Prenatal exposure to maternal smoking and offspring DNA methylation across the lifecourse: findings from the Avon Longitudinal Study of Parents and Children (ALSPAC)

Abstract

Maternal smoking during pregnancy has been found to influence newborn DNA methylation in genes involved in fundamental developmental processes. It is pertinent to understand the degree to which the offspring methylome is sensitive to the intensity and duration of prenatal smoking. An investigation of the persistence of offspring methylation associated with maternal smoking and the relative roles of the intrauterine and postnatal environment is also warranted. In the Avon Longitudinal Study of Parents and Children, we investigated associations between prenatal exposure to maternal smoking and offspring DNA methylation at multiple time points in approximately 800 mother-offspring pairs. In cord blood, methylation at 15 CpG sites in seven gene regions (AHRR, MYO1G, GFI1, CYP1A1, CNTNAP2, KLF13 and ATP9A) was associated with maternal smoking, and a dose-dependent response was observed in relation to smoking duration and intensity. Longitudinal analysis of blood DNA methylation in serial samples at birth, age 7 and 17 years demonstrated that some CpG sites showed reversibility of methylation (GFI1, KLF13 and ATP9A), whereas others showed persistently perturbed patterns (AHRR, MYO1G, CYP1A1 and CNTNAP2). Of those showing persistence, we explored the effect of postnatal smoke exposure and found that the major contribution to altered methylation was attributed to a critical window of in utero exposure. A comparison of paternal and maternal smoking and offspring methylation showed consistently stronger maternal associations, providing further evidence for causal intrauterine mechanisms. These findings emphasize the sensitivity of the methylome to maternal smoking during early development and the long-term impact of such exposure.

Figure 1.

Manhattan and QQ plot for epigenome-wide association study of sustained smoking in pregnancy on cord blood DNA methylation. *Results are from the analysis adjusted for batch only (N = 790).

Figure 2.

Methylation level (beta) at key CpG sites associated with sustained smoking in pregnancy by the duration of smoking (number of trimesters).

Figure 3.

Methylation level (beta) at key CpG sites associated with sustained smoking in pregnancy by the intensity of smoking (number of cigarettes per day).

Figure 4.

Longitudinal trajectories of methylation at key CpG sites in the offspring of non-smokers and sustained smokers during pregnancy from birth to age 17.

Figure 5.

Parental comparisons of associations between any versus no smoking in pregnancy on offspring methylation at CpG sites most associated with sustained maternal smoking in pregnancy at all three time points.