorder. For the eight genes for which the same variant has been studied in three or more
case–control or family-based studies, seven show statistically significant evidence of association with ADHD on the basis of the pooled
odds ratio across studies: DRD4, DRD5, DAT, DBH, 5-HTT, HTR1B, and SNAP-25.
Key Words: ADHD, genetics, linkage, candidate genes, twins
disorders. Its name reflects the range of possible clinical presen-
tations, which can include hyperactivity as well as inattention
and impulsivity (Wilens et al 2002). In spite of this heterogeneity
and some shift in diagnostic criteria (American Psychiatric Asso-
ciation 1987), it is also among the best-validated childhood
diagnoses from both clinical and neurobiological perspectives
(Faraone and Biederman 1998; Faraone et al 2000b). This feature,
along with early observations that family members of children
with ADHD were at elevated risk for ADHD (Morrison and
Stewart 1971), made ADHD an attractive target for genetic
studies. In this review, we examine evidence showing that
ADHD is strongly influenced by genes and review the progress
of molecular genetic studies seeking to find these genes and the
variants that increase susceptibility to ADHD.
ith a prevalence of 8%–12% worldwide (Faraone et al
2003), attention-deficit/hyperactivity disorder (ADHD)
is among the most common childhood psychiatric
Family, Twin, and Adoption Studies of ADHD
Several studies have reported an elevated prevalence of
ADHD among family members of individuals with ADHD
(here and elsewhere we use the term “ADHD” to refer to
current and prior terms used to describe the syndrome). Early
studies found the risk of ADHD among parents of children
with ADHD to be increased by two- to eightfold, with similarly
elevated risk among the siblings of ADHD subjects (for a
review of this literature, see Faraone and Biederman 2000).
Because other environmental differences could account for
elevated risk, two double-blind, case–control studies specifi-
cally examined the risk to siblings of ADHD children when
environmental factors are considered as well (Biederman et al
1990, 1992; Faraone et al 1992, 2000a). After controlling for
gender, intactness of family, and socioeconomic status, these
studies confirmed the familiality of ADHD.
Because, in the absence of molecular genetic data, family
studies cannot disentangle genetic from environmental sources
of transmission, we turn to adoption and twin studies to deter-
mine whether genes account for the familial transmission of a
disorder. If genes contribute significantly to ADHD risk, biolog-
ical relatives of ADHD children should be at greater risk for
ADHD than adoptive relatives of adopted ADHD children. Two
studies found that biological relatives of hyperactive children
were more likely to have hyperactivity than adoptive relatives
(Cantwell 1975; Morrison and Stewart 1973). A more recent study
likewise found rates of ADHD to be greater among biological
relatives of nonadopted ADHD children than adoptive relatives
of adopted ADHD children (Sprich et al 2000). The adoptive
relatives had a risk for ADHD similar to the risk in relatives of
A more direct method of examining the heritability of
ADHD is to study twins: monozygotic (“identical”) twins share
essentially 100% of their genes, whereas dizygotic (“fraternal”)
twins, like other siblings, share 50% of their genes. The extent
to which identical twins are more concordant for ADHD than
fraternal twins can be used to compute heritability, which is
the degree to which variability in ADHD in the population can
be accounted for by genes. Figure 1 shows estimates of
heritability from 20 twin studies from the United States,
Australia, Scandinavia, and the European Union: the mean
heritability estimate of 76% shows that ADHD is among the
most heritable of psychiatric disorders (Coolidge et al 2000;
Edelbrock et al 1992; Gillis et al 1992; Gjone et al 1996;
Goodman and Stevenson 1989; Hudziak et al 2000; Levy et al
1997; Martin et al 2002; Matheny and Brown 1971; Nadder et
al 1998; Rietveld et al 2003; Schmitz et al 1995; Sherman et al
1997; Silberg et al 1996; Stevenson 1992; Thapar et al 1995;
Thapar et al 2000; Willcutt et al 2000; Willerman 1973).
Molecular Genetic Studies of ADHD
In an attempt to find regions of chromosomes that might
harbor genes for ADHD, three groups have conducted genome-
wide linkage scans. By this approach, many DNA acid markers
across the genome are examined to determine whether any
From the Medical Genetics Research Center and Department of Psychiatry
General Hospital and Harvard Medical School; and the Massachusetts
General Hospital (JJG, MAH), Boston, Massachusetts.
Address reprint requests to Stephen V. Faraone, Ph.D., Department of Psy-
chiatry and Behavioral Sciences, SUNY Upstate Medical University, 750
East Adams Street, Syracuse, NY 13210; E-mail: email@example.com.
Received June 2, 2004; revised October 14, 2004; accepted November 10,
BIOL PSYCHIATRY 2005;57:1313–1323
© 2005 Society of Biological Psychiatry
chromosomal regions are shared more often than expected
among ADHD family members. Regions identified in these
studies can then be examined in more detail with additional
A study of 126 American affected sib-pairs found four regions
showing some evidence of linkage (log odds ratio [LOD] scores
?1.5): 5p12, 10q26, 12q23, and 16p13 (Fisher et al 2002). An
expanded sample of 203 families found stronger evidence for the
16p13 region, previously implicated in autism, with a maximum
LOD score of 4 (Smalley et al 2002). A study of 164 Dutch
affected sib-pairs also identified a peak previously noted in
autism, at 15q15, with a peak LOD score of 3.5 (Bakker et al
2003). Two other peaks, at 7p13 and 9q33, yielded LOD scores of
3.0 and 2.1, respectively. A genome-wide scan of families from a
genetically isolated community in Colombia implicated 8q12,
11q23, 4q13, 17p11, 12q23, and 8p23 (Arcos-Burgos et al 2004).
