A common genetic variant in the 15q24 nicotinic
acetylcholine receptor gene cluster (CHRNA5–
CHRNA3–CHRNB4) is associated with a reduced
ability of women to quit smoking in pregnancy
Rachel M. Freathy1, Susan M. Ring2, Beverley Shields3, Bruna Galobardes2, Beatrice Knight3,
Michael N. Weedon1, George Davey Smith2,4, Timothy M. Frayling1and Andrew T. Hattersley3,?
1Genetics of Complex Traits, Peninsula Medical School, Institute of Biomedical and Clinical Science, Magdalen Road,
Exeter EX1 2LU, UK,2Department of Social Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol
BS8 2BN, UK,3Peninsula National Institute for Health Research Clinical Research Facility, Peninsula Medical School,
Barrack Road, Exeter EX2 5DW, UK and4MRC Centre for Causal Analyses in Translational Epidemiology, University
of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK
Received March 1, 2009; Revised and Accepted May 5, 2009
Maternal smoking during pregnancy is associated with low birth weight and adverse pregnancy outcomes.
Women are more likely to quit smoking during pregnancy than at any other time in their lives, but some preg-
nant women continue to smoke. A recent genome-wide association study demonstrated an association
between a common polymorphism (rs1051730) in the nicotinic acetylcholine receptor gene cluster
(CHRNA5–CHRNA3–CHRNB4) and both smoking quantity and nicotine dependence. We aimed to test
whether the same polymorphism that predisposes to greater cigarette consumption would also reduce the
likelihood of smoking cessation in pregnancy. We studied 7845 pregnant women of European descent
from the South-West of England. Using 2474 women who smoked regularly immediately pre-pregnancy,
we analysed the association between the rs1051730 risk allele and both smoking cessation during pregnancy
and smoking quantity. Each additional copy of the risk allele was associated with a 1.27-fold higher odds
(95% CI 1.11–1.45) of continued smoking during pregnancy (P 5 0.0006). Adjustment for pre-pregnancy
smoking quantity weakened, but did not remove this association [odds ratio (OR) 1.20 (95% CI 1.03–1.39);
P 5 0.018]. The same risk allele was also associated with heavier smoking before pregnancy and in the
first, but not the last, trimester [OR for smoking 101 cigarettes/day versus 1–9/day in first trimester 5 1.30
(95% CI 1.13–1.50); P 5 0.0003]. To conclude, we have found strong evidence of association between the
rs1051730 variant and an increased likelihood of continued smoking in pregnancy and have confirmed the
previously observed association with smoking quantity. Our data support the role of genetic factors in
influencing smoking cessation during pregnancy.
Maternal smoking in pregnancy is associated with a number of
adverse outcomes including fetal growth restriction and
various pregnancy complications (1,2). Clinical trials of inter-
ventions to promote smoking cessation have effectively
reduced smoking and the prevalence of low birth weight and
preterm birth (3), but despite a strong and direct public
health message, many pregnant women continue to smoke.
In the year 2000, prevalence estimates for the USA, Sweden
and UK, were 12, 13 and 20%, respectively (2,4).
Observational data suggest that 20–40% of female smokers
quit during pregnancy (2). Smoking cessation during preg-
nancy is influenced by multiple factors, including maternal
?To whom correspondence should be addressed. Tel: þ44 1392406806; Fax: þ44 1392406767; Email: email@example.com
# 2009 The Author(s).
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Human Molecular Genetics, 2009, Vol. 18, No. 15
Advance Access published on May 9, 2009
age, socioeconomic position, parity and partner’s smoking
(5,6). In addition, genetic susceptibility to the addictive prop-
erties of nicotine is likely to be important. Evidence from twin
studies suggests that up to 70% of the variance in nicotine
dependence is due to genetic factors (7). Consistent with
this, a study of 840 adoptive families demonstrated high con-
cordance between the smoking behaviour of adoptees and their
biological full siblings (8).
Recently, a genome-wide association study of 15 771
Europeans showed that a single nucleotide polymorphism
(SNP rs1051730) on chromosome 15q24 was associated with
smoking quantity and nicotine dependence [assessed by ques-
tionnaire incorporating the Fagerstrom test (9)] among
smokers (10). The polymorphism was equally prevalent in
smokers and never-smokers, suggesting that it does not predis-
pose to smoking initiation, but to dependence among those
who smoke. Each additional copy of the minor, T, allele of
the rs1051730 variant was associated with an increase of
0.095 (95% CI 0.075–0.115) smoking quantity units, approxi-
mately equal to one cigarette per day (P ¼ 6 ? 10220). The
SNP lies within the nicotinic acetylcholine receptor gene,
CHRNA3, in a linkage disequilibrium block containing two
other strong candidate genes, CHRNA5 and CHRNB4 (10).
