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

English version

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): e32767. doi:10.1371/journal.pgen.1008104
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008104

Souhrn

'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

Zdroje

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