With the exception of 17p11, genomic regions implicated by
these studies do not overlap. Nevertheless, given that these
studies individually had low power to detect linkage to genes of
small effect, these regions remain of interest for replication
studies and for fine mapping efforts.
In contrast to the scarcity of linkage studies, many candidate
gene studies have used the method of association to determine
whether biologically relevant genes influence the susceptibility
to ADHD. In these studies, investigators choose genes on the
basis of neurobiological studies or theoretical considerations
suggesting that the gene product is relevant to the etiology of
ADHD. Candidate gene studies have used case–control or
family-based designs. Case–control designs compare allele fre-
quencies between patients with ADHD and non-ADHD control
subjects. Alleles that confer risk for ADHD should be more
common among ADHD patients. The family-based design com-
pares the alleles that parents transmit to ADHD children with
those they do not transmit. If an allele increases the risk for
ADHD, it should be more common among the transmitted alleles
than the nontransmitted alleles. From both study designs, it is
possible to derive an odds ratio (OR) or relative risk (RR) statistic,
which assesses the magnitude of the association between ADHD
and the putative risk alleles (an OR or RR of 1.0 indicate no
association, those greater than 1.0 indicate that the allele in-
creases risk for ADHD, and those less than 1.0 indicate that the
allele decreases the risk for ADHD). In the following section, we
summarize the candidate gene results from these two study
designs and, to facilitate the interpretation of results, we compute
pooled ORs across studies for gene variants examined in three or
more case–control or family-based studies.
The Dopamine D4 Receptor. Both noradrenaline and dopa-
mine are potent agonists of the dopamine D4 receptor (DRD4)
(Lanau et al 1997), and DRD4 is prevalent in frontal–subcortical
networks implicated in the pathophysiology of ADHD by neu-
roimaging and neuropsychological studies (Faraone and Bieder-
man 1998). Researchers have predominantly focused on a tan-
dem repeat polymorphism in exon III of DRD4 because in vitro
studies have shown that one variant (the 7-repeat allele) pro-
duces a blunted response to dopamine (Asghari et al 1995; Van
Tol et al 1992).
Faraone et al ( 2001b) examined the ADHD–DRD4 association
in meta-analyses of both case–control and family-based associ-
ation studies. In each analysis, a small but statistically significant
association emerged between ADHD and the 7-repeat allele. For
case–control studies, the combined estimate of the OR was 1.9
(95% confidence interval [CI] 1.4–2.2). For family-based studies,
the combined estimate was 1.4 (95% CI 1.1-1.6). There was no
evidence for heterogeneity of the OR across studies, no evidence
that a single study accounted for the significance or magnitude of
the association, and no evidence for publication bias for either
In more recent studies, positive case–control associations
with DRD4-7 have been documented in reports from the United
States (Grady et al 2003) and Brazil (Roman et al 2001), although
in this latter study, a family-based analysis with 49 triads did not
show biased transmission. A family-based study from the United
Kingdom and Ireland also found evidence for the association
between ADHD and DRD4-7 (Holmes et al 2002). Other recent
studies have been unable to document significant associations
with DRD4-7 but have still found ORs greater than 1.0. Payton et
al (2001b) found a nonsignificant association between the 7-re-
peat allele and high scores on the DuPaul ADHD rating scale (OR
1.4; 95% CI .6–2.9) in a population-based twin sample. Addition-
ally, a family study in a genetically isolated community in
Colombia reported a near-significant association of DRD4-7 and
ADHD (Arcos-Burgos et al 2004).
Yet, divergent findings have also been reported. Mill et al
(2001) found no evidence for biased transmission of the 7-repeat
allele in a family-based analysis of DSM-III attention-deficit
disorder. Kustanovich et al (2003a) expanded an earlier family
study and found no significant association between ADHD and
the 7-repeat allele. A case–control study of Han Chinese found
no ADHD or control subjects with the 7-repeat allele. This study
found no overall association of any allele with ADHD, although
longer alleles (4 through 6) were more common in ADHD than
control subjects after stratification by gender (Qian et al 2003a).
Interestingly, Manor et al (2002a) found an excess of short alleles
(i.e., 2–5 repeats) in ADHD cases from an Israeli sample and
biased transmission of the short alleles in a family-based analysis.
Subjects with short alleles also performed more poorly on a
continuous performance test. In an American sample, Smith and
colleagues (Smith KM et al 2003) found a trend toward a lower
Figure 1. Estimated heritability of attention-deficit/hyperactivity disorder,
based on pooled results from 20 twin studies.
1314 BIOL PSYCHIATRY 2005;57:1313–1323
S.V. Faraone et al
prevalence of the 4-repeat allele in ADHD subjects due to an
excess of 2- and 3-repeat alleles. Results of these latter two
studies raise the possibility of allelic heterogeneity in DRD4 or
suggest that the Exon III polymorphism is in linkage disequilib-
rium with the true risk allele. Despite these divergent findings,
when all studies of the exon III polymorphism are pooled, the
association with ADHD remains statistically significant: case–
control OR ? 1.45 (95% CI 1.27–1.65); family based OR ? 1.16
(95% CI 1.03–1.31).