A recent study showed that the minor allele of the missense
polymorphism, D398N, in CHRNA5 (rs16969968), which is
highly correlated with rs1051730 (r2. 0.79), conferred a
reduced response to a nicotinic agonist in vitro (P , 0.0001)
(11). This polymorphism may therefore be the functional
variant responsible for the association with smoking quantity.
We considered that pregnancy would be a situation charac-
terized by considerable health and social pressure to stop
smoking and proposed that the same genetic factor that
leads individual smokers to consume more cigarettes could
also influence smoking cessation in pregnancy. We aimed to
test the hypothesis that the rs1051730 risk allele is associated
with an increased likelihood of continued smoking in
The basic characteristics of the study subjects are presented in
Association between rs1051730 genotype and the odds
of continued smoking in pregnancy
We observed a strong association between the rs1051730 risk
allele and the odds of continuing to smoke in pregnancy. Each
additional copy of the risk allele conferred a 1.27-fold higher
odds (95% CI 1.11–1.45) of continuing to smoke during the
first trimester (P ¼ 0.0006). The association based on third tri-
mester smoking was very similar (P ¼ 0.0003; Table 2 and
Supplementary Material, Table S1). Adjustment for pre-
pregnancy smoking quantity weakened, but did not remove
the associations (Table 2). The genetic associations were
little altered by adjustment for covariates of smoking cessation
in pregnancy (Supplementary Material, Table S1). These vari-
ables were not themselves associated with the rs1051730 risk
allele (Supplementary Material, Table S2).
Association between rs1051730 genotype
and smoking quantity
Within smokers (N ¼ 1361–2379), the rs1051730 genotype
was associated with smoking quantity before pregnancy
[odds ratio (OR) for heavy (10þ cigarettes/day) versus light
smoking (1–9 cigarettes/day) ¼ 1.28 (95% CI 1.12–1.47);
P ¼ 0.0004] and during the first trimester [OR ¼ 1.30 (95%
CI 1.13–1.50); P ¼ 0.0003], but not the third trimester
[OR ¼ 1.12 (95% CI 0.96–1.32); P ¼ 0.15] (Table 3 and Sup-
plementary Material, Table S3). Using all 7845 subjects with
data on pre-pregnancy smoking status, we found no difference
in the frequency of the risk allele between smokers and non-
smokers [OR for being a smoker¼1.02 (95% CI 0.95–1.10);
P ¼ 0.57].
Association between maternal rs1051730 genotype
and offspring birth weight
We hypothesized that each copy of the rs1051730 risk allele
carried by the mother would be associated with reduced off-
spring birth weight in women who smoked during the first
and/or third trimester of pregnancy. In this group (n ¼ 1829),
we observed a trend in the expected direction [per-risk allele
change in birth weight ¼ 228 g (95% CI 259 to 2 g);
P ¼ 0.07]. We additionally used a triangulation approach and
first trimester data to estimate the expected effect size of the
association between maternal genotype and offspring birth
weight, assuming that it is mediated through the polymorph-
ism’s association with smoking quantity. The 95% CIs of our
Table 1. Basic characteristics of study subjects
Total number of pregnant
Median age in years (IQR)
Median pre-pregnancy BMI
Percentage of women who
had ever smoked regularly
Percentage of women who
smoked regularly just
Percentage of women who
smoked regularly during
the first trimester of
Percentage of women who
smoked regularly during
the third trimester of
IQR, inter-quartile range.
aIncludes women of white ethnicity with rs1051730 genotype and data
available on whether or not they smoked regularly during the first 3 months of
bWomen were questioned during the 18th week (ALSPAC) or the 28th week
(EFSOCH) of pregnancy about their smoking behaviour during the first 3
months of pregnancy.
cWomen were questioned during the 32nd week (ALSPAC) or the 28th week
(EFSOCH) of pregnancy about their current smoking behaviour.
Human Molecular Genetics, 2009, Vol. 18, No. 152923
effect size, estimated using the birth weight–smoking quantity
and smoking quantity–rs1051730 associations (Supplementary
Material, Fig. S1). After adjustment for first trimester smoking
quantity, the association with offspring birth weight was 221 g
(95% CI 253 to10 g) per maternal risk allele (P ¼ 0.19). There
was no association with offspring birth weight in the 5446
women who did not smoke in either the first or third trimester
(P ¼ 0.86).
