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

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.

Figure 1. Methylation levels of 58 CpGs among deceased (N=231) and survivors (N=769) in the validation panel of the ESTHER cohort.

(a) Mean and s.d. (error bar) of 22 mortality-related CpGs (also discovered to be associated with smoking in both current and previous studies) by vital status; (b) mean and s.d. (error bar) of 26 mortality-related CpGs (also discovered to be associated with smoking in the current study) by vital status; (c) mean and s.d. (error bar) of other 10 mortality-related CpGs by vital status.

Figure 2. Dose–response relationships between continuous risk score and all-cause mortality.

(a) Dose–response curve in the ESTHER study (N=1,000 (231 deaths)); (b) dose–response curve in the KORA study (N=1,727 (61 deaths)).

Figure 3. Kaplan–Meier estimates of survival by risk score in the ESTHER study (N=1,000).

(a) Survival curves with respect to death from any causes; (b) survival curves with respect to death from cancer; (c) survival curves with respect to death from CVD. P_log-rank was derived from log-rank test.