DNA methylation age acceleration and risk factors for Alzheimer’s disease

Dl, McCartney; Aj, Stevenson; Rm, Walker; Gibson, Jude; Sw, Morris; Campbell, Archie; Ad, Murray; Whalley, Heather C.; Porteous, David J.; McIntosh, Andrew M.; Kl, Evans; Ij, Deary; Marioni, Riccardo E.

doi:10.1101/278945

Cited by 2 publications

(13 citation statements)

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“…Our LD score regression analysis replicated the positive genetic correlations with central adiposity reported by Lu et al (2018) at nominal significance levels, supporting the suggestion that observed phenotypic associations (14,18) may result in part from a shared genetic aetiology. We did not, however, replicate previously reported correlations between Horvath-EAA and metabolic disease-related traits or diabetes, and found these traits to be correlated with Hannum-EAA at only nominal significance levels in our larger sample (19).…”

Section: Discussionsupporting

confidence: 89%

“…A number of the genes significantly associated with Horvath-EAA are related to metabolism ( NHLRC1 , TPMT , KDM1B , and ESYT3 ), consistent with several studies reporting phenotypic associations between Horvath-based EAA and metabolic syndrome characteristics and supporting the suggestion of a role in tracking metabolic ageing (14,18). Others are involved in immune system pathways ( TRIM59 , KPNA4 , EDARADD ), while several have roles in cellular processes linked to ageing: apoptosis and autophagy ( FAIM ), ageing and autophagy ( TERT ), and coordinating vital cell functions ( PIK3CB ).…”

Section: Discussionsupporting

confidence: 88%

“…We also found no correlation between epigenetic age acceleration and age at menopause. Nominally significant genetic correlations between Hannum-based, but not Horvath-based, epigenetic age acceleration, and lifestyle factors such as smoking behaviour and education level, provide some evidence for a genetic basis underlying the phenotypic results we reported previously (18), and provide tentative support to the hypothesis that Hannum-based epigenetic ageing is relatively sensitive to changes in environment and lifestyle. Father’s age at death, a rough proxy for lifespan (46), was nominally significantly correlated with both EAA measures, and parents’ age at death was additionally correlated with Hannum-EAA, consistent with a body of work demonstrating robustly that EAA predicts life span (10,11).…”

Section: Discussionsupporting

confidence: 71%

“…Higher EAA has been associated with poorer measures of physical and cognitive fitness (9) and higher risk of all-cause mortality (11). Many associations are specific to either Horvath-EAA or Hannum-EAA, a discordance that may reflect the differences in the two estimates and supports the theory that they represent different aspects of ageing (14,17,18).…”

Section: Introductionmentioning

confidence: 57%

“…Horvath-based and Hannum-based epigenetic age acceleration are thought to represent different aspects of ageing. Hannum-EAA has been described as a biomarker of immune system ageing, and has been found to be associated with a wide range of traits (14,18), indicating a sensitivity to variations in environment and lifestyle. By contrast, Horvath-EAA is considered to be a fundamental, intrinsic cellular ageing process, largely unrelated to lifestyle factors, although associations with a range of metabolic syndrome characteristics suggest a role in tracking metabolic ageing processes.…”

Section: Discussionmentioning

confidence: 99%

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A meta-analysis of genome-wide association studies of epigenetic age acceleration

