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

Seeboth, Anne; McCartney, Daniel L.; Wang, Yunzhang; Hillary, Robert F.; Stevenson, Anna J.; Walker, Rosie M.; Campbell, Archie; Evans, Kathryn L.; McIntosh, Andrew M.; Hägg, Sara; Deary, Ian J.; Marioni, Riccardo E.

doi:10.1186/s13148-020-00838-0

Cited by 13 publications

(7 citation statements)

References 36 publications

(67 reference statements)

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“…This discrepancy can be due to the different analytical approaches and/or to cohort-specific effects, as Wang et al investigated monozygotic and dizygotic twins longitudinally assessed. A recent paper assessed epimutations in 3 large cohorts and did not find significant differences between males and females [55]. Similarly, we did not find sex-related differences in age-related changes in Shannon entropy, another measure of epigenetic drift.…”

Section: Epimutations and Entropysupporting

confidence: 71%

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

Yusipov¹,

Bacalini²,

Kalyakulina³

et al. 2020

Aging

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The existence of a sex gap in human health and longevity has been widely documented. Autosomal DNA methylation differences between males and females have been reported, but so far, few studies have investigated if DNA methylation is differently affected by aging in males and females. We performed a metaanalysis of 4 large whole blood datasets, comparing 4 aspects of epigenetic age-dependent remodeling www.aging-us.com AGING between the two sexes: differential methylation, variability, epimutations and entropy. We reported that a large fraction (43%) of sex-associated probes undergoes age-associated DNA methylation changes, and that a limited number of probes show age-by-sex interaction. We experimentally validated 2 regions mapping in FIGN and PRR4 genes and showed sex-specific deviations of their methylation patterns in models of decelerated (centenarians) and accelerated (Down syndrome) aging. While we did not find sex differences in the ageassociated increase in epimutations and entropy, we showed that the number of probes having an age-related increase in methylation variability is 15 times higher in males compared to females. Our results can offer new epigenetic tools to study the interaction between aging and sex and can pave the way to the identification of molecular triggers of sex differences in longevity and age-related diseases prevalence.

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Section: Epimutations and Entropysupporting

confidence: 71%

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

Yusipov¹,

Bacalini²,

Kalyakulina³

et al. 2020

Aging

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“…We acknowledge that our study also has limitations including the sample sizes of the lung datasets, paucity of longitudinal lung tissue data, limited phenotype data including race, geography, socioeconomic status in the fetal lung dataset and potential residual confounding by cellular heterogeneity associated with the lung samples even after surrogate variable adjustment. Evidence of high genomic inflation, despite adjusting for confounders as we have in this study, has also been observed and discussed frequently in other age EWAS studies and in principle could be used as a marker of development and biological age [ 11 , 53 , 54 ]. Moreover, limited association in fetal and adult lung tissue with the epigenetic clock metrics could be due to lack of a true association or the consideration that a lung specific clock would perform better, given the richness of the age associated EWAS findings.…”

Section: Discussionsupporting

confidence: 76%

DNA methylation perturbations may link altered development and aging in the lung

Kachroo

Morrow

Vyhlidal

et al. 2021

Aging

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Fetal perturbations in DNA methylation during lung development may reveal insights into the enduring impacts on adult lung health and disease during aging that have not been explored altogether before. We studied the association between genome-wide DNA-methylation and post-conception age in fetal-lung (n=78, 42 exposed to in-utero-smoke (IUS)) tissue and chronological age in adult-lung tissue (n=160, 114 with Chronic Obstructive Pulmonary Disease) using multi-variate linear regression models with covariate adjustment and tested for effect modification by phenotypes. Overlapping age-associations were evaluated for functional and tissue-specific enrichment using the Genotype-Tissue-Expression (GTEx) project. We identified 244 age-associated differentially methylated positions and 878 regions overlapping between fetal and adult-lung tissues. Hyper-methylated CpGs (96%) were enriched in transcription factor activity (FDR adjusted P=2x10 -33 ) and implicated in developmental processes including embryonic organ morphogenesis, neurogenesis and growth delay. Hypo-methylated CpGs (2%) were enriched in oxido-reductase activity and VEGFA-VEGFR2 Signaling. Twenty-one age-by-sex and eleven age-by-pack-years interactions were statistically significant (FDR<0.05) in adult-lung tissue. DNA methylation in transcription factors during development in fetal lung recapitulates in adult-lung tissue with aging. These findings reveal molecular mechanisms and pathways that may link disrupted development in early-life and age-associated lung diseases.

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“…Set 1 comprised 5,190 related individuals whereas Set 2 comprised 4,583 individuals, unrelated to each other and to those in Set 1. During quality control, probes were removed based on visual outlier inspection, bead count <3 in over 5% of samples and samples with detection P value below adequate thresholds (McCartney, Stevenson, Walker, et al, 2018; Seeboth et al, 2020). Samples were removed based on sex mismatches, low detection P values for CpGs and saliva samples and genetic outliers (Amador et al, 2015).…”

Section: Methodsmentioning

confidence: 99%

“…Prior to quality control, Set 1 comprised 5,190 related individuals whereas Set 2 comprised 4,583 individuals, unrelated to each other and to those in Set 1. Quality control details have been reported previously 73,74 . Briefly, probes were removed based on (i) outliers from visual inspection of the log median intensity of the methylated versus unmethylated signal per array, (ii) a bead count <3 in more than 5% of samples, and (iii) ≥ 0.5% of samples having a detection P value >0.05 in Set 1 and ≥ 1% of samples having a detection P value >0.01 in Set 2.…”

Section: Dna Methylation In Generation Scotland and Stradlmentioning

confidence: 99%

Epigenetic scores for the circulating proteome as tools for disease prediction

Gadd

Hillary

McCartney

et al. 2020

Preprint

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Chronic morbidities place longstanding burdens on our health as we age. Although protein biomarkers are critical for the early detection of such diseases, current studies are limited by low sample sizes, variability in proteomics methods and fluctuations in inflammatory protein expression. Here, we present a novel framework for protein-by-proxy analysis of incident disease. We show that DNA methylation proxies for nine inflammatory and seven neurology plasma proteins (generated in up to 875 individuals in the Lothian Birth Cohort 1936) predict the incidence of seven leading causes of morbidity in the Generation Scotland cohort (n=9,537), ascertained via electronic health data linkage over a follow-up period of up to 14 years. After correction for multiple testing and adjustment for common disease risk factors, these included proxy associations between CCL11 and depression (Hazard Ratio: HR = 1.45, P = 1.8 x 10-4), VEGFA and ischaemic heart disease (HR = 1.16, P = 0.02) and associations between incident diabetes and FGF-21 (HR = 1.39, P = 9.7 x 10-7), NEP (HR = 1.32, P = 2.8 x 10-6) and N-CDase (HR = 1.16, P = 0.02). Several of the protein-proxy associations with disease pinpoint proteins that are already therapeutic targets for the diseases in question. These results provide new opportunities to identify circulating biomarkers for disease detection and candidate pathways for drug targeting.

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

Cited by 13 publications

References 36 publications

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

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

DNA methylation perturbations may link altered development and aging in the lung

Epigenetic scores for the circulating proteome as tools for disease prediction

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