A meta-analysis of genome-wide association studies of epigenetic age acceleration

Autoři: Jude Gibson aff001;  Tom C. Russ aff001;  Toni-Kim Clarke aff001;  David M. Howard aff001;  Robert F. Hillary aff005;  Kathryn L. Evans aff004;  Rosie M. Walker aff004;  Mairead L. Bermingham aff005;  Stewart W. Morris aff005;  Archie Campbell aff005;  Caroline Hayward aff007;  Alison D. Murray aff008;  David J. Porteous aff004;  Steve Horvath aff009;  Ake T. Lu aff009;  Andrew M. McIntosh aff001;  Heather C. Whalley aff001;  Riccardo E. Marioni aff004
Působiště autorů: Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom aff001;  Centre for Dementia Prevention, University of Edinburgh, Edinburgh, United Kingdom aff002;  Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, United Kingdom aff003;  Centre for Cognitive Ageing & Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom aff004;  Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom aff005;  Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, United Kingdom aff006;  MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom aff007;  Aberdeen Biomedical Imaging Centre, University of Aberdeen, Aberdeen, United Kingdom aff008;  Department of Human Genetics, David Geffen School of Medicine, Los Angeles, CA, United States of America aff009;  Department of Biostatistics, School of Public Health, University of California-Los Angeles, Los Angeles, CA, United States of America aff010
Vyšlo v časopise: A meta-analysis of genome-wide association studies of epigenetic age acceleration. PLoS Genet 15(11): e1008104. doi:10.1371/journal.pgen.1008104
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008104


'Epigenetic age acceleration' is a valuable biomarker of ageing, predictive of morbidity and mortality, but for which the underlying biological mechanisms are not well established. Two commonly used measures, derived from DNA methylation, are Horvath-based (Horvath-EAA) and Hannum-based (Hannum-EAA) epigenetic age acceleration. We conducted genome-wide association studies of Horvath-EAA and Hannum-EAA in 13,493 unrelated individuals of European ancestry, to elucidate genetic determinants of differential epigenetic ageing. We identified ten independent SNPs associated with Horvath-EAA, five of which are novel. We also report 21 Horvath-EAA-associated genes including several involved in metabolism (NHLRC, TPMT) and immune system pathways (TRIM59, EDARADD). GWAS of Hannum-EAA identified one associated variant (rs1005277), and implicated 12 genes including several involved in innate immune system pathways (UBE2D3, MANBA, TRIM46), with metabolic functions (UBE2D3, MANBA), or linked to lifespan regulation (CISD2). Both measures had nominal inverse genetic correlations with father’s age at death, a rough proxy for lifespan. Nominally significant genetic correlations between Hannum-EAA and lifestyle factors including smoking behaviours and education support the hypothesis that Hannum-based epigenetic ageing is sensitive to variations in environment, whereas Horvath-EAA is a more stable cellular ageing process. We identified novel SNPs and genes associated with epigenetic age acceleration, and highlighted differences in the genetic architecture of Horvath-based and Hannum-based epigenetic ageing measures. Understanding the biological mechanisms underlying individual differences in the rate of epigenetic ageing could help explain different trajectories of age-related decline.

Klíčová slova:

DNA methylation – Epigenetics – Gene expression – Gene regulation – Genetic loci – Genome-wide association studies – Molecular genetics


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