RT Journal Article SR Electronic T1 GWAS of epigenetic ageing rates in blood reveals a critical role for TERT JF bioRxiv FD Cold Spring Harbor Laboratory SP 157776 DO 10.1101/157776 A1 Ake T. Lu A1 Luting Xue A1 Elias L. Salfati A1 Brian H. Chen A1 Luigi Ferrucci A1 Daniel Levy A1 Roby Joehanes A1 Joanne M Murabito A1 Douglas P. Kiel A1 Pei-Chien Tsai A1 Idil Yet A1 Jordana T. Bell A1 Massimo Mangino A1 Toshiko Tanaka A1 Allan F. McRae A1 Riccardo E. Marioni A1 Peter M. Visscher A1 Naomi R. Wray A1 Ian J. Deary A1 Morgan E. Levine A1 Austin Quach A1 Themistocles Assimes A1 Philip S. Tsao A1 Devin Absher A1 James D. Stewart A1 Yun Li A1 Alex P. Reiner A1 Lifang Hou A1 Andrea A. Baccarelli A1 Eric A. Whitsel A1 Abraham Aviv A1 Alexia Cardona A1 Felix R. Day A1 John R.B. Perry A1 Ken K. Ong A1 Kenneth Raj A1 Kathryn L. Lunetta A1 Steve Horvath YR 2017 UL http://biorxiv.org/content/early/2017/06/30/157776.abstract 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 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<2.7×10-11). 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.