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Optimized Analysis of DNA Methylation and Gene Expression from Small, Anatomically-defined Areas of the Brain
Published on: July 12, 2012
DNA methylation in relation to gestational age and brain dysmaturation in preterm infants
Emily N W Wheater1, Paola Galdi1, Daniel L McCartney2
1MRC Centre for Reproductive Health, The University of Edinburgh, Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK.
Insights
Preterm birth significantly impacts the neonatal methylome, affecting brain development pathways. DNA methylation variations may link preterm birth to altered brain connectivity in infants.
Area of Science:
- Epigenetics and Developmental Neuroscience
- Genomics and Neuroimaging
Background:
- Preterm birth is a major cause of childhood neurocognitive impairment, linked to structural brain network dysconnectivity.
- DNA methylation variations are associated with early extrauterine exposure, but their role in brain development requires further investigation.
Purpose of the Study:
- To investigate the impact of gestational age on the neonatal methylome using genome-wide DNA methylation data from saliva.
- To explore the relationship between DNA methylation patterns and white matter brain connectivity in preterm infants.
Main Methods:
- Genome-wide DNA methylation analysis of saliva from 258 neonates.
- Functional analysis to identify enriched gene sets associated with differential methylation.
- Correlation analysis linking differentially methylated probes with diffusion MRI metrics of white matter connectivity.
Main Results:
- Gestational age at birth was associated with widespread differential DNA methylation at term equivalent age, with significant associations for thousands of CpG probes and regions.
- Functional analysis revealed enriched gene ontology terms related to cell-cell and cell-extracellular matrix contacts.
- A principal component of DNA methylation variation was negatively associated with gestational age and correlated with white matter microstructure metrics (mean diffusivity and neurite density index).
Conclusions:
- Low gestational age profoundly affects the neonatal saliva methylome, with implications for brain development pathways.
- Differential DNA methylation may serve as a molecular link between preterm birth, altered brain connectivity, and neurodevelopmental outcomes.
Abstract:
Preterm birth is associated with dysconnectivity of structural brain networks and is a leading cause of neurocognitive impairment in childhood. Variation in DNA methylation is associated with early exposure to extrauterine life but there has been little research exploring its relationship with brain development. Using genome-wide DNA methylation data from the saliva of 258 neonates, we investigated the impact of gestational age on the methylome and performed functional analysis to identify enriched gene sets from probes that contributed to differentially methylated probes or regions. We tested the hypothesis that variation in DNA methylation could underpin the association between low gestational age at birth and atypical brain development by linking differentially methylated probes with measures of white matter connectivity derived from diffusion MRI metrics: peak width skeletonized mean diffusivity, peak width skeletonized fractional anisotropy and peak width skeletonized neurite density index. Gestational age at birth was associated with widespread differential methylation at term equivalent age, with genome-wide significant associations observed for 8870 CpG probes (P < 3.6 × 10-8) and 1767 differentially methylated regions. Functional analysis identified 14 enriched gene ontology terms pertaining to cell-cell contacts and cell-extracellular matrix contacts. Principal component analysis of probes with genome-wide significance revealed a first principal component that explained 23.5% of the variance in DNA methylation, and this was negatively associated with gestational age at birth. The first principal component was associated with peak width of skeletonized mean diffusivity (β = 0.349, P = 8.37 × 10-10) and peak width skeletonized neurite density index (β = 0.364, P = 4.15 × 10-5), but not with peak width skeletonized fraction anisotropy (β = -0.035, P = 0.510); these relationships mirrored the imaging metrics' associations with gestational age at birth. Low gestational age at birth has a profound and widely distributed effect on the neonatal saliva methylome that is apparent at term equivalent age. Enriched gene ontology terms related to cell-cell contacts reveal pathways that could mediate the effect of early life environmental exposures on development. Finally, associations between differential DNA methylation and image markers of white matter tract microstructure suggest that variation in DNA methylation may provide a link between preterm birth and the dysconnectivity of developing brain networks that characterizes atypical brain development in preterm infants.
