09 Mar 22. Featured Paper
DNA methylation in relation to gestational age and brain dysmaturation in preterm infants
Link to paper on Brain Communications
Emily N. W. Wheater, Paola Galdi, Daniel L. McCartney, Manuel Blesa, Gemma Sullivan, David Q. Stoye, Gillian Lamb, Sarah Sparrow, Lee Murphy, Nicola Wrobel, Alan J. Quigley, Scott Semple, Michael J. Thrippleton, Joanna M. Wardlaw, Mark E. Bastin, Riccardo E. Marioni, Simon R. Cox, James P. Boardman
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 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 skeletonised mean diffusivity, peak width skeletonised fractional anisotropy and peak width skeletonised neurite density index.
Gestational age at birth was associated with widespread differential methylation at term equivalent age, with genome-wide significant associations observed for 8,870 CpG probes (p < 3.6 × 10−8) and 1,767 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 variance in DNA methylation, and this was negatively associated with gestational age at birth.
The first principal component was associated with peak width of skeletonised mean diffusivity (β=0.349, p = 8.37 × 10−10) and peak width skeletonised neurite density index (β=0.364, p = 4.15 × 10−5), but not with peak width skeletonised 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 characterises atypical brain development in preterm infants.
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