A small number of studies have assessed other DRD4 poly-
morphisms; however, these data have not been conclusive.
McCracken and colleagues (Kustanovich et al 2003a; McCracken
et al 2000) found an association between ADHD and a 120-base
pair (bp) repeat 1.2 kilobases (kb) upstream of the initiation
codon, in the promoter. The association with the 240 allele was
strongest for the Inattentive subtype; however, Barr et al (2001a)
found no association between ADHD and three polymorphisms
in the promoter region, including the 120-bp repeat and two
single nucleotide polymorphisms (SNPs) (FspI -521 C to T and
Ava –II -616 C to G). Todd et al (2001b) also found no association
between the 5=120-bp repeat and ADHD as well as seven latent
classes based on ADHD symptoms. Most recently, this 5=120-bp
repeat was significantly associated with ADHD only when the
240 allele was included with the 7-repeat allele in a haplotype
analysis (Arcos-Burgos et al 2004).
Studies using symptom dimensions rather than categoric
diagnoses suggest that DRD4 might be particularly relevant to
symptoms of inattention. Rowe et al (2001) found that fathers of
ADHD children with the 7-repeat allele had higher levels of
retrospectively reported inattention symptoms, and Levitan et al
(2004) found an association between this allele and greater
self-reported childhood inattention in women with seasonal
The Dopamine D5 Receptor. The most widely studied poly-
morphism for the dopamine D5 receptor (DRD5) has been a
dinucleotide repeat that maps approximately 18.5 kb 5= to the
transcription start site (Hawi et al 2003). In a study of 111 Irish
families, Daly et al (1999) found excess transmission of the
148-bp allele to ADHD patients. The effect was strongest among
families without parental history of ADHD. Modest support for
this association was seen in a sample of 111 Turkish families
(Tahir et al 2000b) and in a case– control sample of Tourette’s
syndrome children with symptoms of ADHD (Comings et al
2000b). In contrast, a study of 81 families from the United
Kingdom found no evidence for an association with the dinucle-
otide repeat polymorphism (Payton et al 2001a), and a Canadian
study found no significant association with the 148-bp allele but
significant under-transmission of the 146-bp allele (Barr et al
2000c), which was also reported by an American group
(Kustanovich et al 2003a). Another study of three markers found
an association only for a downstream dinucleotide repeat not
assessed in other studies (Mill et al 2004a).
Despite the variability of these results, a meta-analysis of
family-based studies found a significant association with DRD5 in
ADHD, suggesting that the nonsignificant findings were due to
low statistical power (Maher et al 2002). Consistent with this
result, a more recent family-based analysis that combined 14
independent samples identified a significant association of the
148-bp allele with ADHD (OR ? 1.2; 95% CI 1.1–1.4) (Lowe et al
2004), as did another family-based replication study (Manor et al
2004). Of note, Lowe et al’s association was limited to the
inattentive and combined subtypes.
Hawi et al (2003) expanded analyses of the Irish sample to
include two additional 5= microsatellite markers (further up-
stream than the dinucleotide repeat described above) and an SNP
in the 3= untranslated region. The 3= SNP was associated with
ADHD (RR ? 1.6). In addition, haplotype analyses showed an
association with ADHD for a two-marker haplotype of one of the
5= microsatellite markers (D4S1582) and the dinucleotide repeat
(DRD5-PCR1), as well as a different two-marker haplotype
comprising DRD5-PCR1 and the 3= SNP, and a haplotype com-
prising all three of these markers.
The Dopamine D2 Receptor. The dopamine D2 receptor
(DRD2) has been less extensively studied in ADHD than DRD4
and DRD5. Comings et al (1991)compared 104 ADHD subjects
(nearly all with comorbid Tourette’s syndrome) with control
subjects and found a significant association with the TaqIA1
allele of DRD2. This result was replicated in a subsequent study
by the same group (Comings et al 1996a).
Three studies used a family-based design to examine DRD2.
Rowe et al (1999) examined 164 ADHD children from 125
families and found no excess transmission of the Taq1A1 allele.
A subsequent study of Taiwanese families likewise found no
association (Huang et al 2003). Kirley et al (2002) examined two
polymorphisms in 118 ADHD children and their families. No
significant associations were identified, though they reported a
trend toward significance (p ? .07) for the Ser311 polymorphism
when paternally transmitted. The discordance between family-
based and case–control studies here might relate to differences
in study populations, because the positive studies examined
subjects with comorbid Tourette’s syndrome (Comings et al 1991,
1996a). On aggregate, the studies to date suggest little or no
association with ADHD.
The Dopamine D3 Receptor. Barr et al (2000d) examined a
Ser9Gly exon 1 polymorphism and an intron 5 MspI restriction
site polymorphism in 100 Canadian families. The two loci were
found to be in strong linkage disequilibrium, but neither the
individual loci nor haplotypes of the two were associated with
ADHD. Negative results for the Ser9Gly polymorphism were also
reported in a United Kingdom family-based study of 105 families
(Payton et al 2001a) and a study of 39 families of ADHD adults
(Muglia et al 2002b). In their Tourette’s syndrome sample,
Comings et al (2000b) also found no evidence for association. In
a sample of 146 German patients referred for forensic evaluation
(Retz et al 2003), heterozygosity at this polymorphism was
associated with higher impulsivity scores, although this effect
was only seen among those with a history of violence. When all
extant studies are combined, the pooled OR (1.2) is not statisti-
The Dopamine Transporter Gene. There are several reasons
that the dopamine transporter gene (DAT, SLC6A3) has been
considered a suitable candidate for ADHD. The stimulant medi-
cations, which are efficacious in treating ADHD, block the
dopamine transporter as one mechanism of action for achieving
their therapeutic effects (Spencer et al 2000). In mice, eliminating
SLC6A3 gene function leads to two features suggestive of ADHD:
hyperactivity and deficits in inhibitory behavior. And like ADHD
children, treating these “knockout” mice with stimulants reduces
their hyperactivity (Gainetdinov et al 1999b; Giros et al 1996).
