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Methylation age acceleration does not predict mortality in schizophrenia.

ABSTRACT: Schizophrenia (SCZ) is associated with high mortality. DNA methylation levels vary over the life course, and pre-selected combinations of methylation array probes can be used to estimate "methylation age" (mAge). mAge correlates highly with chronological age but when it differs, termed mAge acceleration, it has been previously associated with all-cause mortality. We tested the association between mAge acceleration and mortality in SCZ and controls. We selected 190 SCZ cases and 190 controls from the Sweden Schizophrenia Study. Cases were identified from the Swedish Hospital Discharge Register with ?5 specialist treatment contacts and ?5 antipsychotic prescriptions. Controls had no psychotic disorder or antipsychotics. Subjects were selected if they had died or survived during follow-up (2:1 oversampling). Extracted DNA was assayed on the Illumina MethylationEPIC array. mAge was regressed on age at sampling to obtain mAge acceleration. Using Cox proportional hazards regression, the association between mAge acceleration and mortality was tested. After quality control, the following were available: n?=?126 SCZ died, 63 SCZ alive, 127 controls died, 62 controls alive. In the primary analyses, we did not find a significant association between mAge acceleration and SCZ mortality (adjusted p?>?0.005). Sensitivity analyses excluding SCZ cases with pre-existing cancer demonstrated a significant association between the Hannum mAge acceleration and mortality (hazard ratio?=?1.13, 95% confidence interval?=?1.04-1.22, p?=?0.005). Per our pre-specified criteria, we did not confirm our primary hypothesis that mAge acceleration would predict subsequent mortality in people with SCZ, but we cannot rule out smaller effects or effects in patient subsets.

SUBMITTER: Kowalec K

PROVIDER: S-EPMC6548770 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Methylation age acceleration does not predict mortality in schizophrenia.

Kowalec Kaarina K Hannon Eilis E Mansell Georgina G Burrage Joe J Ori Anil P S APS Ophoff Roel A RA Mill Jonathan J Sullivan Patrick F PF

Translational psychiatry 20190604 1

Schizophrenia (SCZ) is associated with high mortality. DNA methylation levels vary over the life course, and pre-selected combinations of methylation array probes can be used to estimate "methylation age" (mAge). mAge correlates highly with chronological age but when it differs, termed mAge acceleration, it has been previously associated with all-cause mortality. We tested the association between mAge acceleration and mortality in SCZ and controls. We selected 190 SCZ cases and 190 controls from ...[more]

PMID: 31164630

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Project description:BackgroundThere is a large body of evidence linking muscular weakness, as determined by low grip strength, to a host of negative ageing-related health outcomes. Given these links, grip strength has been labelled a 'biomarker of aging'; and yet, the pathways connecting grip strength to negative health consequences are unclear. The objective of this study was to determine whether grip strength was associated with measures of DNA methylation (DNAm) age acceleration.MethodsMiddle age and older adults from the 2006 to 2008 waves of the Health and Retirement Study with 8-10 years of follow-up were included. Cross-sectional and longitudinal regression modelling was performed to examine the association between normalized grip strength (NGS) and three measures of DNAm age acceleration, adjusting for cell composition, sociodemographic variables and smoking. Longitudinal modelling was also completed to examine the association between change in absolute grip strength and DNAm age acceleration. The three DNAm clocks used for estimating age acceleration include the established DunedinPoAm, PhenoAge and GrimAge clocks.ResultsThere was a robust and independent cross-sectional association between NGS and DNAm age acceleration for men using the DunedinPoAm (β: -0.36; P < 0.001), PhenoAge (β: -8.27; P = 0.01) and GrimAge (β: -4.56; P = 0.01) clocks and for women using the DunedinPoAm (β: -0.36; P < 0.001) and GrimAge (β: -4.46; P = 0.01) clocks. There was also an independent longitudinal association between baseline NGS and DNAm age acceleration for men (β: -0.26; P < 0.001) and women (β: -0.36; P < 0.001) using the DunedinPoAm clock and for women only using the PhenoAge (β: -8.20; P < 0.001) and GrimAge (β: -5.91; P < 0.001) clocks. Longitudinal modelling revealed a robust association between change in grip strength from wave 1 to wave 3 was independently associated with PhenoAgeAA (β: -0.13; 95% CI: -0.23, -0.03) and GrimAgeAA (β: -0.07; 95% CI: -0.14, -0.01) in men only (both P < 0.05).ConclusionsOur findings provide some initial evidence of age acceleration among men and women with lower NGS and loss of strength over time. Future research is needed to understand the extent to which DNAm age mediates the association between grip strength and chronic disease, disability and mortality.

