Epigenome-wide association study of leukocyte telomere length

Yunsung Lee, Dianjianyi Sun, Anil P S Ori, Ake T Lu, Anne Seeboth, Sarah E Harris, Ian J Deary, Riccardo E Marioni, Mette Soerensen, Jonas Mengel-From, Jacob Hjelmborg, Kaare Christensen, James G Wilson, Daniel Levy, Alex P Reiner, Wei Chen, Shengxu Li, Jennifer R Harris, Per Magnus, Abraham Aviv & 2 others Astanand Jugessur, Steve Horvath

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Abstract

Telomere length is associated with age-related diseases and is highly heritable. It is unclear, however, to what extent epigenetic modifications are associated with leukocyte telomere length (LTL). In this study, we conducted a large-scale epigenome-wide association study (EWAS) of LTL using seven large cohorts (n=5,713) - the Framingham Heart Study, the Jackson Heart Study, the Women's Health Initiative, the Bogalusa Heart Study, the Lothian Birth Cohorts of 1921 and 1936, and the Longitudinal Study of Aging Danish Twins. Our stratified analysis suggests that EWAS findings for women of African ancestry may be distinct from those of three other groups: males of African ancestry, and males and females of European ancestry. Using a meta-analysis framework, we identified DNA methylation (DNAm) levels at 823 CpG sites to be significantly associated (P<1E-7) with LTL after adjusting for age, sex, ethnicity, and imputed white blood cell counts. Functional enrichment analyses revealed that these CpG sites are near genes that play a role in circadian rhythm, blood coagulation, and wound healing. Weighted correlation network analysis identified four co-methylation modules associated with LTL, age, and blood cell counts. Overall, this study reveals highly significant relationships between two hallmarks of aging: telomere biology and epigenetic changes.

Original languageEnglish
JournalAging
Volume11
Issue number16
Pages (from-to)5876-5894
ISSN1945-4589
DOIs
Publication statusPublished - 26. Aug 2019

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Telomere
Epigenomics
Women's Health
DNA Methylation
Circadian Rhythm
Longitudinal Studies
Meta-Analysis

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Lee, Y., Sun, D., Ori, A. P. S., Lu, A. T., Seeboth, A., Harris, S. E., ... Horvath, S. (2019). Epigenome-wide association study of leukocyte telomere length. Aging, 11(16), 5876-5894. https://doi.org/10.18632/aging.102230
Lee, Yunsung ; Sun, Dianjianyi ; Ori, Anil P S ; Lu, Ake T ; Seeboth, Anne ; Harris, Sarah E ; Deary, Ian J ; Marioni, Riccardo E ; Soerensen, Mette ; Mengel-From, Jonas ; Hjelmborg, Jacob ; Christensen, Kaare ; Wilson, James G ; Levy, Daniel ; Reiner, Alex P ; Chen, Wei ; Li, Shengxu ; Harris, Jennifer R ; Magnus, Per ; Aviv, Abraham ; Jugessur, Astanand ; Horvath, Steve. / Epigenome-wide association study of leukocyte telomere length. In: Aging. 2019 ; Vol. 11, No. 16. pp. 5876-5894.
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title = "Epigenome-wide association study of leukocyte telomere length",
abstract = "Telomere length is associated with age-related diseases and is highly heritable. It is unclear, however, to what extent epigenetic modifications are associated with leukocyte telomere length (LTL). In this study, we conducted a large-scale epigenome-wide association study (EWAS) of LTL using seven large cohorts (n=5,713) - the Framingham Heart Study, the Jackson Heart Study, the Women's Health Initiative, the Bogalusa Heart Study, the Lothian Birth Cohorts of 1921 and 1936, and the Longitudinal Study of Aging Danish Twins. Our stratified analysis suggests that EWAS findings for women of African ancestry may be distinct from those of three other groups: males of African ancestry, and males and females of European ancestry. Using a meta-analysis framework, we identified DNA methylation (DNAm) levels at 823 CpG sites to be significantly associated (P<1E-7) with LTL after adjusting for age, sex, ethnicity, and imputed white blood cell counts. Functional enrichment analyses revealed that these CpG sites are near genes that play a role in circadian rhythm, blood coagulation, and wound healing. Weighted correlation network analysis identified four co-methylation modules associated with LTL, age, and blood cell counts. Overall, this study reveals highly significant relationships between two hallmarks of aging: telomere biology and epigenetic changes.",
author = "Yunsung Lee and Dianjianyi Sun and Ori, {Anil P S} and Lu, {Ake T} and Anne Seeboth and Harris, {Sarah E} and Deary, {Ian J} and Marioni, {Riccardo E} and Mette Soerensen and Jonas Mengel-From and Jacob Hjelmborg and Kaare Christensen and Wilson, {James G} and Daniel Levy and Reiner, {Alex P} and Wei Chen and Shengxu Li and Harris, {Jennifer R} and Per Magnus and Abraham Aviv and Astanand Jugessur and Steve Horvath",
year = "2019",
month = "8",
day = "26",
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language = "English",
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pages = "5876--5894",
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Lee, Y, Sun, D, Ori, APS, Lu, AT, Seeboth, A, Harris, SE, Deary, IJ, Marioni, RE, Soerensen, M, Mengel-From, J, Hjelmborg, J, Christensen, K, Wilson, JG, Levy, D, Reiner, AP, Chen, W, Li, S, Harris, JR, Magnus, P, Aviv, A, Jugessur, A & Horvath, S 2019, 'Epigenome-wide association study of leukocyte telomere length', Aging, vol. 11, no. 16, pp. 5876-5894. https://doi.org/10.18632/aging.102230