Similar findings were seen when SLC6A3 activity was reduced to
10% of normal (Zhuang et al 2001).
The SLC6A3 knockout mouse model shows the potential
complexities of gene–disease associations. The loss of the
SLC6A3 gene has many biological effects: initially, these mice
show increased extracellular dopamine, a doubling of the rate of
dopamine synthesis (Gainetdinov et al 1998), decreased dopa-
S.V. Faraone et al
BIOL PSYCHIATRY 2005;57:1313–1323 1315
mine and tyrosine hydroxylase in the striatum (Jaber et al 1999),
and a nearly complete loss of functioning of dopamine autore-
ceptors (Jones et al 1999). Eventually, feedback mechanisms
reduce the output of dopamine from striatal neurons, leading to
a hypodopaminergic state (Gainetdinov et al 1999a). Bezard et al
(1999) showed that mice without SLC6A3 function did not
experience neurotoxin-induced dopaminergic cell death, and
another study found a gradient effect such that mice with zero,
one, and two functional SLC6A3 genes showed increasing sus-
ceptibility to neurotoxins (Gainetdinov et al 1997). These studies
suggest that individual differences in SLC6A3 might mediate
susceptibility to neurotoxins having an affinity for the dopamine
In ADHD adults, Dougherty et al (1999) measured striatal
dopamine transporter activity by single photon emission com-
puted tomography with the radiopharmaceutical iodine-123-
labeled Altropane. They found dopamine transporter activity to
be elevated by approximately 70% in ADHD adults. This finding
was replicated by Krause et al (2000) with a different ligand
(TRODAT-1). After treatment with methylphenidate, ligand-bind-
ing to the dopamine transporter was reduced to normal levels. In
contrast, van Dyck et al (2002) did not find altered dopamine
transporter levels, possibly owing to use of a different ligand,
Using a family-based association study, Cook et al (1995) first
reported an association between ADHD and the 10-repeat allele
of a tandem repeat polymorphism located in the 3= untranslated
region of SLC6A3. A meta-analysis by Curran et al (2001) of nine
independent samples from 664 informative heterozygous paren-
tal transmissions found a small positive but nonsignificant OR
(1.16). These investigators found evidence for significant heter-
ogeneity among data sets. Several of the original studies included
in the meta-analysis presented stronger findings when all data
(not just data from complete trios) were considered (Daly et al
1999; Waldman et al 1998). One study (Barr et al 2001c)
examined a haplotype between the 10-repeat allele and SNPs in
intron 9 and exon 9 that were in strong linkage disequilibrium
and found a haplotype significantly associated with ADHD. In a
meta-analysis of 11 family-based samples (9 of which overlap
with the Curran et al  meta-analysis), Maher et al (2002)
reported a nonsignificant OR of 1.27.
Since the publication of the two meta-analyses, several addi-
tional studies have appeared in the literature. Todd et al (2001a)
reported on a large family-based twin sample, finding no asso-
ciation with the 10-repeat allele for either the categoric DSM-IV
ADHD diagnosis, subtypes, or a series of eight latent classes
based on ADHD symptoms. In a sample of 110 Taiwanese
families, Chen et al (2003) found an association with the 10-
repeat allele (OR ? 2.9). Payton et al (2001b) stratified pairs of
identical twins on the DuPaul rating scale and compared con-
cordant high scorers (n ? 50) with low scorers (n ? 42) and
found a nonsignificant trend for increased frequency of the
10-repeat allele among high scorers. One case–control study
found essentially equal allele frequencies in the cases and control
subjcts (Smith EA et al 2003). Two other studies examined
quantitative traits, rather than the presence or absence of ADHD,
for association with SLC6A3. One group reported an association
with increasing symptom severity as assessed by a DSM-IV
criteria checklist (Waldman et al 1998). Muglia et al (2002a)
tested for association between SLC6A3 alleles and ADHD using
quantitative data derived from two rating scales, but no associa-
tion was detected when ADHD was considered as a continuous
When results from the family-based studies noted above are
pooled, the OR is small (1.13; 95% CI 1.03-1.24) but significant,
suggesting that the dopamine transporter gene merits further
investigation but that its effect is modest.
Dopamine Beta-Hydroxylase. Dopamine beta-hydroxylase
(DBH) is the primary enzyme responsible for conversion of
dopamine to norepinephrine. In their Tourette’s syndrome sam-
ple, Comings et al (1996b) examined a Taq1 restriction site
polymorphism in intron 5 and found a significant association
with ADHD symptom scores. Smith and colleagues (Smith KM et
al 2003) reported a case– control analysis of two DBH polymor-
phisms: the TaqI A polymorphism (intron 5) and a GT repeat
polymorphism located approximately 4.5 kb upstream of the
transcription start site; the latter allele had previously been
associated with DBH serum levels (Cubells et al 1998). In their
sample of 105 ADHD cases and 68 community control subjects,
logistic regression analysis indicated a significant association
between the A1 allele of the Taq 1 polymorphism and ADHD
(OR ? 1.96; 95% CI 1.01–3.79). For the GT repeat polymorphism,
the A4 allele was nonsignificantly more common among cases
than control subjects.
