Interaction of dopamine transporter genotype with prenatal smoke exposure on ADHD symptoms.
ABSTRACT To demonstrate that children homozygous for the 10-repeat allele of the common dopamine transporter (DAT1) polymorphism who were exposed to maternal prenatal smoke exhibited significantly higher hyperactivity-impulsivity than children without these environmental or genetic risks.
We performed a prospective longitudinal study from birth into early adulthood monitoring the long-term outcome of early risk factors. Maternal prenatal smoking was determined during a standardized interview with the mother when the child was 3 months old. At age 15 years, 305 adolescents participated in genotyping for the DAT1 40 base pair variable number of tandem repeats polymorphism and assessment of inattention, hyperactivity-impulsivity, and oppositional defiant/conduct disorder symptoms with the Kiddie-Sads-Present and Lifetime Version.
There was no bivariate association between DAT1 genotype, prenatal smoke exposure and symptoms of attention deficit hyperactivity disorder. However, a significant interaction between DAT1 genotype and prenatal smoke exposure emerged (P = .012), indicating that males with prenatal smoke exposure who were homozygous for the DAT1 10r allele had higher hyperactivity-impulsivity than males from all other groups. In females, no significant main effects of DAT1 genotype or prenatal smoke exposure or interaction effects on any symptoms were evident (all P > .25).
This study provides further evidence for the multifactorial nature of attention deficit hyperactivity disorder and the importance of studying both genetic and environmental factors and their interaction.
- SourceAvailable from: Wendong Li[Show abstract] [Hide abstract]
ABSTRACT: Trait theories of leadership have documented the role of individual characteristics in affecting leadership. Twin studies have further revealed significant genetic effects on leadership role occupancy. In the era of genomics, the current research examines how a dopamine transporter gene, DAT1, is involved in genetic influences on leadership role occupancy. Study 1 found DAT1 10-repeat allele to negatively relate to proactive personality, which in turn was positively associated with leadership role occupancy. The negative indirect effect was significant, but the overall relationship between this gene and leadership was not. In addition to replicating Study 1's findings using a nationally representative sample, Study 2 revealed another countervailing mechanism: DAT1 was positively related to (moderate) rule breaking, which was positively associated with leadership role occupancy. Consistent findings across the two studies suggest that the pathways linking specific genes to leadership are complex and a middle-ground approach is needed in such multidisciplinary investigations.The Leadership Quarterly 01/2015; · 2.70 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: ADHD and incontinence are common childhood disorders which co-occur at much higher rates than expected by chance. The aim of this review was to provide an overview both of the comorbidity of nocturnal enuresis (NE), daytime urinary incontinence (DUI) and faecal incontinence (FI) in children with ADHD; and, vice versa, of the co-occurrence of ADHD in children with NE, DUI and FI. Most clinical studies have focussed on the association of ADHD and NE. Population-based studies have shown that children with DUI have an even greater risk for ADHD than those with NE. While children with FI have the highest overall comorbidity rates of psychological disorders, these are heterogeneous with a wide range of internalising and externalising disorders-not necessarily of ADHD. Genetic studies indicate that ADHD and NE, DUI and FI do not share the same genetic basis. The comorbidity is conferred by non-genetic factors. Possible aetiological and pathogenetic links between ADHD and incontinence are provided by neurophysiological, imaging and pharmacological studies. The co-occurrence has clinical implications: children with ADHD and NE, DUI and FI are more difficult to treat, show lower compliance and have less favourable treatment outcomes for incontinence. Therefore, both groups of disorders have to be assessed and treated specifically.European Child & Adolescent Psychiatry 07/2014; 24(2). · 3.55 Impact Factor
- Kindheit und Entwicklung 01/2014; 23(1):23-33. · 6.00 Impact Factor
Interaction of Dopamine Transporter Genotype with Prenatal Smoke
Exposure on ADHD Symptoms
KATJA BECKER, MD, MAHHA EL-FADDAGH, MD, MARTIN H. SCHMIDT, MD, PHD, GÜNTER ESSER, PHD, AND MANFRED LAUCHT, PHD
Objective To demonstrate that children homozygous for the 10-repeat allele of the common dopamine transporter (DAT1)
polymorphism who were exposed to maternal prenatal smoke exhibited significantly higher hyperactivity-impulsivity than
children without these environmental or genetic risks.
