Aim

To investigate whether smoking during pregnancy is causally associated with offspring dietary fat intake and obesity using a Mendelian randomization approach.

Hypotheses

There is strong observational evidence that maternal smoking during pregnancy is associated with higher adiposity in offspring. (1) It has also been suggested that prenatal tobacco exposure may lead to alteration of amygdala volume in the brain in utero, leading to changes in dietary fat intake and subsequent obesity.(2)

However, there is little robust evidence to suggest that the maternal smoking- offspring obesity association is causal and it is likely to be at least partly confounded by sociodemographic and lifestyle factors. Recent analyses in ALSPAC, comparing the associations of maternal and paternal smoking during pregnancy on offspring trajectories of height and adiposity demonstrated that whilst maternal smoking was likely to be causally associated with smaller birth length and adiposity in infancy, there was little evidence for causal effects on height and adiposity after 2 years.(3)

Mendelian randomisation analyses will allow further exploration of whether the maternal smoking offspring obesity and dietary fat intake associations are causal. Genetic variants in the CHRNA5-A3-B4 gene cluster (rs16969968/rs1051730) are robustly associated with smoking heaviness and to a lesser extent, smoking cessation. (4) These can be used as proxies for smoking behaviour during pregnancy in Mendelian randomisation analyses to investigate whether smoking during pregnancy is causally associated with outcomes in offspring. Within the ALSPAC cohort, the minor alleles of rs16969968/rs1051730 have been shown to be associated with increased heaviness of smoking in women who continued to smoke during pregnancy and reduced ability to quit smoking among women who smoked prior to pregnancy.(5)

We propose to investigate the associations of rs16969968/rs1051730 with trajectories of offspring BMI and trajectories of offspring dietary energy and fat intake, which have previously been developed in ALSPAC using random effects models. In these random effects models, age is the exposure and height, weight or adiposity (BMI or DXA-assessed fat mass) is the outcome. The SNPs will be included in the random effects models with an interaction parameter between the SNP and age, such that different mean trajectories are estimated for levels of the SNP. If an association between the SNPs and growth trajectories is observed, we will take this forward to a formal Mendelian Randomization analysis using two stage IV analysis.

Exposure variables

Mother

Genotype for rs1051730/rs16969968

Outcome variables

Child

Height (birth to 17 years)

Weight (birth to 17 years)

DXA scans (9 -17 years)

Dietary measures of fat intake (3 to 13 years)

Confounding variables

Age

Sex

1. Oken E, Levitan EB, Gillman MW. Maternal smoking during pregnancy and child overweight: systematic review and meta-analysis. International journal of obesity 2008;32:201-10.

2. Haghighi A, Schwartz DH, Abrahamowicz M et al. Prenatal Exposure to Maternal Cigarette Smoking, Amygdala Volume, and Fat Intake in Adolescence. JAMA Psychiatry 2013;70:98-105.

3. Howe LD, Matijasevich A, Tilling K et al. Maternal smoking during pregnancy and offspring trajectories of height and adiposity: comparing maternal and paternal associations. International journal of epidemiology 2012;41:722-32.

4. Munafo MR, Timofeeva MN, Morris RW et al. Association between genetic variants on chromosome 15q25 locus and objective measures of tobacco exposure. Journal of the National Cancer Institute 2012;104:740-8.

5. Freathy RM, Ring SM, Shields B et al. 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. Human molecular genetics 2009;18:2922-2927.