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Weighted gene co-regulation network analysis (WGCNA) of promoter DNA methylation on all-cause mortality in old-aged birth cohorts finds modules of high-risk associated biomarkers

Research output: Contribution to journalArticle

Original languageEnglish
JournalJournals of Gerontology, Series A
Early online date10 Mar 2020
Publication statusE-pub ahead of print - 10 Mar 2020


Overall or all-cause mortality is a key measure of health in a population. Multiple epigenome-wide association studies have been conducted on all-cause mortality with limited significant findings and low replication. In order to elucidate the co-regulated DNA methylation patterns associated with all-cause mortality, we conducted a weighted DNA methylation co-regulation network analysis on whole-blood samples of 1,425 older individuals from the Lothian Birth Cohorts of 1921 and 1936. Our network-based analysis defined coregulated DNA methylation patterns in gene promoters into clusters or modules whose correlation with all-cause mortality was assessed by survival analysis. We found two significant modules or gene clusters associated with all-cause mortality in LBC1921 based on their eigengenes; one negatively correlated (p=8.14E-03, 698 genes) and one positively correlated (p=4.26E-02, 1431 genes) with the risk of death. The two modules were replicated in LBC1936 with the same directions of correlation (p=6.35E-02 and p=3.64E-02, respectively). Furthermore, the modules revealed 32 genes associated with all-cause mortality (FDR<0.05) linked to various diseases, including cancer and diabetes. Additionally, we performed pathway analysis and found 22 pathways (FDR<0.05), including a pathway for taste transduction, which has been shown to be associated with poor prognosis in acutely hospitalized patients and several pathways were linked to different types of cancer. The results from our network analysis show that DNA methylation of multiple genes could have been co-regulated in an association with the overall risk of death. The identified epigenetic markers might help with our understanding of the molecular basis of all-cause mortality and general health.

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