Epigenome-Wide Scans Identify Differentially Methylated Regions for Age and Age-Related Phenotypes in a Healthy Ageing Population

Bell, Jordana T.; Tsai, Pei-Chien; Yang, Tsun-Po; Pidsley, Ruth; Nisbet, James; Glass, Daniel; Mangino, Massimo; Zhai, Guangju; Zhang, Feng; Valdes, Ana M.; Shin, So–Youn; Dempster, Emma; Murray, Robin M.; Grundberg, Elin; Hedman, Åsa K.; Nica, Alexandra C.; Small, Kerrin S.; Dermitzakis, Emmanouil T.; McCarthy, Mark I.; Mill, Jonathan; Spector, Tim D.; Deloukas, Panos

doi:10.1371/journal.pgen.1002629

Cited by 624 publications

(623 citation statements)

References 55 publications

(85 reference statements)

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“…Some evidence show that age-related hypermethylation are more conserved across different tissues than hypomethylation [5,26]. However, we only studied blood samples and adjusted methylation data using estimated cellular compositions [20].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, it has been suggested that age-related methylation alterations depend on genetic effects [9], and another recent study on mother-children pairs reported that meQTL associations were stable over time [12]. Twin studies of the epigenome have been used to estimate methylation heritability [9,13], and higher methylation correlation has been observed in monozygotic (MZ) than dizygotic (DZ) twin pairs [5,14]. However, the change of intra-twin-pair methylation difference over time has not been studied.…”

Section: Introductionmentioning

confidence: 99%

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Epigenetic influences on aging: a longitudinal genome-wide methylation study in old Swedish twins

et al. 2018

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Age-related changes in DNA methylation were observed in cross-sectional studies, but longitudinal evidence is still limited. Here, we aimed to characterize longitudinal age-related methylation patterns using 1011 blood samples collected from 385 Swedish twins (age at entry: mean 69 and standard deviation 9.7, 73 monozygotic and 96 dizygotic pairs) up to five times (mean 2.6) over 20 years (mean 8.7). We identified 1316 age-associated methylation sites (P<1.3×10−7) using a longitudinal epigenome-wide association study design. We measured how estimated cellular compositions changed with age and how much they confounded the age effect. We validated the results in two independent longitudinal cohorts, where 118 CpGs were replicated in Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS, 390 samples) (P<3.9×10−5), 594 in Lothian Birth Cohort (LBC, 3018 samples) (P<5.1×10−5) and 63 in both. Functional annotation of age-associated CpGs showed enrichment in CCCTC-binding factor (CTCF) and other transcription factor binding sites. We further investigated genetic influences on methylation and found no interaction between age and genetic effects in the 1316 age-associated CpGs. Moreover, in the same CpGs, methylation differences within twin pairs increased with 6.4% over 10 years, where monozygotic twins had smaller intra-pair differences than dizygotic twins. In conclusion, we show that age-related methylation changes persist in a longitudinal perspective, and are fairly stable across cohorts. The changes are under genetic influence, although this effect is independent of age. Moreover, methylation variability increase over time, especially in age-associated CpGs, indicating the increase of environmental contributions on DNA methylation with age.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Epigenetic influences on aging: a longitudinal genome-wide methylation study in old Swedish twins

et al. 2018

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“…The eQTL analysis revealed that this region also affects the expression of the WRD55 and ARL4A genes, primarily in brain tissue. Epigenetic changes in ARL4A have previously been found to associate with maternal longevity in an epigenome‐wide association study of age and age‐related phenotypes (Bell et al ., 2012), indicating a possible link between the 5q31.3 deletion and longevity.…”

