346 - Cord Blood DNA Methylation Levels in Genes regulating Hematopoietic and Mesenchymal Cells are Associated with Infant White Matter Microstructure

Poster Number: 346
Publication Number: 346.443

Douglas C. Dean, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States; Marissa DiPiero, University of Wisconsin Neuroscience Training Program, Madison, WI, United States; Elizabeth Planalp, University of Wisconson, Madison, WI, United States; Andy Madrid, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States; Ligia A. Papale, University of Wisconsin, Madison, WI, United States; Ryan M. McAdams, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States; Christopher L. Coe, University of Wisconsin, Madison, WI, United States; Reid S. Alisch, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States; Pamela J. Kling, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States

Background: Maternal health and environmental stressors may initiate epigenetic modifications in genes regulating brain networks and architecture. We previously found that 1) prenatal maternal depression and anxiety were associated with infant white matter microstructure and 2) cord blood (CB) DNA methylation levels in key neurodevelopmental gene networks were also associated with these same neural areas. Because hematopoietic and mesenchymal progenitor cells present in CB are under study to improve neonatal encephalopathy, we investigated DNA methylation levels in genes regulating hematopoietic and mesenchymal networks.

Objective: To determine if CB DNA methylation levels in genes regulating hematopoietic and mesenchymal networks are related to infant brain microstructure previously found to be associated with maternal depression and anxiety symptoms.

Design/Methods: 55 mother-infant dyads with CB collected at delivery and diffusion MRI of the infant at 1 month of age were evaluated. Neurite density index (V-IC) was measured using the neurite orientation dispersion and density imaging (NODDI) model from bilateral prefrontal cortex regions that included the frontal gyrus and corona radiata. These regions were previously shown to be influenced by maternal depression and anxiety symptoms during pregnancy. DNA methylation levels were determined using the Infinium HumanMethylationEPIC array. To assess the associations between DNA methylation and V-IC, linear regressions were performed, controlling for CB cell numbers, sex of the infant, gestation corrected age at delivery, Hollingshead socioeconomic status, and motion during MRI acquisition. Genes exhibiting differential methylation were subjected to gene ontological analysis.

Results: 351 differentially methylated genomic positions (DMPs) in CB were with associated with infant MRI neurite density (V-IC) (p < 0.05, FDR-corrected). Gene ontological annotation of these V-IC-associated DMPs revealed that 50% of the top 24 significant pathways were involved in hematopoietic and mesodermal stem cell development and function, including genes such as TAL1, JAK3, SMAD1, HOXA11, and FOXC1.Conclusion(s): Although preliminary, these findings suggest that the impact of maternal depression and anxiety on fetal development of bilateral prefrontal white matter microstructure may act by modifying gene expression patterns of hematopoietic and mesenchymal cells in the circulation. Understanding these processes in early microstructural maturation helps to inform genetics and epigenetic contributions guiding early brain development.