DNA Methylation-estimated Phenotypes, Telomere length, Aging and Risk of Intracranial Aneurysms: Evidence from genetic studies

Background: The risk of intracranial aneurysm (IA) is increased in older population, suggesting a role for aging. To evaluate the association of genetic variants linked to DNA methylation-estimated phenotypes, telomere length, and aging, with the risk of IA by employing two-sample Mendelian randomization. Methods Sex-specific summary-level outcome data were extracted from the GWAS of IA, including 23 cohorts with a total of 5140 cases and 71934 controls. All the study participants were of European ancestry. To improve validity, five varying Mendelian randomization techniques were used in the analysis (MR-Egger, weighted median, inverse variance weighted, simple mode, and weighted mode). Results There was a negative causal relationship between Intrinsic epigenetic age acceleration and unruptured IA (P = 0.022272, OR = 0.9059 [95% CI, 0.83–0.99]). No causal effect existed between any other estimated methylation phenotype and aneurysmal subarachnoid hemorrhage (aSAH) (P > 0.05). There was a causal relationship between longevity and risk of developing aSAH (P = 0.020289, OR = 1.099528 [1.01–1.19]), with a 9.95% increase in the risk of disease for every 1-SD increase in age. In addition, each 1-SD rise in telomere length caused a 0.9% increase in the estimated proportion of granulocytes with DNA methylation (P = 0.002518, OR = 1.009041[1.003166,1.01495]) and a 55% increase in the intrinsic epigenetic age acceleration (P = 0.017597, OR = 1.55152[ 1.079562,1.551152]). Conclusion A negative causal relationship between intrinsic epigenetic age acceleration and IA suggests that an increase in intrinsic apparent age acceleration reduces the risk of IA. The underlying mechanisms and their potential to lower the prevalence of IA as an intervention target require further research.