Maternal smoking DNA methylation risk score associated with health outcomes in offspring of European and South Asian ancestry

Abstract

AbstractMaternal smoking has been linked to adverse health outcomes in newborns but the extent to which it impacts newborn health has not been quantified through an aggregated cord blood DNA methylation (DNAm) score. Here we propose the first cord blood DNAm score to capture the epigenetic signature of maternal smoking. We first examined the association between individual CpGs and cigarette smoking during pregnancy in two White European birth cohorts (n = 763), and smoking exposure in the White European and the South Asian birth cohorts (n = 887). Several previously reported genes for maternal smoking were supported, with the strongest and most consistent signal from theGFI1gene (ps< 5×10-5). Leveraging previously reported CpGs for maternal smoking, we constructed a cord blood epigenetic score of maternal smoking that was internally validated in one of the European-origin cohorts. This score was then tested for association with smoking status, secondary smoking exposure during pregnancy, and health outcomes in offspring measured after birth. The epigenetic maternal smoking score was strongly associated with smoking status during pregnancy (p=1.04×10-23) and self-reported smoking exposure (p=6.56×10-8) in White Europeans, but not with self-reported exposure (p> 0.05) in South Asians. The same score was consistently associated with smaller birth size (p=1.19×10-6) and lower birth weight (p=8.79×10-7) in the combined South Asian and White European cohorts. This cord blood epigenetic score can help identify babies exposed to maternal smoking and assess its long-term impact on growth. Notably, even minimal smoking exposure in South Asian mothers who were not active smokers showed a DNAm signature of small body size and low birthweight in newborns.