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

被引：143

作者：

Lu, Ake T. ^{[1
]}

Xue, Luting ^{[2
]}

Salfati, Elias L. ^{[3
]}

Chen, Brian H. ^{[4
,5
]}

Ferrucci, Luigi ^{[4
]}

Levy, Daniel ^{[5
]}

Joehanes, Roby ^{[5
]}

Murabito, Joanne M. ^{[6
]}

Kiel, Douglas P. ^{[7
]}

Tsai, Pei-Chien ^{[8
]}

Yet, Idil ^{[8
]}

Bell, Jordana T. ^{[8
]}

Mangino, Massimo ^{[8
]}

Tanaka, Toshiko ^{[4
]}

McRae, Allan F. ^{[9
,10
]}

Marioni, Riccardo E. ^{[9
,11
,12
]}

Visscher, Peter M. ^{[9
,10
]}

Wray, Naomi R. ^{[9
,10
]}

Deary, Ian J. ^{[11
]}

Levine, Morgan E. ^{[1
]}

Quach, Austin ^{[1
]}

Assimes, Themistocles ^{[3
]}

Tsao, Philip S. ^{[3
,13
]}

Absher, Devin ^{[14
]}

Stewart, James D. ^{[15
]}

Li, Yun ^{[16
,17
]}

Reiner, Alex P. ^{[18
]}

Hou, Lifang ^{[19
,20
]}

Baccarelli, Andrea A. ^{[21
,22
]}

Whitsel, Eric A. ^{[15
,23
]}

Aviv, Abraham ^{[24
]}

Cardona, Alexia ^{[25
]}

Day, Felix R. ^{[25
]}

Wareham, Nicholas J. ^{[25
]}

Perry, John R. B. ^{[25
]}

Ong, Ken K. ^{[25
,26
]}

Raj, Kenneth ^{[27
]}

Lunetta, Kathryn L. ^{[2
]}

Horvath, Steve ^{[1
,28
]}

机构：

[1] Univ Calif Los Angeles, David Geffen Sch Med, Human Genet, Los Angeles, CA 90095 USA

[2] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA

[3] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA

[4] NIA, Intramural Res Program, NIH, Baltimore, MD 21224 USA

[5] NHLBI, Bethesda, MD 20824 USA

[6] Boston Univ, Sch Med, Dept Med, Sect Gen Med, Boston, MA 02118 USA

[7] Beth Israel Deaconess Med Ctr, Harvard Med Sch, Inst Aging Res, Hebrew SeniorLife, Boston, MA 02215 USA

[8] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England

[9] Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072, Australia

[10] Univ Queensland, Queensland Brain Inst, Brisbane, Qld 4072, Australia

[11] Univ Edinburgh, Ctr Cognit Aging & Cognit Epidemiol, Dept Psychol, 7 George Sq, Edinburgh EH8 9JZ, Midlothian, Scotland

[12] Univ Edinburgh, Ctr Genom & Expt Med, Inst Genet & Mol Med, Med Genet Sect, Edinburgh EH4 2XU, Midlothian, Scotland

[13] VA Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USA

[14] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA

[15] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA

[16] Univ N Carolina, Sch Med, Dept Genet, Chapel Hill, NC 27599 USA

[17] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Biostat, Chapel Hill, NC 27599 USA

[18] Fred Hutchinson Canc Res Ctr, WHI Clin Coordinating Ctr, Publ Hlth Sci M3 A4, Box 358080, Seattle, WA 98109 USA

[19] Northwestern Univ Chicago, Feinberg Sch Med, Dept Prevent Med, Evanston, IL 60611 USA

[20] Northwestern Univ Chicago, Feinberg Sch Med, Robert H Lurie Comprehens Canc Ctr, Ctr Populat Epigenet, Evanston, IL 60611 USA

[21] Columbia Univ, Mailman Sch Publ Hlth, Dept Environm Hlth Sci, Lab Environm Epigenet, New York, NY 10032 USA

[22] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, Lab Environm Epigenet, New York, NY 10032 USA

[23] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC 27516 USA

[24] Univ Med & Dent, New Jersey Med Sch Rutgers, Ctr Human Dev & Aging, Newark, NJ 07103 USA

[25] Univ Cambridge, Sch Clin Med, Inst Metab Sci, MRC,Epidemiol Unit, Cambridge Biomed Campus, Cambridge CB2 0SL, England

