Placental CpG methylation of HPA-axis genes is associated with cognitive impairment at age 10 among children born extremely preterm.

A major component of the neuroendocrine system is the hypothalamus-pituitary adrenal (HPA) axis. HPA axis genes are also known to play a role in placental physiology. Thus, disruptions in the signaling of HPA axis-associated genes may adversely impact the placenta as well as fetal development, with adverse consequences for health and development of the child. In support of this, recent studies have shown that placental epigenetic methylation of HPA axis genes has an impact on infant behavior. In this study, we evaluated CpG methylation of 14 placental HPA axis-associated genes from a subcohort (n=228) of the Extremely Low Gestational Age Newborns (ELGAN) cohort in relation to cognitive function in mid-childhood (e.g. 10 yrs). Multivariable logistic regression revealed that placental CpG methylation of 10 HPA-axis associated genes were significantly associated with cognition at age 10. Specifically, placental CpG methylation levels of the glucocorticoid receptor gene, Nuclear Receptor Subfamily Group 3 C Member 1 () and Brain-derived Neurotropic Factor () were significantly associated with increased odds in developing moderate/severe adverse cognitive impairment at age 10. Methyl-CpG Binding Protein 2 (MECP2) was the major transcriptional regulator of the ten identified HPA genes. The data suggest that placental CpG methylation is associated with cognitive outcomes in mid-childhood.