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Newborn Differential DNA Methylation and Subcortical Brain Volumes as Early Signs of Severe Delay in Neurodevelopment

By Anke Hüls, Catherine J Wedderburn, Nynke A. Groenewold, Nicole Gladish, Meaghan Jones, Nastassja Koen, Julia L. MacIsaac, David TS Lin, Katia E Ramadori, Michael P. Epstein, Kirsten A. Donald, Michael S Kobor, Heather J. Zar, Dan J. Stein

Posted 17 Mar 2020
medRxiv DOI: 10.1101/2020.03.13.20035501

ObjectiveThe 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 levels from cord blood, neonatal MRI imaging data, and neurodevelopmental delay at two years of age. MethodsNeurodevelopment 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. We performed an epigenome-wide association study of neurodevelopmental delay using DNA methylation levels from cord blood. A mediation analysis was conducted to analyze if associations between differential methylation and neurodevelopmental delay were mediated by changes in neonatal brain volumes. ResultsWe found epigenome-wide significant associations between severe neurodevelopmental delay and differential methylation in the SPTBN4 locus (cg26971411, p-value=3.10x10-08), an intergenic region on chromosome 11 (cg00490349, p-value=2.41x10-08) and in the NBPF8 locus (FDR p-value for the region=9.06x10-05). While these associations were not mediated by neonatal brain volume, neonatal caudate volumes were independently associated with severe neurodevelopmental delay, particularly with language development (p-value=0.0443) and delay in motor function (p-value=0.0082). ConclusionDifferential methylation levels from cord blood and increased neonatal caudate volumes were associated with severe neurodevelopmental delay at two years of age. If confirmed by future studies, our findings could have implications for early detection of developmental delay and timely implementation of interventions, which are essential for positive child development.

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