Epigenome-wide association study of leukocyte telomere length. / Lee, Yunsung; Sun, Dianjianyi; Ori, Anil P S; Lu, Ake T; Seeboth, Anne; Harris, Sarah E; Deary, Ian J; Marioni, Riccardo E; Soerensen, Mette; Mengel-From, Jonas; Hjelmborg, Jacob; Christensen, Kaare; Wilson, James G; Levy, Daniel; Reiner, Alex P; Chen, Wei; Li, Shengxu; Harris, Jennifer R; Magnus, Per; Aviv, Abraham; Jugessur, Astanand; Horvath, Steve.

In: Aging, Vol. 11, No. 16, 26.08.2019, p. 5876-5894.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Epigenome-wide association study of leukocyte telomere length

AU - Lee, Yunsung

AU - Sun, Dianjianyi

AU - Ori, Anil P S

AU - Lu, Ake T

AU - Seeboth, Anne

AU - Harris, Sarah E

AU - Deary, Ian J

AU - Marioni, Riccardo E

AU - Soerensen, Mette

AU - Mengel-From, Jonas

AU - Hjelmborg, Jacob

AU - Christensen, Kaare

AU - Wilson, James G

AU - Levy, Daniel

AU - Reiner, Alex P

AU - Chen, Wei

AU - Li, Shengxu

AU - Harris, Jennifer R

AU - Magnus, Per

AU - Aviv, Abraham

AU - Jugessur, Astanand

AU - Horvath, Steve

PY - 2019/8/26

Y1 - 2019/8/26

N2 - Telomere length is associated with age-related diseases and is highly heritable. It is unclear, however, to what extent epigenetic modifications are associated with leukocyte telomere length (LTL). In this study, we conducted a large-scale epigenome-wide association study (EWAS) of LTL using seven large cohorts (n=5,713) - the Framingham Heart Study, the Jackson Heart Study, the Women's Health Initiative, the Bogalusa Heart Study, the Lothian Birth Cohorts of 1921 and 1936, and the Longitudinal Study of Aging Danish Twins. Our stratified analysis suggests that EWAS findings for women of African ancestry may be distinct from those of three other groups: males of African ancestry, and males and females of European ancestry. Using a meta-analysis framework, we identified DNA methylation (DNAm) levels at 823 CpG sites to be significantly associated (P<1E-7) with LTL after adjusting for age, sex, ethnicity, and imputed white blood cell counts. Functional enrichment analyses revealed that these CpG sites are near genes that play a role in circadian rhythm, blood coagulation, and wound healing. Weighted correlation network analysis identified four co-methylation modules associated with LTL, age, and blood cell counts. Overall, this study reveals highly significant relationships between two hallmarks of aging: telomere biology and epigenetic changes.

AB - Telomere length is associated with age-related diseases and is highly heritable. It is unclear, however, to what extent epigenetic modifications are associated with leukocyte telomere length (LTL). In this study, we conducted a large-scale epigenome-wide association study (EWAS) of LTL using seven large cohorts (n=5,713) - the Framingham Heart Study, the Jackson Heart Study, the Women's Health Initiative, the Bogalusa Heart Study, the Lothian Birth Cohorts of 1921 and 1936, and the Longitudinal Study of Aging Danish Twins. Our stratified analysis suggests that EWAS findings for women of African ancestry may be distinct from those of three other groups: males of African ancestry, and males and females of European ancestry. Using a meta-analysis framework, we identified DNA methylation (DNAm) levels at 823 CpG sites to be significantly associated (P<1E-7) with LTL after adjusting for age, sex, ethnicity, and imputed white blood cell counts. Functional enrichment analyses revealed that these CpG sites are near genes that play a role in circadian rhythm, blood coagulation, and wound healing. Weighted correlation network analysis identified four co-methylation modules associated with LTL, age, and blood cell counts. Overall, this study reveals highly significant relationships between two hallmarks of aging: telomere biology and epigenetic changes.

U2 - 10.18632/aging.102230

DO - 10.18632/aging.102230

M3 - Journal article

VL - 11

SP - 5876

EP - 5894

JO - Aging

JF - Aging

SN - 1945-4589

IS - 16

ER -

Lee Y, Sun D, Ori APS, Lu AT, Seeboth A, Harris SE et al. Epigenome-wide association study of leukocyte telomere length. Aging. 2019 Aug 26;11(16):5876-5894. https://doi.org/10.18632/aging.102230