American Journal of Medical Genetics (Neuropsychiatric Genetics) 114:154 ±158 (2002)
Further Evidence for the Association Between
Attention-De®cit/Hyperactivity Disorder and the
Dopamine-b-Hydroxylase Gene
Tatiana Roman,1* Marcelo Schmitz,2 Guilherme V. Polanczyk,2 Mariana Eizirik,2 Luis A. Rohde,2
and Mara H. Hutz1
1
Departamento de GeneÂtica, Instituto de BiocieÃncias, Universidade Federal do Rio Grande do Sul, Porto Alegre,
Rio Grande do Sul, Brazil
2
ServicËo de Psiquiatria da InfaÃncia e AdolesceÃncia, Departamento de Psiquitria e Medicina Legal,
Hospital de ClõÂnicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
Attention-de®cit/hyperactivity disorder
(ADHD) is a very common and heteroge-
neous psychiatric disorder of childhood
with marked inattentive, hyperactive, and
impulsive symptoms. The DBH gene, the
locus that encodes the enzyme dopamine-b-
hydroxylase (DbH), seems to be an impor-
tant candidate gene for association studies,
since DbH catalyzes the conversion of dopa-
mine to norepinephrine. The aim of this
study was to test for association between the
DBH gene and ADHD in a sample of 88
Brazilian nuclear families. Haplotype rela-
tive risk (HRR) analysis of the DBH TaqI
restriction site polymorphism showed a
preferential transmission of the TaqI A2
allele in our whole ADHD sample (x2 ˆ 3.61,
one-tailed P ˆ 0.03). The signi®cant effect of
the A2 allele was stronger when only
families with no ADHD parental diagnosis
were considered (x2 ˆ 5.42, one-tailed
P ˆ 0.01). Our results suggest a contribution
of this gene to ADHD susceptibility, par-
tially replicating previous ®ndings that
have demonstrated an association between
the DBH TaqI A2 allele and ADHD.
ß 2002 Wiley-Liss, Inc.
Grant sponsor: Programa de Apoio a NuÂcleos de ExceleÃncia;
Grant sponsor: Financiadora de Estudos e Projetos; Grant
sponsor: Conselho Nacional de Desenvolvimento Cientõ®co e
TecnoloÂgico; Grant sponsor: FundacËaÄo de Amparo aÁ Pesquisa do
Estado do Rio Grande do Sul; Grant sponsor: Fundo de Incentivo aÁ
Pesquisa e Eventos±Hospital de ClõÂnicas de Porto Alegre.
*Correspondence to: Tatiana Roman, Departamento de GeneÂt-
ica, Instituto de BiocieÃncias±UFRGS, Caixa Postal 15053, 91501-
970 Porto Alegre, RS, Brazil. E-mail: tatiana.roman@ufrgs.br
Received 31 July 2001; Accepted 10 October 2001
ß 2002 Wiley-Liss, Inc.
DOI 10.1002/ajmg.10194
KEY WORDS: ADHD; dopamine-b-hydro-
xylase; DBH gene; associa-
tion; susceptibility
INTRODUCTION
Attention-de®cit/hyperactivity disorder (ADHD) is a
very common and heterogeneous psychiatric disorder of
childhood with marked inattentive, hyperactive, and
impulsive symptoms. Although the precise causes of
ADHD are not well understood, family, twin, and
adoption studies strongly support a role for genetic
components in its etiology [Thapar et al., 1999]. These
observations have motivated a great number of mole-
cular investigations. Initial association studies have
focused on genes that regulate dopamine neurotrans-
mission, based on the dopamine theories for ADHD
[Levy, 1991; Castellanos, 1997]. Dopamine transporter
gene (DAT1) and dopamine D4 receptor gene (DRD4)
have been the most investigated genes of the dopami-
nergic system. Although there are several reports of
association with this disorder, the data are con¯icting
[Swanson et al., 2000; Faraone et al., 2001]. More
recently, pharmacological, biochemical, and neuropsy-
chological ®ndings have suggested that noradrenergic
imbalances are likely important in ADHD [Pliszka
et al., 1996; Barkley, 1997; Biederman and Spencer,
1999]. Despite the increasing body of literature that
suggests a noradrenergic involvement in the disorder,
few association studies have investigated the effect of
norepinephrine genes [Comings et al., 1996, 1999; Barr
et al., 2001; Xu et al., 2001]. These studies have
examined different a adrenergic receptors genes, and
the results are also inconsistent.