Using data from 2474 European women, who smoked
regularly before becoming pregnant, we have shown that the
risk allele of the rs1051730 SNP in the CHRNA5–CHRNA3–
CHRNB4 gene cluster is associated with a 1.27-fold higher
odds (95% CI 1.11–1.45) of continuing to smoke during preg-
nancy. We have also shown that the same risk allele is associ-
ated with the quantity of cigarettes smoked before pregnancy
and in the first trimester. The association of the risk allele
with continued smoking in pregnancy was reduced after
adjustment for pre-pregnancy smoking quantity, but was not
removed. This is consistent with the risk allele having two
related effects, each reflecting a predisposition to nicotine
dependence: (i) an effect on the likelihood of quitting through
a primary effect on smoking quantity, whereby carriers find it
harder to quit because they smoke in greater quantities and
(ii) an effect on the likelihood of quitting, regardless of
smoking quantity at the time of attempting to quit.
Previously, Thorgeirsson et al. (10) observed that the same
variant was associated with smoking quantity in smokers, but
not with smoking prevalence, implicating the variant in nic-
otine dependence rather than smoking initiation. Our data
are consistent with this and with other studies reporting associ-
ations between SNPs in linkage disequilibrium with rs1051730
and nicotine dependence or smoking quantity (12–14). The
lack of association with smoking quantity in our third trimester
smokers may reflect this group being enriched with the
most nicotine-dependent subjects. Two additional studies
have demonstrated highly significant associations between
rs1051730 and lung cancer (OR ? 1.3; P , 1028) but found
either weak or no evidence of association with smoking behav-
iour, suggesting that further work is necessary to determine
whether the variant has a role in disease susceptibility inde-
pendently of smoking behaviour (15,16).
We observed a trend to reduced birth weight with each copy
of the rs1051730 risk allele carried by the mother (P ¼ 0.07).
The size and direction of effect were consistent with those
expected, given the smoking quantity–birth weight and
smoking quantity–risk allele associations. However, the
sample size was limited. Further well-powered studies are
needed to investigate more thoroughly the hypothesized
associations with fetal growth.
Our finding is the first robust association between a
common genetic variant and smoking cessation. Previous can-
didate gene association studies investigating smoking cessa-
tion have used much smaller sample sizes and have either
shown inconsistent results or require replication in indepen-
dent larger studies (17,18). While our statistical evidence
does not meet generally accepted criteria for ‘genome-wide
Table 2. Association between smoking cessation in pregnancy and the rs1051730 risk allele: combined analysis of data from the ALSPAC and EFSOCH studies
Number with questionnaire data
available on smoking status (out of
2474 women who smoked regularly
just before pregnancy)
% of women who had
stopped smoking since
Risk allele frequency in
women who continued to
Per-risk allele OR
(95% CI) for
continuing to smoke
Per-risk allele OR (95%CI) for
continuing to smoke, adjusted
for pre-pregnancy smoking
P-value, adjusted for
2924 Human Molecular Genetics, 2009, Vol. 18, No. 15
significance’ (P , 5 ? 1028), the prior genome-wide associ-
ation with smoking quantity (P ¼ 6 ? 10220) (10), coupled
with the strong evidence for association in our study
(P ¼ 0.0003–0.0006), suggests that our result is unlikely to
be a false-positive.
Motivated by concern for the health of their babies (2),
women are more likely to quit smoking in pregnancy than at
any other time (17). However, many pregnant women continue
to smoke. Our data support the role of genetic factors in pre-
disposing to this detrimental behavioural phenotype. The
association is not deterministic: approximately one-third of
women carrying two copies of the risk allele did quit
smoking in pregnancy. However, the 1.66-fold (95% CI
1.21–2.26) higher odds of continued smoking in women
with two risk alleles (11% of the total) versus women with
none (44%) is a strong evidence that the polymorphism is a
susceptibility factor for an important human behavioural
trait. This may have implications for the design of interven-
tions to help women quit smoking in pregnancy, and possibly
for smoking cessation strategies more generally. It will be
important to investigate this possibility.
