Epigenome-Wide Association Study Reveals Methylation Loci Associated With Offspring Gestational Diabetes Mellitus Exposure and Maternal Methylome

<i>Objective: </i>Gestational diabetes mellitus (GDM) is associated with a future offspring risk for the development of obesity and insulin resistance in Gestational diabetes mellitus (GDM) is associated with an increased risk of obesity and insulin resistance in offspring later in life, which might be explained by epigenetic changes in response to maternal hyperglycaemic exposure. <p><i>Research Design and Methods: </i>We explored the association of GDM exposure on maternal blood and newborn cord-blood methylation of 536 mother-offspring pairs from the prospective FinnGeDi cohort, using Illumina’s methylationEPIC BeadChip 850K arrays. We assessed two hypotheses First, we tested for shared maternal and offspring epigenetic effects due to GDM exposure. Second, we tested whether GDM exposure and maternal methylation has an epigenetic effect on the offspring.</p> <p><i>Results: </i>We did not find any epigenetic marks (differentially methylated CpG probes) with shared and consistent effects between mothers and offspring. After including maternal methylation in the model, we identified a single significant (FDR = 1.38 x 10<sup>-2</sup>) CpG at the cg22790973 probe (<i>TFCP2)</i> associated with GDM. We identified seven additional FDR-significant interactions of maternal methylation and GDM status, with the strongest association at the same cg22790973 probe (<i>TFCP2)</i>, plus cg03456133, cg24440941 (<i>H3C6</i>), cg20002843 (<i>LOC127841)</i>, cg19107264, cg11493553 located in the <i>UBE3C</i> gene and cg17065901 in <i>FAM13A, </i>both<i> </i> susceptibility genes for type 2 diabetes and BMI and cg23355087, within the <i>DLGAP2</i> gene, known to be involved in insulin resistance during pregnancy.</p> <p><i>Conclusion: </i>Our study reveals the potential complexity of the epigenetic transmission between GDM mothers and their offspring, likely determined by not only GDM exposure, but also other factors indicated by maternal epigenetic status, such as maternal metabolic history.<br> </p>