Since changes in both dopaminergic and noradrener-
gic networks could be underlying the pathophysiology
of ADHD, dopamine-b-hydroxylase (DbH), the enzyme
that catalyzes the conversion of dopamine to norepi-
nephrine, may be implicated in the development of the
disorder. This enzyme is expressed within the secretory
vesicles of norepinephrine and epinephrine-producing
 Association Between ADHD and the DBH Gene
neurons and neurosecretory cells. DbH is also present
in human plasma and cerebrospinal ¯uid (CSF), where
its activity and level are highly stable and correlated.
Serum and CSF DbH levels seem to be under a strong
genetic control. Both the major genetic determinant of
these DbH biochemical phenotypes and the structural
gene encoding DbH (DBH locus) are tightly linked to
the ABO locus on chromosome 9q34 [Cubells et al.,
1998]. This evidence suggests that DBH is a quantita-
tive trait locus (QTL) exerting a large effect on DbH
levels. Recent data, showing associations between
allelic variation at DBH and plasma DbH activity in
three distinct human populations, strongly support
this conclusion [Zabetian et al., 2001]. Since DbH body
¯uid levels have already been reported to be lower in
patients suffering from a variety of psychiatric condi-
tions, such as schizophrenia, psychotic depression
(reviewed in Cubells et al. [1997]), and conduct disorder
(reviewed in Comings et al. [1996]), it is possible that
similar alterations might be related to ADHD. There-
fore, the DBH locus seems to be an important candidate
gene in association studies with this disorder.
Several polymorphisms have been described in this
locus, all of which are correlated with the levels of DbH
activity [Wei et al., 1997; Cubells et al., 1998, 2000;
Zabetian et al., 2001]. However, the effect on the DbH
levels of the TaqI restriction site polymorphism
[D'Amato et al., 1989; Wu et al., 1997] is not completely
understood. The possibility that this variant might be
associated to ADHD was investigated by Comings et al.
[1996, 1999] in a sample of probands with Tourette
syndrome. In both studies, an additive effect of the
DBH gene on continuous ADHD scores was detected.
The presence of at least one TaqI B1 allele (absence of
the TaqI site) was associated with the highest ADHD
scores. However, the affected subjects did not seem
the most appropriate for ADHD molecular studies,
since this disorder was assessed as a comorbidity of
Tourette syndrome. The DBH TaqI polymorphism was
also investigated by Daly et al. [1999] in a sample of
ADHD children and their parents, using the haplotype-
based haplotype relative risk method (HHRR). They
found an association with the TaqI (present) DBH allele
(A2) in their sample that was stronger for families with
at least one parent who was retrospectively diagnosed
as ADHD. These authors also detected linkage dis-
equilibrium of the DBH gene with ADHD in combined
type probands, when the transmission disequilibrium
test (TDT) was applied. Even though the studies from
Comings et al. [1996, 1999] and Daly et al. [1999] have
probably examined the same TaqI site of the 5th intron,
both the different nomenclature of the alleles (A and B)
and the characteristics of the samples prevent compar-
isons among their ®ndings.
The aim of this study was to test for association
between the DBH TaqI polymorphism and ADHD in a
sample of nuclear families obtained through the
affected children. Subgroups of probands de®ned by
the combined type of the disorder and the presence of
familial history of ADHD were also evaluated. Based on
the literature, we hypothesized that the DBH TaqI A2
allele is associated with ADHD.
