DNA methylation age is accelerated in alcohol dependence.
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ABSTRACT:
SUBMITTER: Rosen AD
PROVIDER: S-EPMC6125381 | biostudies-literature | 2018 Sep
REPOSITORIES: biostudies-literature
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Project description:Accumulating evidence suggests that posttraumatic stress disorder (PTSD) may accelerate cellular aging and lead to premature morbidity and neurocognitive decline.This study evaluated associations between PTSD and DNA methylation (DNAm) age using recently developed algorithms of cellular age by Horvath (2013) and Hannum et al. (2013). These estimates reflect accelerated aging when they exceed chronological age. We also examined if accelerated cellular age manifested in degraded neural integrity, indexed via diffusion tensor imaging.Among 281 male and female veterans of the conflicts in Iraq and Afghanistan, DNAm age was strongly related to chronological age (rs ?.88). Lifetime PTSD severity was associated with Hannum DNAm age estimates residualized for chronological age (?=.13, p=.032). Advanced DNAm age was associated with reduced integrity in the genu of the corpus callosum (?=-.17, p=.009) and indirectly linked to poorer working memory performance via this region (indirect ?=-.05, p=.029). Horvath DNAm age estimates were not associated with PTSD or neural integrity.Results provide novel support for PTSD-related accelerated aging in DNAm and extend the evidence base of known DNAm age correlates to the domains of neural integrity and cognition.
| S-EPMC4695261 | biostudies-literature
Project description:BACKGROUND:Recent studies examining the association between posttraumatic stress disorder (PTSD) and accelerated aging, as defined by DNA methylation-based estimates of cellular age that exceed chronological age, have yielded mixed results. METHODS:We conducted a meta-analysis of trauma exposure and PTSD diagnosis and symptom severity in association with accelerated DNA methylation age using data from 9 cohorts contributing to the Psychiatric Genomics Consortium PTSD Epigenetics Workgroup (combined N?=?2186). Associations between demographic and cellular variables and accelerated DNA methylation age were also examined, as was the moderating influence of demographic variables. RESULTS:Meta-analysis of regression coefficients from contributing cohorts revealed that childhood trauma exposure (when measured with the Childhood Trauma Questionnaire) and lifetime PTSD severity evidenced significant, albeit small, meta-analytic associations with accelerated DNA methylation age (ps?=?0.028 and 0.016, respectively). Sex, CD4T cell proportions, and natural killer cell proportions were also significantly associated with accelerated DNA methylation age (all ps?<?0.02). PTSD diagnosis and lifetime trauma exposure were not associated with advanced DNA methylation age. There was no evidence of moderation of the trauma or PTSD variables by demographic factors. CONCLUSIONS:Results suggest that traumatic stress is associated with advanced epigenetic age and raise the possibility that cells integral to immune system maintenance and responsivity play a role in this. This study highlights the need for additional research into the biological mechanisms linking traumatic stress to accelerated DNA methylation age and the importance of furthering our understanding of the neurobiological and health consequences of PTSD.
| S-EPMC5924645 | biostudies-literature
Project description:DNA methylation age acceleration, the discrepancy between epigenetic age and chronological age, is associated with mortality and chronic diseases, including diabetes, hypertension, and hyperlipidemia. In this study, we investigate whether medications commonly used to treat these diseases in 15 drug categories are associated with four epigenetic age acceleration measures: HorvathAge acceleration (HorvathAA), HannumAge acceleration (HannumAA), PhenoAge acceleration, and GrimAge acceleration (GrimAA) using cross-sectional (Phase 1, N=1,100) and longitudinal (Phases 1 and 2, N=266) data from African Americans in the Genetic Epidemiology Network of Arteriopathy (GENOA) study. In cross-sectional analyses, the use of calcium channel blockers was associated with 1.27 years lower HannumAA after adjusting for covariates including hypertension (p=0.001). Longitudinal analyses showed that, compared to those who never used antihypertensives, those who started to take antihypertensives after Phase 1 had a 0.97-year decrease in GrimAA (p=0.007). In addition, compared to those who never used NSAID analgesics, those who started to take them after Phase 1 had a 2.61-year increase in HorvathAA (p=0.0005). Our study demonstrates that three commonly used medications are associated with DNAm age acceleration in African Americans and sheds light on the potential epigenetic effects of pharmaceuticals on aging at the cellular level.
