title: DNA methylation signatures in peripheral blood strongly predict all-cause mortality.
abstract: DNA methylation (DNAm) has been revealed to play a role in various diseases. Here we performed epigenome-wide screening and validation to identify mortality-related DNAm signatures in a general population-based cohort with up to 14 years follow-up. In the discovery panel in a case-cohort approach, 11,063 CpGs reach genome-wide significance (FDR<0.05). 58 CpGs, mapping to 38 well-known disease-related genes and 14 intergenic regions, are confirmed in a validation panel. A mortality risk score based on ten selected CpGs exhibits strong association with all-cause mortality, showing hazard ratios (95% CI) of 2.16 (1.10-4.24), 3.42 (1.81-6.46) and 7.36 (3.69-14.68), respectively, for participants with scores of 1, 2-5 and 5+ compared with a score of 0. These associations are confirmed in an independent cohort and are independent from the 'epigenetic clock'. In conclusion, DNAm of multiple disease-related genes are strongly linked to mortality outcomes. The DNAm-based risk score might be informative for risk assessment and stratification.
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Research Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
authors.forename: Yan
authors.identifier: 0000-0001-9913-6490
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Center for Environmental Health, D-85764 Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, D-85764 Neuherberg, Germany.
authors.forename: Rory
authors.initials: R
authors.lastname: Wilson
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Research Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Heiss
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Research Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
authors.forename: Lutz P
authors.initials: LP
authors.lastname: Breitling
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Research Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
authors.forename: Kai-Uwe
authors.initials: KU
authors.lastname: Saum
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Research Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.|Network Ageing Research, University of Heidelberg, Bergheimer Strasse 20, D-69115 Heidelberg, Germany.
authors.forename: Ben
authors.initials: B
authors.lastname: Schöttker
authors.affiliation: Saarland Cancer Registry, Präsident Baltz Strasse 5, D-66119 Saarbrücken, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Holleczek
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Center for Environmental Health, D-85764 Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, D-85764 Neuherberg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Waldenberger
authors.affiliation: Research Unit of Molecular Epidemiology, Helmholtz Zentrum München, German Center for Environmental Health, D-85764 Neuherberg, Germany.|Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, D-85764 Neuherberg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Peters
authors.affiliation: Division of Clinical Epidemiology and Aging Research, German Research Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.|Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, D-69120 Heidelberg, Germany.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
mesh_terms: D000368:Aged; D002318:Cardiovascular Diseases / Q000453:epidemiology; D002423:Cause of Death; D015331:Cohort Studies; D018899:CpG Islands; D019175:DNA Methylation / Q000235:genetics*; D003920:Diabetes Mellitus / Q000453:epidemiology; D044127:Epigenesis, Genetic; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006973:Hypertension / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009026:Mortality; D009369:Neoplasms / Q000453:epidemiology; D009765:Obesity / Q000453:epidemiology; D050177:Overweight / Q000453:epidemiology; D016016:Proportional Hazards Models; D012907:Smoking / Q000453:epidemiology; D013851:Thinness / Q000453:epidemiology