Nicotine & Tobacco Research, Volume 14, Number 2 (February 2012) 229–233
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symptoms to influence initial reactions to cigarette smoking.
Given that an initial pleasant reaction to cigarettes increases risk
for lifetime smoking, these results add to a growing body of liter-
ature that suggests that ADHD symptoms increase risk for smoking
and should be accounted for in genetic studies of smoking.
Substantial research supports the heritability of smoking onset
and dependence (Vink, Willemsen, & Boomsma, 2005), but the
specific genetic pathways that confer risk have yet to be identi-
fied. Genetic factors putatively linked to neurotransmission of
dopamine and serotonin may influence sensitivity to nicotine
(e.g., Marks, Stitzel, & Collins, 1989; Perkins et al., 2008), and
there is evidence that reactions to initial smoking experiences
predict later regular smoking (Chen et al., 2003; DiFranza
et al., 2004; O’Connor et al., 2005; Pomerleau, Pomerleau, &
Namenek, 1998; Riedel et al., 2003), suggesting that specific genes
may influence the onset of nicotine dependence by influencing
initial responses to smoking.
Symptoms of attention deficit hyperactivity disorder (ADHD)
represent another risk factor for smoking. Individuals with
ADHD are significantly more likely to smoke and start smoking
earlier compared with those without ADHD (Lambert &
Hartsough, 1998; Milberger et al., 1997; Molina & Pelham, 2003;
Pomerleau et al., 1995). Candidate gene studies have identified
overlap among genetic markers associated with both ADHD
and smoking phenotypes (e.g., DRD2, DRD4, DAT1, CHRNA4),
suggesting that several common neurobiological mechanisms
Introduction: Initial reactions to cigarettes predict later regular
smoking. Symptoms of attention deficit hyperactivity disorder
(ADHD) have also been shown to increase smoking risk and
may moderate the relationship between genotype and smoking.
We conducted an exploratory study to assess whether ADHD
symptoms interact with genetic variation to predict self-reported
initial reactions to smoking.
Methods: Participants were a subsample of 1,900 unrelated
individuals with genotype data drawn from the National Longi-
tudinal Study of Adolescent Health (Add Health), a nationally
representative sample of adolescents followed from 1995
to 2002. Linear regression was used to examine relationships
among self-reported ADHD symptoms, genotype, and self-
reported initial reactions to cigarettes (index scores reflecting
pleasant and unpleasant reactions).
Results: Polymorphisms in the DRD2 gene, SLC6A4 gene,
and among males, the MAOA gene interacted with retrospec-
tive reports of ADHD symptoms in predicting pleasant initial
reaction to cigarettes. Polymorphisms in the CYP2A6 gene
and, among females, the MAOA gene interacted with retro-
spective reports of ADHD symptoms in predicting unpleasant
initial reaction to cigarettes. No main effect for any of these
polymorphisms was observed nor were any interactions with
DRD4 and DAT genes.
Conclusions: These findings suggest that genotypes associated
with monoamine neurotransmission interact with ADHD
A Preliminary Analysis of Interactions
Between Genotype, Retrospective ADHD
Symptoms, and Initial Reactions to
Smoking in a Sample of Young Adults
L. Cinnamon Bidwell, Ph.D.,1 Melanie E. Garrett, M.S.,2 F. Joseph McClernon, Ph.D.,3,4 Bernard F. Fuemmeler, M.P.H,
Ph.D.,5,6 Redford B. Williams, M.D.,3 Allison E. Ashley-Koch, Ph.D.,2 & Scott H. Kollins, Ph.D.3
1 Division of Behavioral Genetics, Department of Psychiatry and Human Behavior, Warren Alpert School of Medicine, Brown University,
2 Center for Human Genetics, Department of Medicine, Duke University Medical Center, Durham, NC
3 Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC
4 Durham Veterans Affairs Medical Center, VISN 6 Mental Illness Research, Education, and Clinical Center, Durham Veterans Affairs
Medical Center, Durham, NC
5 Department of Community and Family Medicine, Duke University Medical Center, Durham, NC
6 Department of Psychology and Neuroscience, Duke University Medical Center, Durham, NC
Corresponding Author: L. Cinnamon Bidwell, Ph.D., Department of Psychiatry and Human Behavior, Warren Alpert School
of Medicine, Brown University, 1 Hoppin Street, Providence, RI 02903, USA. Telephone: 401-793-8396; Fax: 401-444-8742;
Received December 3, 2010; accepted May 16, 2011
ADHD, genes, and early smoking
may give rise to this comorbidity (McClernon & Kollins, 2008).
