A genetic analysis of smoking and low birth weight

This study has utilised the pregnant woman’s genetic make-up to investigate the relationship between smoking and birth weight. It has strengthened the evidence that smoking during pregnancy causes low birth weight in full term babies.

A growing body of evidence has suggested an association between smoking and low birth weight, with mothers who smoke giving birth to babies who are on average 200 grams lighter than babies with non-smoking mothers. Low birth weight is a major risk factor in the development of disease for new born babies, and is also associated with an increased risk of chronic illness – such as cardiovascular disease, high blood pressure, coronary heart disease and type 2 diabetes – later in adulthood.

We utilised the genetic approach of Mendelian randomization to investigate the role of smoking on birth weight. This has enabled us to investigate associations between smoking and birth weight without potentially confounding environmental influences. We utilised the single-nucleotide polymorphism rs1051730 for this study because it has already been associated with an increase in the number of cigarettes smoked, as well as reducing the ability of women to quit smoking whilst pregnant.

As most common gene variants that are robustly associated with disease have small effects, very large numbers of individuals are often required to provide sufficient power to examine their roles. Therefore, investigating the association between birth weight and the rs1051730 variant requires collaboration with many groups to obtain data from numerous studies. We carried out a meta-analysis of more than 26,000 individuals, a sample size that provided sufficient power for us to draw robust conclusions about the relationship between rs1051730 and birth weight.

We separated women who smoked from those who did not smoke during pregnancy and then analysed the association between rs1051730, and child birth weight. We observed that smoking status during pregnancy modifies the association between maternal rs1051730 genotype and offspring birth weight. Each additional copy of the risk allele in smokers resulted in a significant 20 gram reduction in birth weight. In contrast in non-smoking mothers no significant association between the rs1051730 variant and birth weight were observed. These results suggest that smoking during pregnancy causes lower birth weight babies.

For 4279 women who smoked during pregnancy, data were available on whether or not they continued to smoke after the first trimester. This further subdivision of the pregnancy-smoker suggested that the association between maternal genotype and birth weight may differ depending on whether women smoked during the first trimester only. Whilst power was limited for this analysis it does correspond to previous evidence that if women quit smoking during the first trimester of pregnancy, the adverse effects of smoking on birth weight are reduced.

The study strengthens the evidence that smoking during pregnancy is causally related to lower offspring birth weight and suggests that population interventions that effectively reduce smoking in pregnant women would result in a reduced prevalence of low birth weight.

The paper is published in the journal Human Molecular Genetics.

Full citation

Tyrrell J et al. Genetic variation in the 15q25 nicotinic acetylcholine receptor gene cluster (CHRNA5–CHRNA3–CHRNB4) interacts with maternal self reported smoking status during pregnancy to influence birth weight. Human Molecular Genetics, 2012 1–15.