155
MATERIALS AND METHODS
Subjects
Patients were drawn from the ADHD outpatient
clinic at the Child and Adolescent Psychiatric Division
of Hospital de ClõÂnicas de Porto Alegre (HCPA). A
consensus diagnosis of ADHD, based on the fourth
edition of the Diagnostic and Statistical Manual,
revised (DSM-IV) [American Psychiatric Association,
1994] criteria, was achieved through a three-stage
process, described in detail previously [Roman et al.,
2001]. Brie¯y, it comprised: a) evaluation with a semi-
structured interview (Schedule for Affective Disorders
and Schizophrenia for School-Age Children, Epidemio-
logical Version±K-SADS-E) [Orvaschel, 1985] modi®ed
to assess DSM-IV criteria and applied to the parents by
trained research assistants; b) discussion of each
diagnosis derived through the K-SADS-E in a clinical
committee chaired by one of us (L.A.R.); and c) clinical
evaluation of ADHD and comorbid conditions using
DSM-IV criteria by a child psychiatrist. In addition to
this diagnostic procedure, parents completed the Child
Behavior Checklist (CBCL) [Achenbach, 1991], a be-
havior symptom checklist that assesses children's
behavioral problems and social competencies. For pro-
bands who were attending school, teachers completed
the Attention Problems scale of the CBCL-Teacher
Report Form (TRF) [Achenbach, 1991], which includes
items related to ADHD in the classroom. Cognitive
evaluation based on vocabulary and block design
subtests of the Weschler Intelligence Scale-third edi-
tion (WISC-III) was applied by a trained psychologist
to estimate the probands overall IQ [Weschler, 1991].
Information about socio-demographic data was system-
atically collected from the parents. The parents were
also evaluated for past (childhood) or present diagnosis
of ADHD by a child psychiatrist, using the ADHD
module from the K-SADS-E, modi®ed to assess DSM-IV
criteria. Familiality was de®ned as the presence of at
least one parent with a positive diagnosis of ADHD.
Parents who ful®lled all criteria except age-of-onset
of impairment criterion were included in the parental
ADHD group to increase its sample size, since retro-
spective recall of the exact moment when the symptoms
began is frequently imprecise, and recent research do
not support the validity of this criterion [Barkley and
Biederman, 1997; Rohde et al., 2000].
This investigation was approved by the Ethical
Committee of HCPA and by the Coordinating Commit-
tee of the Graduate Program in Genetics and Molecular
Biology of the Federal University of Rio Grande do Sul.
Parents provided written informed consent and pro-
bands provided verbal assent to participate.
Genotyping
High molecular weight genomic DNA was extracted
from whole blood by a salting out procedure [Miller
et al., 1988]. The TaqI polymorphism in intron 5 of the
DBH gene was ampli®ed by the polymerase chain
reaction (PCR) using the primers and conditions
described by Daly et al. [1999]. The 464 base pair (bp)
156 Roman et al.
PCR fragments were digested with TaqI for two hr at
658C, and the digested products were separated using
2% agarose gels. TaqI identi®ed a bi-allelic polymorph-
ism with an undigested band of 464 bp (allele A1) and
two bands of 300 bp and 164 bp (allele A2). A 100 bp
ladder was used to score the alleles. We used the allele
terminology ``A1'' (TaqI absent) and ``A2'' (TaqI pre-
sent), as used by Daly et al. [1999], to avoid confusion.
Statistical Analyses
Allele frequencies were estimated by counting, and
the Hardy-Weinberg equilibrium was calculated based
on these allele frequencies by the goodness-of-®t Chi-
square test. The haplotype relative risk (HRR) statis-
tics [Terwilliger and Ott, 1992] was performed for
family-based association analysis. This method was
chosen to avoid any potential effect of population
strati®cation. Both trios composed by father, mother,
and affected child and parent/proband pairs were
included in the HRR analyses. Heterozygote parent/
proband pairs with the same genotype were excluded
because the transmission status of parental alleles
could not be determined [Schaid and Sommer, 1994;
Curtis and Sham, 1995]. As we had a previous hypo-
thesis of association, a one-tailed signi®cance level of
5% was used for each test.
