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 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.