Study design We performed a prospective longitudinal study from birth into early adulthood monitoring the long-term
outcome of early risk factors. Maternal prenatal smoking was determined during a standardized interview with the mother
when the child was 3 months old. At age 15 years, 305 adolescents participated in genotyping for the DAT1 40 base pair
variable number of tandem repeats polymorphism and assessment of inattention, hyperactivity-impulsivity, and oppositional
defiant/conduct disorder symptoms with the Kiddie-Sads-Present and Lifetime Version.
Results There was no bivariate association between DAT1 genotype, prenatal smoke exposure and symptoms of attention
deficit hyperactivity disorder. However, a significant interaction between DAT1 genotype and prenatal smoke exposure
emerged (P ? .012), indicating that males with prenatal smoke exposure who were homozygous for the DAT1 10r allele had
higher hyperactivity-impulsivity than males from all other groups. In females, no significant main effects of DAT1 genotype or
prenatal smoke exposure or interaction effects on any symptoms were evident (all P > .25).
Conclusions This study provides further evidence for the multifactorial nature of attention deficit hyperactivity disorder and
the importance of studying both genetic and environmental factors and their interaction. (J Pediatr 2008;152:263-9)
restlessness, and impulsivity and is associated with severe social consequences and sub-
stantial health care costs.2
The exact etiologic pathways of ADHD are still unknown, but a considerable
heritability with genetic factors contributing 65% to 90% of the phenotypic variation in
the population is beyond dispute.3 Many molecular genetics studies found associations
with various dopamine genes, including the human dopamine transporter (DAT1)
gene.4-6 The DAT1 gene has a polymorphic 40 base pair (40 bp) variable number of
tandem repeats (VNTR) sequence located in the 3=-untranslated region (3= UTR) on
chromosome 5p15.3.7 This polymorphism varied between 3 and 13 copies, of which the
common 10-repeat allele was associated with an increased expression of the transporter.8-10
However, association studies on DAT1 polymorphisms and ADHD yielded con-
flicting results.11-13 One reason for this inconsistency may be that environmental factors
associated with ADHD, such as prenatal and perinatal complications, low birth weight,
and prenatal exposure to different drugs,3,14,15 may moderate the gene effect. Smoking in
pregnancy was a risk factor for long-term intellectual and development disabilities in the
offspring in general,16-18 and for ADHD in particular.14,19,20 Behavior genetics studies
suggest a role for gene-environment interactions,21 and it is hypothesized that fetal
adaptation to an unfavorable intrauterine environment might increase susceptibility to
chronic diseases or disorders.14 Kahn et al22 investigated the independent and joint effects
ttention deficit hyperactivity disorder (ADHD) is the most common, often persistent behavior disorder in childhood,
with rates of 3% to 5% among school-aged children.1 ADHD, a severe impair-
ment of psychological development resulting from a high level of inattention,
3= Untranslated region
Dopamine transporter polymorphism
DSM Diagnostic and Statistical Manual of Mental
Oppositional defiant disorderODD
From the Department of Child and Ad-
olescent Psychiatry and Psychotherapy,
Central Institute of Mental Health (K.B.,
M.S., M.L.), Mannheim, the Department
of Child and Adolescent Psychiatry and
Psychotherapy, Clinical Center Karlsruhe
(M.E.), Karlsruhe, and the Department of
Psychology, Division of Clinical Psychology,
University of Potsdam (G.E.), Potsdam,
Supported by grants from the Deutsche
Forschungsgemeinschaft (DFG) as part of
the Special Research Program SFB 258 “In-
dicators and Risk Models of the Genesis
and Course of Mental Disorders” at the
University of Heidelberg, Germany.
Submitted for publication Sept 6, 2006; last
revision received May 14, 2007; accepted
July 2, 2007.
Reprint requests: Katja Becker, MD, De-
partment of Child and Adolescent Psychi-
atry and Psychotherapy, Central Institute of
Mental Health, PO Box 12 21 20, D-68072
Mannheim, Germany. E-mail: katja.becker@
0022-3476/$ - see front matter
Copyright © 2008 Mosby Inc. All rights
of the common DAT1 polymorphism and maternal pre-
natal smoking on behavior problems among 5-year-olds in a
prospective longitudinal study. Children with 2 copies of the
high-risk 10-repeat allele of DAT1 (homozygous: DAT
?/?) were compared with all other children (heterozygous:
DAT?/? or homozygous for the 9-repeat allele: DAT
?/?). The children with prenatal smoke exposure and DAT
?/? had significantly more hyperactive-impulsive (P ? .01)
and oppositional symptoms (P ? .001) than all other groups.
