Prenatal Smoking Exposures and Epigenome-Wide Methylation in Newborn Blood

BACKGROUND: Maternal sustained smoking during
pregnancy
is associated with thousands of differentially methylated CpGs in
newborns, but impacts of other prenatal tobacco smoking exposures
remain unclear. OBJECTIVE: To identify differential DNA
methylation in newborns from maternal sustained smoking and less studied
prenatal smoking exposures (i.e., maternal exposure to secondhand
smoke [SHS] exposure during pregnancy, maternal quitting before pregnancy,
paternal smoking around conception, and paternal quitting before pregnancy). METHODS: We conducted a large meta-analysis of prenatal tobacco
smoking exposures and epigenome-wide newborn blood DNA methylation
through the Pregnancy And Childhood Epigenetics Consortium (PACE).
Across 19 cohorts, 11,175 parent-newborn pairs contributed information
on at least one prenatal smoking exposure, mostly from questionnaires.
Maternal blood or urine cotinine measurements, available in a few
studies, provided objective data for maternal SHS and smoking during
pregnancy. Primary analyses used Illumina450 K methylation data; secondary
analyses in 5 cohorts examined CpGs unique to the EPIC array. RESULTS: Maternal sustained smoking associated with differential
DNA methylation (false discovery rate [FDR] < 0.05) at 8,862 CpGs
on the 450 K (n = 8,148) and did not differ by infant
sex. We identified over 300 novel genes not previously identified
in EWAS of smoking. No differential methylation was associated with
maternal SHS, maternal former smoking, or paternal smoking around
conception. However, cg24805739 (MED13L) was associated
with former paternal former smoking. Forty-one novel genes were identified
using maternal cotinine measurements compared to questionnaire. In
EPIC unique analyses (n = 3,415), differential methylation
was observed with maternal sustained smoking (211 CpGs), maternal
SHS (5 CpGs), and paternal former smoking (4 CpGs). Smoking-associated
CpGs in blood were strongly enriched for functional elements across
multiple tissues. CONCLUSIONS: Maternal sustained smoking
has the largest impact on newborn DNA methylation, suggesting a strong
influence of the intrauterine environment. We observed minimal impacts
for less studied exposures including SHS, maternal former smoking,
and paternal smoking.