Causal Associations of Epigenetic Age Acceleration With Stroke and Its Functional Outcome: A Two-Sample, Two-Step Mendelian Randomization Study

BACKGROUND: Emerging evidence from observational studies suggested that epigenetic age acceleration may result in an increased incidence of stroke and poorer functional outcomes after a stroke. However, the causality of these associations remains controversial and may be confounded by bias. We aimed to investigate the causal effects of epigenetic age on stroke and its functional outcomes. METHODS: We conducted a two-sample Mendelian randomization (MR) analysis to explore the causal relationships between epigenetic age and stroke and its outcomes. Additionally, a two-step MR analysis was performed to investigate whether lifestyle factors affect stroke via epigenetic age. Datasets of epigenetic age were obtained from a recent meta-analysis (n = 34,710), while those of stroke and its outcomes were sourced from the MEGASTROKE (n = 520,000) consortium and Genetics of Ischaemic Stroke Functional Outcome (GISCOME) network (n = 6165). RESULTS: Two-sample MR analysis revealed a causal relationship between PhenoAge and small vessel stroke (SVS) (OR = 1.07; 95% CI, 1.03-1.12; p = 2.01 × 10⁻³). Mediation analysis through two-step MR indicated that the increased risk of SVS due to smoking initiation was partially mediated by PhenoAge, with a mediation proportion of 9.5% (95% CI, 1.6%-20.6%). No causal relationships were identified between epigenetic age and stroke outcomes. CONCLUSIONS: Our study supports using epigenetic age as a biomarker to predict stroke occurrence. Interventions specifically aimed at decelerating epigenetic aging, such as specific lifestyle changes, offer effective strategies for reducing stroke risk.