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

Abstract

BackgroundThe 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.MethodsGenome‐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.ResultsWe 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.ConclusionAAM and ICH, particularly NLICH, are causally related, but not LICH, IS, or its subtypes in European population.

Inflammatory cytokines and stroke and its subtypes: a genetic correlation and two-sample Mendelian randomization study

“…IS subtypes accounted for 34,217 cases, including 4,373 cases of large artery strokes (LAS), 7,193 cases of cardiac embolic strokes (CES), 5,386 cases of small vessel strokes (SVS), and 6,030 cases of lacunar ischemic strokes (LIS). For the ICH, the International Federation of Stroke Genetics provided GWAS data, including 1,545 cases and 1,481 healthy controls ( Zou et al, 2023 ). These cases were divided into two groups: lobal intracerebral hemorrhage (LICH) and non-lobal intracerebral hemorrhage (NLICH) ( Table 1 ; Zou et al, 2023 ).…”

“…For the ICH, the International Federation of Stroke Genetics provided GWAS data, including 1,545 cases and 1,481 healthy controls ( Zou et al, 2023 ). These cases were divided into two groups: lobal intracerebral hemorrhage (LICH) and non-lobal intracerebral hemorrhage (NLICH) ( Table 1 ; Zou et al, 2023 ). Instrumental variables, namely single-nucleotide polymorphisms (SNPs), were extracted from the GWAS data of the exposure variables ( Chen et al, 2022 ).…”

Inflammatory bowel disease and the risk of intracerebral hemorrhage: A Mendelian randomization study and meta‐analysis

“…When the intercept of MR‐Egger regression is zero, it shows that there is no genetic pleiotropy, which is another way to measure pleiotropy 19 . A cutting‐edge technique for determining causation is MR‐PRESSO 21,22 . The MR‐PRESSO global test can also determine whether directional pleiotropy exists in addition to causality 22 .…”

Exploring causal correlations between inflammatory cytokines and stroke and its subtypes: a Mendelian randomization study

“…IS subtypes accounted for 34,217 cases, including 4373 cases of large artery strokes (LAS), 7193 cases of cardiac embolic strokes (CES), 5386 cases of mall vessel strokes (SVS), and 6030 cases of lacunar ischemic strokes (LIS). For the ICH, the International Federation of Stroke Genetics provided GWAS data, including 1,545 cases and 1,481 healthy controls [15]. These cases were divided into two groups: lobal intracerebral hemorrhage (LICH)…”

“…and non-lobal intracerebral hemorrhage (NLICH) (Table 1) [15]. Instrumental variables, namely single-nucleotide polymorphisms (SNPs), were extracted from the GWAS data of the exposure variables [16].…”