Association between epigenome-wide DNA methylation changes and early neurodevelopment in preschool children: Evidence from a former impoverished county in Central China.

BACKGROUND

Existing epigenome-wide association studies (EWAS) investigating the association between DNA methylation (DNAm) and child neurodevelopment have been predominantly conducted within Western populations, and yielded inconsistent results, leading to a significant gap within non-Western setting, particularly in resource-limited rural areas of Central China.

OBJECTIVES

To investigate the association between altered epigenome-wide DNAm and neurodevelopment in preschool children from resource-limited rural areas of Central China.

METHODS

This case-control study involved 64 preschoolers. We assessed children's neurodevelopment using the Gesell Developmental Diagnostic Scale. The neurodevelopmental potential was expressed as a global developmental quotient (DQ) score. We conducted an EWAS with an Illumina Infinium MethylationEPIC v1.0 BeadChip array, using blood samples from 32 suspected developmental delay children (DQ scores < 85) and 32 controls (DQ scores ≥ 85). Differentially methylated probes (DMPs) and differentially methylated regions (DMRs) between the suspected developmental delay and control groups were analyzed. Multivariate linear regression models were used to evaluate the association between global DQ scores and DNAm. Functional enrichment analyses were conducted using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). The BECon tool was utilized to estimate the concordance of CpGs between blood and the human brain.

RESULTS

A total of 66 DMRs (P < 0.05) were identified between the two groups, but no DMPs were found. After FDR correction, 844 methylated CpG sites exhibited significant associations with the global DQ scores in children. Genes annotated by methylated CpGs were mainly enriched in the "oxytocin signaling pathway", "mTOR signaling pathway", and "thyroid hormone signaling pathway". They were also involved in the "regulation of cell development", "cell-cell junction", and "ATPase activity". Among the top 20 CpGs, nine global DQ scores related-CpGs had blood-brain DNA methylation correlations, and six CpGs among them had an absolute Spearman correlation coefficient bigger than 0.2.

CONCLUSIONS

Preschoolers from a former impoverished county exhibited epigenome-wide DNAm changes strongly linked to early neurodevelopment. This study enhances our understanding of the epigenetic landscape associated with early neurodevelopment, and suggests the potential for developmenting epigenetic biomarkers that could facilitate the early identification of children at a higher risk of compromised neurodevelopment, as well as holding implication to inform novel interventions, especially in underprivileged regions.