Multi-omic brain and behavioral correlates of cell-free fetal DNA methylation in macaque maternal obesity models (GC-FID dataset infant brains)

Maternal obesity during pregnancy is associated with neurodevelopmental
disorder (NDD) risk. We utilized integrative multi-omics to examine
maternal obesity effects on offspring neurodevelopment in rhesus macaques
by comparison to lean controls and two interventions. Differentially
methylated regions (DMRs) from longitudinal maternal blood-derived
cell-free fetal DNA (cffDNA) significantly overlapped with DMRs from
infant brain. The DMRs were enriched for neurodevelopmental functions,
methylation-sensitive developmental transcription factor motifs, and human
NDD DMRs identified from brain and placenta. Brain and cffDNA methylation
levels from a large region overlapping mir-663 correlated with maternal
obesity, metabolic and immune markers, and infant behavior. A DUX4
hippocampal co-methylation network correlated with maternal obesity,
infant behavior, infant hippocampal lipidomic and metabolomic profiles,
and maternal blood measurements of DUX4 cffDNA methylation, cytokines, and
metabolites. Ultimately, maternal obesity altered infant brain and
behavior, and these differences were detectable in pregnancy through
integrative analyses of cffDNA methylation with immune and metabolic
factors.