| S-EPMC8221348 | biostudies-literature
Project description:Epigenetic regulation through DNA methylation may influence vulnerability to numerous disorders, including alcohol dependence (AD).Peripheral blood DNA methylation levels of 384 CpGs in the promoter regions of 82 candidate genes were examined in 285 African Americans (AAs; 141 AD cases and 144 controls) and 249 European Americans (EAs; 144 AD cases and 105 controls) using Illumina GoldenGate Methylation Array assays. Association of AD and DNA methylation changes was analyzed using multivariate analyses of covariance with frequency of intoxication, sex, age, and ancestry proportion as covariates. CpGs showing significant methylation alterations in AD cases were further examined in a replication sample (49 EA cases and 32 EA controls) using Sequenom's MassARRAY EpiTYPER technology.In AAs, 2 CpGs in 2 genes (GABRB3 and POMC) were hypermethylated in AD cases compared with controls (p ? 0.001). In EAs, 6 CpGs in 6 genes (HTR3A, NCAM1, DRD4, MBD3, HTR2B, and GRIN1) were hypermethylated in AD cases compared with controls (p ? 0.001); CpG cg08989585 in the HTR3A promoter region showed a significantly higher methylation level in EA cases than in EA controls after Bonferroni correction (p = 0.00007). Additionally, methylation levels of 6 CpGs (including cg08989585) in the HTR3A promoter region were analyzed in the replication sample. Although the 6 HTR3A promoter CpGs did not show significant methylation differences between EA cases and EA controls (p = 0.067 to 0.877), the methylation level of CpG cg08989585 was nonsignificantly higher in EA cases (26.9%) than in EA controls (18.6%; p = 0.139).The findings from this study suggest that DNA methylation profile appears to be associated with AD in a population-specific way and the predisposition to AD may result from a complex interplay of genetic variation and epigenetic modifications.
| S-EPMC3511647 | biostudies-literature
Project description:OBJECTIVE:Recently developed indices of cellular age based on DNA methylation (DNAm) data, referred to as DNAm age, are being used to study factors that influence the rate of aging and the health correlates of these metrics of the epigenetic clock. This study evaluated associations between trauma exposure, posttraumatic stress disorder (PTSD) symptoms, and accelerated versus decelerated DNAm age among military veterans. We also examined whether accelerated DNAm age predicted mortality over the course of a 6.5-year medical record review period. METHODS:Three hundred thirty-nine genotype-confirmed white, non-Hispanic, middle-aged, trauma-exposed veterans underwent psychiatric assessment and genome-wide DNAm analysis. DNAm age was calculated using a previously validated algorithm. Medical records were available for a subset of 241 veterans and were reviewed approximately 6.5 years after DNA collection and PTSD assessment. RESULTS:PTSD hyperarousal symptoms were associated with accelerated DNAm age (? = 0.20, p = .009) but trauma exposure and total PTSD severity were not. Accelerated DNAm age was also associated with 13% increased risk for all-cause mortality (hazard ratio = 1.13, 95% confidence interval = 1.01-1.26) during the medical record review period. CONCLUSIONS:Findings of this study replicate the association between PTSD and accelerated DNAm age and suggest that this effect may be specific to the hyperarousal symptom cluster. Results point to the potential utility of DNAm age algorithms for identifying individuals who are aging at an accelerated rate and for determining the factors that influence this process.
| S-EPMC5775924 | biostudies-literature
Project description:Interaction of DNA methylation and sequence variants that are methylation quantitative trait loci (mQTLs) may influence susceptibility to diseases such as alcohol dependence (AD). We used genome-wide genotype data from 268 African Americans (AAs: 129 AD cases and 139 controls) and 143 European Americans (EAs: 129 AD cases and 14 controls) to identify mQTLs that were associated with promoter CpGs in 82 AD risk genes. 282 significant mQTL-CpG pairs (9.9 × 10(-100) ? P(nominal) ? 7.7 × 10(-8)) in AAs and 313 significant mQTL-CpG pairs (2.7 × 10(-53) ? P(nominal) ? 9.9 × 10(-8)) in EAs were identified [i.e., mQTL-CpG associations survived multiple-testing correction, q values (false discovery rate) ? 0.05]. The most significant mQTL was rs1800759, which was strongly associated with CpG cg12011299 in both AAs (P(nominal) = 9.9 × 10(-100); q = 6.7 × 10(-91)) and EAs (P(nominal) = 2.7 × 10(-53); q = 1.4 × 10(-44)). Rs1800759 (previously known to be associated to AD) and CpG cg12011299 (distance: 37 bp) are both located in alcohol dehydrogenase (ADH) 4 gene (ADH4) promoter region. In general, the strength of association between mQTLs and CpGs was inversely correlated with the distance between them. Association was also influenced by race and AD. Additionally, 48.3 % of the mQTLs identified in AAs and 65.6 % of the mQTLs identified in EAs were predicted to be expression QTLs. Three mQTLs (rs2173201, rs4147542, and rs4147541 in ADH1B-AHD1C gene cluster region) found in AAs were previously identified by our genome-wide association studies as being significantly associated with AD in AAs. Thus, DNA methylation, which can be influenced by sequence variants and is implicated in gene expression regulation, appears to at least partially underlie the association of genetic variation with AD.
