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

Lu, Ake T., Xue, Luting, Salfati, Elias L., Chen, Brian H., Ferrucci, Luigi, Levy, Daniel, Joehanes, Roby, Murabito, Joanne M., Kiel, Douglas P., Tsai, Pei-Chien, Yet, Idil, Bell, Jordana T., Mangino, Massimo, Tanaka, Toshiko, McRae, Allan F., Marioni, Riccardo E., Visscher, Peter M., Wray, Naomi R., Deary, Ian J., Levine, Morgan E., Quach, Austin, Assimes, Themistocles, Tsao, Philip S., Absher, Devin, Stewart, James D., Li, Yun, Reiner, Alex P., Hou, Lifang, Baccarelli, Andrea A., Whitsel, Eric A., Aviv, Abraham, Cardona, Alexia, Day, Felix R., Wareham, Nicholas J., Perry, John R. B., Ong, Ken K., Raj, Kenneth, Lunetta, Kathryn L. and Horvath, Steve (2018) GWAS of epigenetic aging rates in blood reveals a critical role for TERT. Nature Communications, 9 1: 387. doi:10.1038/s41467-017-02697-5

Author Lu, Ake T.
Xue, Luting
Salfati, Elias L.
Chen, Brian H.
Ferrucci, Luigi
Levy, Daniel
Joehanes, Roby
Murabito, Joanne M.
Kiel, Douglas P.
Tsai, Pei-Chien
Yet, Idil
Bell, Jordana T.
Mangino, Massimo
Tanaka, Toshiko
McRae, Allan F.
Marioni, Riccardo E.
Visscher, Peter M.
Wray, Naomi R.
Deary, Ian J.
Levine, Morgan E.
Quach, Austin
Assimes, Themistocles
Tsao, Philip S.
Absher, Devin
Stewart, James D.
Li, Yun
Reiner, Alex P.
Hou, Lifang
Baccarelli, Andrea A.
Whitsel, Eric A.
Aviv, Abraham
Cardona, Alexia
Day, Felix R.
Wareham, Nicholas J.
Perry, John R. B.
Ong, Ken K.
Raj, Kenneth
Lunetta, Kathryn L.
Horvath, Steve
Title GWAS of epigenetic aging rates in blood reveals a critical role for TERT
Journal name Nature Communications   Check publisher's open access policy
ISSN 2041-1723
Publication date 2018-01-26
Year available 2018
Sub-type Article (original research)
DOI 10.1038/s41467-017-02697-5
Open Access Status DOI
Volume 9
Issue 1
Start page 387
Total pages 13
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Subject 1600 Chemistry
1300 Biochemistry, Genetics and Molecular Biology
3100 Physics and Astronomy
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.
Keyword Genome-Wide Association
Dna Methylation Age
Normal Human Fibroblasts
Mean Telomere Length
Genotype Imputation
Biological Age
Clock Analysis
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID HHSN268201100001I
R01 ES020836
R01 AR061162
R01 HL076784
R01 AR041398
U01 HL053941
R01 AG029451
U34 AG051425
U01 HG005152
R01 HL070100
R01 AG042511
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Queensland Brain Institute Publications
Institute for Molecular Bioscience - Publications
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Created: Wed, 31 Jan 2018, 12:05:30 EST