RESULTS
We genotyped 88 ADHD probands and 155 parents
assessed from 67 mother, father, and affected child
trios, and 21 parent/child pairs. Whereas most of
the probands presented DSM-IV ADHD combined type
(77%), 16% of the probands were of the inattentive
type, and 7% of the hyperactive/impulsive type of
the disorder. The age ranged between four and 17
years, and males accounted for 87% of the sample.
Eighty-six percent of the subjects were from European
descent. Only 25% of the probands did not meet
diagnostic criteria for other psychiatric disorders. The
most common comorbid condition was oppositional
de®ant disorder (41%), but anxiety disorders (15%),
conduct disorder (14%), and bipolar disorder (8%) also
co-occurred with ADHD. The mean IQ in the subjects
was 91. Forty-one percent of the families had ADHD
parental diagnosis.
The allele frequencies in the unrelated Caucasian
parents were 0.40 for the A1 allele and 0.60 for the A2
TABLE I. HRR Analyses of DBH A2 Allele for the Whole Sample of ADHD Probands,* for Families With ADHD Parental Diagnosis
(FH‡),{ and for Families With no Familial History of ADHD (FH ){
Full sample
A2 A1 Total
T 99 50 149
NT 83 66 149
Total 182 116 298
*
82 patients from 67 trios and 15 parent/child pairs; w2 ˆ 3.61, one-tailed P ˆ 0.03.
{
30 patients from 23 trios and 7 parent/child pairs; w2 ˆ 0.04, one-tailed P ˆ 0.42.
{
44 patients (only trios); w2 ˆ 5.42, one-tailed P ˆ 0.01.
T, transmitted; NT, not transmitted.
allele. The genotype frequencies in these individuals
were 0.12, 0.56, and 0.32 for A1A1, A1A2, and A2A2
individuals, respectively. These frequencies were under
Hardy-Weinberg equilibrium.
We used the HRR method to test for the biased
transmission of the DBH TaqI alleles from parents to
offspring. The transmissions for the HRR tests could
be determined unambiguously in 82 families. The data
are presented in Table I. The HRR analysis in the whole
sample con®rmed the association between the DBH
gene and ADHD previously described by Daly et al.
[1999]. The A2 allele was signi®cantly more trans-
mitted than not transmitted (99 to 83; one-tailed
P ˆ 0.03). Preferential transmission was also observed
when the inattentive and the hyperactive/impulsive
type probands were excluded from this analysis (one-
tailed P ˆ 0.03, data not shown). This was not an
unexpected ®nding because the great majority of the
sample (77%) was of the ADHD combined type. In an
attempt to further replicate the ®ndings from Daly et al.
[1999], sub-sets of probands de®ned by the presence
and the absence of familial history of ADHD were also
evaluated (Table I). No preferential transmission was
observed in the families with ADHD parental diagnosis
(one-tailed P ˆ 0.42). However, the signi®cant associa-
tion with the A2 allele was maintained in families
where there was no familial history of the disorder
because it was transmitted 62 times and not trans-
mitted 47 times (one-tailed P ˆ 0.01). These ®ndings
differ from those reported by Daly et al. [1999]
regarding similar sub-groups of ADHD families.
DISCUSSION
In the present study, an association between the
DBH TaqI A2 allele and ADHD was detected in a
sample of Brazilian ADHD families, suggesting a role
for this gene in the susceptibility for this disorder. The
effect was similar when both the whole sample and only
DSM-IV ADHD combined type probands were consid-
ered. A greater in¯uence of the A2 allele was observed
when families with no ADHD parental diagnosis were
evaluated. Moreover, there was no association with the
DBH gene in the families that had at least one parent
with a positive diagnosis of ADHD.
