Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Canada; Peter Boris Centre for Addictions Research, St. Joseph’s Healthcare Hamilton, Hamilton, Canada; Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Canada
Nathan Cawte
Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Canada
Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Canada
Sandi M Azab
Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada
Russell J de Souza
Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada
Amel Lamri
Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Canada; Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Canada
Katherine M Morrison
Department of Pediatrics, McMaster University, Hamilton, Canada
Stephanie A Atkinson
Department of Pediatrics, McMaster University, Hamilton, Canada
Padmaja Subbarao
Department of Pediatrics, University of Toronto, Toronto, Canada
Stuart E Turvey
Department of Pediatrics, BC Children’s Hospital, The University of British Columbia, Vancouver, Canada
Theo J Moraes
Department of Pediatrics, University of Toronto, Toronto, Canada; Program in Translational Medicine, SickKids Research Institute, Toronto, Canada
Koon K Teo
Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Canada; Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada
Piush J Mandhane
Department of Pediatrics, University of Alberta, Edmonton, Canada
Meghan B Azad
Children’s Hospital Research Institute of Manitoba, Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Canada
Elinor Simons
Section of Allergy and Immunology, Department of Pediatrics and Child Health, University of Manitoba, Manitoba, Canada
Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada; Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Canada; Department of Pathology and Molecular Medicine, McMaster University, Michael G. DeGroote School of Medicine, Hamilton, Canada
Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, Canada; Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Canada; Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada
Background: 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 examine the feasibility of using cord blood DNAm scores leveraging large external studies as discovery samples to capture the epigenetic signature of maternal smoking and its influence on newborns in White European and South Asian populations. Methods: We first examined the association between individual CpGs and cigarette smoking during pregnancy, and smoking exposure in two White European birth cohorts (n=744). Leveraging established CpGs for maternal smoking, we constructed a cord blood epigenetic score of maternal smoking that was validated in one of the European-origin cohorts (n=347). This score was then tested for association with smoking status, secondary smoking exposure during pregnancy, and health outcomes in offspring measured after birth in an independent White European (n=397) and a South Asian birth cohort (n=504). Results: Several previously reported genes for maternal smoking were supported, with the strongest and most consistent association signal from the GFI1 gene (6 CpGs with p<5 × 10-5). The epigenetic maternal smoking score was strongly associated with smoking status during pregnancy (OR = 1.09 [1.07, 1.10], p=5.5 × 10-33) and more hours of self-reported smoking exposure per week (1.93 [1.27, 2.58], p=7.8 × 10-9) in White Europeans. However, it was not associated with self-reported exposure (p>0.05) among South Asians, likely due to a lack of smoking in this group. The same score was consistently associated with a smaller birth size (–0.37±0.12 cm, p=0.0023) in the South Asian cohort and a lower birth weight (–0.043±0.013 kg, p=0.0011) in the combined cohorts. Conclusions: This cord blood epigenetic score can help identify babies exposed to maternal smoking and assess its long-term impact on growth. Notably, these results indicate a consistent association between the DNAm signature of maternal smoking and a small body size and low birth weight in newborns, in both White European mothers who exhibited some amount of smoking and in South Asian mothers who themselves were not active smokers. Funding: This study was funded by the Canadian Institutes of Health Research Metabolomics Team Grant: MWG-146332.
