Epigenome-wide analyis of neurobehavioral variation in preterm infants

Neonatal molecular biomarkers of neurobehavioral responses (measures of brain-behavior relationships), when combined with neurobehavioral performance measures, could lead to better predictions of long-term developmental outcomes. To this end, we examined whether variability in epigenomic measures from buccal cells were associated with neurobehavioral profiles in a cohort of infants born less than 30 weeks postmenstrual age (PMA) and participating in the Neonatal Neurobehavior and Outcomes in Very Preterm Infants (NOVI) Study (N=536). We tested whether epigenetic age, age acceleration, or DNA methylation (DNAm) levels at individual loci, measured via the Illumina EPIC microarray, differed between infants based on their NICU Network Neurobehavioral Scale (NNNS) profile classifications, ranging from most optimal to atypical. We adjusted for recruitment site, infant sex, PMA, and tissue heterogeneity. Infants with an optimally well-regulated NNNS profile had older epigenetic age compared to other NOVI infants (β1 = 0.201, p-value = 0.026), but no significant difference in age acceleration. In contrast, infants with an atypical NNNS profile had differential methylation at 29 CpG sites (FDR < 10%). Some of the genes annotated to these CpGs included PLA2G4E, TRIM9, GRIK3, and MACROD2, which have previously been associated with neurological structure and function, or with neurobehavioral disorders. These findings contribute to the existing evidence that neonatal epigenetic variations in buccal cells may be informative for infant neurobehavior. DNA methylation was assessed for 542 samples using the Illumina MethylationEPIC Beadarray **Additional samples (537-542) are added and the 'MatrixProcessed.txt.gz' is updated on Feb 18, 2021.