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 suggestive negative causal relationship between Intrinsic epigenetic age acceleration and unruptured IA (P = 0.022, OR=0.906 [95% CI, 0.83-0.99]), though this did not remain significant after multiple testing correction (corrected P threshold=0.00208). No causal effect was observed between any other methylation-estimated phenotype and aSAH or UIA (all P > 0.05 after correction). A suggestive causal relationship between longevity and aSAH (P = 0.020, OR=1.100 [1.01-1.19]) was observed, with a 9.95% increase in disease risk per 1-SD increase in age, but this also did not withstand multiple testing correction. Each 1-SD increase in telomere length was associated with a 0.9% increase in DNA methylation-estimated granulocyte proportions (P = 0.0025, OR=1.009 [1.003-1.015]) and a 55% increase in intrinsic epigenetic age acceleration (P = 0.018, OR=1.552 [1.080-1.551]), with the former remaining significant after correction. 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.