Additionally, among children with DAT ?/? or ?/?, pre-
natal smoke exposure was associated with higher oppositional
scores compared with those without prenatal tobacco expo-
Notwithstanding the fact that the biologic mechanisms
underlying this gene-environment interaction are still not well
understood, the study by Kahn et al22is one of a small number
of studies in human beings to date that have ascertained that
environmental factors moderate the effect of genes on ADHD,
representing a first step in need of replication. Brookes et al23
examined the interaction of DAT1 and maternal substance
use during pregnancy, a gene-environment interaction for
tobacco use was not confirmed. Neuman et al24showed no
significant interaction for the DSM-IV ADHD phenotype
between prenatal smoking and the DAT1 10-repeat allele.
However, the odds for a diagnosis of ADHD were 1.8 times
greater in twins whose genotype at the DAT1 contained the
9-repeat allele and whose mother smoked during pregnancy.
Given the conflicting results of these studies and the
relevance of understanding this gene-environment interaction
as a possibility for prevention of ADHD, this study attempts
to further examine the association between prenatal smoking
and the DAT1 gene with ADHD and ODD/CD symptoms
in a longitudinal study monitoring children from a high-risk
This investigation was conducted as part of the ongoing
Mannheim Study of Risk Children, a prospective longitudinal
study from birth into early adulthood following the long-term
outcome of early risk factors. A total of 384 infants from the
Rhine-Neckar region of Germany born between 1986 and
1988 were recruited consecutively according to a 2-factorial
design intended to enrich and control the risk status of the
sample. To control for confounding effects of family environ-
ment and infant medical status, only firstborn children with
singleton birth, German-speaking parents, and no severe
physical handicaps, obvious genetic defects, or metabolic dis-
eases were included. The children were primarily white and
from a disadvantaged family background. Additional details
on this sample have been reported previously.25,26Assess-
ments were conducted at regular intervals from the age of 3
months onward. The current investigation included 305 ad-
olescents (146 male, 159 female) who participated in the
15-year assessment and for whom genetic data were available.
Of the original sample of 384 participants, 18 (4.7%) were
excluded because of severe handicaps (neurologic impairment
or IQ ? 70), 26 (6.7%) were dropouts, and 35 (10.4%)
refused to participate in blood sampling. The study was
approved by the ethics committee of the University of Hei-
delberg, and all participants gave their written informed con-
Assessment of psychiatric disorders in 15-year-olds was
conducted with the Schedule for Affective Disorders and
Schizophrenia in School Age Children K-SADS-PL (Kid-
die-Sads-Present and Lifetime Version) by Kaufman et al.
The K-SADS is a widely used structured diagnostic interview
completed independently by parents and adolescents. The
assessment tool was recently translated into German27and a
considerable body of reliability and validity data has been
published for the English version. Informants were asked
about the presence or absence of symptoms during the 12-
month period before assessment. Symptoms were rated on a
3-point scale (0 ? absent, 1 ? present below threshold, 2 ?
present above threshold), and, after dichotomization (0 vs 1,
2), were counted if they were endorsed by either the parent or
the adolescent. Symptoms of ADHD and oppositional defi-
ant/conduct disorder (ODD/CD) were assigned to domains
as given in DSM-IV, and the number of symptoms present
was calculated. Three symptom scores indexing severity of
inattention (9 items, M ? 1.82, SD ? 2.67, ? ? .9),
hyperactivity-impulsivity (9 items, M ? 1.13, SD ? 2.14, ?
? .88), and ODD/CD symptoms (23 items, M ? 3.5, SD ?
3.97, ? ? .86) were formed (all ? from this study). ADHD
symptom scores were strongly correlated (r ? .75, P ? .0001),
and correlations with ODD/CD symptoms were moderate
(inattention: r ? .51; hyperactivity-impulsivity: r ? .57, all P
Maternal prenatal smoking was determined during a
standardized interview with the mother at the 3-month as-
sessment. Eighty-two (26.9%) of the mothers who reported
any regular smoking during pregnancy were assigned to the
prenatal smoking group. Postnatal smoking of the parents was
recorded within the framework of a standardized interview
conducted with the mother at all assessment waves. A post-
natal smoking score was formed counting the number of time
points during child development at which the mother or
father reported regular smoking.
