Menopause accelerates biological aging Levine, Morgan E.; Lu, Ake T.; Chen, Brian H. ...
Proceedings of the National Academy of Sciences - PNAS,
08/2016, Letnik:
113, Številka:
33
Journal Article
Recenzirano
Odprti dostop
Although epigenetic processes have been linked to aging and disease in other systems, it is not yet known whether they relate to reproductive aging. Recently, we developed a highly accurate ...epigenetic biomarker of age (known as the “epigenetic clock”), which is based on DNA methylation levels. Here we carry out an epigenetic clock analysis of blood, saliva, and buccal epithelium using data from four large studies: the Women’s Health Initiative (n = 1,864); Invecchiare nel Chianti (n = 200); Parkinson’s disease, Environment, and Genes (n = 256); and the United Kingdom Medical Research Council National Survey of Health and Development (n = 790). We find that increased epigenetic age acceleration in blood is significantly associated with earlier menopause (P = 0.00091), bilateral oophorectomy (P = 0.0018), and a longer time since menopause (P = 0.017). Conversely, epigenetic age acceleration in buccal epithelium and saliva do not relate to age at menopause; however, a higher epigenetic age in saliva is exhibited in women who undergo bilateral oophorectomy (P = 0.0079), while a lower epigenetic age in buccal epithelium was found for women who underwent menopausal hormone therapy (P = 0.00078). Using genetic data, we find evidence of coheritability between age at menopause and epigenetic age acceleration in blood. Using Mendelian randomization analysis, we find that two SNPs that are highly associated with age at menopause exhibit a significant association with epigenetic age acceleration. Overall, our Mendelian randomization approach and other lines of evidence suggest that menopause accelerates epigenetic aging of blood, but mechanistic studies will be needed to dissect cause-and-effect relationships further.
Dyskinesia is a known side-effect of the treatment of Parkinson's Disease (PD). We examined the influence of haplotypes in three dopamine receptors (DRD1, DRD2 and DRD3) and the Brain Derived ...Neurotrophic Factor (BDNF) on dyskinesia.
Patient data were drawn from a population-based case-control study. We included 418 patients with confirmed diagnoses by movement disorder specialists, using levodopa and a minimum three years disease duration at the time of assessment. Applying Haploview and Phase, we created haploblocks for DRD1-3 and BDNF. Risk scores for DRD2 and DRD3 were generated. We calculated risk ratios using Poisson regression with robust error variance.
There was no difference in dyskinesia prevalence among carriers of various haplotypes in DRD1. However, one haplotype in each DRD2 haploblocks was associated with a 29 to 50% increase in dyskinesia risk. For each unit increase in risk score, we observed a 16% increase in dyskinesia risk for DRD2 (95%CI: 1.05–1.29) and a 17% (95%CI: 0.99–1.40) increase for DRD3. The BDNF haploblock was not associated, but the minor allele of the rs6265 SNP was associated with dyskinesia (adjusted RR 1.31 (95%CI: 1.01–1.70)).
Carriers of DRD2 risk haplotypes and possibly the BDNF variants rs6265 and DRD3 haplotypes, were at increased risk of dyskinesia, suggesting that these genes may be involved in dyskinesia related pathomechanisms. PD patients with these genetic variants might be prime candidates for treatments aiming to prevent or delay the onset of dyskinesia.
•DRD genes (DRD1-3) and BDNF have been proposed to be involved in the development of dyskinesia.•DRD2 haplotypes, and potentially DRD3 haplotypes and rs6265 BDNF-SNP, were associated with dyskinesia.•Patients with these genetic markers appear prime candidate for testing approaches to prevent or delay dyskinesia development.
