Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Department of Pharmacy, Wuhan First Hospital, Wuhan, China.
CNS Neurosci Ther. 2023 Oct;29(10):3043-3052. doi: 10.1111/cns.14245. Epub 2023 May 11.
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 ) and NLICH (OR = 0.68, 95% CI: 0.61-0.75, p = 3.4 × 10 ) 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.
背景：月经初潮年龄（AAM）与颅内出血（ICH）和缺血性卒中（IS）风险之间的关系仍存在争议。本研究旨在探讨它们之间潜在的因果关系。
方法：利用 MRC-IEU 联盟进行的全基因组关联分析（GWAS）对 ICH 和 IS 进行两样本 Mendelian 随机化（MR）研究的关联分析。使用基于家系的 GWAS 联盟的 AAM 数据作为验证阶段的数据，以验证彼此之间的因果关系。反向方差加权（IVW）法是本 MR 研究的主要方法。为了提供额外的证据，进行了加权中位数估计、MR-Egger 回归、MR-PRESSO 检验和 MR-Robust Adjusted Profile Score 评估。分别使用 Cochran's Q 检验和 MR-PRESSO 全局检验来检测敏感性和多效性。利用随机效应荟萃分析对来自两个联盟的因果数据进行分析，以进一步探讨 AAM 与 ICH 之间的因果关系。
结果：我们发现 AAM 与 ICH 风险呈因果关系（OR=0.48，95%CI：0.28-0.80，p=0.006）。相反，AAM 与 IS（OR=0.98，95%CI：0.91-1.06，p=0.64）之间的因果效应尚未得到证实。对于所有 ICH 亚型，我们发现非脑叶颅内出血（NLICH，OR=0.41，95%CI：0.23-0.75，p=0.004）而不是脑叶颅内出血（LICH，OR=0.65，95%CI：0.34-1.24，p=0.19）与 AAM 有关。同样，我们使用基于家系的 GWAS 联盟数据来探索因果关系，发现 AAM 可能会降低 ICH（OR=0.78，95%CI：0.72-0.86，p=9.5×10）和 NLICH（OR=0.68，95%CI：0.61-0.75，p=3.4×10）的风险，但与 IS 无关（OR=0.97，95%CI：0.93-1.02，p=0.26）。这些发现通过荟萃分析得到进一步支持。Cochran's Q 检验和 MR-PRESSO 全局检验均未能检测到敏感性的存在。
结论：在欧洲人群中，AAM 与 ICH，特别是 NLICH，呈因果关系，但与 LICH、IS 或其亚型无关。
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