Psychosocial adversity was assessed according to an
“enriched” family adversity index as proposed by Rutter and
Quinton.28The index measures the presence of 11 adverse
family factors, covering characteristics of the parents, the
partnership, and the family environment during a period of 1
year before birth (M ? 1.96; SD ? 2.05; range, 0-7). A
description of the study sample and definitions of the index
items are presented in Table I (available at www.jpeds.com).
Information was derived from a standardized parent interview
conducted at the 3-month assessment.
264 Becker et alThe Journal of Pediatrics • February 2008
Five-milliliter blood samples were collected from ado-
lescents, and genomic DNA was isolated with the Qiamp
(Qiagen, Chatsworth, CA) DNA extraction kit. The DAT1
40bp VNTR polymorphism was genotyped by polymerase
chain reaction, as reported elsewhere.7The frequency of the
10-repeat (?) was 73.9%. Frequencies of the DAT ?/?,
?/? and ?/? genotypes were 55.4%, 37.4%, and 7.2%,
respectively. The distribution of genotypes was in accordance
with Hardy-Weinberg equilibrium (P ? .656). The allele
frequencies for the ? and ? variants, as well as the frequen-
cies for the genotypes were similar to those from other pub-
lished studies of Caucasian populations.10There were no
significant differences in allele frequencies according to pre-
natal smoking, psychosocial adversity and sex. Consistent with
the work of Kahn et al,22adolescents homozygous for the pos-
tulated high-risk 10-repeat allele (DAT ?/?) were compared
with all other adolescents (DAT ?/? or DAT ?/?).
To test bivariate associations of the group variables
(DAT1 genotype, prenatal smoke exposure) with control
variables and symptom scores, ?2tests and F-tests/t-tests
were computed as appropriate. To further examine genotype-
phenotype associations, multiple linear regression analyses
were performed with the ADHD and ODD/CD symptom
scores as outcome variables. DAT1 genotype and prenatal
smoke exposure were the predictor variables, adjusting for the
effects of psychosocial adversity, postnatal smoke exposure,
and sex, which are other potentially associated variables. To
examine gene-environment effects, an interaction term was
added (DAT1 ? prenatal smoking). Because of previous
findings that had revealed sex-specific associations,4,29inter-
action terms with sex were also included. Because there was a
significant DAT1 ? Prenatal smoking ? Sex interaction
effect on the hyperactivity-impulsivity score (F(1295)? 5.33,
P ? .022), data were analyzed separately by sex.
Demographic and clinical characteristics for males and
females in the genotype and prenatal smoking groups are
presented in Table II. There were no significant differences
between DAT1 groups with regard to age, psychosocial ad-
versity, postnatal smoke exposure, and maternal smoking dur-
ing pregnancy. Prenatal smoking groups differed significantly
regarding psychosocial risk and postnatal smoking, with the
prenatally exposed participants showing higher psychosocial
adversity (F(1301)? 35.64, P ? .001) and higher postnatal
smoke exposure (F(1301)? 158.56, P ? .001). Furthermore,
no significant differences according to sex were observed on
any of these variables. In bivariate analyses with ADHD and
ODD/CD symptoms (Table III), no significant differences
between DAT1 groups on any of the symptom scores were
observed. However, smoke exposure groups differed signifi-
cantly in terms of ODD/CD symptoms, with higher scores in
males exposed to prenatal smoking than in those not exposed
(t(144)? ?2.07, P ? .04).
