Abstract
DNA methylation has fundamental roles in gene programming and aging that may help predict mortality. However, no large-scale study has investigated whether site-specific DNA methylation predicts all-cause mortality. We used the Illumina-HumanMethylation450-BeadChip to identify blood DNA methylation sites associated with all-cause mortality for 12, 300 participants in 12 Cohorts of the Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium. Over an average 10-year follow-up, there were 2,561 deaths across the cohorts. Nine sites mapping to three intergenic and six gene-specific regions were associated with mortality (P < 9.3x10-7) independently of age and other mortality predictors. Six sites (cg14866069, cg23666362, cg20045320, cg07839457, cg07677157, cg09615688)—mapping respectively to BMPR1B, MIR1973, IFITM3, NLRC5, and two intergenic regions—were associated with reduced mortality risk. The remaining three sites (cg17086398, cg12619262, cg18424841)—mapping respectively to SERINC2, CHST12, and an intergenic region—were associated with increased mortality risk. DNA methylation at each site predicted 5%–15% of all deaths. We also assessed the causal association of those sites to age-related chronic diseases by using Mendelian randomization, identifying weak causal relationship between cg18424841 and cg09615688 with coronary heart disease. Of the nine sites, three (cg20045320, cg07839457, cg07677157) were associated with lower incidence of heart disease risk and two (cg20045320, cg07839457) with smoking and inflammation in prior CHARGE analyses. Methylation of cg20045320, cg07839457, and cg17086398 was associated with decreased expression of nearby genes (IFITM3, IRF, NLRC5, MT1, MT2, MARCKSL1) linked to immune responses and cardiometabolic diseases. These sites may serve as useful clinical tools for mortality risk assessment and preventative care.
Highlights
The human epigenome contains DNA methylation marks that progressively change as we age
Across studies in the Cohorts of the Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium, mortality rates ranged from 3%–70% of all participants, and the average time to death or censoring ranged from 4.4–16.6 years (Supplementary Table 1)
We identified three Bonferroni-significant and nine false discovery rate (FDR)-significant (P < 9.3x10-7) CpGs in a fully-adjusted model adjusting for education, smoking status, pack-years smoked, body mass index, recreational physical activity, alcohol consumption, hypertension, diabetes, and history of cancer and coronary heart disease (Figures 2B, 3A and Supplementary Table 3)
Summary
The human epigenome contains DNA methylation marks that progressively change as we age. Biological age estimations, constructed from DNA methylation marks and referred to as “epigenetic aging clocks”, have been associated with environmental exposures, morbidities, and mortality [9,10,11,12,13]. As these clocks were designed to track chronological age, not to predict mortality, further study is necessary to fully elucidate indicators of all-cause mortality. We assessed the causal relationship of identified sites with age-related chronic diseases using Mendelian randomization approaches, and we related the sites to epigenetic aging clocks and a mortality risk score, an epigenetic indicator of mortality previously created and validated with DNA methylation arrays in two European cohorts
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