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

Abstract

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.