Results of linear regression analyses predicting ADHD
and ODD/CD symptoms in 15-year-old males are summa-
rized in Table IV. With one exception, no significant main
effect of DAT1 genotype or prenatal smoke exposure was
observed on any of the symptom scores. However, there was
a significant interaction between DAT1 genotype and prena-
tal smoke exposure with regard to hyperactivity-impulsivity
(P ? .012), accompanied by compensatory main effects of
prenatal smoking (P ? .024) and DAT1 (P ? .066) in the
opposite direction. In addition, a marginally significant inter-
action emerged with regard to ODD/CD symptoms (P ? .1),
Table II. Demographic and clinical characteristics of males and females grouped by DAT1 genotype and by
prenatal smoke exposure
DAT1 genotypePrenatal smoke exposure
Males (n ? 146)
(n ? 108)
Males (n ? 146) Females (n ? 159)Females (n ? 159)
(n ? 82)
(n ? 64)
(n ? 87)
(n ? 72)
(n ? 38)
(n ? 44)
(n ? 115)
Age: mean (SD)
score*: mean (SD)
exposure:‡ n (%)
22(26.8%) 16(25%) 21(24.1%) 23 (31.9%)————
4.05 (3.45) 3.78 (3.69)4.17 (3.4)3.35 (3.12)7.34 (2.75)†2.73 (2.97)7(2.35)†2.57 (2.73)
*“Enriched” family adversity index as proposed by Rutter and Quinton28measuring the presence of 11 adverse family factors covering characteristics of the parents, the partnership,
and the family environment during a period of 1 year before birth.
†P ? .001 significant difference between prenatal exposure groups.
‡Any regular maternal tobacco use during pregnancy assessed at the 3-month interview.
§Number of time points during child development at which the mother and/or father reported regular smoking.
Interaction of Dopamine Transporter Genotype with Prenatal Smoke Exposure on ADHD Symptoms265
and the interaction with regard to inattention was not signif-
icant (P ? .784). Interaction effects were independent of
psychosocial adversity and postnatal smoke exposure (hyper-
active-impulsive: P ? .019; ODD/CD: P ? .031).
Subsequent analysis revealed that hyperactive-impulsive
symptom scores (Figure) were significantly higher in males
from the prenatally exposed group who were homozygous for
the 10-repeat allele (DAT ?/?) than in all other groups
(Fisher PLSD, all P ? .01). The difference between the DAT
?/? or ?/? children with smoke exposure and those with-
out exposure was not significant (P ? .8 and P ? .59). Similar
results were obtained for ODD/CD symptoms: males with
prenatal smoke exposure carrying the risk genotype (DAT
?/?) exhibited higher scores than those carrying other ge-
notypes or without exposure (Fisher PLSD, P ? .011 [DAT
?/? or ?/?, not exposed], P ? .021 [DAT ?/?, not
exposed], and P ? .102 [DAT ?/? or ?/?, exposed],
In females, neither significant main effects of DAT1
genotype or prenatal smoke exposure nor interaction effects
on any of the symptom scores were found (all P ? .25). The
only predictor reaching significance for all outcome variables
(all P ? .025) was psychosocial adversity, demonstrating that
females from adverse family backgrounds exhibited more
symptoms than those from less disadvantaged environments.
Table III. Inattention, hyperactive-impulsive and ODD/CD symptoms in males and females grouped by
DAT1 genotype and prenatal smoke exposure: Means and SD (in parentheses)
DAT1 genotype Prenatal smoke exposure
(n ? 159)
(n ? 108)
(n ? 146)
(n ? 159)
(n ? 146)
(n ? 146)
(n ? 159)
(n ? 115)
(n ? 82)
(n ? 64)
(n ? 87)
(n ? 72)
(n ? 38)
(n ? 44)
4.35 (4.52)3.48 (3.83)3.23 (3.84) 2.86 (3.45)5.18 (4.4)*3.55 (4.11)3.95 (4.14)2.72 (3.41)
*P ? .05 significant difference between prenatal exposure groups among males.
Table IV. Multiple regression analyses testing the
effect of a DAT1 genotype by prenatal smoking
interaction on ADHD and ODD/CD symptom
scores in 15-year-old males
Postnatal smoke exposure
Prenatal smoke exposure
DAT1?/? ? prenatal
Postnatal smoke exposure
Prenatal smoke exposure
DAT1?/? ? prenatal
Postnatal smoke exposure
Prenatal smoke exposure
DAT1?/? ? prenatal
Note: the table presents the final models with control variables, main effects and
interactions entered simultaneously.
b ? unstandardized regression coefficient, ? ? standardized regression coefficient.
Figure. Mean hyperactive-impulsive score in male adolescents grouped by
DAT1 genotype and prenatal smoke exposure. Values are expressed as
means ? SEM.
