DNA methylome profiling of all-cause mortality in comparison with age-associated methylation patterns

Jesper Lund, Shuxia Li, Jan Baumbach, Anne Marie Svane, Jacob v. B. Hjelmborg, Lene Christiansen, Kaare Christensen, Paul Redmond, Riccardo E. Marioni, Ian J. Deary, Qihua Tan

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Abstract

BACKGROUND: Multiple epigenome-wide association studies have been performed to identify DNA methylation patterns regulated by aging or correlated with risk of death. However, the inter-relatedness of the epigenetic basis of aging and mortality has not been well investigated. METHODS: Using genome-wide DNA methylation data from the Lothian Birth Cohorts, we conducted a genome-wide association analysis of all-cause mortality and compared this with age-associated methylation patterns reported on the same samples. RESULTS: Survival analysis using the Cox regression model identified 2552 CpG sites with genome-wide significance (false discovery rate < 0.05) for all-cause mortality. CpGs whose methylation levels are associated with increased mortality appear more distributed from the gene body to the intergenic regions whereas CpGs whose methylation levels are associated with decreased mortality is more concentrated at the promoter regions. In comparison with reported CpGs displaying significant age-dependent methylation patterns in the same samples, we observed a limited but highly significant overlap between mortality-associated and age-associated CpGs (p value 2.52e-06). Most importantly, the overlapping CpGs are dominated by those whose overall age-related methylation patterns reduce the risk of death. CONCLUSION: All-cause mortality is significantly associated with altered methylation at multiple genomic sites with differential distribution in gene regions for CpGs correlated with increased or decreased risk of death. The age-dependent methylation changes could reflect an active response to the aging process that contributes to maintain individual survival.
Original languageEnglish
Article number23
JournalClinical Epigenetics
Volume11
Number of pages8
ISSN1868-7075
DOIs
Publication statusPublished - 8. Feb 2019

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DNA Methylation
Genome-Wide Association Study
Survival Analysis
Proportional Hazards Models
Epigenomics

Keywords

  • Aging; DNA methylation; Epigenome-wide association study; Mortality; Old cohorts

Cite this

@article{2c0a23f23065467899c8df55c9efe934,
title = "DNA methylome profiling of all-cause mortality in comparison with age-associated methylation patterns",
abstract = "BACKGROUND: Multiple epigenome-wide association studies have been performed to identify DNA methylation patterns regulated by aging or correlated with risk of death. However, the inter-relatedness of the epigenetic basis of aging and mortality has not been well investigated. METHODS: Using genome-wide DNA methylation data from the Lothian Birth Cohorts, we conducted a genome-wide association analysis of all-cause mortality and compared this with age-associated methylation patterns reported on the same samples. RESULTS: Survival analysis using the Cox regression model identified 2552 CpG sites with genome-wide significance (false discovery rate < 0.05) for all-cause mortality. CpGs whose methylation levels are associated with increased mortality appear more distributed from the gene body to the intergenic regions whereas CpGs whose methylation levels are associated with decreased mortality is more concentrated at the promoter regions. In comparison with reported CpGs displaying significant age-dependent methylation patterns in the same samples, we observed a limited but highly significant overlap between mortality-associated and age-associated CpGs (p value 2.52e-06). Most importantly, the overlapping CpGs are dominated by those whose overall age-related methylation patterns reduce the risk of death. CONCLUSION: All-cause mortality is significantly associated with altered methylation at multiple genomic sites with differential distribution in gene regions for CpGs correlated with increased or decreased risk of death. The age-dependent methylation changes could reflect an active response to the aging process that contributes to maintain individual survival.",
keywords = "Aging; DNA methylation; Epigenome-wide association study; Mortality; Old cohorts",
author = "Jesper Lund and Shuxia Li and Jan Baumbach and Svane, {Anne Marie} and Hjelmborg, {Jacob v. B.} and Lene Christiansen and Kaare Christensen and Paul Redmond and Marioni, {Riccardo E.} and Deary, {Ian J.} and Qihua Tan",
year = "2019",
month = "2",
day = "8",
doi = "10.1186/s13148-019-0622-4",
language = "English",
volume = "11",
journal = "Clinical Epigenetics (Print)",
issn = "1868-7075",
publisher = "BioMed Central",

}

DNA methylome profiling of all-cause mortality in comparison with age-associated methylation patterns. / Lund, Jesper; Li, Shuxia; Baumbach, Jan; Svane, Anne Marie; Hjelmborg, Jacob v. B.; Christiansen, Lene; Christensen, Kaare; Redmond, Paul ; Marioni, Riccardo E. ; Deary, Ian J. ; Tan, Qihua.

