Placental epigenetic clocks derived from crowdsourcing: Implications for the study of accelerated aging in obstetrics

Epigenetic gestational age acceleration has been implicated in obstetric syndromes including preeclampsia, yet robust conclusions require accurate and unbiased epigenetic age models. Herein, we curated 1,842 public placental methylomes and organized a DREAM challenge to develop models of gestational age. Participants were blinded to the test data that we generated from 384 placentas encompassing normal and complicated pregnancies. Models developed during and post-challenge compared favorably to existing models in terms of accuracy, yet they were better calibrated throughout gestation and indicated that reports of accelerated epigenetic aging in preterm preeclampsia were likely due to modeling artifacts. The models show that accelerated aging is associated with a decrease in birthweight percentiles in male neonates delivered at term. By contrast, preterm accelerated aging was protective against delivery of a small-for-gestational-age neonate regardless of fetal sex. This work informs our understanding of the fetal sex-dimorphic role of the placenta epigenome in obstetrics.