Newborn Differential DNA Methylation and Subcortical Brain Volumes as Early Signs of Severe Neurodevelopmental Delay in a South African Birth Cohort Study

Abstract Objective The first two years of life are a critical period of rapid brain development. Since early neurodevelopment is influenced by prenatal risk factors and genetics, neonatal biomarkers can potentially provide the opportunity to detect early signs of neurodevelopmental delay. We analyzed associations between DNA methylation (DNAm) levels from cord blood, neonatal magnetic resonance imaging (MRI) neuroimaging data, and neurodevelopment at two years of age. Methods Neurodevelopment was assessed in 161 children from the South African Drakenstein Child Health Study at two years of age using the Bayley Scales of Infant and Toddler Development III. We performed an epigenome-wide association study of neurodevelopmental delay using DNAm levels from cord blood. A mediation analysis was conducted in 51 children to analyze if associations between differential DNAm and neurodevelopmental delay were mediated by altered neonatal brain volumes. Results We found epigenome-wide significant associations between differential DNAm at the SPTBN4 locus (cg26971411, p-value=3.10×10 −08 ), an intergenic region on chromosome 11 (cg00490349, p-value=2.41×10 −08 ) and a differentially methylated region on chromosome 1 (FDR p-value for the region=9.06×10 −05 ) and severe neurodevelopmental delay. While these associations were not mediated by neonatal brain volume, neonatal caudate volumes were independently associated with neurodevelopmental delay, particularly in language (p=0.0443) and motor (p=0.0082) domains. Conclusion Differential DNAm levels from cord blood and increased neonatal caudate volumes were independently associated with severe neurodevelopmental delay at two years of age. These findings suggest that neurobiological signals for severe developmental delay may be detectable in very early life with implications for identification and intervention design.