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

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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 & 19 more 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

Original languageEnglish
Article number387
JournalNature Communications
Volume9
Issue number1
Early online date26 Jan 2018
DOIs
Accepted/In press19 Dec 2017
E-pub ahead of print26 Jan 2018

King's Authors

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.

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