The ®nding regarding our whole sample con®rms the
previous report from Daly et al. [1999]. Our study can
be considered a true replication of their work, since we
used the same family-based method and laboratory
FH‡ FH
A2 A1 Total A2 A1 Total
31 22 53 62 26 88
32 21 53 47 41 88
63 43 106 109 67 176
 Association Between ADHD and the DBH Gene
procedures and a similar clinical assessment. The
particular effect of the DBH gene in the combined type
probands reported by Daly et al. [1999] was also seen in
our combined type patients. As already noted, the effect
of the A2 allele in this sub-set was similar to that
observed in our whole sample, which simply could be
due to the predominance of this type of the disorder.
However, it is possible that the DBH gene affects the
two ADHD domains, i.e., inattention and hyperactivity/
impulsivity. Both dopamine and norepinephrine sys-
tems seem to underlie the pathophysiology of ADHD,
probably with distinct in¯uences on each set of
symptoms [Pliszka et al., 1996; Barkley, 1997]. Since
the DbH enzyme converts dopamine to norepinephrine,
coupling both systems, this enzyme could be considered
a link between the two ADHD domains. Thus, a
pronounced effect of the DBH locus in samples where
both inattentive and hyperactive/impulsive symptoms
are overrepresented would not be surprising.
Despite the HRR results in the total sample, our
®ndings regarding the sub-sets of probands de®ned by
the presence or absence of ADHD parental diagnosis
differed from those of the study conducted by Daly et al.
[1999]. In our sample, a stronger effect of the A2 allele
was observed only in families with no ADHD parental
diagnosis. Daly et al. [1999] found the stronger
association with the DBH gene in familial cases,
suggesting that this gene could confer risk, particularly
for a familial subtype of ADHD. However, it is
important to note that there was a trend for prefer-
ential transmission of the A2 allele in their families
with no ADHD parental diagnosis. It is possible that
such a trend would reach signi®cance in larger
samples; thus, an in¯uence of the DBH gene in this
sub-set of families would also be evidenced. Further-
more, the criteria for ADHD parental diagnosis used by
Daly et al. [1999] was different from the criteria applied
by our group, which could account for some hetero-
geneity regarding familial cases in both studies. It is
important to note that 60% of our sample had no ADHD
parental diagnosis, which increases the possibility for
detecting an association with the DBH A2 allele in this
group of families. The ®nding of a stronger association
of the DBH A2 allele in our non-familial cases suggests
that this gene could be conferring a general risk for
traits related to ADHD, common to several ``types'' and
sub-sets of probands suffering from this disorder. This
hypothesis is further supported by the data from our
combined type probands. A similar explanation was
suggested by Daly et al. [1999] for the DRD5 gene,
which had a greater in¯uence in their non-familial
cases. The possibility of genetic heterogeneity in ADHD
with more general genetic in¯uences for non-familial
cases has been also considered elsewhere [Palmer et al.,
1999].
The effect of the DBH TaqI polymorphism on DbH
activity is not clear. Although the functional signi®-
cance of this enzyme in ADHD still needs to be clari®ed,
the replication of a previously reported association
between the DBH TaqI polymorphism and ADHD in an
independent sample supports the contribution of this
gene to the susceptibility for this disorder. Further
157
investigations are needed to clarify the exact involve-
ment of the DBH gene in ADHD (familial or non-
familial?) and to understand the functional signi®cance
of this polymorphism. The search for other polymorph-
isms within the gene that could be in linkage disequili-
brium with the TaqI RSP increasing the susceptibility
to ADHD is also open for further investigations.
ACKNOWLEDGMENTS
The authors thank Drs. ClaÂudia M. Szobot, Natalia
Soncini, SõÂlvia O. Martins, and Silza Tramontina and
the staff of the AmbulatoÂrio de TerapeÃuticas ClõÂnicas,
ServicËo de Psiquiatria da InfaÃncia e AdolesceÃncia,
Departamento de Psiquiatria e Medicina Legal, Hospi-
tal de ClõÂnicas de Porto Alegre for help in data
collection, and to Maria IneÃs S. Martins for technical
assistance.