266Becker et alThe Journal of Pediatrics • February 2008
There is evidence of an environmentally moderated risk
for ADHD, suggesting that effects are dependent on genetic
susceptibility, operating through gene-environment interac-
tion. One example of a nature-nurture interplay was described
by Kahn et al,22indicating that children whose mothers had
smoked during pregnancy in combination with a specific
DAT ?/? genotype showed significantly more hyperactive-
impulsive and oppositional symptoms. This study represented
a first step in ascertaining how genes and environment may
interact to influence child behavior problems. In this study,
we tried to replicate this finding in a longitudinal sample of
305 adolescents, participating in the Mannheim Study of Risk
Children since infancy. Consistent with Kahn et al22and oth-
ers,11-13no bivariate association was found between DAT1 ge-
notype and symptoms of ADHD. However, a significant in-
teraction between DAT1 10-repeat ?/? genotype and
prenatal smoke exposure was obtained for hyperactive-impul-
sive symptoms, revealing higher scores in adolescents from
the prenatally exposed group who were homozygous for the
10-repeat allele (DAT ?/?) than in all other groups. The
interaction was controlled for confounding variables such as
postnatal smoke exposure or psychosocial adversity. In con-
trast to Kahn et al,22the interaction was restricted to males
and was not evident in females.
However, sex-specific effects of exposure to environ-
mental adversity have been reported previously. In line with
the observed sex difference in this study, Biederman et al30
found greater levels of environmental adversity associated
with a greater risk for ADHD, with more detrimental effects
observed in boys than in girls. In animal studies, developmen-
tal programming often has differing effects in males and
females, with responses to exposures differing according
to the sex of the fetus.31Some human studies have also
detected varying behavioral effects of prenatal smoke exposure
in boys versus girls.32The sex differences may reflect the
distinctive sexual dimorphism of the brain, including hor-
monal and structural factors, which emerge during develop-
ment. Whereas these authors32suggest that prenatal exposure
could potentiate different genetic vulnerabilities for boys and
girls, others,19looking specifically at ADHD, have not doc-
umented sex-specific effects. However, none of these studies
has considered the potential role of DAT1 in sex-specific
effects of prenatal smoke exposure. Accordingly, Ernst et al33
stated that sex-specific vulnerability to the deleterious effects
of in utero exposure to nicotine is underexplored and deserves
Brookes et al23were unable to establish an interaction
between DAT1 and smoking during pregnancy but demon-
strated an interaction with maternal alcohol use during preg-
nancy. However, the authors conceded that their study was
underpowered to identify small interaction effects. Neuman
et al24found that the DAT1 and the dopamine D4 receptor
gene polymorphisms contributed independently to the mater-
nal smoking by child genotype interaction, speculating that
there might be a gene-gene interaction present as well.
Up to now, the biologic mechanisms underlying the
described gene-environment interaction are not well under-
stood. Several indirect and direct effects of maternal tobacco
smoking during pregnancy are known, with nicotine produc-
ing anorexigenic, hypoxic, vascular, and placental effects that
can adversely and indirectly affect fetal development.33In
developing, immature systems, receptor stimulation interacts
with genes that control cell differentiation, and changes in
gene expression may affect the processes of cell replication,
differentiation, function, and death.33In animal models, in
utero exposure to nicotine affected multiple neurotransmitter
pathways. The dopamine system was hypoactive and hypore-
sponsive to exogenous nicotine stimulation after prenatal ex-
posure to nicotine. Further long-lasting alterations of dopa-
mine activity in rat pups receiving chronic nicotine infusions
during pregnancy were also reported.33Finally, increased re-
ceptor binding of dopamine receptors was demonstrated in
offspring prenatally exposed to nicotine, which may reflect a
compensatory up-regulation of these receptors.
A possible biologic explanation for this finding is that
the DAT1 polymorphism affects gene expression. This hy-
pothesis is supported by neuroimaging studies showing higher
striatal DAT1 availability in adults with ADHD and an effect
of nicotine on DAT1 availability.34However, evidence has
been controversial. Whereas in Korean children diagnosed
with ADHD, higher DAT1 availability in single photon
emission computed tomography was observed,35a study of
adult patients from a Caucasian sample failed to replicate this
finding.36Sex effects may play an additional role, as Lavalaye
et al37reported higher DAT1 density in females in a study
with healthy volunteers. Van Dyck et al38found in healthy
Caucasians an effect of genotype on DAT1 availability in
striatum, with carriers of the DAT1 9-repeat allele showing
significantly higher striatal DAT1 availability than did the
homozygotes for 10-repeat allele. The combination of studies
on gene-environment interaction (eg, DAT1 and smoking
exposure in utero) with neuroimaging studies, controlling for
age, sex, and different comorbid conditions in large sample
sizes will bring us a step forward in understanding the un-
derlying conditions of ADHD and associated symptoms.