In addition to these case–control studies, several family-based
association analyses of DBH have been reported. Daly et al
(1999) studied the Taq1 polymorphism in an Irish sample of 86
trios and 19 parent–child pairs. They found a significant associ-
ation between the A2 allele and ADHD (RR ? 1.31) that was
largely attributable to cases in which there was a parental history
of ADHD. Further analyses suggested the association was stron-
gest for the combined subtype of ADHD. Roman et al (2002)
found further support for this association in a sample of 88
Brazilian families. In their study, the A2 allele was associated
with ADHD, especially with the combined subtype. In contrast to
Daly et al, however, excess transmission of the A2 allele was
more common among families without a parental history of
In a Canadian study of 117 families with children with ADHD,
Wigg et al (2002) reported a nonsignificant excess transmission
of the A2 allele. They also observed no evidence of linkage or
association for the dinucleotide repeat polymorphism and an
insertion/deletion polymorphism in the region 5= to the tran-
scription start site (both of which had been associated with
serum DBH levels). Analysis of haplotypes of these three poly-
morphisms was also negative. In a family-based analysis of 104
trios from the United Kingdom, Payton et al (2001a) examined a
G/T SNP in exon 5 of DBH and found no evidence of association.
The dinucleotide repeat polymorphism was also studied by Hawi
et al (2003) in the Irish sample in which the Taq1 association was
previously observed. They also examined an EcoN1 restriction
site polymorphism in exon 2 and an MspI polymorphism in
intron 9. There was no evidence of association for these addi-
tional polymorphisms. A two-marker haplotype comprising al-
lele 1 of the exon 2 polymorphism and A2 of the Taq1 polymor-
phism was preferentially transmitted to ADHD cases. Despite the
mixed evidence for association between DBH and ADHD, when
the family-based studies are pooled, they jointly suggest a
significant association between ADHD and the 5= Taq1 polymor-
phism (OR ? 1.33; 95% CI 1.11-1.59).
Tyrosine Hydroxylase. Tyrosine hydroxylase (TH) catalyzes
the conversion of tyrosine to dihydroxy-phenylalanine and thus
plays a role in the synthesis of dopamine. Thus far, only three
studies have examined the association between polymorphisms
in the TH gene and ADHD. All have been negative. Barr et al
(2000b) found no association between ADHD and a tetranucle-
1316 BIOL PSYCHIATRY 2005;57:1313–1323
S.V. Faraone et al
otide repeat in intron 1 in a sample of 72 trios plus 10 one-parent
families and 15 affected siblings. Payton et al (2001a) found no
association with the same polymorphism and 105 triads. Finally,
in a case– control study, Comings et al (1995) found no associa-
tion between this polymorphism and ADHD in a sample of 74
cases and 89 control subjects.
ferase (COMT) catalyzes a major step in the degradation of
dopamine, norepinephrine, and epinephrine. Seven family-
based studies examined the Val108Met polymorphism in the
COMT gene, which yields either a high- or low-active form of
COMT (Syvanen et al 1997). Five of these found no significant
association (Barr et al 1999; Hawi et al 2000; Manor et al 2000;
Payton et al 2001a; Tahir et al 2000a). Two studies reported
statistically significant associations, though one (Eisenberg et al
1999) study of 48 children subsequently corrected their report to
include less over-transmission of the Val allele than originally
reported (revised p ? .048), and the other (Qian et al 2003b), the
only one of these to examine Chinese rather than Caucasian
ADHD cases, was significant only when limited to male cases.
Our pooled analysis of these studies showed no evidence of
association between ADHD and COMT (OR ? 1.0, p ? ns).
Monoamine Oxidase A.
(MAO-A) enzyme moderates levels of norepinephrine, dopa-
mine, and serotonin in the central nervous system, and MAO-A
knockout mice display numerous abnormalities in these neuro-
transmitter systems (Cases et al 1998). A case– control study of
the X-linked MAO-A gene reported an association between a
30-bp tandem repeat in the promoter region and ADHD in 110
male and 19 female Israeli ADHD cases compared with control
subjects, with a particularly large effect noted in the small (n ?
19) subset of female cases (Manor et al 2002b). That study also
found an association between the risk polymorphism and errors
of commission on a neuropsychological test of attention.
The promoter-region repeat was also significantly associated
with ADHD in a sample of 133 Israeli families (Manor et al 2002b)
but not in a similarly-sized family-based study by Lawson et al
(2003). Among 82 Chinese families, a dinucleotide tandem repeat
polymorphism was associated with ADHD (Jiang et al 2001),
though a study in a Caucasian cohort failed to replicate this
association (Payton et al 2001a).
The monoamine oxidase A
The Noradrenergic System
adrenergic receptors have been examined in ADHD. The ?-2A
adrenergic receptor (ADRA2A) has a promoter-region SNP
(C¡G, ?1291) that has been examined in both case–control and
family-based analyses. In their sample of patients with Tourette’s
syndrome, Comings et al (1999) reported an association between
genotypes at this SNP and ADHD symptom scores. A subsequent
analysis of the sample (Comings et al 2003), which examined a
broad range of psychiatric symptoms, concluded that the G allele
was associated with ADHD and oppositional defiant or conduct
disorder symptoms, whereas the C allele was associated with a
spectrum of other conditions, including panic attacks, obsessive
compulsive disorder, addictions, and affective and schizoid
symptoms. In contrast to these positive findings in ADHD
patients with Tourette’s syndrome, two family-based studies
failed to detect association between ADRA2A and the diagnosis
of ADHD (Roman et al 2003; Xu et al 2001), but one of these
found a significant association of the G allele with elevated
inattentive and combined symptom scores (Roman et al 2003).
