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=3.10x10-08), an intergenic region on chromosome 11 (cg00490349, p-value=2.41x10-08) and a differentially methylated region on chromosome 1 (FDR p-value for the region=9.06x10-05) 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.

DNA methylation as a potential mediator of the association between indoor air pollution and neurodevelopmental delay in a South African birth cohort

“…Exposure-mediator models were adjusted for SES score, genetic ancestry, and maternal smoking and mediator-outcome models were adjusted for maternal alcohol use, maternal age, SES score, child sex, genetic ancestry, and maternal smoking. We adjusted for genetic ancestry by including the rst ve genotype PCs to account for population strati cation [14]. Models were also adjusted for the rst three cell type principal components (PCs), which explained >90% of cell type heterogeneity [14,42,43].…”

“…As described previously [14], DNA was measured from cord blood collected at time of delivery [30]. DNA methylation measures were obtained with both the Illumina In nium HumanMethylation450 BeadChips (n=156) and the MethylationEPIC BeadChips (n=160).…”

“…With the rise of high-throughput genomics, the eld of epigenetics has undergone rapid development. Epigenetic modi cation, speci cally DNA methylation (DNAm), has been linked to a number of neuropsychiatric outcomes such as severe neurodevelopmental delay, schizophrenia, ASD, and ADHD [14][15][16][17][18][19][20]. DNAm is known to play a key role in embryonic development and has been hypothesized to impact neural stem cell differentiation and maintenance [21], thereby affecting neuropsychiatric outcomes throughout the life course.…”

DNA Methylation as a Potential Mediator of the Association Between Prenatal Tobacco and Alcohol Exposure and Child Neurodevelopment in a South African Birth Cohort

“…As described previously, DNA methylation was measured from cord blood using either the Illumina Infinium HumanMethylation450 BeadChip (450K; n=119) or the Infinium MethylationEPIC BeadChip (EPIC; n=147) arrays 23 . Pre-processing was conducted separately for each array in R 3.5.1, using an identical pre-processing pipeline.…”

“…The evidence is weaker for an association between PAE and the cord blood methylome 17 , although there has been some evidence of epigenomic changes in other tissues such as placental or buccal tissue 18 . While there is evidence that PTE and PAE influence DNA methylation in cord blood, not much is known about the subsequent adverse outcomes, such as delayed neurodevelopment 19,20 or about the association between newborn DNAm and child neurodevelopment or related disorders in general [21][22][23] . Thus, the biological mechanisms connecting PTE and PAE, DNAm and child neurodevelopment are largely unknown.…”