Comprehensive longitudinal study of epigenetic mutations in aging

Wang, Yunzhang; Karlsson, Robert; Jylhävä, Juulia; Hedman, Åsa K.; Almqvist, Catarina; Karlsson, Ida K.; Pedersen, Nancy L.; Almgren, Malin; Hägg, Sara

doi:10.1101/744250

Cited by 10 publications

(34 citation statements)

References 20 publications

(27 reference statements)

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“…DNA methylation outlier burden measures were strongly associated with cell proportions and other technical factors, again, confirming previous findings (13,14). Moreover, in this study, batch effects were confounded by wave of data collection in the LBC1921 and LBC1936.…”

Section: Dna Methylation Outlier Burden and Agesupporting

confidence: 90%

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DNA methylation outlier burden, health and ageing in Generation Scotland and the Lothian Birth Cohorts of 1921 and 1936

Seeboth

McCartney

Wang

et al. 2019

Preprint

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DNA methylation outlier burden has been suggested as a potential marker of biological age. An outlier is typically defined as DNA methylation levels at any one CpG site that are three times beyond the inter-quartile range from the 25th or 75th percentiles compared to the rest of the population. DNA methylation outlier burden (the number of such outlier sites per individual) increases exponentially with age. However, these findings have been observed in small samples. Here, we showed an association between age and log10-transformed DNA methylation outlier burden in a large cross-sectional cohort, the Generation Scotland Family Health Study (N=7,010, β=0.0091, p<2x10-16), and in two longitudinal cohort studies, the Lothian Birth Cohorts of 1921 (N=430, β=0.033, p=7.9x10-4) and 1936 (N=898, β=7.9x10-3, p=0.074). Significant confounders of both cross-sectional and longitudinal associations between outlier burden and age included white blood cell proportions, BMI, smoking, and batch effects. In Generation Scotland, the increase in epigenetic outlier burden with age was not purely an artefact of an increase in DNA methylation level variability with age (epigenetic drift). Log10-transformed DNA methylation outlier burden in Generation Scotland was not related to self-reported, or family history of, age-related diseases and it was not heritable (SNP-based heritability of 4.4%, p=0.18). Finally, DNA methylation outlier burden was not significantly related to survival in either of the Lothian Birth Cohorts individually but it was in a meta-analysis (HRmeta=1.12; 95%CImeta=[1.02; 1.21]; pmeta=0.021). These findings suggest that, while it does not associate with ageing-related health outcomes, DNA methylation outlier burden does track chronological ageing and may also relate to survival. DNA methylation outlier burden may thus be useful as a marker of biological ageing.

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Section: Dna Methylation Outlier Burden and Agesupporting

confidence: 90%

“…When looking at outlier burden per CpG site rather than per individual, Wang and colleagues (13) reported that at 64% of CpG sites, at least one out of 385 individuals in SATSA had an outlier.…”

Section: Dna Methylation Outlier Burdenmentioning

confidence: 99%

DNA methylation outlier burden, health and ageing in Generation Scotland and the Lothian Birth Cohorts of 1921 and 1936

Seeboth

McCartney

Wang

et al. 2019

Preprint

Self Cite

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“…Accumulation of epimutations has been reported in cancer [47], and we and others demonstrated that number of epimutations increases with age [5,48]. Recently, Wang and colleagues showed that the number of epimutations in whole blood tends to be higher in females compared to males [48]. On the contrary, we failed to detect differences in the age-related increase in epimutations between the two sexes.…”

Section: Iv) Epimutations and Entropycontrasting

confidence: 78%

“…As such, variable probes and epimutations represent distinct aspects of epigenetic instability, that can be differently triggered during aging and that can differently affect aging trajectories. Accumulation of epimutations has been reported in cancer [47], and we and others demonstrated that number of epimutations increases with age [5,48]. Recently, Wang and colleagues showed that the number of epimutations in whole blood tends to be higher in females compared to males [48].…”

