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.
Bibliographical noteFunding Information:
The study was supported by U34AG051425-01, NIA/NIH 5R01AG042511-02, and the Paul G. Allen Frontiers Group. The WHI program is funded by the NIH/NHLBI, U.S. Department of Health and Human Services through contracts NIH/NHLBI 60442456 BAA23 (Assimes, Absher, Horvath), HHSN268201100046C,HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C, Epigenetic Mechanisms of PM-Mediated CVD Risk (WHI-EMPC), NIH/NIEHS R01ES020836 (Whitsel, Baccarelli; Hou). SNP Health Association Resource project (WHI-SHARe), NIH/NHLBI N02HL64278 GWAS of Hormone Treatment and CVD and Metabolic Outcomes within the Genomics and Randomized Trials Network“ (WHI-GARNET), NIH/NHGRI U01HG005152 (Reiner). The Fra-mingham Heart Study is funded by the National Institutes of Health contract to Boston University N01-HC-5195 and HHSN268201500001I and its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278). Funding to support the Omni cohort recruitment, retention, and examination was provided by the NHLBI Contract N01-HC-25195 and HHSN268201500001I, as well as NHLBI grants R01-HL070100, R01-HL076784, R01-HL-49869, and U01-HL-053941.” The DNA methylation resource from the FHS was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health. L.X., K.L.L., and J.M.M. were supported by R01AG029451. D.P.K. was supported by R01AR041398 and R01AR061162. TwinsUK is funded by the Wellcome Trust and European Community’s Seventh Framework Programme (FP7/2007–2013), and also receives support from the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. SNP Genotyping in TwinsUK was performed by The Wellcome Trust Sanger Institute and National Eye Institute via NIH/ CIDR. P.-C.T. and J.T.B. were supported by ESRC (ES/N000404/1). EPIC-Norfolk is supported by the Medical Research Council (MRC) [G9502233; G0401527; G100143; MC_PC_13048; MR/L00002/1] and Cancer Research UK [C864/A8257]. A.C., F.R.D., N. J.W., J.R.B.P., and K.K.O. are supported by the MRC [MC_UU_12015/1; MC_UU_12015/2].
© 2018 The Author(s).