REFERENCES
Achenbach TM. 1991. Manual for the child behavior checklist. Burlington:
University of Vermont. 288 p.
American Psychiatric Association. 1994. Diagnostic and statistical manual
of mental disorders, 4th ed. Washington, DC: American Psychiatric
Association. 340 p.
Barkley RA. 1997. Behavioral inhibition, sustained attention, and execu-
tive functions: constructing a unifying theory of ADHD. Psychol Bull
121:65±94.
Barkley R, Biederman J. 1997. Towards a broader de®nition of the age-of-
onset criterion for attention-de®cit/hyperactivity disorder. J Am Acad
Child Adolesc Psychiatry 36:1204±1210.
Barr CL, Wigg K, Zai G, Roberts W, Malone M, Schachar R, Tannock R,
Kennedy JL. 2001. Attention-de®cit/hyperactivity disorder and the
adrenergic receptors a1C and a2C. Mol Psychiatry 6:334±337.
Biederman J, Spencer T. 1999. Attention-de®cit/hyperactivity disorder
(ADHD) as a noradrenergic disorder. Biol Psychiatry 46:1234±1242.
Castellanos FX. 1997. Neuroimaging of attention-de®cit/hyperactivity
disorder. Child Adolesc Psychiat Clin North Am 6:383±411.
Comings DE, Wu S, Chiu C, Ring RH, Gade R, Ahn C, Mac-Murray JP,
Dietz G, Muhleman D. 1996. Polygenic inheritance of Tourette
syndrome, stuttering, attention-de®cit/hyperactivity, conduct, and
oppositional de®ant disorder: the additive and subtractive effect of
the three dopaminergic genes±DRD2, DBH and DAT1. Am J Med
Genet 67:264±288.
Comings DE, Gade-Andavolu R, Gonzalez N, Blake H, Wu S, Mac-Murray
JP. 1999. Additive effect of three noradrenergic genes (ADRA2A,
ADRA2C, DBH) on attention-de®cit/hyperactivity disorder and learn-
ing disabilities in Tourette syndrome subjects. Clin Genet 55:160±172.
Cubells JF, Kobayashi K, Nagatsu T, Kidd KK, Kidd JR, Calafell F,
Kranzler HR, Ichinose H, Gelernter J. 1997. Population genetics of a
functional variant of the dopamine b-hydroxylase gene (DBH). Am J
Med Genet 74:374±379.
Cubells JF, van Kammen DP, Kelley ME, Anderson GM, O'Connor DT,
Price LH, Malison R, Rao PA, Kobayashi K, Nagatsu T, Gelernter J.
1998. Dopamine b-hydroxylase: two polymorphisms in linkage dis-
equilibrium at the structural gene DBH associate with biochemical
phenotypic variation. Hum Genet 102:533±540.
Cubells JF, Kranzler HR, McCance-Katz E, Anderson GM, Malison RT,
Price LH, Gelernter J. 2000. A haplotype at the DBH locus, associated
with low plasma dopamine b-hydroxylase activity, also associates with
cocaine-induced paranoia. Mol Psychiatry 5:56±63.
Curtis D, Sham PC. 1995. A note on the application of the transmission
disequilibrium test when a parent is missing. Am J Hum Genet 56:811±
812.
D'Amato T, Leboyer M, Malafosse A, Samolyk D, Lamouroux A, Junien C,
Mallet J. 1989. Two TaqI dimorphic sites at the human b-hydroxylase
locus. Nucleic Acids Res 17:5871.
Daly G, Hawi Z, Fitzgerald M, Gill M. 1999. Mapping susceptibility loci in
attention-de®cit/hyperactivity disorder: preferential transmission of
158 Roman et al.
parental alleles at DAT1, DBH and DRD5 to affected children. Mol
Psychiatry 4:192±196.
