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Genes 2018, 9(2), 78;

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

Epidemiology and Biostatistics, Department of Public Health, University of Southern Denmark, 5000 Odense, Denmark
Unit of Human Genetics, Department of Clinical Research, University of Southern Denmark, 5000 Odense, Denmark
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-171 77 Stockholm, Sweden
Department of Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK
Center for Cognitive Aging and Cognitive Epidemiology, University of Edinburgh, lEdinburgh EH8 9JZ, UK
Author to whom correspondence should be addressed.
Received: 29 September 2017 / Revised: 16 January 2018 / Accepted: 25 January 2018 / Published: 8 February 2018
(This article belongs to the Special Issue The Epigenetics of Aging and Longevity)
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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. View Full-Text
Keywords: DNA methylation; mortality; EWAS; survival analysis; survival prediction; twin study; heritability DNA methylation; mortality; EWAS; survival analysis; survival prediction; twin study; heritability

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Svane, A.M.; Soerensen, M.; Lund, J.; Tan, Q.; Jylhävä, J.; Wang, Y.; Pedersen, N.L.; Hägg, S.; Debrabant, B.; Deary, I.J.; Christensen, K.; Christiansen, L.; Hjelmborg, J.B. DNA Methylation and All-Cause Mortality in Middle-Aged and Elderly Danish Twins. Genes 2018, 9, 78.

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