Limitations and Strengths
Compared with the study of Kahn et al,22our study had
some strengths, such as the bigger sample size and an ethnic
homogenous study sample (?99% of European descent). Fur-
thermore, the K-SADS used in our study for assessment of
ADHD and ODD symptoms represents another advantage
because of its reliance on DSM-IV criteria. Another strength
of this study is the more detailed assessment of possible
confounding psychosocial factors, with the family adversity
index of Rutter and Quinton.28
However, there are also several limitations. Associations
with dopamine genes were sex-dependent and confined to
males.4,29,39In addition, as in most studies in the field, the use
of parental report to assess exposure status constitutes a lim-
itation that can only be overcome by the use of biomarkers.
Interaction of Dopamine Transporter Genotype with Prenatal Smoke Exposure on ADHD Symptoms267
Although Kahn et al22investigated preschool children, our
sample included adolescents. This is of some importance,
because symptoms and prevalence of ADHD are reported
to change substantially from childhood into adolescence.
Whereas the 3-month prevalence of ADHD in 9- to 10-year-
olds is 2.2%, it decreases in 15-year-olds to 0.4%.40It can be
suggested that adolescents with symptoms of ADHD or
ODD/CD may represent the more severe cases, with higher
hyperactivity/impulsivity and more delinquent and aggressive
A limitation of both studies is that symptoms of
ADHD and ODD/CD instead of DSM-IV diagnosis were
examined because of a too-small number of children fulfilling
diagnostic criteria. Furthermore, it is possible that the ob-
served interaction could be based not on the factors studied,
but rather on other, unknown factors, meaning that maternal
smoking might only be a marker for maternal ADHD, for
example, or for other important genes transmitted to the
child.22Finally, other gene variants in linkage disequilibrium
with the DAT1 polymorphism studied may actually play the
key role in a DAT1 by smoking interaction.
Several association studies of the DAT1 gene and
ADHD have reported conflicting results. This inconsistency
may be due to the fact that prenatal smoke exposure, which
has not been measured in most of the studies, is an important
cofactor or trigger for children who are genetically susceptible
to ADHD. For further scientific study designs in ADHD, it
is recommended that both environmental (such as prenatal
smoke exposure or family adversity) and genetic factors
should be taken into account because of the multifactorial
nature of ADHD. Our findings further strengthen the im-
portance of prevention programs aimed at smoking preven-
tion and smoking cessation in women planning pregnancy in
general and in pregnant women in particular.
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Interaction of Dopamine Transporter Genotype with Prenatal Smoke Exposure on ADHD Symptoms269
Table I. Description of the study sample according to psychosocial adversity and definition
of adversity items
1 Low educational level of a parent
3 Parental psychiatric disorder
Parent without completed school education or without skilled job training
More than 1 person a room or size of housing ?50 m2
Moderate to severe disorder according to DSM-III-R criteria (interviewer
rating, kappa ? .98)
Institutional care of a parent/more than 2 changes of parental figures until the
age of 18 or history of parental delinquency
Low quality of partnership in 2 of 3 areas (harmony, communication,
emotional warmth) (interviewer rating, kappa ? 1)
Age of a parent ?18 years at child birth or relationship between parents
lasting less than 6 months at time of conception
At child birth
An abortion was seriously considered
Lack of friends and lack of help in child care (interviewer rating, kappa ? .71)
4 History of parental broken home
5 Marital discord
6 Early parenthood25.2
7 One-parent family
8 Unwanted pregnancy
9 Poor social integration and
support of parents
10 Severe chronic difficulties
11 Poor coping skills of a parent
Affecting a parent lasting more than 1 year (interviewer rating, kappa ? .93)
Inadequate coping with stressful events of the past year (interviewer rating,
kappa ? .67)
269.e1 Becker et al The Journal of Pediatrics • February 2008