Genetic associations of sex hormones with cerebral aneurysm formation and subarachnoid hemorrhage: A two-sample Mendelian randomization analysis

Abstract

Background and aim: Women are more likely than men to develop aneurysmal subarachnoid hemorrhage, and this difference is more pronounced in women after menopause, suggesting a possible correlation between sex hormone levels and cerebral aneurysm formation and rupture.

Methods and results: We selected genetic variants closely related to estrogen (estradiol), bioavailable testosterone (Bio T), and sex hormone-binding globulin (SHBG) as instrumental variables from the pooled data of the IEU Open GWAS project and cerebral aneurysm (CA) and subarachnoid hemorrhage (SAH) data from two independent datasets from the same study. Two-sample Mendelian randomization was subsequently performed to determine whether the relevant sex hormones and SHBG are causally associated with the formation and rupture of CA. We identified 14 causal associations of related sex hormones and their binding proteins with cerebral aneurysm formation and rupture. Inverse-variance weighting revealed that genetically predicted increased BioT levels reduced the risk of SAH development and genetically predicted increased levels of SHBG in females influenced reduced the risk of cerebral aneurysm formation. After excluding sex differences, weighted mode revealed opposite results, but there was no difference in the IVW, MR-Egger regression, weighted median, or simple mode analyses. No significant effects of the concentrations of other relevant sex hormones or SHBG on the risk of cerebral aneurysm formation or rupture were found.

Conclusions: Our study may explain the mechanisms underlying the increased incidence of cerebral aneurysms in menopausal women and provide new directions for intervention in cerebral aneurysm formation and rupture, but further studies are needed.

Keywords: Cerebral aneurysm; Mendelian randomization; Sex hormone-binding globulin; Sex hormones; Subarachnoid hemorrhage.