Parkinson's disease (PD), the second most common neurodegenerative disorder, develops sporadically, likely through a combination of polygenic and environmental factors. Previous studies associate ...pesticide exposure and genes involved in lysosomal function with PD risk. We evaluated the frequency of variants in lysosomal function genes among patients from the Parkinson's, Environment, and Genes (PEG) study with ambient pesticide exposure from agricultural sources. 757 PD patients, primarily of White European/non-Hispanic ancestry (75%), were screened for variants in 85 genes using a custom amplicon panel. Variant enrichment was calculated against the Genome Aggregation Database (gnomAD). Enriched exonic variants were prioritized by exposure to a cluster of pesticides used on cotton and severity of disease progression in a subset of 386 patients subdivided by race/ethnicity. Gene enrichment analysis identified 36 variants in 26 genes in PEG PD patients. Twelve of the identified genes (12/26, 46%) had multiple enriched variants and/or a single enriched variant present in multiple individuals, representing 61% (22/36) of the observed variation in the cohort. The majority of enriched variants (26/36, 72%) were found in genes contributing to lysosomal function, particularly autophagy, and were bioinformatically deemed functionally deleterious (31/36, 86%). We conclude that, in this study, variants in genes associated with lysosomal function, notably autophagy, were enriched in PD patients exposed to agricultural pesticides suggesting that altered lysosomal function may generate an underlying susceptibility for developing PD with pesticide exposure. Further study of gene-environment interactions targeting lysosomal function may improve understanding of PD risk in individuals exposed to pesticides.
INTRODUCTION
Increased levels of sex hormones have been hypothesized to decrease Alzheimer's disease (AD) risk. We assessed the association between sex steroid hormones with AD using a Mendelian ...randomization (MR) approach.
METHODS
An inverse‐variance weighting (IVW) MR analysis was performed using effect estimates from external genome‐wide association study (GWAS) summary statistics. We included independent variants (linkage disequilibrium R2 < 0.001) and a p‐value threshold of 5 × 10−8.
RESULTS
An increase in androgens was associated with a decreased AD risk among men: testosterone (odds ratio OR: 0.53; 95% confidence interval CI: 0.32–0.88; p‐value: 0.01; false discovery rate FDR p‐value: 0.03); dehydroepiandrosterone sulfate (DHEAS; OR: 0.56; 95% CI: 0.38–0.85; p‐value: 0.01; FDR p‐value: 0.03); and androsterone sulfate (OR: 0.69; 95% CI: 0.46–1.02; p‐value: 0.06; FDR p‐value: 0.10). There was no association between sex steroid hormones and AD among women, although analysis for estradiol had limited statistical power.
DISCUSSION
A higher concentration of androgens was associated with a decreased risk of AD among men of European ancestry, suggesting that androgens among men might be neuroprotective and could potentially prevent or delay an AD diagnosis.
Highlights
Sex hormones are hypothesized to play a role in developing Alzheimer's disease (AD).
The effect of sex hormones on AD was assessed using Mendelian randomization (MR) analysis.
Among women, genetically determined effects of sex hormones were limited or null.
Among men, a higher concentration of androgens decreased AD risk.
This study suggests a causal relationship between androgens and AD among men.
Abstract
Background
Epigenetic age acceleration (AgeAccel), which indicates faster biological aging relative to chronological age, has been associated with lower cognitive function. However, the ...association of AgeAccel with mild cognitive impairment (MCI) or dementia is not well-understood. We examined associations of 4 AgeAccel measures with incident MCI and dementia.
Methods
This prospective analysis included 578 older women from the Women’s Health Initiative Memory Study selected for a case–cohort study of coronary heart disease (CHD). Women were free of CHD and cognitive impairment at baseline. Associations of AgeAccel measures (intrinsic AgeAccel IEAA, extrinsic AgeAccel EEAA, AgeAccelPheno, and AgeAccelGrim) with risks for incident adjudicated diagnoses of MCI and dementia overall and stratified by incident CHD status were evaluated.
