Cord blood DNA methylation differences associated with gestational diabetes and partial consistency with maternal methylation patterns

Abstract

Gestational diabetes mellitus (GDM) increases offspring cardiometabolic risk, potentially through intrauterine epigenetic programming. We aimed to characterize GDM-associated DNA methylation differences in cord blood, evaluate their consistency with previously identified maternal methylation marks, and explore associations with neonatal anthropometric outcomes. An epigenome-wide association study (EWAS) was performed in cord blood DNA from 22 offspring, including 11 exposed to GDM and 11 controls, using the Infinium MethylationEPIC BeadChip. Differentially methylated positions (DMPs) and regions (DMRs) were evaluated using models adjusted for fetal sex, gestational age, maternal age, pre-pregnancy BMI, and estimated cell-type proportions. Functional enrichment analyses were conducted using Enrichr. A candidate-site analysis evaluated 272 previously identified maternal GDM-associated CpGs and their associations with neonatal anthropometric outcomes. Seventeen DMRs remained significant after FDR correction, including regions annotated to ZFP57 and HIF3A. Functional enrichment identified nominal associations with metabolic and developmental pathways, while four ClinVar terms related to neonatal and monogenic diabetes remained significant after multiple-testing correction, with ZFP57 contributing to all four. Among the 272 maternal candidate CpGs, 25 showed nominal evidence of association in cord blood and 12 displayed the same direction of effect across tissues. Effect estimates across all 272 CpGs were weakly positively correlated between maternal and cord blood. Nominal associations were also observed with birth weight and head circumference percentiles, including two associations with head circumference percentile after adjustment for GDM status. No individual DMP or neonatal association reached FDR-adjusted significance. GDM was associated with FDR-significant regional DNA methylation differences in cord blood, including biologically plausible loci related to imprinting and metabolic regulation. The observed overlap with maternal GDM-associated CpGs and the associations with neonatal anthropometric outcomes support further investigation of cross-tissue epigenetic variation in larger independent cohorts.