title: Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population.
abstract: Age-related changes in DNA methylation have been implicated in cellular senescence and longevity, yet the causes and functional consequences of these variants remain unclear. To elucidate the role of age-related epigenetic changes in healthy ageing and potential longevity, we tested for association between whole-blood DNA methylation patterns in 172 female twins aged 32 to 80 with age and age-related phenotypes. Twin-based DNA methylation levels at 26,690 CpG-sites showed evidence for mean genome-wide heritability of 18%, which was supported by the identification of 1,537 CpG-sites with methylation QTLs in cis at FDR 5%. We performed genome-wide analyses to discover differentially methylated regions (DMRs) for sixteen age-related phenotypes (ap-DMRs) and chronological age (a-DMRs). Epigenome-wide association scans (EWAS) identified age-related phenotype DMRs (ap-DMRs) associated with LDL (STAT5A), lung function (WT1), and maternal longevity (ARL4A, TBX20). In contrast, EWAS for chronological age identified hundreds of predominantly hyper-methylated age DMRs (490 a-DMRs at FDR 5%), of which only one (TBX20) was also associated with an age-related phenotype. Therefore, the majority of age-related changes in DNA methylation are not associated with phenotypic measures of healthy ageing in later life. We replicated a large proportion of a-DMRs in a sample of 44 younger adult MZ twins aged 20 to 61, suggesting that a-DMRs may initiate at an earlier age. We next explored potential genetic and environmental mechanisms underlying a-DMRs and ap-DMRs. Genome-wide overlap across cis-meQTLs, genotype-phenotype associations, and EWAS ap-DMRs identified CpG-sites that had cis-meQTLs with evidence for genotype-phenotype association, where the CpG-site was also an ap-DMR for the same phenotype. Monozygotic twin methylation difference analyses identified one potential environmentally-mediated ap-DMR associated with total cholesterol and LDL (CSMD1). Our results suggest that in a small set of genes DNA methylation may be a candidate mechanism of mediating not only environmental, but also genetic effects on age-related phenotypes.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. jordana.bell@kcl.ac.uk
authors.forename: Jordana T
authors.initials: JT
authors.lastname: Bell
authors.forename: Pei-Chien
authors.initials: PC
authors.lastname: Tsai
authors.forename: Tsun-Po
authors.initials: TP
authors.lastname: Yang
authors.forename: Ruth
authors.initials: R
authors.lastname: Pidsley
authors.forename: James
authors.initials: J
authors.lastname: Nisbet
authors.forename: Daniel
authors.initials: D
authors.lastname: Glass
authors.forename: Massimo
authors.initials: M
authors.lastname: Mangino
authors.forename: Guangju
authors.initials: G
authors.lastname: Zhai
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Ana
authors.initials: A
authors.lastname: Valdes
authors.forename: So-Youn
authors.initials: SY
authors.lastname: Shin
authors.forename: Emma L
authors.initials: EL
authors.lastname: Dempster
authors.forename: Robin M
authors.initials: RM
authors.lastname: Murray
authors.forename: Elin
authors.initials: E
authors.lastname: Grundberg
authors.forename: Asa K
authors.initials: AK
authors.lastname: Hedman
authors.forename: Alexandra
authors.initials: A
authors.lastname: Nica
authors.forename: Kerrin S
authors.initials: KS
authors.lastname: Small
authors.forename: Emmanouil T
authors.initials: ET
authors.lastname: Dermitzakis
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mill
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.forename: Panos
authors.initials: P
authors.lastname: Deloukas
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D016922:Cellular Senescence / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D059647:Gene-Environment Interaction; D056726:Genetic Association Studies; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D008136:Longevity / Q000235:genetics*; D008875:Middle Aged; D040641:Quantitative Trait Loci / Q000235:genetics; D014430:Twins, Monozygotic / Q000235:genetics