A dinucleotide repeat polymorphism located approximately 6
ADRA2A, 2C, and 1C. Three
kb from the gene that codes for the ?-2C adrenergic receptor
(ADRA2C) has also been examined in both case–control and
family-based analyses. Comings et al (1999), in their sample of
Tourette’s syndrome cases and control subjects, found an asso-
ciation between this polymorphism and ADHD symptom scores,
but it was not significant after Bonferroni correction. Two
subsequent family-based analyses, one in 103 families and
another in 128 families, showed no evidence of association (Barr
et al 2001b; De Luca et al 2004b). The former study also
examined a C-to-T SNP in codon 492 of the 1C receptor
(ADRA1C) that changes cysteine to arginine but found no
evidence of linkage (Barr et al 2001b).
In summary, studies of these three adrenergic receptor genes
in ADHD do not suggest an association. But because studies to
date have been limited by small sample sizes and examination of
single polymorphisms, further investigation might be warranted.
The Norepinephrine Transporter.
transporter (SLC6A2) has been examined in ADHD because
drugs that block the norepinephrine transporter are efficacious in
treating ADHD (Biederman and Spencer 2000). In their sample of
patients with Tourette’s syndrome, Comings et al (2000b) found
evidence for association of an SNP in SLC6A2 with ADHD
symptoms. Subsequently, Barr et al (2002) examined three SNPs
in SLC6A2 (one in exon 9, intron 9, and intron 13, respectively)
in 122 ADHD families and found no evidence of association for
these loci or haplotypes comprising them. No association with
intron 7 and intron 9 SNPs was seen in a study of Irish families
(McEvoy et al 2002) or with a restriction fragment length
polymorphism in a set of families with adult ADHD offspring (De
Luca et al 2004a).
The Serotonergic System
based association studies examined a silent SNP (G861C) in the
gene coding for the serotonin HTR1B receptor. In predominantly
Caucasian samples, both studies found over-transmission of the
G allele, though this finding only reached statistical significance
in the very large study by Hawi et al (2002), which reported
pooled results from four sites. When Quist et al (2003) analyzed
paternal transmission, their association reached significance as
well. The pooled OR for the G861C SNP is 1.44 (95% CI
The serotonin HTR2A receptor gene has been examined in
two case– control studies. Zoroglu et al (2002) found no associ-
ations between the T102C and G1438A polymorphisms and
ADHD. Conversely, in a sample of women with seasonal affec-
tive disorder, Levitan et al (2002) found an association between
the number of C alleles and greater scores on a self-report
measure of childhood ADHD. A second coding polymorphism in
the HTR2A receptor gene (His452Tyr) was associated with
ADHD in one family study (Quist et al 2000) but not in another,
much larger study (Hawi et al 2002). Of note, the latter study
found an association with the His allele when families of Irish
origin were analyzed alone. The former study also noted no
association between the T102C polymorphism and ADHD. The
pooled OR for all HTR2A studies is 1.1 and is not statistically
Overall, preliminary findings suggest an association between
the HTR1B gene and ADHD, which merits further investigation.
Evidence is less consistent for the HTR2A gene but largely
negative thus far.
Serotonin Transporter. The serotonin transporter gene (5-
HTT; SLC6A4) is perhaps the best-studied gene in psychiatric
HTR1B and HTR2A. Two family-
S.V. Faraone et al
BIOL PSYCHIATRY 2005;57:1313–1323 1317
genetics, with associations reported for a broad range of diag-
noses and traits (Anguelova et al 2003a, 2003b) Four case–
control studies reported an association between a 44-bp inser-
tion/deletion polymorphism (5-HTTLPR) in the promoter region
of SLC6A4 and a diagnosis of ADHD (Seeger et al 2001). Among
80 children with hyperkinetic disorder with or without conduct
disorder, compared with control subjects, the “long” allele was
over-represented. Two subsequent studies found similar result.
Retz et al (2002), in contrast to other studies, examined a
continuous measure of ADHD symptoms. Zoroglu et al (2002)
also examined a variable number of tandem repeats (VNTR)
polymorphism (STin2) and found a significant association with
ADHD. A small study of aggressive children also noted an
association between the long allele of 5-HTTLPR, though not the
VNTR, and ADHD (Beitchman et al 2003).
Similarly, two family studies reported over-transmission of the
long allele of 5-HTTLPR, consistent with case–control findings,
though neither reached statistical significance. In their sample of
98 trios, Manor et al (2001) found a significant association with
combined-type ADHD. Kent et al (2002) examined two other
polymorphisms (an SNP in the 3= untranslated region and a
tandem repeat) and identified significant associations for the SNP
and for a haplotype including this SNP and 5-HTTLPR. Another
study, which examined behavioral measures in 87 adopted
children, found no association with the 5-HTTLPR overall, but in
a regression model including an interactive effect with parental
alcohol abuse, did identify a significant association (Cadoret et al
2003). When the 5-HTTLPR studies are combined, the pooled OR
for the long allele is 1.31 (95% CI 1.09–1.59).