Thus, it is possible that certain genotypes, in the presence of
ADHD symptoms, work together to enhance risk for smoking.
In a previous study, we assessed relationships among retro-
spectively reported ADHD symptoms, genotype, and risk for
lifetime regular smoking in the same sample used in the current
study (McClernon & Kollins, 2008; McClernon et al., 2008).
Carriers of the DRD2 Taq1 A2/A2 genotype with six or more
hyperactivity–impulsivity symptoms were almost twice as likely
to have a history of smoking as individuals carrying one or two
copies of the A1 allele. Significant Genotype × ADHD Symptom
interactions were also observed for polymorphisms in the
MAOA and DRD4 genes. This study was the first evidence of
ADHD symptom by genotype interactions as predictors of any
smoking outcome and suggested that putative smoking geno-
types may interact with ADHD symptoms to increase risk for
lifetime smoking. These interactions between genotype, ADHD,
and lifetime risk for smoking, in combination with the previ-
ously identified link between initial reactions to cigarettes and
risk for lifetime smoking, suggest that genetic factors may inter-
act with ADHD symptoms to alter risk of nicotine dependence
by influencing initial reactions to cigarettes.
This study used a large epidemiological sample of young adults
(n = 1,900) and evaluated ADHD symptoms as a potential mod-
erator of the relationship between candidate gene variation and ini-
tial reactions to cigarettes. Given previously identified relationships
between lifetime smoking, ADHD, and monoamine neurotrans-
mission (e.g., McClernon et al., 2008), we hypothesized that candi-
date genes associated with monoamine regulation would interact
with ADHD symptoms to influence initial reactions to cigarettes.
Participants were a subsample from the National Longitudinal
Study of Adolescent Health (Add Health), a large nationally
representative study of adolescent health behaviors (http://www.
cpc.unc.edu/projects/addhealth). Details regarding the design
and data collection have been described elsewhere (Harris et al.,
2003; Resnick et al., 1997).
The current study included the same sample (n = 1900) reported
on in our previous paper (McClernon et al., 2008) and included
respondents who (a) provided genetic data and (b) reported
having smoked at least one cigarette in their lifetime. See Table 1
for demographic information on these individuals.
DNA collection, extraction, and genotyping methods have been
described previously (for further details, see www.cpc.unc.edu/
projects/addhealth). Polymorphisms in the following six genes
were genotyped: the rs28363170 of dopamine transporter
(DAT) gene, a 44-bp ins/del polymorphism (5HTTLPR) in the
promoter region of the serotonin transporter (SLC6A4) gene,
the rs1800497 of Taq1A polymorphism of the dopamine D2 receptor
Table 1. Demographics, Genotype, Attention
Deficit Hyperactivity (ADHD) Symptoms,
Conduct Disorder (CD) Symptoms, and
Initial Reactions for Participants (n = 1,900)
Mean age at Wave III
Any seven repeat
No seven repeat
Mean CD symptoms
Pleasant initial reactions
Unpleasant initial reactions
Note. Values are numbers of subjects with percentages, except where
means with SDs are noted. CYP2A6 = the rs1801272 of the cytochrome
P-450-A6 gene; DAT = the rs28363170 of dopamine transporter gene;
DRD2 = the rs1800497 of Taq1A polymorphism of the dopamine D2
receptor gene; DRD4 = a 48-bp VNTR polymorphism of the dopamine
D4 receptor gene; MAOA = a 30-bp VNTR in the promoter of the
monoamine oxidase A gene; SLC6A4 = a 44-bp ins/del polymorphism
(5HTTLPR) in the promoter of the serotonin
transporter gene; HI = hyperactive-impulsive; IN = inattentive.
aNs vary slightly for each gene due to missing genotype information
on some individuals.
(DRD2) gene, a 48-bp VNTR polymorphism of the dopamine
D4 receptor (DRD4) gene, a 30-bp VNTR in the promoter of
the monoamine oxidase A (MAOA) gene, and the rs1801272 of
the cytochrome P-450-A6 (CYP2A6) gene.
