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GWAS of epigenetic ageing rates in blood reveals a critical role for TERT

View ORCID ProfileAke T. Lu, Luting Xue, Elias L. Salfati, Brian H. Chen, View ORCID ProfileLuigi Ferrucci, Daniel Levy, Roby Joehanes, View ORCID ProfileJoanne M Murabito, Douglas P. Kiel, Pei-Chien Tsai, Idil Yet, View ORCID ProfileJordana T. Bell, View ORCID ProfileMassimo Mangino, Toshiko Tanaka, Allan F. McRae, View ORCID ProfileRiccardo E. Marioni, View ORCID ProfilePeter M. Visscher, View ORCID ProfileNaomi R. Wray, Ian J. Deary, Morgan E. Levine, Austin Quach, View ORCID ProfileThemistocles Assimes, Philip S. Tsao, View ORCID ProfileDevin Absher, James D. Stewart, Yun Li, Alex P. Reiner, Lifang Hou, Andrea A. Baccarelli, Eric A. Whitsel, Abraham Aviv, View ORCID ProfileAlexia Cardona, Felix R. Day, John R.B. Perry, Ken K. Ong, Kenneth Raj, Kathryn L. Lunetta, View ORCID ProfileSteve Horvath
doi: https://doi.org/10.1101/157776
Ake T. Lu
1Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
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Luting Xue
2Department of Biostatistics, Boston University School of Public Health, Boston, MA, 0223, USA
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Elias L. Salfati
3Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
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Brian H. Chen
4Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland.
5National Heart, Lung and Blood Institute, Bethesda, MD 20824-0105, USA
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Luigi Ferrucci
4Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland.
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Daniel Levy
5National Heart, Lung and Blood Institute, Bethesda, MD 20824-0105, USA
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Roby Joehanes
5National Heart, Lung and Blood Institute, Bethesda, MD 20824-0105, USA
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Joanne M Murabito
6Department of Medicine, Section of General Medicine, Boston University School of Medicine, Boston, MA, USA
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Douglas P. Kiel
7Institute for Aging Research, Hebrew SeniorLife, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, MA 02215, USA
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Pei-Chien Tsai
8Department of Twin Research and Genetic Epidemiology, Kings College London, London SE1 7EH, UK
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Idil Yet
8Department of Twin Research and Genetic Epidemiology, Kings College London, London SE1 7EH, UK
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Jordana T. Bell
8Department of Twin Research and Genetic Epidemiology, Kings College London, London SE1 7EH, UK
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Massimo Mangino
8Department of Twin Research and Genetic Epidemiology, Kings College London, London SE1 7EH, UK
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Toshiko Tanaka
4Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland.
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Allan F. McRae
9Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072, QLD, Australia
10Queensland Brain Institute, The University of Queensland, Brisbane, 4072, QLD, Australia
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Riccardo E. Marioni
9Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072, QLD, Australia
11Centre for Cognitive Aging and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK
12Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK
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Peter M. Visscher
9Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072, QLD, Australia
10Queensland Brain Institute, The University of Queensland, Brisbane, 4072, QLD, Australia
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Naomi R. Wray
9Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072, QLD, Australia
10Queensland Brain Institute, The University of Queensland, Brisbane, 4072, QLD, Australia
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Ian J. Deary
11Centre for Cognitive Aging and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK
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Morgan E. Levine
1Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
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Austin Quach
1Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
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Themistocles Assimes
3Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
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Philip S. Tsao
3Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
13VA Palo Alto Health Care System, Palo Alto CA, USA
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Devin Absher
14HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA
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James D. Stewart
15Dept. of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA
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Yun Li
16Department of Genetics, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
17Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27599, USA
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Alex P. Reiner
18Fred Hutchinson Cancer Research Center Box 358080, WHI Clinical Coordinating Ctr / Public Health Sciences M3-A4
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Lifang Hou
19Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University Chicago, IL 60611, USA
20Center for Population Epigenetics, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University Chicago, IL 60611, USA
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Andrea A. Baccarelli
21Laboratory of Environmental Epigenetics, Departments of Environmental Health Sciences Epidemiology, Columbia University Mailman School of Public Health, New York, NY 10032, USA
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Eric A. Whitsel
15Dept. of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA
22Dept. of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC, USA
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Abraham Aviv
23The Center for Human Development and Aging, University of Medicine and Dentistry, New Jersey Medical School, Rutgers, Newark, New Jersey 07103, USA
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Alexia Cardona
24Medical Research Council (MRC) Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK
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Felix R. Day
24Medical Research Council (MRC) Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK
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John R.B. Perry
24Medical Research Council (MRC) Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK
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Ken K. Ong
24Medical Research Council (MRC) Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK
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Kenneth Raj
25Radiation Effects Department, Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Chilton, Didcot, Oxfordshire, OX11 0RQ, United Kingdom
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Kathryn L. Lunetta
2Department of Biostatistics, Boston University School of Public Health, Boston, MA, 0223, USA
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Steve Horvath
1Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
26Biostatistics, School of Public Health, University of California Los Angeles, Los Angeles, California, Los Angeles, CA 90095, USA
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  • For correspondence: shorvath@mednet.ucla.edu
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Abstract

DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9,907 individuals, we found gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in 3 loci associated extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggested causal influences of menarche and menopause on IEAA and lipid levels on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) locus at 5p15.33 confer higher IEAA (P<2.7×10-11). Causal modelling indicates TERT-specific and independent effects on LTL and IEAA. Experimental hTERT expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number. Together, these findings indicate a critical role for hTERT in regulating the DNA methylation clock, in addition to its established role of compensating for cell replication-dependent telomere shortening.

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GWAS of epigenetic ageing rates in blood reveals a critical role for TERT
Ake T. Lu, Luting Xue, Elias L. Salfati, Brian H. Chen, Luigi Ferrucci, Daniel Levy, Roby Joehanes, Joanne M Murabito, Douglas P. Kiel, Pei-Chien Tsai, Idil Yet, Jordana T. Bell, Massimo Mangino, Toshiko Tanaka, Allan F. McRae, Riccardo E. Marioni, Peter M. Visscher, Naomi R. Wray, Ian J. Deary, Morgan E. Levine, Austin Quach, Themistocles Assimes, Philip S. Tsao, Devin Absher, James D. Stewart, Yun Li, Alex P. Reiner, Lifang Hou, Andrea A. Baccarelli, Eric A. Whitsel, Abraham Aviv, Alexia Cardona, Felix R. Day, John R.B. Perry, Ken K. Ong, Kenneth Raj, Kathryn L. Lunetta, Steve Horvath
bioRxiv 157776; doi: https://doi.org/10.1101/157776
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GWAS of epigenetic ageing rates in blood reveals a critical role for TERT
Ake T. Lu, Luting Xue, Elias L. Salfati, Brian H. Chen, Luigi Ferrucci, Daniel Levy, Roby Joehanes, Joanne M Murabito, Douglas P. Kiel, Pei-Chien Tsai, Idil Yet, Jordana T. Bell, Massimo Mangino, Toshiko Tanaka, Allan F. McRae, Riccardo E. Marioni, Peter M. Visscher, Naomi R. Wray, Ian J. Deary, Morgan E. Levine, Austin Quach, Themistocles Assimes, Philip S. Tsao, Devin Absher, James D. Stewart, Yun Li, Alex P. Reiner, Lifang Hou, Andrea A. Baccarelli, Eric A. Whitsel, Abraham Aviv, Alexia Cardona, Felix R. Day, John R.B. Perry, Ken K. Ong, Kenneth Raj, Kathryn L. Lunetta, Steve Horvath
bioRxiv 157776; doi: https://doi.org/10.1101/157776

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