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. LevineAustin 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*

*Corresponding author for this work

Research output: Contribution to journalArticle

33 Citations (Scopus)

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.

Original languageEnglish (US)
Article number387
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

Fingerprint

Genome-Wide Association Study
Telomerase
Epigenomics
genes
blood
Blood
Genes
Aging of materials
telomeres
leukocytes
methylation
loci
Telomere
DNA Methylation
Mendelian Randomization Analysis
deoxyribonucleic acid
Leukocytes
lipoproteins
Telomere Shortening
genome

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Lu, A. T., Xue, L., Salfati, E. L., Chen, B. H., Ferrucci, L., Levy, D., ... Horvath, S. (2018). GWAS of epigenetic aging rates in blood reveals a critical role for TERT. Nature communications, 9(1), [387]. https://doi.org/10.1038/s41467-017-02697-5
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. / GWAS of epigenetic aging rates in blood reveals a critical role for TERT. In: Nature communications. 2018 ; Vol. 9, No. 1.
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Lu, AT, Xue, L, Salfati, EL, Chen, BH, Ferrucci, L, Levy, D, Joehanes, R, Murabito, JM, Kiel, DP, Tsai, PC, Yet, I, Bell, JT, Mangino, M, Tanaka, T, McRae, AF, Marioni, RE, Visscher, PM, Wray, NR, Deary, IJ, Levine, ME, Quach, A, Assimes, T, Tsao, PS, Absher, D, Stewart, JD, Li, Y, Reiner, AP, Hou, L, Baccarelli, AA, Whitsel, EA, Aviv, A, Cardona, A, Day, FR, Wareham, NJ, Perry, JRB, Ong, KK, Raj, K, Lunetta, KL & Horvath, S 2018, 'GWAS of epigenetic aging rates in blood reveals a critical role for TERT', Nature communications, vol. 9, no. 1, 387. https://doi.org/10.1038/s41467-017-02697-5

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.; Horvath, Steve.

In: Nature communications, Vol. 9, No. 1, 387, 01.12.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - GWAS of epigenetic aging rates in blood reveals a critical role for TERT

AU - Lu, Ake T.

AU - Xue, Luting

AU - Salfati, Elias L.

AU - Chen, Brian H.

AU - Ferrucci, Luigi

AU - Levy, Daniel

AU - Joehanes, Roby

AU - Murabito, Joanne M.

AU - Kiel, Douglas P.

AU - Tsai, Pei Chien

AU - Yet, Idil

AU - Bell, Jordana T.

AU - Mangino, Massimo

AU - Tanaka, Toshiko

AU - McRae, Allan F.

AU - Marioni, Riccardo E.

AU - Visscher, Peter M.

AU - Wray, Naomi R.

AU - Deary, Ian J.

AU - Levine, Morgan E.

AU - Quach, Austin

AU - Assimes, Themistocles

AU - Tsao, Philip S.

AU - Absher, Devin

AU - Stewart, James D.

AU - Li, Yun

AU - Reiner, Alex P.

AU - Hou, Lifang

AU - Baccarelli, Andrea A.

AU - Whitsel, Eric A.

AU - Aviv, Abraham

AU - Cardona, Alexia

AU - Day, Felix R.

AU - Wareham, Nicholas J.

AU - Perry, John R.B.

AU - Ong, Ken K.

AU - Raj, Kenneth

AU - Lunetta, Kathryn L.

AU - Horvath, Steve

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

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