[26] Univ Cambridge, Sch Clin Med, Dept Paediat, Cambridge Biomed Campus, Cambridge CB2 0SP, England

[27] Publ Hlth England, Ctr Radiat Chem & Environm Hazards, Radiat Effects Dept, Didcot OX11 0RQ, Oxon, England

[28] Univ Calif Los Angeles, Sch Publ Hlth, Biostat, Los Angeles, CA 90095 USA

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

英国生物技术与生命科学研究理事会; 英国惠康基金; 美国国家卫生研究院; 英国医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; NORMAL HUMAN FIBROBLASTS; MEAN TELOMERE LENGTH; DNA METHYLATION AGE; GENOTYPE IMPUTATION; CLOCK; DISEASE; EXPRESSION; IDENTIFICATION; METAANALYSIS;

D O I：

10.1038/s41467-017-02697-5

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 x 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.

引用

页数：13

共 69 条

[1] A general test of association for quantitative traits in nuclear families [J].

Abecasis, GR ;

Cardon, LR ;

Cookson, WOC .

AMERICAN JOURNAL OF HUMAN GENETICS, 2000, 66 (01) :279-292

[2] Multipoint quantitative-trait linkage analysis in general pedigrees [J].

Almasy, L ;

Blangero, J .

AMERICAN JOURNAL OF HUMAN GENETICS, 1998, 62 (05) :1198-1211

[3] The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans [J].

Ardlie, Kristin G. ;

DeLuca, David S. ;

Segre, Ayellet V. ;

Sullivan, Timothy J. ;

Young, Taylor R. ;

Gelfand, Ellen T. ;

Trowbridge, Casandra A. ;

Maller, Julian B. ;

Tukiainen, Taru ;

Lek, Monkol ;

Ward, Lucas D. ;

Kheradpour, Pouya ;

Iriarte, Benjamin ;

Meng, Yan ;

Palmer, Cameron D. ;

Esko, Tonu ;

Winckler, Wendy ;

Hirschhorn, Joel N. ;

Kellis, Manolis ;

MacArthur, Daniel G. ;

Getz, Gad ;

Shabalin, Andrey A. ;

Li, Gen ;

Zhou, Yi-Hui ;

Nobel, Andrew B. ;

Rusyn, Ivan ;

Wright, Fred A. ;

Lappalainen, Tuuli ;

Ferreira, Pedro G. ;

Ongen, Halit ;

Rivas, Manuel A. ;

Battle, Alexis ;

Mostafavi, Sara ;

Monlong, Jean ;

Sammeth, Michael ;

Mele, Marta ;

Reverter, Ferran ;

Goldmann, Jakob M. ;

Koller, Daphne ;

Guigo, Roderic ;

McCarthy, Mark I. ;

Dermitzakis, Emmanouil T. ;

Gamazon, Eric R. ;

Im, Hae Kyung ;

Konkashbaev, Anuar ;

Nicolae, Dan L. ;

Cox, Nancy J. ;

Flutre, Timothee ;

Wen, Xiaoquan ;

Stephens, Matthew .

SCIENCE, 2015, 348 (6235) :648-660

[4] Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer [J].

Bojesen, Stig E. ;

Pooley, Karen A. ;

Johnatty, Sharon E. ;

Beesley, Jonathan ;

Michailidou, Kyriaki ;

Tyrer, Jonathan P. ;

Edwards, Stacey L. ;

Pickett, Hilda A. ;

Shen, Howard C. ;

Smart, Chanel E. ;

Hillman, Kristine M. ;

Mai, Phuong L. ;

Lawrenson, Kate ;

Stutz, Michael D. ;

Lu, Yi ;

Karevan, Rod ;

Woods, Nicholas ;

Johnston, Rebecca L. ;

French, Juliet D. ;

Chen, Xiaoqing ;

Weischer, Maren ;

Nielsen, Sune F. ;

Maranian, Melanie J. ;

Ghoussaini, Maya ;

Ahmed, Shahana ;

Baynes, Caroline ;

Bolla, Manjeet K. ;

Wang, Qin ;

Dennis, Joe ;

McGuffog, Lesley ;

Barrowdale, Daniel ;

Lee, Andrew ;

Healey, Sue ;

Lush, Michael ;

Tessier, Daniel C. ;

Vincent, Daniel ;

Bacot, Francis ;

Vergote, Ignace ;

Lambrechts, Sandrina ;

Despierre, Evelyn ;

Risch, Harvey A. ;

Gonzalez-Neira, Anna ;

Rossing, Mary Anne ;

Pita, Guillermo ;

Doherty, Jennifer A. ;

Alvarez, Nuria ;

Larson, Melissa C. ;

Fridley, Brooke L. ;

Schoof, Nils ;

Chang-Claude, Jenny .

