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 pregnancy. We have also shown that the same risk allele is associated 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
) observed that the same variant was associated with smoking quantity in smokers, but not with smoking prevalence, implicating the variant in nicotine dependence rather than smoking initiation. Our data are consistent with this and with other studies reporting associations between SNPs in linkage disequilibrium with rs1051730 and nicotine dependence or smoking quantity (12
). 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
) but found either weak or no evidence of association with smoking behaviour, suggesting that further work is necessary to determine whether the variant has a role in disease susceptibility independently of smoking behaviour (15
We observed a trend to reduced birth weight with each copy of the rs1051730 risk allele carried by the mother (P = 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 candidate gene association studies investigating smoking cessation have used much smaller sample sizes and have either shown inconsistent results or require replication in independent larger studies (17
). While our statistical evidence does not meet generally accepted criteria for ‘genome-wide significance’ (P
< 5 × 10−8
), the prior genome-wide association with smoking quantity (P
= 6 × 10−20
), coupled with the strong evidence for association in our study (P
= 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 predisposing 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 interventions 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 underestimates. 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
). Importantly, 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 pregnant 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 proportion 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 Childhood 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 bias.
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 association 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
). 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 associations with common genetic variants may help a little to emphasize that physiology plays an important role in ‘socially unacceptable’ phenotypes.