In: Clinical Epigenetics, Vol. 11, 23, 08.02.2019.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - DNA methylome profiling of all-cause mortality in comparison with age-associated methylation patterns

AU - Lund, Jesper

AU - Li, Shuxia

AU - Baumbach, Jan

AU - Svane, Anne Marie

AU - Hjelmborg, Jacob v. B.

AU - Christiansen, Lene

AU - Christensen, Kaare

AU - Redmond, Paul

AU - Marioni, Riccardo E.

AU - Deary, Ian J.

AU - Tan, Qihua

PY - 2019/2/8

Y1 - 2019/2/8

N2 - BACKGROUND: Multiple epigenome-wide association studies have been performed to identify DNA methylation patterns regulated by aging or correlated with risk of death. However, the inter-relatedness of the epigenetic basis of aging and mortality has not been well investigated. METHODS: Using genome-wide DNA methylation data from the Lothian Birth Cohorts, we conducted a genome-wide association analysis of all-cause mortality and compared this with age-associated methylation patterns reported on the same samples. RESULTS: Survival analysis using the Cox regression model identified 2552 CpG sites with genome-wide significance (false discovery rate < 0.05) for all-cause mortality. CpGs whose methylation levels are associated with increased mortality appear more distributed from the gene body to the intergenic regions whereas CpGs whose methylation levels are associated with decreased mortality is more concentrated at the promoter regions. In comparison with reported CpGs displaying significant age-dependent methylation patterns in the same samples, we observed a limited but highly significant overlap between mortality-associated and age-associated CpGs (p value 2.52e-06). Most importantly, the overlapping CpGs are dominated by those whose overall age-related methylation patterns reduce the risk of death. CONCLUSION: All-cause mortality is significantly associated with altered methylation at multiple genomic sites with differential distribution in gene regions for CpGs correlated with increased or decreased risk of death. The age-dependent methylation changes could reflect an active response to the aging process that contributes to maintain individual survival.

AB - BACKGROUND: Multiple epigenome-wide association studies have been performed to identify DNA methylation patterns regulated by aging or correlated with risk of death. However, the inter-relatedness of the epigenetic basis of aging and mortality has not been well investigated. METHODS: Using genome-wide DNA methylation data from the Lothian Birth Cohorts, we conducted a genome-wide association analysis of all-cause mortality and compared this with age-associated methylation patterns reported on the same samples. RESULTS: Survival analysis using the Cox regression model identified 2552 CpG sites with genome-wide significance (false discovery rate < 0.05) for all-cause mortality. CpGs whose methylation levels are associated with increased mortality appear more distributed from the gene body to the intergenic regions whereas CpGs whose methylation levels are associated with decreased mortality is more concentrated at the promoter regions. In comparison with reported CpGs displaying significant age-dependent methylation patterns in the same samples, we observed a limited but highly significant overlap between mortality-associated and age-associated CpGs (p value 2.52e-06). Most importantly, the overlapping CpGs are dominated by those whose overall age-related methylation patterns reduce the risk of death. CONCLUSION: All-cause mortality is significantly associated with altered methylation at multiple genomic sites with differential distribution in gene regions for CpGs correlated with increased or decreased risk of death. The age-dependent methylation changes could reflect an active response to the aging process that contributes to maintain individual survival.

KW - Aging; DNA methylation; Epigenome-wide association study; Mortality; Old cohorts

U2 - 10.1186/s13148-019-0622-4

DO - 10.1186/s13148-019-0622-4

M3 - Journal article

VL - 11

JO - Clinical Epigenetics (Print)

JF - Clinical Epigenetics (Print)

SN - 1868-7075

M1 - 23

ER -