Maternal Smoking DNA Methylation Risk Score Associated with Health Outcomes in Offspring of European and South Asian Ancestry

Maternal 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 the GFI1 gene (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. Maternal smoking has been linked to health issues in newborns, including low birth weight, respiratory problems, developmental delays, and an increased risk for obesity. Research on DNA methylation (DNAm) response in cord blood has provided valuable insights into the potential adverse effects of cigarette smoking during pregnancy on the developing fetus. Specifically, a handful of differentially methylated sites have been identified in newborns exposed to maternal smoking during pregnancy. Building upon these findings, we created a cord blood DNAm score that amalgamates all maternal smoking-associated methylation changes, allowing us to quantify the impact of maternal smoking and smoking exposure on newborns. This score could serve as an objective tool to assess maternal smoking status and even secondary smoking exposure, and its potential effects on newborns. Our maternal smoking DNAm score validated in a White European birth cohort was significantly associated with smoking status and exposure to smoking during pregnancy, and again independently associated in a separate European cohort. Further, the same DNAm score translates to a South Asian cohort, even in the absence of active smoking, revealing a strong correlation with various newborn growth indicators, including small birth size and low birth weight. These findings highlight the potential universality and clinical relevance of our DNAm score in diverse populations.