Results
IEAA was not significantly associated with MCI (HR, 1.23; 95% CI, 0.99–1.53), dementia (HR, 1.10; 95% CI, 0.88–1.38), or cognitive impairment (HR, 1.18; 95% CI, 0.99–1.40). In stratified analysis by incident CHD status, there was a 39% (HR, 1.39; 95% CI, 1.07–1.81) significantly higher risk of MCI for every 5-year increase in IEAA among women who developed CHD during follow-up. Other AgeAccel measures were not significantly associated with MCI or dementia.
Conclusions
IEAA was not significantly associated with cognitive impairment overall but was associated with impairment among women who developed CHD. Larger studies designed to examine associations of AgeAccel with cognitive impairment are needed, including exploration of whether associations are stronger in the setting of underlying vascular pathologies.
Sex hormones are hypothesized to drive sex-specific health disparities. Here, we study the association between sex steroid hormones and DNA methylation-based (DNAm) biomarkers of age and mortality ...risk including Pheno Age Acceleration (AA), Grim AA, and DNAm-based estimators of Plasminogen Activator Inhibitor 1 (PAI1), and leptin concentrations. We pooled data from three population-based cohorts, the Framingham Heart Study Offspring Cohort, the Baltimore Longitudinal Study of Aging, and the InCHIANTI Study, including 1,062 postmenopausal women without hormone therapy and 1,612 men of European descent. Sex-stratified analyses using a linear mixed regression were performed, with a Benjamini-Hochberg (BH) adjustment for multiple testing. Sex Hormone Binding Globulin (SHBG) was associated with a decrease in DNAm PAI1 among men (per 1 standard deviation (SD): -478 pg/mL; 95%CI: -614 to -343; P:1e-11; BH-P: 1e-10), and women (-434 pg/mL; 95%CI: -589 to -279; P:1e-7; BH-P:2e-6). The testosterone/estradiol (TE) ratio was associated with a decrease in Pheno AA (-0.41 years; 95%CI: -0.70 to -0.12; P:0.01; BH-P: 0.04), and DNAm PAI1 (-351 pg/mL; 95%CI: -486 to -217; P:4e-7; BH-P:3e-6) among men. In men, testosterone was associated with a decrease in DNAm PAI1 (-481 pg/mL; 95%CI: -613 to -349; P:2e-12; BH-P:6e-11). SHBG was associated with lower DNAm PAI1 among men and women. Higher testosterone and testosterone/estradiol ratio were associated with lower DNAm PAI and a younger epigenetic age in men. A decrease in DNAm PAI1 is associated with lower mortality and morbidity risk indicating a potential protective effect of testosterone on lifespan and conceivably cardiovascular health via DNAm PAI1.
Graphical Abstract
Stochastic epigenetic mutations (SEM) reflect a deviation from normal site-specific methylation patterns. Epigenetic mutation load (EML) captures the accumulation of SEMs across an individual's ...genome and may reflect dysfunction of the epigenetic maintenance system in response to epigenetic challenges.
We investigate whether EML is associated with PD risk and time to events (i.e., death and motor symptom decline).
We employed logistic regression and Cox proportional hazards regression to assess the association between EML and several outcomes. Our analyses are based on 568 PD patients and 238 controls from the Parkinson's disease, Environment and Genes (PEG) study, for whom blood-based methylation data was available.
We found an association for PD onset and EML in all genes (OR = 1.90; 95%CI 1.52-2.37) and PD-related genes (OR = 1.87; 95%CI 1.50-2.32). EML was also associated with time to a minimum score of 35 points on the motor UPDRS exam (OR = 1.28; 95%CI 1.06-1.56) and time to death (OR = 1.29, 95%CI 1.11-1.49). An analysis of PD related genes only revealed five intragenic hotspots of high SEM density associated with PD risk.
Our findings suggest an enrichment of methylation dysregulation in PD patients in general and specifically in five PD related genes. EML may also be associated with time to death and motor symptom progression in PD patients.
PDF