Nicotine & Tobacco Research, Volume 14, Number 2 (February 2012)
Initial Reactions to Smoking
In Wave III of Add Health, participants were asked to retrospec-
tively report on a 4-point scale of intensity (0 = none, 1 = slight,
2 = moderate, 3 = intense) the extent to which they experienced
nine sensations during their first smoking experiences. Sum-
mary scores from these nine items create three scales (Hu, Davies,
& Kandel, 2006; Pomerleau et al., 1998): (a) dizziness; (b) pleas-
ant symptoms (pleasant sensations, relaxation, pleasurable
rush, or buzz); (c) unpleasant symptoms (unpleasant sensa-
tions, nausea, coughing, difficulty inhaling, and heart
pounding). Consistent with prior studies (Hu et al., 2006),
these scales were grouped into pleasant (Cronbach’s alpha =
.78) and unpleasant (Cronbach’s alpha = .79) initial reac-
tions index scores for the analysis.
Participants retrospectively reported on DSM-IV ADHD symp-
toms in childhood (between 5 and 12 years) using a 4-point
scale: never or rarely, sometimes, often, or very often. One DSM-IV
impulsivity symptom (“often interrupts or intrudes on others”)
was not included in the retrospective ADHD section. Thus, our
analyses included responses to nine inattentive (IN) and eight
hyperactive–impulsive (HI) symptoms. A symptom was consid-
ered present if it was experienced often or very often (Murphy &
Barkley, 1996). For our primary analyses, individuals were clas-
sified into one of two groups for each symptom domain based on
the number of symptoms reported at a level of “often” or “very
often”. The six-symptom cutoff was chosen to be consistent
with DSM-IV ADHD criteria requiring the presence of six or
more symptoms from either the IN or the HI symptom domains.
Statistical analyses were conducted using SAS-callable SUDAAN
(version 8.0) software. SUDAAN allows for control of survey
design effects of individuals clustered in a sampling unit of
school and stratification of geographic region. Linear regressions
were used to determine whether candidate genotypes predicted
the pleasant or unpleasant initial reaction index scores. The
specific genotypes were grouped for analysis according to the
extant literature and are listed in Supplementary Table 1 (Hu
et al., 2006; Munafo et al., 2004; Todd et al., 2005). Separate
models were evaluated for each polymorphism using the Taylor
Linearization method. The models were constructed to include
main effects of the polymorphism, ADHD symptoms (IN or
HI), and the interaction between polymorphisms and ADHD
symptoms in predicting both pleasant and unpleasant initial
reactions. Age, race, parental education level, and the presence
or absence of CD were included as covariates.
Results for all models are listed in Supplementary Table 1. No
main effects were observed for any of the genotypes predicting
either pleasant or unpleasant initial reactions. The following
Genotype × ADHD Symptom interactions were found:
We observed a significant Taq1A DRD2 × HI interaction
predicting pleasant initial reactions (p = .03), whereby, among
those individuals who had at least six HI symptoms, those who
were homozygous for the A2 allele reported significantly higher
initial pleasant reactions to cigarettes (predicted marginal means
for those with at least six HI symptoms: any A1 = 1.81 vs. A2/A2 =
3.16, p = .01).
For the MAOA 30-bp VNTR polymorphism, males and females
were analyzed independently because this gene is located on the
X chromosome. In males, we found a significant MAOA × IN
interaction (p = .01). Among males who had at least six IN
symptoms, we found higher pleasant reactions among those
who were hemizygous for the active form of the gene (predicted
marginals for those with at least six IN symptoms: inactive
variant = 1.5 vs. active variant = 3.1, p = .02). In females, we
found a significant MAOA × IN interaction (p = .004). Among
females who had at least six IN symptoms, the presence of the
homozygous active genotype predicted increased unpleasant
reactions compared with those whose genotype included at least
one copy of the inactive form of the gene (predicted marginals
for those with at least six IN symptoms: one or more inactive =
1.57 vs. homozygous active = 6.12, p = .004).
With regard to the SLC6A4 44-bp ins/del, we found a significant
SLC6A4 × HI interaction predicting pleasant initial reactions
(p = .02). Among those individuals who had at least six HI
symptoms, the presence of the s/s genotype was associated with
higher initial pleasant reactions to cigarettes (predicted mar-
ginals for those with at least six HI symptoms: s/s = 4.09 vs. s/l =
1.87 vs. l/l = 2.79, p = .02).
With regard to the rs1801272 polymorphism of CYP2A6, we
found the following interactions. Among those individuals who
had at least six IN symptoms, the presence of a 1/2 genotype was
associated with fewer initial unpleasant reactions to cigarettes
(predicted marginals for those with at least six IN symptoms:
1/2 = 1.77 vs. 1/1 = 3.35, p = .05). Similarly, among those indi-
viduals who had at least six HI symptoms, the presence of a 1/2
genotype was associated with fewer initial unpleasant reactions
to cigarettes (predicted marginals for those with at least six HI
symptoms: 1/2 = 2.11 vs. 1/1 = 3.57, p = .02).
