DNA Methylation and the Developmental Origins of Health and Disease: Epigenome-Wide Associations in Canadian Birth Cohorts

Abstract

In recent years the developmental origins or health and disease (DOHaD) has been a crucial area of study in the etiology, prevention, and treatment of non-communicable diseases (NCDs). Prenatal exposures such as gestational diabetes (GDM), diet, or smoking may affect fetal development in ways that persist to have a long-term impact on offspring health and disease. Epigenetic modifications such as alterations to DNA methylation may be one of the mechanisms by which these prenatal exposures effect long-term changes to adult health. The Epigenome-Wide Association Study (EWAS) has become a prominent method to study the association between changes in DNA methylation with a variety of outcomes. To assess the body of evidence available for prenatal exposures, we reviewed EWAS papers in the PubMed database that found significant associations between cord blood DNA methylation and: smoking, GDM, maternal diet, BMI, or gestational age. Smoking and gestational age demonstrated consistent changes in DNA methylation across studies, while the other exposures had either inconsistent results or minimal investigation. Sites reported as significant in our literature review were assessed for replication in the START and CHILD birth cohorts. A total of 8/94 sites were significantly associated with smoking in CHILD, while 81/279 gestational age sites were significant in each of START and CHILD (54 were significant in both). We also conducted an EWAS examining the relationship between infant cord blood methylation and the glucose-to-insulin ration (GIR), a metric of fetal insulin sensitivity. 13 significant sites were initially identified, and further pathway and risk score analysis demonstrated that differences in underlying cellular composition, specifically natural kill (NK) cells, were likely driving the results. Our results indicate that both DNA methylation alterations and modifications to the underlying tissue composition may be related to prenatal exposures and influence the long-term health implications of these environments.