GWAS of epigenetic ageing rates in blood reveals a critical role for TERT
By
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 L 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,
John R.B. Perry,
Ken K. Ong,
Kenneth Raj,
Kathryn L. Lunetta,
Steve Horvath
Posted 30 Jun 2017
bioRxiv DOI: 10.1101/157776
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 9,907 individuals, we found gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in 3 loci associated extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggested causal influences of menarche and menopause on IEAA and lipid levels on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) locus at 5p15.33 confer higher IEAA (P<2.7x10-11). Causal modelling 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 DNA methylation clock, in addition to its established role of compensating for cell replication-dependent telomere shortening.
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