Biology subjects

Horvath, S.

Publications and source records attributed to Horvath, S..

5 recordsLinked to original sources

bioRxiv2018

Cell and tissue type independent age-associated DNA methylation changes are not rare but common

Age-associated DNA methylation changes have been widely reported across many different tissue and cell types. Epigenetic clocks that can predict chronological age with a surprisingly high degree of accuracy appear to do so independently of tissue and cell-type, suggesting that a component of epigenetic drift is cell-type independent. However, the relative amount of age-associated DNAm changes that are specific to a cell or tissue type versus the amount that occurs independently of cell or tissue type is unclear and a matter of debate, with a recent study concluding that most epigenetic drift is tissue-specific. Here, we perform a novel comprehensive statistical analysis, including matched multi cell-type and multi-tissue DNA methylation profiles from the same individuals and adjusting for cell-type heterogeneity, demonstrating that a substantial amount of epigenetic drift, possibly over 70%, is shared between significant numbers of different tissue/cell types. We further show that ELOVL2 is not unique and that many other CpG sites, some mapping to genes in the Wnt and glutamate receptor signaling pathways, are altered with age across at least 10 different cell/tissue types. We propose that while most age-associated DNAm changes are shared between cell-types that the putative functional effect is likely to be tissue-specific.

bioinformatics↗

bioRxiv2018

Phenotypic Age: a novel signature of mortality and morbidity risk

BackgroundA persons rate of aging has important implications for his/her risk of death and disease, thus, quantifying aging using observable characteristics has important applications for clinical, basic, and observational research. We aimed to validate a novel aging measure, \"Phenotypic Age\", constructed based on routine clinical chemistry measures, by assessing its applicability for differentiating risk for morbidity and mortality in both healthy and unhealthy populations of various ages.\n\nMethodsA nationally representative US sample, NHANES III, was used to derive \"Phenotypic Age\" based on a linear combination of chronological age and nine multi-system clinical chemistry measures, selected via cox proportional elastic net. Mortality predictions were validated using an independent sample (NHANES IV), consisting of 11,432 participants, for whom we observed a total of 871 deaths, ascertained over 12.6 year of follow-up. Proportional hazard models and ROC curves were used to evaluate predictions.\n\nResultsPhenotypic Age was significantly associated with all-cause mortality and cause-specific mortality. These results were robust to age and sex stratification, and remained even when excluding short-term mortality. Similarly, Phenotypic Age was associated with mortality among seemingly \"healthy\" participants--defined as those who were disease-free and had normal BMI at baseline--as well as the oldest-old (aged 85+)--a group with high disease burden.\n\nConclusionsPhenotypic Age is a reliable predictor of all-cause and cause-specific mortality in multiple subgroups of the population. Risk stratification by this composite measure is far superior to that of the individual measures that go into it, as well as traditional measures of health. It is able to differentiate individuals who appear healthy, who may have otherwise been missed using traditional health assessments. Further, it can differentiate risk among persons with shared disease burden. Overall, this easily measured metric may be useful in the clinical setting and facilitate secondary and tertiary prevention strategies.

epidemiology↗

bioRxiv2018

An epigenetic biomarker of aging for lifespan and healthspan

Identifying reliable biomarkers of aging is a major goal in geroscience. While the first generation of epigenetic biomarkers of aging were developed using chronological age as a surrogate for biological age, we hypothesized that incorporation of composite clinical measures of phenotypic age that capture differences in lifespan and healthspan may identify novel CpGs and facilitate the development of a more powerful epigenetic biomarker of aging. Using a innovative two-step process, we develop a new epigenetic biomarker of aging, DNAm PhenoAge, that strongly outperforms previous measures in regards to predictions for a variety of aging outcomes, including all-cause mortality, cancers, healthspan, physical functioning, and Alzheimers disease. While this biomarker was developed using data from whole blood, it correlates strongly with age in every tissue and cell tested. Based on an in-depth transcriptional analysis in sorted cells, we find that increased epigenetic, relative to chronological age, is associated increased activation of pro-inflammatory and interferon pathways, and decreased activation of transcriptional/translational machinery, DNA damage response, and mitochondrial signatures. Overall, this single epigenetic biomarker of aging is able to capture risks for an array of diverse outcomes across multiple tissues and cells, and provide insight into important pathways in aging.

epidemiology↗

bioRxiv2017

GWAS of epigenetic ageing rates in blood reveals a critical role for TERT

DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9,907 individuals, we found gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in 3 loci associated extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggested causal influences of menarche and menopause on IEAA and lipid levels on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) locus at 5p15.33 confer higher IEAA (P<2.7x10-11). Causal modelling indicates TERT-specific and independent effects on LTL and IEAA. Experimental hTERT expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number. Together, these findings indicate a critical role for hTERT in regulating the DNA methylation clock, in addition to its established role of compensating for cell replication-dependent telomere shortening.

genetics↗

bioRxiv2017

An epigenome-wide association study of educational attainment (n = 10,767)

The epigenome has been shown to be influenced by biological factors, such as disease status, and environmental factors, such as smoking, alcohol consumption, and body mass index. Although there is a widespread perception that environmental influences on the epigenome are pervasive and profound, there has been little evidence to date in humans with respect to environmental factors that are biologically distal. Here, we provide evidence on the associations between epigenetic modifications--in our case, CpG methylation--and educational attainment (EA), a biologically distal environmental factor that is arguably among of the most important life-shaping experiences for individuals. Specifically, we report the results of an epigenome-wide association study meta-analysis of EA based on data from 27 cohort studies with a total of 10,767 individuals. While we find that 9 CpG probes are significantly associated with EA, only two remain associated when we restrict the sample to never-smokers. These two are known to be strongly associated with maternal smoking during pregnancy, and thus their association with EA could be due to correlation between EA and maternal smoking. Moreover, their effect sizes on EA are far smaller than the known associations between CpG probes and biologically proximal environmental factors. Two analyses that combine the effects of many probes--polygenic methylation score and epigenetic-clock analyses--both suggest small associations with EA. If our findings regarding EA can be generalized to other biologically distal environmental factors, then they cast doubt on the hypothesis that such factors have large effects on the epigenome.

genetics↗