DNA methylation signatures in peripheral blood strongly predict all-cause mortality

TLDR

DNA methylation has been shown to influence a range of diseases. The study screened and validated epigenome‑wide DNA methylation signatures associated with mortality in a general population cohort followed for up to 14 years. Genome‑wide analysis identified 11,063 significant CpGs, of which 58 were replicated, and a ten‑CpG risk score was strongly associated with all‑cause mortality (HRs 2.16, 3.42, 7.36 for increasing score categories) and validated independently, indicating that DNA methylation of disease‑related genes predicts mortality beyond the epigenetic clock.

Abstract

Abstract DNA methylation (DNAm) has been revealed to play a role in various diseases. Here we performed epigenome-wide screening and validation to identify mortality-related DNAm signatures in a general population-based cohort with up to 14 years follow-up. In the discovery panel in a case-cohort approach, 11,063 CpGs reach genome-wide significance (FDR<0.05). 58 CpGs, mapping to 38 well-known disease-related genes and 14 intergenic regions, are confirmed in a validation panel. A mortality risk score based on ten selected CpGs exhibits strong association with all-cause mortality, showing hazard ratios (95% CI) of 2.16 (1.10–4.24), 3.42 (1.81–6.46) and 7.36 (3.69–14.68), respectively, for participants with scores of 1, 2–5 and 5+ compared with a score of 0. These associations are confirmed in an independent cohort and are independent from the ‘epigenetic clock’. In conclusion, DNAm of multiple disease-related genes are strongly linked to mortality outcomes. The DNAm-based risk score might be informative for risk assessment and stratification.