Mendelian randomization study and meta-analysis exploring the causality of age at menarche and the risk of intracerebral hemorrhage and ischemic stroke

Abstract

Background: The relationship between the age at menarche (AAM) and the risk of intracerebral hemorrhage (ICH) and ischemic stroke (IS) is still up for debate. The purpose of this study was to investigate potential causal connections between them. Methods: Genome-wide association analysis (GWAS) of AAM conducted by the MRC-IEU consortium was utilized for association analyses of ICH and IS by two-sample Mendelian randomization (MR) study. AAM data of the within-family GWAS consortium were used as replication phase data to verify the causal relationship between each other. Inverse variance weighting (IVW) method was the primary method used in this MR study. For additional proof, the weighted median estimation, MR-Egger regression, MR-PRESSO test, and MR-Robust Adjusted Profile Score evaluation were performed. The Cochran's Q test and the MR-PRESSO global test were used, respectively, to examine the sensitivity and pleiotropy. Random effects meta-analysis was utilized to analyze the causal data from the two consortiums to further explore the causality between AAM and ICH, IS. Results: We found that the AAM was causally linked with the risk of ICH (OR = 0.48, 95% CI: 0.28–0.80, p = 0.006). On the contrary, the causal effect from AAM to IS (OR = 0.98, 95% CI: 0.91–1.06, p = 0.64) has not been confirmed. For all subtypes of ICH, we found that nonlobar intracerebral hemorrhage (NLICH, OR = 0.41, 95% CI: 0.23–0.75, p = 0.004) but not lobar intracerebral hemorrhage (LICH, OR = 0.65, 95% CI: 0.34–1.24, p = 0.19) was associated with AAM without surprise. Similarly, we used the within-family GWAS consortium data to explore causality and found that AAM may reduce the risk of ICH (OR = 0.78, 95% CI: 0.72–0.86, p = 9.5 × 10−8) and NLICH (OR = 0.68, 95% CI: 0.61–0.75, p = 3.4 × 10−13) by IVW methods, but is not related to IS (OR = 0.97, 95% CI: 0.93–1.02, p = 0.26). These findings are further supported by the meta-analysis. Both Cochran's Q test and the MR-PRESSO global test failed to detect the presence of sensitivity. Conclusion: AAM and ICH, particularly NLICH, are causally related, but not LICH, IS, or its subtypes in European population.