Epigenetic age acceleration and risk of aortic valve stenosis: a bidirectional Mendelian randomization study.

Pan W ，Huang Q ，Zhou L ，Lin J ，Du X ，Qian X ，Jiang T ，Chen W ... -  《-》

Assessing the causal role of epigenetic clocks in the development of multiple cancers: a Mendelian randomization study.

Epigenetic clocks have been associated with cancer risk in several observational studies. Nevertheless, it is unclear whether they play a causal role in cancer risk or if they act as a non-causal biomarker. We conducted a two-sample Mendelian randomization (MR) study to examine the genetically predicted effects of epigenetic age acceleration as measured by HannumAge (nine single-nucleotide polymorphisms (SNPs)), Horvath Intrinsic Age (24 SNPs), PhenoAge (11 SNPs), and GrimAge (4 SNPs) on multiple cancers (i.e. breast, prostate, colorectal, ovarian and lung cancer). We obtained genome-wide association data for biological ageing from a meta-analysis (N = 34,710), and for cancer from the UK Biobank (N cases = 2671-13,879; N controls = 173,493-372,016), FinnGen (N cases = 719-8401; N controls = 74,685-174,006) and several international cancer genetic consortia (N cases = 11,348-122,977; N controls = 15,861-105,974). Main analyses were performed using multiplicative random effects inverse variance weighted (IVW) MR. Individual study estimates were pooled using fixed effect meta-analysis. Sensitivity analyses included MR-Egger, weighted median, weighted mode and Causal Analysis using Summary Effect Estimates (CAUSE) methods, which are robust to some of the assumptions of the IVW approach. Meta-analysed IVW MR findings suggested that higher GrimAge acceleration increased the risk of colorectal cancer (OR = 1.12 per year increase in GrimAge acceleration, 95% CI 1.04-1.20, p = 0.002). The direction of the genetically predicted effects was consistent across main and sensitivity MR analyses. Among subtypes, the genetically predicted effect of GrimAge acceleration was greater for colon cancer (IVW OR = 1.15, 95% CI 1.09-1.21, p = 0.006), than rectal cancer (IVW OR = 1.05, 95% CI 0.97-1.13, p = 0.24). Results were less consistent for associations between other epigenetic clocks and cancers. GrimAge acceleration may increase the risk of colorectal cancer. Findings for other clocks and cancers were inconsistent. Further work is required to investigate the potential mechanisms underlying the results. FMB was supported by a Wellcome Trust PhD studentship in Molecular, Genetic and Lifecourse Epidemiology (224982/Z/22/Z which is part of grant 218495/Z/19/Z). KKT was supported by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme) and by the Hellenic Republic's Operational Programme 'Competitiveness, Entrepreneurship & Innovation' (OΠΣ 5047228). PH was supported by Cancer Research UK (C18281/A29019). RMM was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). RMM is a National Institute for Health Research Senior Investigator (NIHR202411). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. GDS and CLR were supported by the Medical Research Council (MC_UU_00011/1 and MC_UU_00011/5, respectively) and by a Cancer Research UK (C18281/A29019) programme grant (the Integrative Cancer Epidemiology Programme). REM was supported by an Alzheimer's Society project grant (AS-PG-19b-010) and NIH grant (U01 AG-18-018, PI: Steve Horvath). RCR is a de Pass Vice Chancellor's Research Fellow at the University of Bristol.

Morales Berstein F ，McCartney DL ，Lu AT ，Tsilidis KK ，Bouras E ，Haycock P ，Burrows K ，Phipps AI ，Buchanan DD ，Cheng I ，PRACTICAL consortium ，Martin RM ，Davey Smith G ，Relton CL ，Horvath S ，Marioni RE ，Richardson TG ，Richmond RC ... -  《eLife》

Causal association of obesity with epigenetic aging and telomere length: a bidirectional mendelian randomization study.

In observational studies, there exists an association between obesity and epigenetic age as well as telomere length. However, varying and partially conflicting outcomes have notably arisen from distinct studies on this topic. In the present study, two-way Mendelian randomization was used to identify potential causal associations between obesity and epigenetic age and telomeres. A genome-wide association study was conducted using data from individuals of European ancestry to investigate bidirectional Mendelian randomization (MR) regarding the causal relationships between obesity, as indicated by three obesity indicators (body mass index or BMI, waist circumference adjusted for BMI or WCadjBMI, and waist-to-hip ratio adjusted for BMI or WHRadjBMI), and four epigenetic age measures (HannumAge, HorvathAge, GrimAge, PhenoAge), as well as telomere length. To assess these causal associations, various statistical methods were employed, including Inverse Variance Weighted (IVW), Weighted Median, MR Egger, Weighted Mode, and Simple Mode. To address the issue of multiple testing, we applied the Bonferroni correction. These methods were used to determine whether there is a causal link between obesity and epigenetic age, as well as telomere length, and to explore potential bidirectional relationships. Forest plots and scatter plots were generated to show causal associations between exposures and outcomes. For a comprehensive visualization of the results, leave-one-out sensitivity analysis plots, individual SNP-based forest plots for MR analysis, and funnel plots were included in the presentation of the results. A strong causal association was identified between obesity and accelerated HannumAge, GrimAge, PhenoAge and telomere length shrinkage. The causal relationship between WCadjBMI and PhenoAge acceleration (OR: 2.099, 95%CI: 1.248-3.531, p = 0.005) was the strongest among them. However, only the p-values for the causal associations of obesity with GrimAge, PhenoAge, and telomere length met the criteria after correction using the Bonferroni multiple test. In the reverse MR analysis, there were statistically significant causal associations between HorvathAge, PhenoAge and GrimAge and BMI, but these associations exhibited lower effect sizes, as indicated by their Odds Ratios (ORs). Notably, sensitivity analysis revealed the robustness of the study results. The present findings reveal a causal relationship between obesity and the acceleration of epigenetic aging as well as the reduction of telomere length, offering valuable insights for further scientific investigations aimed at developing strategies to mitigate the aging process in humans.

