Hypertension Is Associated With Earlier Onset of Nontraumatic Subarachnoid Hemorrhage in Women: A Mendelian Randomization Study

BACKGROUND: Nontraumatic subarachnoid hemorrhage (SAH) is linked to hypertension, a condition highly influenced by common genetic variants. For complex diseases affected by genetic and environmental factors, genetic predisposition plays a key role in early onset. We hypothesize that elevated polygenic susceptibility to hypertension is associated with a younger age of onset in SAH. METHODS: We performed a case-only genetic analysis using data from the UK Biobank, a large cohort study that enrolled over 500 000 Britons aged 40 to 69 years between 2006 and 2010. Participants of European ancestry with a known diagnosis of SAH were included, which was ascertained through an algorithmic combination of coded information from baseline in-person interviews and electronic health records. We constructed a polygenic risk score using 817 independent genetic variants associated with higher systolic blood pressure. Participants were categorized into 3 groups: low (polygenic risk score <20 percentile), intermediate (polygenic risk score 20–80 percentile), and high (polygenic risk score >80 percentile) polygenic susceptibility to hypertension. Linear regression was used to assess the relationship between polygenic susceptibility to hypertension and the age of onset of SAH, with multivariable models adjusting for the first 4 genetic principal components, diabetes, and smoking history. Product terms were added to test for interaction with sex. To evaluate causality, we implemented Mendelian randomization analysis using the inverse variance weighted and weighted median methods. RESULTS: We evaluated a total of 1177 SAH cases (mean age of onset, 55 [12] years; female sex, 722 [61.3%]). When evaluating all participants jointly, there was no association between polygenic susceptibility to hypertension and the age of onset of SAH (test-for-trend P =0.13). However, there was a significant interaction between polygenic susceptibility to hypertension and sex (interaction P =0.003): High polygenic susceptibility to hypertension was associated with earlier onset of SAH in female participants only (β, −4.87 [95% CI, −7.59 to −2.15]; test-for-trend P <0.001). In Mendelian randomization analysis, each 10 mm Hg increase in genetically determined systolic blood pressure was associated with a 3.6-year earlier onset of SAH in female participants using both the inverse variance weighted (β, −3.59 [95% CI, −5.69 to −1.49]; P =0.001) and weighted median approaches (β, −3.68 [95% CI, −6.99 to −0.37]; P =0.029). CONCLUSIONS: Polygenic susceptibility to hypertension is associated with earlier onset of nontraumatic SAH in women. Further studies are needed to replicate these findings in non-European individuals. Genetic predisposition to hypertension could be used for screening and early identification of individuals at risk of SAH.