NATURE GENETICS, 2013, 45 (04) :371-384

[5] Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression [J].

Bowden, Jack ;

Smith, George Davey ;

Burgess, Stephen .

INTERNATIONAL JOURNAL OF EPIDEMIOLOGY, 2015, 44 (02) :512-525

[6] Frailty is associated with the epigenetic clock but not with telomere length in a German cohort [J].

Breitling, Lutz Philipp ;

Saum, Kai-Uwe ;

Perna, Laura ;

Schoettker, Ben ;

Holleczek, Bernd ;

Brenner, Hermann .

CLINICAL EPIGENETICS, 2016, 8 :1-8

[7] Rapid and accurate haplotype phasing and missing-data inference for whole-genome association studies by use of localized haplotype clustering [J].

Browning, Sharon R. ;

Browning, Brian L. .

AMERICAN JOURNAL OF HUMAN GENETICS, 2007, 81 (05) :1084-1097

[8] An atlas of genetic correlations across human diseases and traits [J].

Bulik-Sullivan, Brendan ;

Finucane, Hilary K. ;

Anttila, Verneri ;

Gusev, Alexander ;

Day, Felix R. ;

Loh, Po-Ru ;

Duncan, Laramie ;

Perry, John R. B. ;

Patterson, Nick ;

Robinson, Elise B. ;

Daly, Mark J. ;

Price, Alkes L. ;

Neale, Benjamin M. .

NATURE GENETICS, 2015, 47 (11) :1236-+

[9] Leukocyte telomere length, T cell composition and DNA methylation age [J].

Chen, Brian H. ;

Carty, Cara L. ;

Kimura, Masayuki ;

Kark, Jeremy D. ;

Chen, Wei ;

Li, Shengxu ;

Zhang, Tao ;

Kooperberg, Charles ;

Levy, Daniel ;

Assimes, Themistocles ;

Absher, Devin ;

Horvath, Steve ;

Reiner, Alexander P. ;

Aviv, Abraham .

AGING-US, 2017, 9 (09) :1983-1995

[10] DNA methylation-based measures of biological age: meta-analysis predicting time to death [J].

Chen, Brian H. ;

Marioni, Riccardo E. ;

Colicino, Elena ;

Peters, Marjolein J. ;

Ward-Caviness, Cavin K. ;

Tsai, Pei-Chien ;

Roetker, Nicholas S. ;

Just, Allan C. ;

Demerath, Ellen W. ;

Guan, Weihua ;

Bressler, Jan ;

Fornage, Myriam ;

Studenski, Stephanie ;

Vandiver, Amy R. ;

Moore, Ann Zenobia ;

Tanaka, Toshiko ;

Kiel, Douglas P. ;

Liang, Liming ;

Vokonas, Pantel ;

Schwartz, Joel ;

Lunetta, Kathryn L. ;

Murabito, Joanne M. ;

Bandinelli, Stefania ;

Hernandez, Dena G. ;

Melzer, David ;

Nalls, Michael ;

Pilling, Luke C. ;

Price, Timothy R. ;

Singleton, Andrew B. ;

Gieger, Christian ;

Holle, Rolf ;

Kretschmer, Anja ;

Kronenberg, Florian ;

Kunze, Sonja ;

Linseisen, Jakob ;

Meisinger, Christine ;

Rathmann, Wolfgang ;

Waldenberger, Melanie ;

Visscher, Peter M. ;

Shah, Sonia ;

Wray, Naomi R. ;

McRae, Allan F. ;

Franco, Oscar H. ;

Hofman, Albert ;

Uitterlinden, Andre G. ;

Absher, Devin ;

Assimes, Themistocles ;

Levine, Morgan E. ;

Lu, Ake T. ;

Tsao, Philip S. .

AGING-US, 2016, 8 (09) :1844-1865

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