GWAS of epigenetic aging 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; Nicholas J Wareham; John R B Perry; Ken K Ong; Kenneth Raj; Kathryn L Lunetta; Steve Horvath

doi:10.1038/s41467-017-02697-5

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

Nat Commun. 2018 Jan 26;9(1):387. doi: 10.1038/s41467-017-02697-5.

Authors

Ake T Lu¹, Luting Xue², Elias L Salfati³, Brian H Chen^{4

5}, Luigi Ferrucci⁴, Daniel Levy⁵, Roby Joehanes⁵, Joanne M Murabito⁶, Douglas P Kiel⁷, Pei-Chien Tsai⁸, Idil Yet⁸, Jordana T Bell⁸, Massimo Mangino⁸, Toshiko Tanaka⁴, Allan F McRae^{9

10}, Riccardo E Marioni^{9

11

12}, Peter M Visscher^{9

10}, Naomi R Wray^{9

10}, Ian J Deary¹¹, Morgan E Levine¹, Austin Quach¹, Themistocles Assimes³, Philip S Tsao^{3

13}, Devin Absher¹⁴, James D Stewart¹⁵, Yun Li^{16

17}, Alex P Reiner¹⁸, Lifang Hou^{19

20}, Andrea A Baccarelli²¹, Eric A Whitsel^{15

22}, Abraham Aviv²³, Alexia Cardona²⁴, Felix R Day²⁴, Nicholas J Wareham²⁴, John R B Perry²⁴, Ken K Ong^{24

25}, Kenneth Raj²⁶, Kathryn L Lunetta², Steve Horvath^{27

28}

Affiliations

¹ Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
² Department of Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA.
³ Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
⁴ Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.
⁵ National Heart, Lung and Blood Institute, Bethesda, MD, 20824-0105, USA.
⁶ Department of Medicine, Section of General Medicine, Boston University School of Medicine, Boston, MA, 02118, USA.
⁷ Institute for Aging Research, Hebrew SeniorLife, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, MA, 02215, USA.
⁸ Department of Twin Research and Genetic Epidemiology, Kings College London, London, SE1 7EH, UK.
⁹ Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072, QLD, Australia.
¹⁰ Queensland Brain Institute, The University of Queensland, Brisbane, 4072, QLD, Australia.
¹¹ Centre for Cognitive Aging and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, 7 George Square, Edinburgh, EH8 9JZ, UK.
¹² Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.
¹³ VA Palo Alto Health Care System, Palo Alto, CA, 94304, USA.
¹⁴ HudsonAlpha Institute for Biotechnology, Huntsville, AL, 35806, USA.
¹⁵ Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, 27599, USA.
¹⁶ Department of Genetics, School of Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA.
¹⁷ Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, 27599, USA.
¹⁸ Fred Hutchinson Cancer Research Center Box 358080, WHI Clinical Coordinating Ctr/Public Health Sciences M3-A4, Seattle, WA, 98109, USA.
¹⁹ Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University Chicago, Evanston, IL, 60611, USA.
²⁰ Center for Population Epigenetics, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University Chicago, Evanston, IL, 60611, USA.
²¹ Laboratory of Environmental Epigenetics, Departments of Environmental Health Sciences Epidemiology, Columbia University Mailman School of Public Health, New York, NY, 10032, USA.
²² Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC, 27516, USA.
²³ The Center for Human Development and Aging, University of Medicine and Dentistry, New Jersey Medical School, Rutgers, Newark, NJ, 07103, USA.
²⁴ Medical Research Council (MRC) Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, CB2 0SL, UK.
²⁵ Department of Paediatrics, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge, CB2 0SP, UK.
²⁶ Radiation Effects Department, Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Chilton, Didcot, Oxfordshire, OX11 0RQ, UK.
²⁷ Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA. shorvath@mednet.ucla.edu.
²⁸ Biostatistics, School of Public Health, University of California, Los Angeles, Los Angeles, CA, 90095, USA. shorvath@mednet.ucla.edu.

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 9907 individuals, we find gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in three loci associated with extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggests causal influences of menarche and menopause on IEAA and lipoproteins on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) paradoxically confer higher IEAA (P < 2.7 × 10^-11). Causal modeling 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 epigenetic clock, in addition to its established role of compensating for cell replication-dependent telomere shortening.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adolescent
Adult
Aged
Aged, 80 and over
Aging / genetics*
Cells, Cultured
Child
CpG Islands / genetics
DNA Methylation / genetics*
Epigenesis, Genetic / genetics*
Female
Fibroblasts
Genome-Wide Association Study
Humans
Leukocytes / metabolism
Male
Menarche
Mendelian Randomization Analysis
Menopause
Middle Aged
Telomerase / genetics*
Telomere / metabolism
Young Adult

Substances

TERT protein, human
Telomerase

Abstract

Publication types

MeSH terms

Substances

Grants and funding