A genome-wide association study of aging

Walter, Stefan; Atzmon, Gil; Demerath, Ellen W.; García, Melissa; Kaplan, Robert C.; Kumari, Meena; Lunetta, Kathryn L.; Milaneschi, Yuri; Tanaka, Toshiko; Tranah, Gregory J.; Völker, Uwe; Yu, Lei; Arnold, Alice M.; Benjamin, Emelia J.; Biffar, Reiner; Buchman, Aron S.; Boerwinkle, Eric; Couper, David J.; Jager, Philip L. De; Evans, Denis A.; Harris, Tamara B.; Hoffmann, Wolfgang; Hofman, Albert; Karasik, David; Kiel, Douglas P.; Kocher, Thomas; Kuningas, Maris; Launer, Lenore J.; Lohman, Kurt; Lutsey, Pamela L.; Mackenbach, Johan; Marciante, Kristin D.; Psaty, Bruce M.; Reiman, Eric M.; Rotter, Jerome I.; Seshadri, Sudha; Shardell, Michelle; Smith, Albert V.; Duijn, Cornelia M. van; Walston, Jeremy D.; Zillikens, M. Carola; Bandinelli, Stefania; Baumeister, Sebastian E.; Bennett, David A.; Ferrucci, Luigi; Gudnason, Vilmundur; Kivimäki, Mika; Liu, Yongmei; Murabito, Joanne M.; Newman, Anne B.; Tiemeier, Henning; Franceschini, Nora

doi:10.1016/j.neurobiolaging.2011.05.026

Cited by 136 publications

(118 citation statements)

References 74 publications

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“…However, these may provide starting points for future explorations of aging biology. Notably, genetic variation at the related gene GRIA1 was robustly associated with longevity in a genome-wide association study meta-analysis (55). Several other genes identified by Bell et al were members of gene families represented among our top findings.…”

Section: Consistency Of Specific Findings With Previous Studiesmentioning

confidence: 57%

A methylome-wide study of aging using massively parallel sequencing of the methyl-CpG-enriched genomic fraction from blood in over 700 subjects

McClay¹,

Åberg²,

Clark³

et al. 2013

Human Molecular Genetics

150

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The central importance of epigenetics to the aging process is increasingly being recognized. Here we perform a methylome-wide association study (MWAS) of aging in whole blood DNA from 718 individuals, aged 25 -92 years (mean 5 55). We sequenced the methyl-CpG-enriched genomic DNA fraction, averaging 67.3 million reads per subject, to obtain methylation measurements for the ∼27 million autosomal CpGs in the human genome. Following extensive quality control, we adaptively combined methylation measures for neighboring, highly-correlated CpGs into 4 344 016 CpG blocks with which we performed association testing. Eleven age-associated differentially methylated regions (DMRs) passed Bonferroni correction (P-value < 1.15 3 10 28 ). Top findings replicated in an independent sample set of 558 subjects using pyrosequencing of bisulfite-converted DNA (min P-value < 10 230 ). To examine biological themes, we selected 70 DMRs with false discovery rate of <0.1. Of these, 42 showed hypomethylation and 28 showed hypermethylation with age. Hypermethylated DMRs were more likely to overlap with CpG islands and shores. Hypomethylated DMRs were more likely to be in regions associated with polycomb/regulatory proteins (e.g. EZH2) or histone modifications H3K27ac, H3K4m1, H3K4m2, H3K4m3 and H3K9ac. Among genes implicated by the top DMRs were protocadherins, homeobox genes, MAPKs and ryanodine receptors. Several of our DMRs are at genes with potential relevance for age-related disease. This study successfully demonstrates the application of next-generation sequencing to MWAS, by interrogating a large proportion of the methylome and returning potentially novel age DMRs, in addition to replicating several loci implicated in previous studies using microarrays.

