Research Paper Volume 12, Issue 14 pp 14092—14124
Blood DNA methylation sites predict death risk in a longitudinal study of 12, 300 individuals
- 1 Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- 2 Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK
- 3 US Environmental Protection Agency, Chapel Hill, NC 27514, USA
- 4 Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27514, USA
- 5 Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN 55455, USA
- 6 Longitudinal Study Section, Translational Gerontology Branch, National Institute of Aging, Bethesda, MD 20892, USA
- 7 Department of Twin Research and Genetic Epidemiology, King’s College London, London SE1 7EH, UK
- 8 National Heart, Lung, and Blood Institute, Bethesda, MD 20892, USA
- 9 Columbia University Mailman School of Public Health, New York, NY 10032, USA
- 10 Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
- 11 VA Boston Healthcare System and Boston University Schools of Public Health and Medicine, Boston, MA 02115, USA
- 12 Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh EH8 9JZ, UK
- 13 Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
- 14 University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- 15 Department of Biostatistics and Data Science, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
- 16 Epidemiology and Public Health Group, University of Exeter Medical School, Exeter, UK
- 17 Department of Genetics, University of North Carolina, Chapel Hill, NC 27514, USA
- 18 Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
- 19 Hebrew SeniorLife Institute for Aging Research and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School Boston, MA 02215, USA
- 20 Section General Internal Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA 02215, USA
- 21 Boston University School of Public Health, Boston, MA 02215, USA
- 22 Boston University School of Medicine, Boston, MA 02215, USA
- 23 Stanford University School of Medicine, Stanford, CA 94305, USA
- 24 Hudson Alpha Institute for Biotechnology, Huntsville, AL 35806, USA
- 25 Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
- 26 National Institute of Aging, Bethesda, MD 20892, USA
- 27 Research Unit of Molecular Epidemiology, Helmholtz Zentrum Munich, German Research Center for Environmental Health, Neuherberg D-85764, Germany
- 28 Institute of Human Genetics, Helmholtz Zentrum Munich, German Research Center for Environmental Health, Neuherberg S-85764, Germany
- 29 Geriatric Unit, Azienda Sanitaria Firenze, Florence, Italy
- 30 Framingham Heart Study, Framingham, MA 01702, USA
- 31 Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK
- 32 Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55455, USA
- 33 Institute for Epidemiology II, Helmholtz Zentrum Munich, German Research Center for Environmental Health, Neuherberg D-85764, Germany
Received: February 10, 2020 Accepted: May 25, 2020 Published: July 22, 2020
https://doi.org/10.18632/aging.103408How to Cite
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.