Tryptophan Hydroxylase. Tryptophan hydroxylase (TPH) is
the rate-limiting enzyme in the synthesis of serotonin, and TPH
polymorphisms have been associated with aggression and im-
pulsivity (Manuck et al 1999). Two family-based studies exam-
ined the TPH gene in ADHD. One study of 69 Han Chinese trios
found no association with an SNP (A218C) in intron 7 (Tang et al
2001). A second study examined two SNPs among more than 350
Han Chinese youth with ADHD with and without learning
disability and their families (Li et al 2003). Although neither SNP
showed biased transmission individually, a haplotype composed
of the 218A and 6526G alleles seemed to be under-transmitted,
particularly for ADHD youth with learning disabilities. Thus,
further study of TPH might be warranted.
Other Candidate Genes
Acetylcholine Receptors: CHRNA4 and CHRNA7. The nic-
otinic acetylcholine receptors are ligand-gated ion channels
composed of five subunits, one of which is the ?-4 subunit
(CHRNA4), which has been examined in several studies in
ADHD. In a case–control analysis of ADHD symptom scores
among cases with a primary diagnosis of Tourette’s syndrome,
Comings et al (2000a) found evidence of association with an
intron 1 dinucleotide repeat polymorphism of the CHRNA4 gene.
Two family-based analyses of the gene provide conflicting
evidence. Kent et al (2001) found no significant evidence of
association with a Cfo1 restriction site polymorphism in exon 5 in
a study of 68 trios; however, a larger study of families ascertained
from a twin sample did find association between ADHD symp-
toms and CHRNA4 polymorphisms. Todd et al (2003) examined
seven SNPs encompassing exons 2 and 5, as well as haplotypes
of these markers. In addition to examining the phenotype of
DSM-IV ADHD, they used latent class analysis to derive two
phenotypic subtypes of ADHD symptoms: severe inattentive and
severe combined. Haplotype analysis indicated association be-
tween haplotypes of markers, including exon 2 and haplotypes
of exon 2 and 5 markers with DSM-IV ADHD, the DSM-IV
inattentive subtype, and the latent class inattentive subtype. After
correction for multiple comparisons, further analysis of the SNPs
in and around exon 2 revealed significant association only for
latent class inattentive ADHD with an intronic SNP (G/A) near
the exon/intron boundary at the 3= end of exon 2. The G allele
was over-transmitted, although this finding is based on only 20
In a family-based study of 206 trios, Kent et al (2001)
examined the gene that codes for the ?-7 subunit of the nicotinic
acetylcholine receptor family (CHRNA7). They did not find an
association between ADHD and any of three repeat polymor-
phisms close to the gene.
Glutamate Receptors. Two family-based studies have exam-
ined the GRIN2A gene, which codes a subunit of the N-methyl-
D-aspartate (NMDA) receptor. Glutamate and the NMDA receptor
have been implicated in cognition in both animal and human
studies; the GRIN2A gene is an appealing positional candidate
gene as well, located under a linkage peak at 16p13, previously
associated with ADHD (Smalley et al 2002). In a family-based
analysis of 238 families, an SNP in exon 5 was significantly
associated with ADHD (?2? 3.7, p ? .04); haplotypes including
additional SNPs were more weakly associated (Turic et al 2004).
Among 183 families, however, no evidence for association was
identified for this SNP (?2? .11, p ? .74) or three others (Adams
et al 2004).
Synaptosomal-Associated Protein 25. Several investigators
have used the coloboma mouse model to investigate the genetics
of ADHD. These mice have the coloboma mutation, a hemizy-
gous 2-centimorgan deletion of a segment on chromosome 2q.
The mutation leads to spontaneous hyperactivity, delays in
achieving complex neonatal motor abilities, deficits in hip-
pocampal physiology, which might contribute to learning defi-
ciencies, and deficits in Ca2?-dependent dopamine release in
dorsal striatum (Wilson 2000).
The coloboma deletion region includes the gene encoding
synaptosomal-associated protein 25 (SNAP-25), a neuron-spe-
cific protein implicated in exocytotic neurotransmitter release.
Hess et al (1992) suggested that interference with SNAP-25 might
mediate the mouse’s hyperactivity. As predicted by this hypoth-
esis, when these investigators bred a SNAP-25 transgene into
coloboma mice, their hyperactivity was reduced. Moreover,
other work suggested that reduced SNAP-25 expression leads to
striatal dopamine and serotonin deficiencies, which might be
involved in hyperactivity (Raber et al 1997). Treatment with
amphetamine (but not methylphenidate) reverses the mouse
hyperactivity (Wilson 2000). This latter finding is consistent with
the mechanism of action of these two stimulant drugs. Both treat
ADHD symptoms by blocking the dopamine transporter, but
only amphetamine cases reverse transport of dopamine through
the dopamine transporter, an effect that could compensate for
the reduced exocytotic dopamine release that might be a conse-
quence of the SNAP-25 mutation.
Hess et al (1995) tested the idea that the human homolog of
the mouse coloboma gene could be responsible for ADHD by
completing linkage studies of ADHD families, using markers on
human chromosome 20p11–p12, which is syntenic to the
coloboma deletion region. They used five families for which
segregation analysis suggested that ADHD was due to a sex-
influenced, single gene. But no significant linkage was detected
between ADHD and markers on chromosome 20p11–p12.
