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Research Paper|Volume 11, Issue 16|pp 5895—5923

DNA methylation-based estimator of telomere length

Ake T. Lu1, Anne Seeboth2, Pei-Chien Tsai3,4,5, Dianjianyi Sun6,7, Austin Quach1, Alex P. Reiner8, Charles Kooperberg8, Luigi Ferrucci9, Lifang Hou10, Andrea A. Baccarelli11, Yun Li12, Sarah E. Harris13,14, Janie Corley13,14, Adele Taylor13,14, Ian J. Deary13,14, James D. Stewart15, Eric A. Whitsel15,16, Themistocles L. Assimes17,18, Wei Chen7, Shengxu Li19, Massimo Mangino3, Jordana T. Bell3, James G. Wilson20, Abraham Aviv21, Riccardo E. Marioni2,13, Kenneth Raj22, Steve Horvath1,23
  • 1Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
  • 2Centre for Genomic and Experimental Medicine, Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK
  • 3Department of Twin Research and Genetic Epidemiology, Kings College London, London SE1 7EH, UK
  • 4Department of Biomedical Sciences, Chang Gung University, Taoyuan, Taiwan
  • 5Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan
  • 6Department of Epidemiology and Biostatistics, School of Public Health, Peking University Health Science Center, Beijing, China
  • 7Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 70112, USA
  • 8Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
  • 9Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
  • 10Center for Population Epigenetics, Robert H. Lurie Comprehensive Cancer Center and Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
  • 11Laboratory of Environmental Epigenetics, Departments of Environmental Health Sciences Epidemiology, Columbia University Mailman School of Public Health, New York, NY 10032, USA
  • 12Departments of Genetics, Biostatistics, Computer Science, University of North Carolina, Chapel Hill, NC 27599, USA
  • 13Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK
  • 14Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK
  • 15Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27599, USA
  • 16Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
  • 17VA Palo Alto Health Care System, Palo Alto, CA 94304, USA
  • 18Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
  • 19Children’s Minnesota Research Institute, Children’s Hospitals and Clinics of Minnesota, Minneapolis, MN 55404, USA
  • 20Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA
  • 21Center of Development and Aging, New Jersey Medical School, Rutgers State University of New Jersey, Newark, NJ 07103, USA
  • 22Radiation Effects Department, Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Chilton, Didcot, Oxfordshire OX11 0RQ, UK
  • 23Department of Biostatistics, Fielding School of Public Health, University of California Los Angeles, Los Angeles, CA 90095, USA
* Joint last authors
Received: July 25, 2019Accepted: August 5, 2019Published: August 18, 2019

Copyright © 2019 Lu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution (CC BY 3.0) License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Telomere length (TL) is associated with several aging-related diseases. Here, we present a DNA methylation estimator of TL (DNAmTL) based on 140 CpGs. Leukocyte DNAmTL is applicable across the entire age spectrum and is more strongly associated with age than measured leukocyte TL (LTL) (r ~-0.75 for DNAmTL versus r ~ -0.35 for LTL). Leukocyte DNAmTL outperforms LTL in predicting: i) time-to-death (p=2.5E-20), ii) time-to-coronary heart disease (p=6.6E-5), iii) time-to-congestive heart failure (p=3.5E-6), and iv) association with smoking history (p=1.21E-17). These associations are further validated in large scale methylation data (n=10k samples) from the Framingham Heart Study, Women's Health Initiative, Jackson Heart Study, InChianti, Lothian Birth Cohorts, Twins UK, and Bogalusa Heart Study. Leukocyte DNAmTL is also associated with measures of physical fitness/functioning (p=0.029), age-at-menopause (p=0.039), dietary variables (omega 3, fish, vegetable intake), educational attainment (p=3.3E-8) and income (p=3.1E-5). Experiments in cultured somatic cells show that DNAmTL dynamics reflect in part cell replication rather than TL per se. DNAmTL is not only an epigenetic biomarker of replicative history of cells, but a useful marker of age-related pathologies that are associated with it.