There are some limitations to our study. First, data on
smoking behaviour were self-reported. Multiple validation
studies using biochemical markers such as cotinine have
demonstrated that pregnant women may not admit to
smoking (2), so our prevalence figures are likely to be under-
estimates. In addition, examination of our data suggests that
non-responders in the third trimester in the Avon Longitudinal
Study of Parents and Children (ALSPAC) study were more
likely to be pre-pregnancy smokers than were responders
(Supplementary Material, Fig. S2). However, such sources
of error in the phenotypic data are likely to result in increased
noise and reduced power rather than confounding (19). Impor-
tantly, the associations we observed are unlikely to be due to
bias in self-reporting of smoking cessation. Any bias in our
study of pregnant women is more likely to be towards a null
result than a false-positive result. This is because while preg-
nant smokers may falsely report that they have quit, the
reverse situation, in which pregnant women falsely report
smoking, is extremely unlikely. Women who continue to
smoke in pregnancy are expected to have a higher frequency
of the risk allele due to higher nicotine dependence. If a pro-
portion of these women falsely declared that they had quit
smoking, this would cause the group of ‘quitters’ to be
enriched with the risk allele, causing the association to be
biased towards the null. Another limitation is that our study
participants may not fully represent the general population.
We have previously shown that Exeter Family Study of Child-
hood Health (EFSOCH) study participants had a lower-than-
average level of socioeconomic deprivation and were more
likely to be non-smokers (20). However, the rs1051730 SNP
is not associated with these factors, so this will not introduce
To conclude, our study provides further evidence for a role
of the rs1051730 SNP in the CHRNA5–CHRNA3–CHRNB4
gene cluster in smoking quantity and demonstrates an associ-
ation with smoking cessation in pregnancy. Further studies are
needed to assess the association between the SNP and smoking
cessation in other situations. Our finding provides an example
of how genes can influence what is perceived by many to be a
purely behavioural phenotype. There are parallels between our
results and those of genetic association studies which have
implicated appetite-regulatory pathways in obesity (21,22).
Both phenotypes are thought by many scientists, health-care
professionals and policy-makers to be a matter of ‘self-
control’ and have much social stigma attached. Twin and
other studies have previously shown that these traits have a
heritable component, but the identification of robust associ-
ations with common genetic variants may help a little to
emphasize that physiology plays an important role in ‘socially
MATERIALS AND METHODS
We studied pregnant women of white, European ancestry
from two studies (Table 1). The ALSPAC study (23) is a
Table 3. Association between daily cigarette smoking quantity and the rs1051730 risk allele before and during pregnancy: combined analysis of data from the
ALSPAC and EFSOCH studies
Time period Smoking quantity
Overall per-risk allele
increase in smoking
P-value Overall per-risk allele OR (95% CI) for
heavy (10þ cigarettes per day) versus light
smoking (one to nine cigarettes per day)b
0.099 (0.054, 0.143)1 ? 1025
First trimester 0.088 (0.040, 0.137)0.0004 1.30 (1.13–1.50)0.0003
Third trimester0.042 (20.012, 0.097) 0.13 1.12 (0.96–1.32)0.15
aFrom linear regression of smoking quantity (three categories: 0 ¼ ‘1–9’, 1 ¼ ‘10–19’, 2 ¼ ‘20þ’) on number of risk alleles, adjusted for study.
bFrom logistic regression of heavy (¼1) versus light (¼0) smoking on number of risk alleles, adjusted for study.
cOf the 2474 women who said they smoked regularly pre-pregnancy, 2379 women gave details of smoking quantity.
Human Molecular Genetics, 2009, Vol. 18, No. 152925
prospective study, which recruited pregnant women from
Bristol, UK, with expected delivery dates between April
1991 and December 1992. The EFSOCH study (20) is a pro-
spective study of children born between 2000 and 2004, and
their parents, from a geographically defined region of
Exeter, UK. All women gave informed consent and ethical
approval was obtained from the ALSPAC Law and Ethics
Committee and the local review committee for each study.
Data collection on smoking behaviour and covariates
of smoking cessation in pregnancy
Smoking behaviour of women before and during pregnancy
was determined from questionnaires (Supplementary Material,
Fig. S3). In the ALSPAC study, a questionnaire was adminis-
tered in the 18th gestational week, asking about lifetime, pre-
pregnancy and first-trimester smoking behaviour (whether or
not the woman smoked and, for smokers, the quantity of ciga-
rettes per day). Women were questioned again about current
smoking behaviour during the 32nd week of pregnancy. In
the EFSOCH study, a questionnaire was administered during
the 28th gestational week, asking about lifetime, pre-
pregnancy, first trimester and current smoking quantity. At
each time point, the data on smoking quantity from both
studies were categorized into 1–9, 10–19 and 20þ cigarettes
per day. Data on known covariates of smoking cessation in
pregnancy (5,6) were also collected via questionnaire: age,
Townsend deprivation score (24) (EFSOCH only), occu-
pational position, educational level (ALSPAC only), parity,
partner’s smoking status and age started smoking (ALSPAC
The rs1051730 polymorphism was genotyped in subjects from
both studies using standard methods, details of which are pre-
sented in the Supplementary Material.