Section: Discussionmentioning

confidence: 99%

Copy number variation associates with mortality in long‐lived individuals: a genome‐wide assessment

et al. 2015

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SummaryCopy number variants (CNVs) represent a significant source of genetic variation in the human genome and have been implicated in numerous diseases and complex traits. To date, only a few studies have investigated the role of CNVs in human lifespan. To investigate the impact of CNVs on prospective mortality at the extreme end of life, where the genetic component of lifespan appears most profound, we analyzed genomewide CNV data in 603 Danish nonagenarians and centenarians (mean age 96.9 years, range 90.0–102.5 years). Replication was performed in 500 long‐lived individuals from the Leiden Longevity Study (mean age 93.2 years, range 88.9–103.4 years). First, we assessed the association between the CNV burden of each individual (the number of CNVs, the average CNV length, and the total CNV length) and mortality and found a significant increase in mortality per 10 kb increase in the average CNV length, both for all CNVs (hazard ratio (HR) = 1.024, P = 0.002) and for duplications (HR = 1.011, P = 0.005), as well as per 100 kb increase in the total length of deletions (HR = 1.009, P = 0.0005). Next, we assessed the relation between specific deletions and duplications and mortality. Although no genome–wide significant associations were discovered, we identified six deletions and one duplication that showed consistent association with mortality in both or either of the sexes across both study populations. These results indicate that the genome–wide CNV burden, specifically the average CNV length and the total CNV length, associates with higher mortality in long‐lived individuals.

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“…In both humans and domesticated animals, there is vast literature characterizing genes or genomic regions that either become hyper‐ or hypomethylated with age (Bollati et al., 2009; Christensen et al., 2009; Bell et al., 2012; Gryzinska, Blaszczak, Strachecka, & Jezewska‐Witkowska, 2013; Gryzinska et al., 2016; Spiers et al., 2016). In wild animals, there is growing interest in age‐specific DNA methylation (Paoli‐Iseppi et al., 2017), but few studies have examined this and the results are often contradictory.…”

Section: Discussionmentioning

confidence: 99%

Age‐ and quality‐dependent DNA methylation correlate with melanin‐based coloration in a wild bird

Soulsbury

Lipponen

Wood

et al. 2018

Ecology and Evolution

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Secondary sexual trait expression can be influenced by fixed individual factors (such as genetic quality) as well as by dynamic factors (such as age and environmentally induced gene expression) that may be associated with variation in condition or quality. In particular, melanin‐based traits are known to relate to condition and there is a well‐characterized genetic pathway underpinning their expression. However, the mechanisms linking variable trait expression to genetic quality remain unclear. One plausible mechanism is that genetic quality could influence trait expression via differential methylation and differential gene expression. We therefore conducted a pilot study examining DNA methylation at a candidate gene (agouti‐related neuropeptide: AgRP) in the black grouse Lyrurus tetrix. We specifically tested whether CpG methylation covaries with age and multilocus heterozygosity (a proxy of genetic quality) and from there whether the expression of a melanin‐based ornament (ultraviolet‐blue chroma) correlates with DNA methylation. Consistent with expectations, we found clear evidence for age‐ and heterozygosity‐specific patterns of DNA methylation, with two CpG sites showing the greatest DNA methylation in highly heterozygous males at their peak age of reproduction. Furthermore, DNA methylation at three CpG sites was significantly positively correlated with ultraviolet‐blue chroma. Ours is the first study to our knowledge to document age‐ and quality‐dependent variation in DNA methylation and to show that dynamic sexual trait expression across the lifespan of an organism is associated with patterns of DNA methylation. Although we cannot demonstrate causality, our work provides empirical support for a mechanism that could potentially link key individual factors to variation in sexual trait expression in a wild vertebrate.

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Epigenome-Wide Scans Identify Differentially Methylated Regions for Age and Age-Related Phenotypes in a Healthy Ageing Population

Cited by 624 publications

References 55 publications

Epigenetic influences on aging: a longitudinal genome-wide methylation study in old Swedish twins

Epigenetic influences on aging: a longitudinal genome-wide methylation study in old Swedish twins

Copy number variation associates with mortality in long‐lived individuals: a genome‐wide assessment

Age‐ and quality‐dependent DNA methylation correlate with melanin‐based coloration in a wild bird

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