DNA methylation differences stratified by normalized fetal/placental weight ratios suggest neurodevelopmental deficits in neonates with congenital heart disease.
Marin Jacobwitz, Michael Xie, Jamie Catalano, Ingo Helbig, J William Gaynor, Nancy Burnham, Rebecca L Linn, Juliana Gebb, Mark W Russell, Hakon Hakonarson, Barbara H Chaiyachati, Ana G Cristancho
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Abstract
Background: We lack early biomarkers for predicting neurodevelopment (ND) outcomes in children with congenital heart disease (CHD). Placentas of fetuses with CHD have abnormalities, including unbalanced fetal/placental weight ratios (F/P). Although DNA methylation profiles have revealed insights into the maternal-fetal environment (MFE), it is unknown if DNA methylation correlates to normalized F/P weight ratio groups and how these differences relate to ND outcomes.
Methods: We prospectively recruited a cohort of pregnant women carrying a fetus with CHD. A subset of the cohort had DNA methylation performed on either umbilical cord blood or postnatal blood (45 full-term neonates). We calculated normalized F/P weight ratios, focusing on three normalized F/P ratio groups for analysis. We calculated differential methylation signals in eight ND disabilities-associated gene sets. Normalized F/P ratios were compared to 18-month Bayley Scales of Infant Development-III scores (BSID-III).
Results: Unbiased gene ontology enrichment analysis of differentially methylated regions revealed enrichment for brain development-related pathways. Although there were no significant differences between normalized F/P weight ratio groups and BSID-III, disease-associated gene set pathway analysis revealed significant methylation differences between the most severely unbalanced F/P weight ratio and normal F/P weight ratio groups.
Conclusion: Gene ontology enrichment analysis of differential methylation regions revealed significant differences between normalized F/P weight ratio groups in neurogenesis genes. Furthermore, our data identified methylation differences between unbalanced and balanced normalized F/P weight ratio groups in gene pathways associated with ND dysfunction common in the aging CHD population suggesting converging pathways for ND disorders that should be investigated further.
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