Li J ，Wang W ，Yang Z ，Qiu L ，Ren Y ，Wang D ，Li M ，Li W ，Gao F ，Zhang J ... -  《Lipids in Health and Disease》

Mendelian randomization implicates causal association between epigenetic age acceleration and age-related eye diseases or glaucoma endophenotypes.

Age-related eye diseases (AREDs) have become increasingly prevalent with the aging population, serving as the leading causes of visual impairment worldwide. Epigenetic clocks are generated based on DNA methylation (DNAm) levels and are considered one of the most promising predictors of biological age. This study aimed to investigate the bidirectional causal association between epigenetic clocks and common AREDs or glaucoma endophenotypes. Instrumental variables for epigenetic clocks, AREDs, and glaucoma endophenotypes were obtained from corresponding genome-wide association study data of European descent. Bidirectional two-sample Mendelian randomization (MR) was employed to explore the causal relationship between epigenetic clocks and AREDs or glaucoma endophenotypes. Multivariable MR (MVMR) was used to determine whether glaucoma endophenotypes mediated the association of epigenetic clocks with glaucoma. Multiple sensitivity analyses were conducted to confirm the robustness of MR estimates. The results showed that an increased intrinsic epigenetic age acceleration (HorvathAge) was significantly associated with an increased risk of primary open-angle glaucoma (OR = 1.04, 95% CI 1.02 to 1.06, P = 6.1E-04). The epigenetic age acceleration (EEA) of HannumAge was related to a decreased risk of primary angle-closure glaucoma (OR = 0.92, 95% CI 0.86 to 0.99, P = 0.035). Reverse MR analysis showed that age-related cataract was linked to decreased HannumAge (β = -0.190 year, 95% CI -0.374 to -0.008, P = 0.041). The EEA of HannumAge (β = -0.85 μm, 95% CI -1.57 to -0.14, P = 0.019) and HorvathAge (β = -0.63 μm, 95% CI -1.18 to -0.08, P = 0.024) were associated with decreased central corneal thickness (CCT). PhenoAge was related to an increased retinal nerve fiber layer thickness (β = 0.06 μm, 95% CI 0.01 to 0.11, P = 0.027). MVMR analysis found no mediation effect of CCT in the association of HannumAge and HorvathAge with glaucoma. DNAm-based granulocyte proportions were significantly associated with presbyopia, rhegmatogenous retinal detachment, and intraocular pressure (P < 0.05). DNAm-based plasminogen activator inhibitor-1 levels were significantly related to age-related macular degeneration and intraocular pressure (P < 0.05). The present study revealed a causal association between epigenetic clocks and AREDs. More research is warranted to clarify the potential mechanisms of the biological aging process in AREDs.

Chen J ，Yuan XL ，Zhou X ，Xu J ，Zhang X ，Duan X ... -  《-》

Causality between heart failure and epigenetic age: a bidirectional Mendelian randomization study.

Heart failure (HF) is a prevalent age-related cardiovascular disease with poor prognosis in the elderly population. This study aimed to establish the causal relationship between ageing and HF by conducting a bidirectional Mendelian randomization (MR) analysis on epigenetic age (a marker of ageing) and HF. Genome-wide association study data for epigenetic age (GrimAge, HorvathAge, HannumAge, and PhenoAge) and HF were collected and assessed for significant genetic variables. A bidirectional MR analysis was carried out using the random-effects inverse-variance weighted (IVW) method as the primary approach, while other methods (MR-Egger, weighted median, simple mode, and weighted mode) and multiple sensitivity analyses (heterogeneity analysis, leave-one-out sensitivity analysis, and horizontal pleiotropy analysis) were employed to evaluate the impact of epigenetic age on HF and vice versa. Bidirectional MR analysis of two samples revealed that the epigenetic PhenoAge clock increased the risk of HF [IVW odds ratio (OR) 1.015, 95% confidence interval (CI) 1.002-1.028, P = 0.028 and weighted median OR 1.020, 95% CI 1.001-1.038, P = 0.039]. Other results were not statistically significant. The bidirectional MR analysis demonstrated a causal link between genetically predicted epigenetic age and HF in individuals of European descent. Further research into epigenetic age in other populations and additional genetic information related to HF is warranted.

Zhang F ，Deng S ，Zhang J ，Xu W ，Xian D ，Wang Y ，Zhao Q ，Liu Y ，Zhu X ，Peng M ，Zhang L ... -  《ESC Heart Failure》