Section: Iv) Epimutations and Entropymentioning

confidence: 66%

Age-related DNA methylation changes are sex-specific: a comprehensive assessment

Yusipov

Bacalini

Kalyakulina

et al. 2020

Preprint

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Current epidemiological data indicate that, in humans, females live longer than males but experience a worse quality of life in advanced age. The reasons for this sex disparity are still unknown, but it is likely that it derives from a strict interplay between biological and cultural factors. Epigenetic modifications likely contribute to shape sex gap in aging and longevity, and genome-wide DNA methylation differences between males and females in autosomal chromosomes have been reported. Several studies showed that DNA methylation patterns are profoundly remodelled during aging, modulated in part by environmental exposures. However, few studies have specifically investigated if DNA methylation is differently affected by aging in males and females. Here we performed a meta-analysis of 4 large whole blood datasets including males and females of different ages and we compared 4 aspects of epigenetic age-dependent remodelling between males and females: normative changes, variability, epimutations, and entropy. While we did not find differences in the ageassociated increase in epimutations and in entropy, we reported a list of highly reproducible sex-specific age-associated differentially methylated positions (saDMPs) and sex-specific age-associated variably methylated positions (saVMPs). We investigated the enrichment in saDMPs and saVMPs in genomic regions, imprinted and sex hormone-related genes and Reactome pathways. Furthermore, we experimentally validated the most robust saDMPs, mapping in FIGN and PRR4 genes, and showed sex-specific deviations of their methylation patterns in models of successful (centenarians) and unsuccessful (Down syndrome) aging.In conclusion, we provided a comprehensive description of sex-differences in DNA methylation changes with aging in whole blood. Our results can pave the way to the identification of possible molecular triggers of the sex gap in aging and longevity. DNA methylation profiles tend to diverge among individuals during life course [4][5][6], shaped by an intricated combination of environmental exposures, random events and genetically-driven mechanisms. At the same time, several epigenome-wide association studies (EWAS) have shown that a subset of the about 28 million CpG sites of the genome undergoes age-associated normative changes, i.e. reproducible hypermethylation or hypomethylation events that characterize aging individuals [7,8]. Despite some controversial results [9,10], at least a fraction of normative changes is tissue specific, indicating that the cellular microenvironment affects the activity of the molecular writers of DNA methylation patterns during aging. The number of studies identifying age-associated DNA methylation changes at the level of single CpG sites has exponentially increased in the last 10 years, paving the way for the development of mathematical models, termed "epigenetic clocks", that predict the age of an individual on the basis of his/her epigenetic profile [11]. Epigenetic clocks are an appealing resource for chronological age estimation in ...

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“…However, distinguishing the cause of disease pathogenesis is critical since it will clarify the functional role of disease‐associated variation and can be helpful in terms of prevention and therapeutics. For that reason, more longitudinal twin cohort designs are necessary 157, 158 . The most ideal longitudinal study will follow initially disease‐free twins over the course of many years, which become disease discordant over the years.…”

Section: Genome‐wide Integrative Analysis In Adipose Tissue Results Imentioning

confidence: 99%

Insights into the multifactorial causation of obesity by integrated genetic and epigenetic analysis

2020

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Obesity is a highly heritable multifactorial disease that places an enormous burden on human health. Its increasing prevalence and the concomitant-reduced life expectancy has intensified the search for new analytical methods that can reduce the knowledge gap between genetic susceptibility and functional consequences of the disease pathology. Although the influence of genetics and epigenetics has been studied independently in the past, there is increasing evidence that genetic variants interact with environmental factors through epigenetic regulation. This suggests that a combined analysis of genetic and epigenetic variation may be more effective in characterizing the obesity phenotype. To date, limited genome-wide integrative analyses have been performed. In this review, we provide an overview of the latest findings, advantages, and challenges and discuss future perspectives.

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Comprehensive longitudinal study of epigenetic mutations in aging

Cited by 10 publications

References 20 publications

DNA methylation outlier burden, health and ageing in Generation Scotland and the Lothian Birth Cohorts of 1921 and 1936

DNA methylation outlier burden, health and ageing in Generation Scotland and the Lothian Birth Cohorts of 1921 and 1936

Age-related DNA methylation changes are sex-specific: a comprehensive assessment

Insights into the multifactorial causation of obesity by integrated genetic and epigenetic analysis

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