Integrative Co-methylation Network Analysis Identifies Novel DNA Methylation Signatures and Their Target Genes in Alzheimer?s Disease

BACKGROUND: DNA methylation is a key epigenetic marker, and its alternations may be involved in Alzheimer's disease (AD). CpGs sharing similar biological functions or pathways tend to be co-methylated.METHODS: We performed an integrative network-based DNA methylation analysis on 2 independent cohorts (N = 941) using brain DNA methylation profiles and RNA-sequencing as well as AD pathology data.RESULTS: Weighted co-methylation network analysis identified 6 modules as significantly associated with neuritic plaque burden. In total, 15 hub CpGs including 3 novel CpGs were identified and replicated as being significantly associated with AD pathology. Furthermore, we identified and replicated 4 target genes (ATP6V1G2, VCP, RAD52, and LST1) as significantly regulated by DNA methylation at hub CpGs. In particular, VCP gene expression was also associated with AD pathology in both cohorts.CONCLUSIONS: This integrative network-based multiomics study provides compelling evidence for a potential role of DNA methylation alternations and their target genes in AD.