Maternal DNA Methylation Signatures of Gestational Diabetes across all Stages of Pregnancy

Abstract Gestational diabetes mellitus (GDM) is a common metabolic disorder characterized by hyperglycemia that is first detected during pregnancy, which is not overt diabetes. GDM poses a substantial risk for prenatal and postnatal adverse outcomes affecting both the mother and the offspring. These complications include, but are not limited to, fetal macrosomia, shoulder dystocia, respiratory distress, neonatal hypoglycemia, type 2 diabetes, and cardiovascular diseases. Screening for GDM typically occurs between 24 and 28 weeks of gestation, a timing that is considered late and may increase the risk of all the adverse outcomes associated with GDM. Treatment and prevention strategies are not standardized globally, may be suboptimal, and are often initiated after a diagnosis has been made. Therefore, our primary goal was to identify DNA methylation signatures specific to GDM to understand its underlying mechanisms. We conducted genome-wide DNA methylation profiling for normal and GDM pregnant women across the three trimesters of pregnancy in the discovery cohort. In addition, we validated our findings in a second cohort collected in Qatar. In this study, we uncovered and validated new DNA methylation signatures that may significantly influence the expression of genes associated with GDM. Furthermore, we discovered new genes (RSL1D1, HOXD4, and MROH6) that may play a role in GDM and might be related to the risk of developing T2D and cardiovascular disease later in life. We conclude that DNA methylation changes during pregnancy might not fully explain GDM pathogenesis but can reflect population-specific environmental and behavioral factors before and during pregnancy. Some of these discovered CpG sites might regulate previously reported genes linked to GDM and diabetes, highlighting shared and distinct epigenetic mechanisms across populations. Competing Interest Statement The authors have declared no competing interest. Funding Statement This work was supported by an NPRP13 grant (NPRP13S_0113_200050) from the Qatar National Research Fund (QNRF). The findings herein reflect the work and are solely the responsibility of the authors. The work done by Noha A. Yousri on QBB data was made possible by PPM2 grant # PPM2_0226_170020 from the Qatar National Research Fund (QNRF) and Qatar Genome Program (QGP). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the institutional review boards (IRB) of QBB (Ex-2022-QF-QBB-RES-ACC-00100-0203) and Hamad Bin Khalifa University with approval number: QBRI-IRB 2021-09-107. The Medical Research Center (MRC), Hamad Medical Corporation, approved the study with the approval number: MRC-03-22-119. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability The datasets generated and analyzed in this study are available from the corresponding author upon reasonable request, subject to institutional and ethical approvals.