DNA methylation age acceleration is associated with ALS age of onset and survival

Zhang, Ming; McKeever, Paul M.; Xi, Zhengrui; Moreno, Danielle; Sato, Christine; Bergsma, Tessa; McGoldrick, Philip; Keith, Julia; Robertson, Janice; Zinman, Lorne; Rogaeva, Ekaterina

doi:10.1007/s00401-020-02131-z

Cited by 39 publications

(43 citation statements)

References 10 publications

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“…Third, we do not replicate the recently reported association between epigenetic age acceleration and survival 81 . Importantly, in our analyses we adjusted for sampling age, as it has been shown to be crucial when studying epigenetic age acceleration 82 , especially given that age of onset affects disease progression in ALS 83 .…”

Section: Discussioncontrasting

confidence: 99%

Genome-wide study of DNA methylation in Amyotrophic Lateral Sclerosis identifies differentially methylated loci and implicates metabolic, inflammatory and cholesterol pathways

Hop¹,

Zwamborn²,

Hannon³

et al. 2021

Preprint

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability of around 50%. DNA methylation patterns can serve as biomarkers of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study (EWAS) meta-analysis in 10,462 samples (7,344 ALS patients and 3,118 controls), representing the largest case-control study of DNA methylation for any disease to date. We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We show that DNA-methylation-based proxies for HDL-cholesterol, BMI, white blood cell (WBC) proportions and alcohol intake were independently associated with ALS. Integration of these results with our latest GWAS showed that cholesterol biosynthesis was causally related to ALS. Finally, we found that DNA methylation levels at several DMPs and blood cell proportion estimates derived from DNA methylation data, are associated with survival rate in patients, and could represent indicators of underlying disease processes.

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Section: Discussioncontrasting

confidence: 99%

Genome-wide study of DNA methylation in Amyotrophic Lateral Sclerosis identifies differentially methylated loci and implicates metabolic, inflammatory and cholesterol pathways

Hop¹,

Zwamborn²,

Hannon³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…18 A study of genetically unexplained ALS patients (n = 249) also revealed a strong reverse correlation of DNAmage acceleration with disease onset and survival. 19 A 5-year increase in DNAm-age acceleration was linked to a 6.4-year earlier onset using blood collected at ALS diagnosis and 8.5year earlier onset using CNS tissues, indicating further acceleration of DNAm-age by the end-stage of disease.…”

Section: Studies Of Dnam Clocks In Neurodegenerative Diseasesmentioning

confidence: 86%

“…DNAm-age acceleration (difference between DNAm-age and chronological age) was associated with major neurodegenerative diseases, such as AD, 15 Parkinson disease (PD), 16 Huntington disease 17 and amyotrophic lateral sclerosis (ALS). 18,19 Similarly, HIV-infected individuals exhibit premature aging based on methylome-wide changes and Horvath DNAm clock. 20,21 Furthermore, individuals with Werner or Down syndromes also display accelerated DNAm clocks.…”

Section: Introductionmentioning

confidence: 99%

DNA Methylation Clocks and Their Predictive Capacity for Aging Phenotypes and Healthspan

2020

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The number of age predictors based on DNA methylation (DNAm) profile is rising due to their potential in predicting healthspan and application in age-related illnesses, such as neurodegenerative diseases. The cumulative assessment of DNAm levels at age-related CpGs (DNAm clock) may reflect biological aging. Such DNAm clocks have been developed using various training models and could mirror different aspects of disease/aging mechanisms. Hence, evaluating several DNAm clocks together may be the most effective strategy in capturing the complexity of the aging process. However, various confounders may influence the outcome of these age predictors, including genetic and environmental factors, as well as technical differences in the selected DNAm arrays. These factors should be taken into consideration when interpreting DNAm clock predictions. In the current review, we discuss 15 reported DNAm clocks with consideration for their utility in investigating neurodegenerative diseases and suggest research directions towards developing a more optimal measure for biological aging.

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“…In line with this, we additionally demonstrated that a risk score based on DNA methylation of three identified sites predicts disease duration. Work from Zhang et al recently demonstrated that DNA methylation age acceleration associated with ALS survival [ 65 ]. The finding that DNA methylation levels on two sites ( KIAA0513 and UHRF1 ) refined survival information driven by PRNP codon 129 genotype is informative, particularly for individuals most at risk.…”

Section: Discussionmentioning

confidence: 99%

Altered DNA methylation profiles in blood from patients with sporadic Creutzfeldt–Jakob disease

et al. 2020

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Prion diseases are fatal and transmissible neurodegenerative disorders caused by the misfolding and aggregation of prion protein. Although recent studies have implicated epigenetic variation in common neurodegenerative disorders, no study has yet explored their role in human prion diseases. Here we profiled genome-wide blood DNA methylation in the most common human prion disease, sporadic Creutzfeldt–Jakob disease (sCJD). Our case–control study (n = 219), when accounting for differences in cell type composition between individuals, identified 38 probes at genome-wide significance (p < 1.24 × 10–7). Nine of these sites were taken forward in a replication study, performed in an independent case–control (n = 186) cohort using pyrosequencing. Sites in or close to FKBP5, AIM2 (2 probes), UHRF1, KCNAB2 successfully replicated. The blood-based DNA methylation signal was tissue- and disease-specific, in that the replicated probe signals were unchanged in case–control studies using sCJD frontal-cortex (n = 84), blood samples from patients with Alzheimer’s disease, and from inherited and acquired prion diseases. Machine learning algorithms using blood DNA methylation array profiles accurately distinguished sCJD patients and controls. Finally, we identified sites whose methylation levels associated with prolonged survival in sCJD patients. Altogether, this study has identified a peripheral DNA methylation signature of sCJD with a variety of potential biomarker applications.

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DNA methylation age acceleration is associated with ALS age of onset and survival

Abstract: Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Cited by 39 publications

References 10 publications

Genome-wide study of DNA methylation in Amyotrophic Lateral Sclerosis identifies differentially methylated loci and implicates metabolic, inflammatory and cholesterol pathways

Genome-wide study of DNA methylation in Amyotrophic Lateral Sclerosis identifies differentially methylated loci and implicates metabolic, inflammatory and cholesterol pathways

DNA Methylation Clocks and Their Predictive Capacity for Aging Phenotypes and Healthspan

Altered DNA methylation profiles in blood from patients with sporadic Creutzfeldt–Jakob disease

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