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Section: Consistency Of Specific Findings With Previous Studiesmentioning

confidence: 57%

A methylome-wide study of aging using massively parallel sequencing of the methyl-CpG-enriched genomic fraction from blood in over 700 subjects

McClay¹,

Åberg²,

Clark³

et al. 2013

Human Molecular Genetics

150

View full text Add to dashboard Cite

show abstract

“…Thus, the intensity and efficacy of clearance of the damaged molecules largely determines the progression of neurodegenerative disorders [100][101][102] but also the pace of brain ageing in healthy individuals [46,103,104]. The significance of autophagic processes in normal ageing is shown by a genome-wide association study which found a significant association between genetic variance in autophagy associated genes and survival in healthy aged humans [105]. It is generally observed that improving clearance with the induction of autophagy [10,106] or proteasome activity [107,108] slows down the ageing process and improves cognitive functions.…”

Section: Processes Contributing To Brain Ageingmentioning

confidence: 99%

The endocannabinoid system in normal and pathological brain ageing

Bilkei-Gorzó

2012

Phil. Trans. R. Soc. B

120

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The role of endocannabinoids as inhibitory retrograde transmitters is now widely known and intensively studied. However, endocannabinoids also influence neuronal activity by exerting neuroprotective effects and regulating glial responses. This review centres around this less-studied area, focusing on the cellular and molecular mechanisms underlying the protective effect of the cannabinoid system in brain ageing. The progression of ageing is largely determined by the balance between detrimental, proageing, largely stochastic processes, and the activity of the homeostatic defence system. Experimental evidence suggests that the cannabinoid system is part of the latter system. Cannabinoids as regulators of mitochondrial activity, as anti-oxidants and as modulators of clearance processes protect neurons on the molecular level. On the cellular level, the cannabinoid system regulates the expression of brainderived neurotrophic factor and neurogenesis. Neuroinflammatory processes contributing to the progression of normal brain ageing and to the pathogenesis of neurodegenerative diseases are suppressed by cannabinoids, suggesting that they may also influence the ageing process on the system level. In good agreement with the hypothesized beneficial role of cannabinoid system activity against brain ageing, it was shown that animals lacking CB1 receptors show early onset of learning deficits associated with age-related histological and molecular changes. In preclinical models of neurodegenerative disorders, cannabinoids show beneficial effects, but the clinical evidence regarding their efficacy as therapeutic tools is either inconclusive or still missing.

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“…In some instances, single gene mutants have been observed to increase maximum life span by as much as 40% (3). Other studies have focused on identifying genes that are associated with longevity in humans-that is, genes observed to have a higher allele frequency in centenarians (4)(5)(6). However, such human longevity-associated genes (LAGs) seem to be very rare, and although a few have been confirmed in independent studies (2,3), their existence remains controversial.…”

mentioning

confidence: 99%

Distinctive topology of age-associated epigenetic drift in the human interactome

West

Widschwendter

Teschendorff

2013

Proc. Natl. Acad. Sci. U.S.A.

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Recently, it has been demonstrated that DNA methylation, a covalent modification of DNA that can regulate gene expression, is modified as a function of age. However, the biological and clinical significance of this age-associated epigenetic drift is unclear. To shed light on the potential biological significance, we here adopt a systems approach and study the genes undergoing age-associated changes in DNA methylation in the context of a protein interaction network, focusing on their topological properties. In contrast to what has been observed for other age-related gene classes, including longevity-and disease-associated genes, as well as genes undergoing age-associated changes in gene expression, we here demonstrate that age-associated epigenetic drift occurs preferentially in genes that occupy peripheral network positions of exceptionally low connectivity. In addition, we show that these genes synergize topologically with disease and longevity genes, forming unexpectedly large network communities. Thus, these results point toward a potentially distinct mechanistic and biological role of DNA methylation in dictating the complex aging and disease phenotypes.biological networks | epigenomics | aging | network topology

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A genome-wide association study of aging

Cited by 136 publications

References 74 publications

A methylome-wide study of aging using massively parallel sequencing of the methyl-CpG-enriched genomic fraction from blood in over 700 subjects

A methylome-wide study of aging using massively parallel sequencing of the methyl-CpG-enriched genomic fraction from blood in over 700 subjects

The endocannabinoid system in normal and pathological brain ageing

Distinctive topology of age-associated epigenetic drift in the human interactome

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