Analysis of the association between rs1051730 genotype and
the odds of continued smoking in pregnancy. We selected
women reporting smoking regularly immediately before
n ¼ 233). We pooled subjects from both studies for analysis,
after verifying that there was no difference in allele frequency
(P ¼ 0.35). Patients were classified, using data collected on
first trimester smoking, as ‘stopped smoking’ or ‘continued
to smoke’. A similar dichotomous variable was created
using data on third trimester smoking (assessed in ALSPAC
at 32 weeks and EFSOCH at 28 weeks gestation). We per-
formed logistic regression (multiplicative model) to assess
the association between each dichotomized variable and
number of copies of the rs1051730 risk allele carried, adjust-
ing for study. In the separate studies, we repeated the logistic
regression analysis including known covariates of smoking
cessation in pregnancy.
It is possible that any association observed in our study
between rs1051730 and smoking cessation in pregnancy
would be secondary to the known association with smoking
n ¼ 2241; EFSOCH:
quantity. To test this hypothesis, we repeated the analysis
with pre-pregnancy smoking quantity included as a covariate.
Analysis of the association between rs1051730 genotype and
smoking quantity. In the pooled data set, we assessed the
association between the pre-pregnancy, first trimester and
third trimester smoking quantity (cigarettes per day) and the
rs1051730 polymorphism, by performing linear regression of
smoking quantity level on number of risk alleles (10). We
also dichotomized smoking quantity to reflect ‘light’ (1–9
cigarettes per day) and ‘heavy’ (10þ cigarettes per day)
smoking, because the previous study found the largest differ-
ence in allele frequency between equivalent categories (10)
We assessed the association between this variable and the
number of risk alleles using logistic regression.
Analysis of the association between maternal rs1051730
genotype and offspring birth weight. We hypothesized that
each copy of the risk allele carried by the mother would be
associated with reduced offspring birth weight, via its associ-
ation with smoking quantity, in women who smoked during
pregnancy. To test this, we selected subjects who said that
they smoked during the first and/or the third trimester of preg-
nancy (excluding multiple births and babies born before 36
full weeks’ gestation). We performed linear regression of
birth weight on the number of maternal risk alleles carried,
with sex, gestational age and study as covariates. We then
repeated this analysis including first trimester smoking quan-
tity as an additional covariate. We additionally used a triangu-
lation approach to estimate the expected effect size of the
association between maternal genotype and offspring birth
weight. We hypothesized that this effect size would be deter-
mined by (A) the effect size of the association between
maternal genotype and smoking quantity and (B) the effect
size of the association between smoking quantity and birth
weight (see Supplementary Material, Fig. S1). We estimated
(A) and (B) in the 1649 mothers with data available on off-
spring birth weight and first trimester smoking quantity,
using linear regression, with sex, gestational age and study
as covariates. The expected effect size was then estimated
by multiplying (A) ? (B). We previously used the same
approach to investigate associations between a common
variant in the FTO gene, BMI and related metabolic traits (25).
Supplementary Material is available at HMG online.
We are extremely grateful to the ALSPAC and EFSOCH study
participants, the midwives for their help in recruiting them and
the ALSPAC and EFSOCH teams, which include interviewers,
computerand laboratory technicians,
research scientists, volunteers, managers, receptionists and
Conflict of Interest statement. None declared.
2926 Human Molecular Genetics, 2009, Vol. 18, No. 15
FUNDING Download full-text
This work was supported by a Sir Henry Wellcome
Postdoctoral Fellowship, awarded to R.M.F. (Wellcome
Trust grant: 085541/Z/08/Z). B.S. is funded by the Peninsula
National Institute for Health Research Clinical Research Facil-
ity. M.N.W. is a Vandervell Foundation Research Fellow.
A.T.H. is a Wellcome Trust Research Leave Fellow. The
UK Medical Research Council, the Wellcome Trust and the
University of Bristol provide core support for ALSPAC.
Funding to pay the Open Access charge was provided by the
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