Four family-based studies of SNAP-25 examined two biallelic
1318 BIOL PSYCHIATRY 2005;57:1313–1323
S.V. Faraone et al
SNPs (T1069C and T1065G) separated by 4 bp at the 3= end of the
gene (Barr et al 2000a; Brophy et al 2002; Kustanovich et al
2003b; Mill et al 2004b). Barr et al (2000a) initially reported a
modest association of a haplotype formed by these two adjacent
SNPs. In the largest study of these SNPs, Kustanovich et al
(2003b) did not detect an association to these SNPs but noted a
slight predominance of paternal over-transmission of the haplo-
type implicated by Barr et al. But this finding was not supported
by Brophy et al ( 2002). Two of these studies, which seem to
examine overlapping samples, investigated a microsatellite in
intron 1, again with marginal evidence for an association (Mill et
al 2002, 2004b). In another study from the same group, eight
polymorphisms were investigated (two microsatellites and six
SNPs) (Mill et al 2004b). Three individual markers (SNP -2015
A/T located in the putative promoter region, a microsatellite in
intron 1, and 80609 G/A located in intron 7), were associated
with ADHD. Using a sliding window approach to investigating
the haplotypes, the investigators examined sets of three marker
haplotypes and detected stronger evidence for association than
for individual markers. Each of the SNAP-25 candidate gene
studies tested the same two adjacent SNPs, and there is little
agreement between them as to whether there is an association
and which allele is associated. Despite these conflicting results,
the pooled analyses for T1065G shows significant evidence for
an association with ADHD (OR ? 1.19; 95% CI 1.03–1.38).
Although twin studies demonstrate that ADHD is a highly
heritable condition, molecular genetic studies suggest that the
genetic architecture of ADHD is complex. The handful of ge-
nome-wide scans that have been conducted thus far show
divergent findings and are, therefore, not conclusive. In contrast,
the many candidate gene studies of ADHD have produced
substantial evidence implicating several genes in the etiology of
the disorder. As Table 1 shows, for the eight genes for which the
same variant has been studied in three or more case–control or
family-based studies, seven show significant evidence of associ-
ation with ADHD on the basis of the pooled OR: DRD4, DRD5,
DAT, DBH, 5-HTT, HTR1B, and SNAP-25.
The ORs for these associations range from 1.18 to 1.46. These
small ORs are consistent with the idea that the genetic vulnera-
bility to ADHD is mediated by many genes of small effect.
Moreover, they suggest one explanation for the frequent failure
to replicate initial reports of association: many individual studies
might be underpowered to find significant associations if the
effects are modest (Ioannidis et al 2001; Lohmueller et al 2003).
Several other factors mighty contribute to inconsistent results.
For example, studies in which case–control designs are used are
also vulnerable to identifying spurious associations because of
population admixture, a limitation not present in family-based
studies (Devlin et al 2001). Other studies examined different
ethnic groups, in which allele frequencies might differ, or used
different methods of ascertainment or phenotyping.
These small and sometimes inconsistent effects emphasize the
need for future candidate gene studies to implement strategies
that will provide enough statistical power to detect such small
effects. Such strategies, which have already been used for some
ADHD candidate genes, include meta-analyses, collaborative
studies with large sample sizes, or examination of refined
phenotypes that might reduce heterogeneity. Such refined phe-
notypes might be defined by examining disease subtypes de-
fined by symptoms (Curran et al 2003), illness persistence
(Faraone et al 2000b), or concurrent psychiatric diagnoses, such
as bipolar disorder (Faraone et al 1997b, 2001a; Wozniak et al
1995) or conduct disorder (Faraone 2001; Faraone et al 1991,
1997a). The use of measurements of neuropsychiatric function or
brain imaging might also aid in phenotypic refinement, as it has
been applied in schizophrenia, for example (Egan et al 2001).
Additionally, rather than examining a single polymorphism,
strategies that examine groups of polymorphisms spanning
haplotype blocks should provide a more complete assessment of
candidate genes. Finally, ecogenetic studies of gene–gene inter-
actions and gene–environment interactions have yielded impor-
tant leads in other psychiatric diagnoses, such as major depres-
sive disorder (see, e.g., Caspi et al 2003), and will likely be
necessary to further clarify the mechanisms by which risk genes
interact with each other and with nongenetic factors to yield the
behavioral phenotype of ADHD.
This work was supported by National Institute of Health
grants R01HD37694, R01HD37999, and R01MH66877 to SVF,
K23MH67060 to RHP, and K08MH66072 to AED.
Aspects of this work were presented at the conference, “Ad-
vancing the Neuroscience of ADHD,” February 28, 2004 in
Boston, Massachusetts. The conference was sponsored by the
Society of Biological Psychiatry through an unrestricted educa-
tional grant from McNeil Consumer & Specialty Pharmaceuti-
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Table 1. Significant Pooled Odds Ratios for Gene Variants Examined in Three or More Case–Control or Family-
Gene Study DesignPooled OR95% CI
Dopamine D4 Receptor (exon III VNTR, 7-repeat)
Dopamine D4 Receptor (exon III VNTR, 7-repeat)
Dopamine D5 Receptor (CA repeat, 148 bp)
Dopamine Transporter (VNTR, 10-repeat)
Dopamine ?-Hydroxylase (Taql A)
Serotonin Transporter (5-HTTLPR long)
OR, odds ratio; CI, confidence interval; VNTR, variable number of tandem repeats.
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