Assessing the effect of childbearing on blood DNA methylation through comparison of parous and nulliparous females

Abstract

Background Pregnancy and childbirth have been connected to modified risk of a wide variety of conditions in later life, including neurodegenerative disorders and cancers. The presence, extent, and direction of the effect that childbearing status has on decreasing or increasing the risk of these conditions differs depending on the disease. The mechanisms by which pregnancy and childbirth modify the risk of diseases are still unknown. DNA methylation (DNAm) alterations that occur during pregnancy and persist after childbirth may help us understand this phenomenon. Results Blood DNAm was available from 89 women (28 parous; 61 nulliparous) at ages 18 and 26 years in the Isle of Wight birth cohort; no significant differences in the population characteristics were present between the analyzed population and the full cohort. We performed an epigenome-wide association study on 389,355 CpGs and identified 184 CpGs to be significantly differentially methylated between parous and nulliparous women after adjusting for confounders and multiple testing. Of these CpGs, 105 had regression coefficients in the same direction in an independent Mexico City based ELEMENT cohort, of which 13 were significant (replication P < 0.05). These 13 CpGs were associated with 16 unique genes. DNAm levels tracked with gene expression in 3 of the replicated genes, one of which (TM2D3) was differentially expressed in parous vs nulliparous women. Gene disease association analysis identified a network of parous-associated diseases. Conclusions Our results suggest that pregnancy and childbirth lead to DNAm changes in parous women and these changes persist at least 6 months and up to 8 years postpartum. Parous-related CpG sites may play a role in how childbearing status modifies risk of later life diseases in women. Further studies are needed to explore the linkage and mechanism.