| S-EPMC4127343 | biostudies-literature
Project description:Several studies have shown an association of alcohol dependence with DNA methylation (DNAm), suggesting that environmentally-induced changes on epigenomic variation may play an important role in alcohol dependence. In the present study, we analysed genome-wide DNAm profiles of purified CD3+ T-cells from pre- and post-treatment alcohol dependent patients, as well as closely matched healthy controls. We identified 59 differentially methylated CpG sites comparing patients prior to treatment with healthy controls and were able to confirm 8 of those sites in additional analyses for differentially methylated regions. Comparing patients before and after a 3-week alcohol treatment program we revealed another unique set of 48 differentially methylated CpG sites. Additionally, we found that the mean global DNAm was significantly lower in patients prior to treatment compared to controls, but reverted back to levels similar to controls after treatment. We validated top-ranked hits derived from the epigenome-wide analysis by pyrosequencing and further replicated two of them in an independent cohort and confirmed differential DNAm of HECW2 and SRPK3 in whole blood. This study is the first to show widespread DNAm variation in a disease-relevant blood cell type and implicates HECW2 and SRPK3 DNAm as promising blood-based candidates to follow up in future studies.
| S-EPMC5529570 | biostudies-literature
Project description:The premature aging hypothesis of alcohol dependence proposes that the neurobiological and behavioural deficits in individuals with alcohol dependence are analogous to those of chronological aging. However, to date no systematic neurobiological evidence for this hypothesis has been provided. To test the hypothesis, 119 alcohol-dependent subjects and 97 age- and gender-matched healthy control subjects underwent structural MRI. Whole-brain grey matter volume maps were computed from structural MRI scans using voxel-based morphometry and parcelled into a comprehensive set of anatomical brain regions. Regional grey matter volume averages served as the basis for cross-regional similarity analyses and a brain age model. We found a striking correspondence between regional patterns of alcohol- and age-related grey matter loss across 110 brain regions. The brain age model revealed that the brain age of age-matched AD subjects was increased by up to 11.7 years. Interestingly, while no brain aging was detected in the youngest AD subjects (20-30 years), we found that alcohol-related brain aging systematically increased in the following age decades controlling for lifetime alcohol consumption and general health status. Together, these results provide strong evidence for an accelerated aging model of AD and indicate an elevated risk of alcohol-related brain aging in elderly individuals.
| S-EPMC5802586 | biostudies-literature
Project description:The discrepancy of DNA methylation age (DNAmAge) with chronological age (termed as age acceleration, AA) has been identified to be associated with many aging-related health outcomes including hypertension. Since taking antihypertensive medication (AHM) could prevent aging-related diseases caused by hypertension, we hypothesized that using AHM could also reduce the AA. We examined this hypothesis among 546 males aged 55-85 years by exploring the associations of AHM use with AA and its change rate (?AA) in two visits with a median follow-up of 3.86 years. Horvath DNAmAge was derived from DNA methylation profiles measured by Illumina HumanMethylation450 BeadChip and information on AHM use was collected by physician interview. A general decreasing pattern of AA was observed between the two visits. After the fully adjusting for potential covariates including hypertension, any AHM use showed a cross-sectional significant association with higher AA at each visit, as well as a longitudinal association with increased ?AA between visits. Particularly, relative to participants who never took any AHM, individuals with continuous AHM use had a higher ?AA of 0.6 year/chronological year. This finding underlines that DNAmAge and AA may not be able to capture the preventive effects of AHMs that reduce cardiovascular risks and mortality.
| S-EPMC6286862 | biostudies-literature
Project description:Individuals with schizophrenia (SZ) exhibit multiple premature age-related phenotypes and die ~20years prematurely. The accelerated aging hypothesis of SZ has been advanced to explain these observations, it posits that SZ-associated factors accelerate the progressive biological changes associated with normal aging. Testing the hypothesis has been limited by the absence of robust, meaningful, and multi-tissue measures of biological age. Recently, a method was described in which DNA methylation (DNAm) levels at 353 genomic sites are used to produce "DNAm age", an estimate of biological age with advantages over existing measures. We used this method and 3 publicly-available DNAm datasets, 1 from brain and 2 from blood, to test the hypothesis. The brain dataset was composed of data from the dorsolateral prefrontal cortex of 232 non-psychiatric control (NPC) and 195 SZ subjects. Blood dataset #1 was composed of data from whole blood of 304 NPC and 332 SZ subjects, and blood dataset #2 was composed of data from whole blood of 405 NPC and 260 SZ subjects. DNAm age and chronological age correlated strongly (r=0.92-0.95, p<0.0001) in both NPC and SZ subjects in all 3 datasets. DNAm age acceleration did not differ between NPC and SZ subjects in the brain dataset (t=0.52, p=0.60), blood dataset #1 (t=1.51, p=0.13), or blood dataset #2 (t=0.93, p=0.35). Consistent with our previous findings from a smaller study of postmortem brains, our findings suggest there is no acceleration of brain or blood aging in SZ and, thus, do not support the accelerated aging hypothesis of SZ.
| S-EPMC5886835 | biostudies-literature