To further validate our results, we repeated our analyses
employing the Jackknife bootstrapping method in SUDAAN.
The p values were slightly smaller using the Jackknife estimation
method, but the interaction effects remained statistically signif-
icant (see Supplementary Table 1).
The present study assessed relationships among retrospectively
reported ADHD symptoms, genotype, and initial reactions to
smoking in a U.S. sample of young adults. Significant Genotype ×
ADHD Symptom interactions were observed for variants of the
DRD2, MAOA, SLC6A4, and CYP2A6 genes. This is the first ev-
idence of ADHD symptom by genotype interactions as pre-
dictors of initial reactions to cigarettes, which are thought to
predict the likelihood of future smoking.
ADHD, genes, and early smoking
The present study extends our previous finding of significant
relationships between DRD2 and MAOA genotypes, self-
reported ADHD symptoms, and lifetime smoking (McClernon
et al., 2008) by suggesting that these same genetic variants influ-
ence initial reactions to cigarettes in the presence of ADHD
symptoms. Thus, it may be that one of the mechanisms under-
lying the association among ADHD symptoms, genotype, and
regular smoking is the effect that the Gene × Symptom interac-
tion has on initial reactions to smoking experiences.
The present study is limited by factors related to the measure-
ment of the dependent and independent variables. First, initial
reactions to smoking were assessed retrospectively. While this is
a limitation commonly faced by studies of initial reactions to
cigarettes, studies examining initial reactions more proximal to
actual early smoking experiences would be beneficial. Second,
ADHD symptoms were assessed using retrospective self-report.
Although this approach to characterizing childhood ADHD
symptoms has been shown to be both reliable and valid, it
is, nevertheless, not ideal (Kollins, McClernon, & Fuemmeler,
2005; Ward, Wender, & Reimherr, 1993; Zucker et al., 2002).
Third, the genetic data available for analysis were limited as only
six polymorphisms across six candidate genes were available
for analysis. Moreover, the frequency of some of the genetic
variants in the current study (e.g., variants of the MAOA and
CYP2A6 genes) is very low and, when considered along with the
ADHD symptom variables, produced very low cell counts.
Fourth, a large number of statistical tests were conducted in the
present analyses, which may have inflated the risk of Type I
error. However, the risk of Type I error was likely mitigated to a
large degree by our theory-based approach and by the fact that
the genes examined have been studied previously in the context
of smoking or ADHD. Therefore, replication is needed to fur-
ther substantiate these findings.
Despite these limitations, this study is strengthened by the fact
that it is the first study to systematically examine the influence
of genetic variation and ADHD symptoms on initial reactions
to smoking. The associations found with initial reactions to
cigarettes and interactions with specific genotypes (e.g., DRD2,
SLC6A4, CYP2A6, and MAOA) and ADHD symptoms add to a
growing body of literature examining Genotype × Trait inter-
actions to predict smoking outcomes (Audrain-McGovern
et al., 2004; Breslau et al., 1998; de Leon et al., 1995; Lerman
et al., 2000) Taken together, these findings indicate that the
relationship between genetic risk factors and smoking may be
further qualified by psychiatric symptoms and personality traits
that increase risk for smoking. The present study provides
an important step toward identifying psychiatric and genetic
determinants of smoking initiation and progression among
adolescents, and additional work is needed to identify the neu-
robiological and molecular genetic mechanisms that underlie
these unique associations.
Supplementary Table 1 can be found online at http://www.ntr.
Portions of this work were supported by the following
grants: NS049067 (AEA-K, MEG, SHK), T32DA16184 (LCB),
K07CA124905 (BFF), R01DA030487 (BFF), K24DA023464
(SHK), K23 DA017261 (FJM), and P01 HL36587 (RBW). This
research uses data from the National Longitudinal Study of
Adolescent Health (Add Health) project, a program project
designed by J. Richard Udry, Ph.D., principal investigator, and
Peter Bearman, Ph.D., and funded by grant P01 HD31921
from the National Institute of Child Health and Human Devel-
opment, Bethesda, MD, to the Carolina Population Center,
University of North Carolina at Chapel Hill, with cooperative
funding participation by the National Institutes of Health,
the U.S Department of Health and Human Services, and the
National Science Foundation.
Declaration of Interests
Redford Williams holds U.S. patent 7,371,522 on the use of the
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