Placental DNA methylation in normal and complicated pregnancies

DNA methylation, a partially reversible process, is critical in tissue development and aging. The discrepancy between biological age, as estimated from methylation, and chronological age has been proposed as a potential indicator of health and disease. Epigenetic age acceleration has been implicated as a contributing mechanism in obstetric conditions such as preeclampsia and small-for-gestational-age, yet future studies could benefit from more accurate models. Herein, we curated 1,842 placental methylomes from the public domain and organized a DREAM challenge to develop models that infer gestational age. Challenge participants were blinded to the test data that we generated from 384 placentas encompassing normal and complicated pregnancies. The mean absolute error of the top performing model (0.99 weeks of gestation) and of a post-challenge placental clock model (PCPC, 1.04 weeks) compared favorably to the accuracy of existing models. Moreover, predictions obtained with new models were better calibrated across the gestational age spectrum and suggest that previous reports of accelerated aging in preterm preeclampsia were likely due to modeling artifacts. Based on predictions from previous and newly developed epigenetic models we found that accelerated placental ageing was associated with a decrease in birthweight percentiles in male neonates delivered at term in our test cohort (about 10 birthweight percentiles drop per week of age acceleration for PCPC model, p<0.001). By contrast, preterm accelerated aging was protective against delivery of a small-for-gestational-age neonate regardless of fetal sex. The test set data was obtained from a study designed to compare the DNA methylome of placental tissues among various obstetrical syndromes. Samples were obtained from term controls (n = 82), preterm prelabor rupture of membranes (PPROM) (n = 76), preterm and term preeclampsia (PE) (n = 85), preterm labor (PTL) (n = 91), and pregnancies with small-for-gestational-age (SGA) fetuses (n = 50). Patients were enrolled in a study conducted at Wayne State University / Detroit Medical Center / Pregnancy Research Branch (NICHD). Participants provided written informed consent, and the collection and use of the samples and clinical data for research purposes were approved by the Institutional Review Boards of Wayne State University and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services. The raw methylation data included in this GSE series includes data from a subset of 18 patients who were asked and agreed to broad data sharining.