A meta-analysis of pre-pregnancy maternal body mass index and placental DNA methylation identifies 27 CpG sites with implications for mother-child health

Abstract

Higher maternal pre-pregnancy body mass index (ppBMI) is associated with increased neonatal morbidity, as well as with pregnancy complications and metabolic outcomes in offspring later in life. The placenta is a key organ in fetal development and has been proposed to act as a mediator between the mother and different health outcomes in children. The overall aim of the present work is to investigate the association of ppBMI with epigenome-wide placental DNA methylation (DNAm) in 10 studies from the PACE consortium, amounting to 2631 mother-child pairs. We identify 27 CpG sites at which we observe placental DNAm variations of up to 2.0% per 10 ppBMI-unit. The CpGs that are differentially methylated in placenta do not overlap with CpGs identified in previous studies in cord blood DNAm related to ppBMI. Many of the identified CpGs are located in open sea regions, are often close to obesity-related genes such as GPX1 and LGR4 and altogether, are enriched in cancer and oxidative stress pathways. Our findings suggest that placental DNAm could be one of the mechanisms by which maternal obesity is associated with metabolic health outcomes in newborns and children, although further studies will be needed in order to corroborate these findings.

Fig. 1. QQ-plots of the meta-analyses of the association between maternal ppBMI and placental DNAm.

Analyses were carried out a adjusting for putative cellular heterogeneity or b without adjusting for putative cellular heterogeneity (N = 2631 placental DNA samples). The red line represents the normal distribution and 95% confidence interval (gray shading).

Fig. 2. Association between maternal ppBMI and placental DNAm (N = 2631 placental DNA samples), after adjusting for maternal age, parity, maternal education, maternal smoking and putative cellular heterogeneity.

Association results are displayed as a volcano plot, where the X-axis shows the effect sizes (ranging between 0 and 1) in DNAm and b Manhattan plot, where the X-axis represents the genomic location of each CpG. In both panels blue dots indicate significantly associated CpGs (meta-analysis p-value < 1.2e-07).

Fig. 3. Forest plots of the leave-one-out analysis showing the fixed effects meta-analysis estimates of association between maternal ppBMI and placental DNAm.

Association of a cg08219219, b cg14704941, c cg04724807, d cg00423969, e cg14163484, f cg26433445, g cg15933729, h and cg08539067 with maternal ppBMI. In all panels, cohort names indicate the cohort excluded in each row, and error bars represent the 95% confidence interval of the effect size. Numerical source data for the figure are available in file Supplementary Data 9.