Gibson

Russ

Clarke

et al. 2019

Preprint

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Abstract‘Epigenetic age acceleration’ is a valuable biomarker of ageing, predictive of morbidity and mortality, but for which the underlying biological mechanisms are not well established. Two commonly used measures, derived from DNA methylation, are Horvath-based (Horvath-EAA) and Hannum-based (Hannum-EAA) epigenetic age acceleration. We conducted genome-wide association studies of Horvath-EAA and Hannum-EAA in 13,493 unrelated individuals of European ancestry, to elucidate genetic determinants of differential epigenetic ageing. We identified ten independent SNPs associated with Horvath-EAA, five of which are novel. We also report 21 Horvath-EAA-associated genes including several involved in metabolism (NHLRC,TPMT) and immune system pathways (TRIM59,EDARADD). GWAS of Hannum-EAA identified one associated variant (rs1005277), and implicated 12 genes including several involved in innate immune system pathways (UBE2D3,MANBA,TRIM46), with metabolic functions (UBE2D3,MANBA), or linked to lifespan regulation (CISD2). Both measures had nominal inverse genetic correlations with father’s age at death, a rough proxy for lifespan. Nominally significant genetic correlations between Hannum-EAA and lifestyle factors including smoking behaviours and education support the hypothesis that Hannum-based epigenetic ageing is sensitive to variations in environment, whereas Horvath-EAA is a more stable cellular ageing process. We identified novel SNPs and genes associated with epigenetic age acceleration, and highlighted differences in the genetic architecture of Horvath-based and Hannum-based epigenetic ageing measures. Understanding the biological mechanisms underlying individual differences in the rate of epigenetic ageing could help explain different trajectories of age-related decline.Author SummaryDNA methylation, a type of epigenetic process, is known to vary with age. Methylation levels at specific sites across the genome can be combined to form estimates of age known as ‘epigenetic age’. The difference between epigenetic age and chronological age is referred to as ‘epigenetic age acceleration’, with positive values indicating that a person is biologically older than their years. Understanding why some people seem to age faster than others could shed light on the biological processes behind age-related decline; however, the mechanisms underlying differential rates of epigenetic ageing are largely unknown. Here, we investigate genetic determinants of two commonly used epigenetic age acceleration measures, based on the Horvath and Hannum epigenetic clocks. We report novel genetic variants and genes associated with epigenetic age acceleration, and highlight differences in the genetic factors influencing these two measures. We identify ten genetic variants and 21 genes associated with Horvath-based epigenetic age acceleration, and one variant and 12 genes associated with the Hannum-based measure. There were no genome-wide significant variants or genes in common between the Horvath-based and Hannum-based measures, supporting the hypothesis that they represent different aspects of ageing. Our results suggest a partial genetic basis underlying some previously reported phenotypic associations.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 71%

Section: Introductionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

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A meta-analysis of genome-wide association studies of epigenetic age acceleration

Gibson

Russ

Clarke

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

A meta-analysis of genome-wide association studies of epigenetic age acceleration

et al. 2019

Self Cite

View full text Add to dashboard Cite

'Epigenetic age acceleration' is a valuable biomarker of ageing, predictive of morbidity and mortality, but for which the underlying biological mechanisms are not well established. Two commonly used measures, derived from DNA methylation, are Horvath-based (Horvath-EAA) and Hannum-based (Hannum-EAA) epigenetic age acceleration. We conducted genome-wide association studies of Horvath-EAA and Hannum-EAA in 13,493 unrelated individuals of European ancestry, to elucidate genetic determinants of differential epigenetic ageing. We identified ten independent SNPs associated with Horvath-EAA, five of which are novel. We also report 21 Horvath-EAA-associated genes including several involved in metabolism (NHLRC, TPMT) and immune system pathways (TRIM59, EDARADD). GWAS of Hannum-EAA identified one associated variant (rs1005277), and implicated 12 genes including several involved in innate immune system pathways (UBE2D3, MANBA, TRIM46), with metabolic functions (UBE2D3, MANBA), or linked to lifespan regulation (CISD2). Both measures had nominal inverse genetic correlations with father’s age at death, a rough proxy for lifespan. Nominally significant genetic correlations between Hannum-EAA and lifestyle factors including smoking behaviours and education support the hypothesis that Hannum-based epigenetic ageing is sensitive to variations in environment, whereas Horvath-EAA is a more stable cellular ageing process. We identified novel SNPs and genes associated with epigenetic age acceleration, and highlighted differences in the genetic architecture of Horvath-based and Hannum-based epigenetic ageing measures. Understanding the biological mechanisms underlying individual differences in the rate of epigenetic ageing could help explain different trajectories of age-related decline.

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DNA methylation age acceleration and risk factors for Alzheimer’s disease

Abstract: (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

Cited by 2 publications

References 66 publications

A meta-analysis of genome-wide association studies of epigenetic age acceleration

A meta-analysis of genome-wide association studies of epigenetic age acceleration

A meta-analysis of genome-wide association studies of epigenetic age acceleration

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