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

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

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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 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 language	English
Article number	387
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-02697-5
Publication status	Published - 1 Dec 2018

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© 2018 The Author(s).

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Lu, A. T., Xue, L., Salfati, E. L., Chen, B. H., Ferrucci, L., Levy, D., Joehanes, R., Murabito, J. M., Kiel, D. P., Tsai, P. C., Yet, I., Bell, J. T., Mangino, M., Tanaka, T., McRae, A. F., Marioni, R. E., Visscher, P. M., Wray, N. R., Deary, I. J., ... Horvath, S. (2018). GWAS of epigenetic aging rates in blood reveals a critical role for TERT. Nature Communications, 9(1), Article 387. https://doi.org/10.1038/s41467-017-02697-5

@article{09f6571b303f4a0381092702444613f8,

title = "GWAS of epigenetic aging rates in blood reveals a critical role for TERT",

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.",

author = "Lu, {Ake T.} and Luting Xue and Salfati, {Elias L.} and Chen, {Brian H.} and Luigi Ferrucci and Daniel Levy and Roby Joehanes and Murabito, {Joanne M.} and Kiel, {Douglas P.} and Tsai, {Pei Chien} and Idil Yet and Bell, {Jordana T.} and Massimo Mangino and Toshiko Tanaka and McRae, {Allan F.} and Marioni, {Riccardo E.} and Visscher, {Peter M.} and Wray, {Naomi R.} and Deary, {Ian J.} and Levine, {Morgan E.} and Austin Quach and Themistocles Assimes and Tsao, {Philip S.} and Devin Absher and Stewart, {James D.} and Yun Li and Reiner, {Alex P.} and Lifang Hou and Baccarelli, {Andrea A.} and Whitsel, {Eric A.} and Abraham Aviv and Alexia Cardona and Day, {Felix R.} and Wareham, {Nicholas J.} and Perry, {John R.B.} and Ong, {Ken K.} and Kenneth Raj and Lunetta, {Kathryn L.} and Steve Horvath",

note = "Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = dec,

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doi = "10.1038/s41467-017-02697-5",

language = "English",

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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

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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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U2 - 10.1038/s41467-017-02697-5

DO - 10.1038/s41467-017-02697-5

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AN - SCOPUS:85041131712

SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 387

ER -

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

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