Project description:Patients with treated HIV-1-infection experience earlier occurrence of aging-associated diseases, raising speculation that HIV-1-infection, or antiretroviral treatment, may accelerate aging. We recently described an age-related co-methylation module comprised of hundreds of CpGs; however, it is unknown whether aging and HIV-1-infection exert negative health effects through similar, or disparate, mechanisms. We investigated whether HIV-1-infection would induce age-associated methylation changes. We evaluated DNA methylation levels at >450,000 CpG sites in peripheral blood mononuclear cells (PBMC) of young (20-35) and older (36-56) adults in two separate groups of participants. Each age group for each data set consisted of 12 HIV-1-infected and 12 age-matched HIV-1-uninfected samples for a total of 96 samples. The effects of age and HIV-1 infection on methylation at each CpG revealed a strong correlation of 0.49, p<1 x 10(-200) and 0.47, p<1 x 10(-200). Weighted gene correlation network analysis (WGCNA) identified 17 co-methylation modules; module 3 (ME3) was significantly correlated with age (cor=0.70) and HIV-1 status (cor=0.31). Older HIV-1+ individuals had a greater number of hypermethylated CpGs across ME3 (p=0.015). In a multivariate model, ME3 was significantly associated with age and HIV status (Data set 1: ?age=0.007088, p=2.08 x 10(-9); ?HIV=0.099574, p=0.0011; Data set 2: ?age=0.008762, p=1.27 x 10(-5); ?HIV=0.128649, p=0.0001). Using this model, we estimate that HIV-1 infection accelerates age-related methylation by approximately 13.7 years in data set 1 and 14.7 years in data set 2. The genes related to CpGs in ME3 are enriched for polycomb group target genes known to be involved in cell renewal and aging. The overlap between ME3 and an aging methylation module found in solid tissues is also highly significant (Fisher-exact p=5.6 x 10(-6), odds ratio=1.91). These data demonstrate that HIV-1 infection is associated with methylation patterns that are similar to age-associated patterns and suggest that general aging and HIV-1 related aging work through some common cellular and molecular mechanisms. These results are an important first step for finding potential therapeutic targets and novel clinical approaches to mitigate the detrimental effects of both HIV-1-infection and aging.

Project description:ImportanceNeighborhood segregation and poverty may be important drivers of health inequities. Epigenomic factors, including DNA methylation clocks that may mark underlying biological aging, have been implicated in the link between social factors and health.ObjectiveTo examine the associations of neighborhood segregation and poverty with 4 DNA methylation clocks trained to capture either chronological age or physiological dysregulation.Design, setting, and participantsThis cohort study uses data from the Multi-Ethnic Study of Atherosclerosis (MESA), a longitudinal study that started in 2000 to 2002, with follow-up in 2002 to 2004, 2004 to 2005, 2005 to 2007, and 2010 to 2012. In 2000 to 2002, adults who identified as White or Black race or Hispanic or Chinese ethnicity in 6 US sites (Baltimore, Maryland; Chicago, Illinois; Forsyth County, North Carolina; Los Angeles County, California; Northern Manhattan, New York; and St. Paul, Minnesota) were sampled for recruitment. A random subsample of 4 sites (Maryland, North Carolina, New York, and Minnesota) were selected for inclusion in the MESA epigenomics ancillary study at examination 5 (2010-2012). Participants who identified as White or Black race or Hispanic ethnicity, were aged 45 to 84 years, and did not have clinical cardiovascular disease were included in this analysis. Data were analyzed from May 2021 to October 2023.ExposureInformation on 2000 census tract poverty and Getis-Ord G statistic segregation of Hispanic residents, non-Hispanic Black residents, or non-Hispanic White residents were linked to participant addresses at examination 1 (2000-2002).Main outcomes and measuresAt examination 5, DNA methylation was measured in purified monocytes. DNA methylation age acceleration was calculated using 4 clocks trained on either chronological age or physiological dysregulation. Linear regressions were used to test associations.ResultsA total of 1102 participants (mean [SD] age, 69.7 [9.4] years; 562 [51%] women) were included, with 348 Hispanic participants, 222 non-Hispanic Black participants, and 533 non-Hispanic White participants. For non-Hispanic Black participants, living in tracts with greater segregation of Black residents was associated with GrimAge DNA methylation age acceleration, a clock designed to capture physiological dysregulation. A 1-SD increase in segregation was associated with 0.42 (95% CI, 0.20-0.64) years age acceleration (P < .001); this association was not observed with other clocks. This association was particularly pronounced for participants living in high poverty tracts (interaction term, 0.24; 95% CI, 0.07-0.42; P = .006). In the overall sample, census tract poverty level was associated with GrimAge DNA methylation age acceleration (β = 0.45; 95% CI, 0.20-0.71; adjusted P = .005).Conclusions and relevanceThese findings suggest that epigenomic mechanisms may play a role in the associations of segregated and poor neighborhoods with chronic conditions.

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Methylation age acceleration does not predict mortality in schizophrenia.

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Methylation age acceleration does not predict mortality in schizophrenia.

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