Faraone SV, Doyle AE, Mick E, Biederman J. 2001. Meta-analysis of the
association between the dopamine D4 gene 7-repeat allele and attention-
de®cit/hyperactivity disorder. Am J Psychiatry 158:1052±1057.
Levy F. 1991. The dopamine theory of attention-de®cit/hyperactivity
disorder (ADHD). Aust N Z J Psychiatry 25:277±283.
Miller SA, Dykes DD, Polesky HF. 1988. A simple salting out procedure for
extracting DNA from human nucleated cells. Nucleic Acids Res
16:1215.
Orvaschel H. 1985. Psychiatric interviews suitable for use in research with
children and adolescents. Psychopharmacol Bull 21:737±744.
Palmer CGS, Bailey JN, Ramsey C, Cantwell D, Sinsheimer JS,
Del'Homme M, McGough J, Woodward JA, Asarnow R, Asarnow J,
Nelson S, Smalley SL. 1999. No evidence of linkage or linkage
disequilibrium between DAT1 and attention-de®cit/hyperactivity dis-
order in a large sample. Psychiatr Genet 9:157±160.
Pliszka SR, McCracken JT, Maas JW. 1996. Catecholamines in attention-
de®cit/hyperactivity disorder: current perspectives. J Am Acad Child
Adolesc Psychiatry 35:264±272.
Rohde LA, Biederman J, Zimmerman H, Schmitz M, Martins S,
Tramontina S. 2000. Exploring ADHD age-of-onset criterion in
Brazilian adolescents. Eur Child Adolesc Psychiatry 9:212±218.
Roman T, Schmitz M, Polanczyk G, Eizirik M, Rohde LA, Hutz MH. 2001.
Attention-de®cit/hyperactivity disorder: a study of association with
both the dopamine transporter gene and the dopamine D4 receptor
gene. Am J Med Genet 105:471±478.
Schaid DJ, Sommer SS. 1994. Comparison of statistics for candidate-gene
association studies using cases and parents. Am J Hum Genet 55:402±
409.
Swanson JM, Flodman P, Kennedy J, Spence MA, Moyzis R, Schuck S,
Murias M, Moriarity J, Barr C, Smith M, Posner M. 2000. Dopamine
genes and ADHD. Neurosci Biobehav Rev 24:21±25.
Terwilliger J, Ott J. 1992. A haplotype-based ``haplotype relative risk''
approach to detecting allelic associations. Hum Hered 42:337±346.
Thapar A, Holmes J, Poulton K, Harrington R. 1999. Genetic basis of
attention de®cit and hyperactivity. Br J Psychiary 174:105±111.
Wei J, Ramchand CN, Hemmings GP. 1997. Possible control of dopamine b-
hydroxylase via a codominant mechanism associated with the poly-
morphic (GT)n repeat at its gene locus in healthy individuals. Hum
Genet 99:52±55.
Weschler DI. 1991. Examiner's manual: Weschler intelligence scale for
children, 3rd ed. New York: Psychological Corporation. 294 p.
Wu S, Muhleman D, Comings D. 1997. PCR ampli®cation of the TaqI B1/B2
polymorphism at intron 5 of the dopamine b-hydroxylase gene.
Psychiatr Genet 7:39±40.
Xu C, Schachar R, Tannock R, Roberts W, Malone M, Kennedy JL, Barr CL.
2001. Linkage study of the a2A-adrenergic receptor in attention-de®cit/
hyperactivity disorder. Am J Med Genet 105:159±162.
Zabetian CP, Anderson GM, Buxbaum SG, Elston RC, Ichinose H, Nagatsu
T, Kim KS, Kim CH, Malison RT, Gelernter J, Cubells JF. 2001. A
quantitative-trait analysis of human plasma-dopamine b-hydroxylase
activity: evidence for a major functional polymorphism at the DBH
locus. Am J Hum Genet 68:515±522.