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

posted on 11.06.2021, 16:19 by Mickaël Canouil, Amna Khamis, Elina Keikkala, Sandra Hummel, Stephane Lobbens, Amélie Bonnefond, Fabien Delahaye, Evangelia Tzala, Sanna Mustaniemi, Marja Vääräsmäki, Marjo-Riitta Jarvelin, Sylvain Sebert, Eero Kajantie, Philippe Froguel, Toby Andrew
Objective: 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.

Research Design and Methods: 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.

Results: 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 10-2) CpG at the cg22790973 probe (TFCP2) 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 (TFCP2), plus cg03456133, cg24440941 (H3C6), cg20002843 (LOC127841), cg19107264, cg11493553 located in the UBE3C gene and cg17065901 in FAM13A, both susceptibility genes for type 2 diabetes and BMI and cg23355087, within the DLGAP2 gene, known to be involved in insulin resistance during pregnancy.

Conclusion: 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.


This study was funded by the French National Research Agency (Agence Nationale de la Recherche; ANR). This study has been granted from the FFRD, sponsored by Fédération Française des Diabétiques (FFD), Abbott, AstraZeneca, Eli Lilly, Merck Sharp & Dohme (MSD) and Novo Nordisk. The co-authors were supported by PRECISE, LONGITOOLS and The Medical Research Council, UK (grants no. MR/M013138/1, MRC/BBSRC MR/S03658X/1 (JPI HDHL)). FinnGeDi study was supported by: Academy of Finland, Signe and Ane Gyllenberg Foundation, Sigrid Jusélius Foundation, Foundation for Pediatric Research, Finnish Diabetes Research Foundation, Novo Nordisk Foundation.