title: Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms.
abstract: BACKGROUND
  Epigenetic change is a hallmark of ageing but its link to ageing mechanisms in humans remains poorly understood. While DNA methylation at many CpG sites closely tracks chronological age, DNA methylation changes relevant to biological age are expected to gradually dissociate from chronological age, mirroring the increased heterogeneity in health status at older ages.
  
  
  RESULTS
  Here, we report on the large-scale identification of 6366 age-related variably methylated positions (aVMPs) identified in 3295 whole blood DNA methylation profiles, 2044 of which have a matching RNA-seq gene expression profile. aVMPs are enriched at polycomb repressed regions and, accordingly, methylation at those positions is associated with the expression of genes encoding components of polycomb repressive complex 2 (PRC2) in trans. Further analysis revealed trans-associations for 1816 aVMPs with an additional 854 genes. These trans-associated aVMPs are characterized by either an age-related gain of methylation at CpG islands marked by PRC2 or a loss of methylation at enhancers. This distinct pattern extends to other tissues and multiple cancer types. Finally, genes associated with aVMPs in trans whose expression is variably upregulated with age (733 genes) play a key role in DNA repair and apoptosis, whereas downregulated aVMP-associated genes (121 genes) are mapped to defined pathways in cellular metabolism.
  
  
  CONCLUSIONS
  Our results link age-related changes in DNA methylation to fundamental mechanisms that are thought to drive human ageing.
authors.affiliation: Molecular Epidemiology section, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, The Netherlands.
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authors.affiliation: Molecular Epidemiology section, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, The Netherlands.
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authors.affiliation: Molecular Epidemiology section, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, The Netherlands.
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authors.affiliation: Molecular Epidemiology section, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, The Netherlands.
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authors.affiliation: Department of Genetics, University Medical Centre Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
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authors.affiliation: Molecular Epidemiology section, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, The Netherlands.
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authors.affiliation: Sequence Analysis Support Core, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, The Netherlands.
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authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, The Netherlands.
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authors.lastname: van Galen
authors.affiliation: Department of Genetics, University Medical Centre Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors.forename: Patrick
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authors.lastname: Deelen
authors.affiliation: Department of Genetics, University Medical Centre Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors.forename: Marc Jan
authors.initials: MJ
authors.lastname: Bonder
authors.affiliation: Department of Genetics, University Medical Centre Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zhernakova
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
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authors.affiliation: Department of Genetics, University Medical Centre Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors.forename: Ettje F
authors.initials: EF
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authors.affiliation: Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands.
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authors.initials: CD
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authors.affiliation: Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands.
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authors.initials: CG
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authors.affiliation: Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands.
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authors.initials: CJ
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authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, Dr. Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands.
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authors.affiliation: Department of Gerontology and Geriatrics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
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authors.affiliation: Department of Biological Psychology, VU University Amsterdam, Neuroscience Campus Amsterdam, Van der Boechorststraat 1, 1081 BT, Amsterdam, The Netherlands.
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authors.affiliation: Department of Biological Psychology, VU University Amsterdam, Neuroscience Campus Amsterdam, Van der Boechorststraat 1, 1081 BT, Amsterdam, The Netherlands.
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authors.affiliation: Molecular Epidemiology section, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, The Netherlands.
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authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, Wytemaweg 80, 3015 CN, Rotterdam, The Netherlands.
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authors.affiliation: Department of Psychiatry, VU University Medical Center, Neuroscience Campus Amsterdam, A.J. Ernststraat 1187, 1081 HL, Amsterdam, The Netherlands.
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authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, The Netherlands.
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authors.initials: PA
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authors.affiliation: Department of Genetics, University Medical Centre Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
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authors.affiliation: Department of Genetics, University Medical Centre Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
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authors.affiliation: Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands.
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authors.initials: JH
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authors.affiliation: Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands.
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authors.initials: MM
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authors.affiliation: Department of Genetic Epidemiology, Erasmus University Medical Center, Dr. Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands.
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authors.initials: CM
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authors.affiliation: Department of Biological Psychology, VU University Amsterdam, Neuroscience Campus Amsterdam, Van der Boechorststraat 1, 1081 BT, Amsterdam, The Netherlands.
authors.forename: Dorret I
authors.initials: DI
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authors.affiliation: Molecular Epidemiology section, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, The Netherlands.
authors.forename: P Eline
authors.initials: PE
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authors.affiliation: Molecular Epidemiology section, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, The Netherlands. bas.heijmans@lumc.nl.
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keywords: 450k; Ageing; DNA damage; DNA methylation; Variability