Blood DNA methylation sites predict death risk in a longitudinal study of 12,300 individuals

Elena Colicino, Riccardo Marioni, Cavin Ward-Caviness, Rahul Gondalia, Weihua Guan, Brian Chen, Pei Chien Tsai, Tianxiao Huan, Gao Xu, Agha Golareh, Joel Schwartz, Pantel Vokonas, Allan Just, John M. Starr, Allan F. McRae, Naomi R. Wray, Peter M. Visscher, Jan Bressler, Wen Zhang, Toshiko TanakaAnn Zenobia Moore, Luke C. Pilling, Guosheng Zhang, James D. Stewart, Yun Li, Lifang Hou, Juan Castillo-Fernandez, Tim Spector, Douglas P. Kiel, Joanne M. Murabito, Chunyu Liu, Mike Mendelson, Tim Assimes, Devin Absher, Phil S. Tsaho, Ake T. Lu, Luigi Ferrucci, Rory Wilson, Melanie Waldenberger, Holger Prokisch, Stefania Bandinelli, Jordana T. Bell, Daniel Levy, Ian J. Deary, Steve Horvath, Jim Pankow, Annette Peters, Eric A. Whitsel, Andrea Baccarelli

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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.

Original languageEnglish
Pages (from-to)14092-14124
Number of pages33
Issue number14
StatePublished - 31 Jul 2020


  • Aging
  • All-cause mortality
  • DNA methylation, 450K
  • Epigenome-wide association studies


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