DNA Methylation and All-Cause Mortality in Middle-Aged and Elderly Danish Twins

Anne Marie Svane, Mette Soerensen, Jesper Lund, Qihua Tan, Juulia Jylhävä, Yunzhang Wang, Nancy L Pedersen, Sara Hägg, Birgit Debrabant, Ian J Deary, Kaare Christensen, Lene Christiansen, Jacob B Hjelmborg

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Abstract

Several studies have linked DNA methylation at individual CpG sites to aging and various diseases. Recent studies have also identified single CpGs whose methylation levels are associated with all-cause mortality. In this study, we perform an epigenome-wide study of the association between CpG methylation and mortality in a population of 435 monozygotic twin pairs from three Danish twin studies. The participants were aged 55-90 at the time of blood sampling and were followed for up to 20 years. We validated our results by comparison with results from a British and a Swedish cohort, as well as results from the literature. We identified 2806 CpG sites associated with mortality (false discovery rate (FDR) < 0.05), of which 24 had an association p-value below 10 -7. This was confirmed by intra-pair comparison controlling for confounding effects. Eight of the 24 top sites could be validated in independent datasets or confirmed by previous studies. For all these eight sites, hypomethylation was associated with poor survival prognosis, and seven showed monozygotic correlations above 35%, indicating a potential moderate to strong heritability, but leaving room for substantial shared or unique environmental effects. We also set up a predictor for mortality using least absolute shrinkage and selection operator (LASSO) regression. The predictor showed good performance on the Danish data under cross-validation, but did not perform very well in independent samples.

Original languageEnglish
Article number78
JournalGenes
Volume9
Issue number2
Number of pages15
ISSN2073-4425
DOIs
Publication statusPublished - 8. Feb 2018

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DNA Methylation
Twin Studies
Monozygotic Twins
Population

Keywords

  • DNA methylation
  • EWAS
  • Heritability
  • Mortality
  • Survival analysis
  • Survival prediction
  • Twin study

Cite this

@article{593b706a6581418d84848b89065b8891,
title = "DNA Methylation and All-Cause Mortality in Middle-Aged and Elderly Danish Twins",
abstract = "Several studies have linked DNA methylation at individual CpG sites to aging and various diseases. Recent studies have also identified single CpGs whose methylation levels are associated with all-cause mortality. In this study, we perform an epigenome-wide study of the association between CpG methylation and mortality in a population of 435 monozygotic twin pairs from three Danish twin studies. The participants were aged 55-90 at the time of blood sampling and were followed for up to 20 years. We validated our results by comparison with results from a British and a Swedish cohort, as well as results from the literature. We identified 2806 CpG sites associated with mortality (false discovery rate (FDR) < 0.05), of which 24 had an association p-value below 10 -7. This was confirmed by intra-pair comparison controlling for confounding effects. Eight of the 24 top sites could be validated in independent datasets or confirmed by previous studies. For all these eight sites, hypomethylation was associated with poor survival prognosis, and seven showed monozygotic correlations above 35{\%}, indicating a potential moderate to strong heritability, but leaving room for substantial shared or unique environmental effects. We also set up a predictor for mortality using least absolute shrinkage and selection operator (LASSO) regression. The predictor showed good performance on the Danish data under cross-validation, but did not perform very well in independent samples.",
keywords = "DNA methylation, EWAS, Heritability, Mortality, Survival analysis, Survival prediction, Twin study",
author = "Svane, {Anne Marie} and Mette Soerensen and Jesper Lund and Qihua Tan and Juulia Jylh{\"a}v{\"a} and Yunzhang Wang and Pedersen, {Nancy L} and Sara H{\"a}gg and Birgit Debrabant and Deary, {Ian J} and Kaare Christensen and Lene Christiansen and Hjelmborg, {Jacob B}",
year = "2018",
month = "2",
day = "8",
doi = "10.3390/genes9020078",
language = "English",
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DNA Methylation and All-Cause Mortality in Middle-Aged and Elderly Danish Twins. / Svane, Anne Marie; Soerensen, Mette; Lund, Jesper; Tan, Qihua; Jylhävä, Juulia; Wang, Yunzhang; Pedersen, Nancy L; Hägg, Sara; Debrabant, Birgit; Deary, Ian J; Christensen, Kaare; Christiansen, Lene; Hjelmborg, Jacob B.

In: Genes, Vol. 9, No. 2, 78, 08.02.2018.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - DNA Methylation and All-Cause Mortality in Middle-Aged and Elderly Danish Twins

AU - Svane, Anne Marie

AU - Soerensen, Mette

AU - Lund, Jesper

AU - Tan, Qihua

AU - Jylhävä, Juulia

AU - Wang, Yunzhang

AU - Pedersen, Nancy L

AU - Hägg, Sara

AU - Debrabant, Birgit

AU - Deary, Ian J

AU - Christensen, Kaare

AU - Christiansen, Lene

AU - Hjelmborg, Jacob B

PY - 2018/2/8

Y1 - 2018/2/8

N2 - Several studies have linked DNA methylation at individual CpG sites to aging and various diseases. Recent studies have also identified single CpGs whose methylation levels are associated with all-cause mortality. In this study, we perform an epigenome-wide study of the association between CpG methylation and mortality in a population of 435 monozygotic twin pairs from three Danish twin studies. The participants were aged 55-90 at the time of blood sampling and were followed for up to 20 years. We validated our results by comparison with results from a British and a Swedish cohort, as well as results from the literature. We identified 2806 CpG sites associated with mortality (false discovery rate (FDR) < 0.05), of which 24 had an association p-value below 10 -7. This was confirmed by intra-pair comparison controlling for confounding effects. Eight of the 24 top sites could be validated in independent datasets or confirmed by previous studies. For all these eight sites, hypomethylation was associated with poor survival prognosis, and seven showed monozygotic correlations above 35%, indicating a potential moderate to strong heritability, but leaving room for substantial shared or unique environmental effects. We also set up a predictor for mortality using least absolute shrinkage and selection operator (LASSO) regression. The predictor showed good performance on the Danish data under cross-validation, but did not perform very well in independent samples.

AB - Several studies have linked DNA methylation at individual CpG sites to aging and various diseases. Recent studies have also identified single CpGs whose methylation levels are associated with all-cause mortality. In this study, we perform an epigenome-wide study of the association between CpG methylation and mortality in a population of 435 monozygotic twin pairs from three Danish twin studies. The participants were aged 55-90 at the time of blood sampling and were followed for up to 20 years. We validated our results by comparison with results from a British and a Swedish cohort, as well as results from the literature. We identified 2806 CpG sites associated with mortality (false discovery rate (FDR) < 0.05), of which 24 had an association p-value below 10 -7. This was confirmed by intra-pair comparison controlling for confounding effects. Eight of the 24 top sites could be validated in independent datasets or confirmed by previous studies. For all these eight sites, hypomethylation was associated with poor survival prognosis, and seven showed monozygotic correlations above 35%, indicating a potential moderate to strong heritability, but leaving room for substantial shared or unique environmental effects. We also set up a predictor for mortality using least absolute shrinkage and selection operator (LASSO) regression. The predictor showed good performance on the Danish data under cross-validation, but did not perform very well in independent samples.

KW - DNA methylation

KW - EWAS

KW - Heritability

KW - Mortality

KW - Survival analysis

KW - Survival prediction

KW - Twin study

U2 - 10.3390/genes9020078

DO - 10.3390/genes9020078

M3 - Journal article

VL - 9

JO - Genes

JF - Genes

SN - 2073-4425

IS - 2

M1 - 78

ER -