A two-sample Mendelian randomization analysis of modifiable risk factors and intracranial aneurysms

Way of life

Genetically predicted cigarettes per day and smoking initiation were significantly associated with an increased risk of AI (odds ratio (OR) 2.67, 95% confidence interval (CI) 1.75–4.07, p= 5.36 × 10^–6and OR 1.53, 95% CI 1.32–1.77, p= 9.58 × 10^–9respectively), which means that people whose cigarettes per day or smoking initiation were 1 SD higher than the population will have a risk of IA 2.67 or 1.53 times higher compared to the prevalence in population Genetically predicted vigorous physical activity ≥ 3 vs 0 days/week is suggestively associated with a reduced risk of IA (OR 0.59, 95% CI 0.36-0.96, p= 0.04). (Fig. 2) The significant association between cigarettes per day, smoking initiation, and AI was consistent in sensitivity analyzes that used simple and weighted median analyzes and MR-Egger analysis, but not l association between physical activity and AI (Supplementary Table 3). No SNPs were detected to possibly drive the positive association in analyzes without a single one (Supplementary Data). No evidence of directional pleiotropy was found in MR-Egger analyzes (p= 0.19, 0.26 and 0.60, respectively, Supplement Table 3).

Cardiometabolic characteristics

Genetically predicted systolic blood pressure, hypertension and body fat percentage were significantly associated with an increased risk of AI (OR 1.05, 95% CI 1.02-1.08, p= 1.18 × 10^–3OR 1.65, 95% CI 1.19–2.28, p= 2.56 × 10^–3 and OR 1.29, 95% CI 1.11–1.52, p= 1.33 × 10^–3, respectively). Genetically predicted type 2 diabetes mellitus was significantly associated with a reduced risk of IA (OR 0.89, 95% CI 0.83-0.95, p= 8.54 × 10^–4). Genetically predicted fasting blood glucose, hemoglobin A1c (HbA1c), and total cholesterol were suggestively associated with a reduced risk of AI (OR 0.56, 95% CI 0.36-0.87, p= 0.01, OR 0.77, 95% CI 0.60–0.98, p= 0.04 and OR 0.86, 95% CI 0.75–0.99, p= 0.04, respectively) (Fig. 2, 3). The significant association between systolic blood pressure, hypertension, type 2 diabetes, and IA was consistent in sensitivity analyzes that used simple median and weighted median analyses. The significant association between body fat percentage, fasting blood glucose, HbA1c and AI was consistent in sensitivity analyzes that used simple median analyzes (Supplementary Table 3). The suggestive association between HbA1c and AI may have been induced by rs12219514, rs12221133, rs174584, rs7356034, and rs895636 in the analysis without a (p= 0.06, 0.05, 0.05, 0.07 and 0.05, respectively, additional data). Directional pleiotropy might exist in the suggestive association between HbA1c and AI in the MR-Egger analysis (p= 0.02, Supplementary Table 3).

Mendelian randomization for associations between traits of cardiometabolic, nutritional, and dietary intake, renal failure, and risk factors for inflammation and intracranial aneurysm. SNP: single nucleotide polymorphism; OR: odds ratios; CI: confidence interval; BMI: body mass index; CIMT: median carotid intima thickness; CRP: C-reactive protein; GFR: estimated glomerular filtration rate; SLE: systemic lupus erythematosus; TMAO: trimethylamine-n-oxide.

Nutrients and Dietary Intake

Genetically predicted betaine and carnitine were suggestively associated with an increased risk of AI (OR 1.07, 95% CI 1.00-1.14, p= 0.04, OR 1.12, 95% CI 1.02–1.22, p= 0.02, respectively) (Fig. 3) The significant association between carnitine and AI was consistent in sensitivity analyzes that used simple median and weighted median analyses. The significant association between betaine and AI was consistent in sensitivity analyzes that used simple median analyzes (Supplementary Table 3). No SNPs were detected to possibly drive the positive association in the analysis without a single one (Supplemental Data). No evidence of directional pleiotropy was found in the MR-Egger analysis (p= 0.53 and 0.81, respectively, Supplementary Table 3).

Kidney failure and inflammation and immune abnormalities

No significant association was found between associated risk factors and AI. (Fig. 3).

The impact of significant risk factors on ruptured and unruptured AIs

The impact of significant risk factors on ruptured and unruptured AIs is shown in Fig. 4. The impact of number of cigarettes per day, smoking initiation, and systolic blood pressure on ruptured and unruptured AIs was significant (p= 5.71 × 10^–61.16×10^-7 and 1.71×10^–2 on IA broken; p= 5.74 × 10^–63.86×10^–11 and 2.90 × 10^–3 on unbroken IA, respectively). The impact of hypertension and body fat percentage on IA rupture was significant (p= 1.00 × 10^–4 and 5.70×10^–5respectively), but it was not significant on the unbroken AI (p= 0.19 and 0.06, respectively). The impact of type 2 diabetes mellitus on ruptured and unruptured AIs was not significant (p= 0.47 for broken AI and 0.25 for unbroken AI).

Mendelian randomization for associations between significant risk factors and intracranial aneurysm, subarachnoid hemorrhage, and unruptured intracranial aneurysm. SNP: single nucleotide polymorphism; OR: odds ratios; CI: confidence interval; IA: intracranial aneurysm; SAH: subarachnoid hemorrhage; UIA: unruptured intracranial aneurysm; TRANS: transethnic.

Multivariate MR analysis

Since there is a relatively clear conclusion between hypertension and AI in previous clinical research, hypertension is not included in the multivariate MR analysis. Cigarettes per day, smoking initiation, systolic blood pressure, body fat percentage are included. In multivariate MR analysis, systolic blood pressure and cigarettes per day are significantly associated with AI. (pp= 0.001, respectively) (Supplementary Table 7).