Headache and Intracranial Aneurysm: A Bidirectional Mendelian Randomization Study

Introduction: Headaches affect up to 95% of individuals during their lifetime and are a major global cause of disability. Intracranial Aneurysm (IA) is a cerebrovascular disorder affecting approximately 3.2% of the general population. Observational studies have suggested an association between headaches and IA, but the causal relationship remains unclear. This Mendelian Randomization (MR) analysis aims to elucidate the causal relationship between headaches and IA. Methods: A two-sample bidirectional Mendelian Randomization (MR) analysis was performed using publicly available Genome-Wide Association Study (GWAS) data to assess the causal relationships between IA and four headache subtypes, namely, Chronic Headache (CH), Tension- Type Headache (TTH), Migraine Without Aura (MO), and Migraine With Aura (MA). The inverse variance weighted method was employed as the primary method, with sensitivity analyses conducted to evaluate the robustness of the results. Mediation analysis was performed to investigate the potential mediating role of hypertension. Results: The MR analysis revealed that MO was associated with an increased risk of aneurysmal Subarachnoid Hemorrhage (aSAH) (Odds Ratio [OR] = 1.422, 95% Confidence Interval [CI]: 1.054–1.918, and P = 0.021), while MA (OR = 1.527, 95% CI: 1.115–2.091, and P = 0.008) was associated with an elevated risk of unruptured IA (uIA). Mediation analysis indicated that hypertension did not significantly mediate these associations. Discussion: This study highlights the potential role of MO in aSAH and MA in uIA, where hypertension does not serve as a significant mediator. Further research is necessary to investigate the underlying mechanisms, which may offer valuable insights into the prevention and management of IA. Conclusion: Bidirectional MR analysis of four headache subtypes and IA provides evidence that MO is associated with an increased risk of aSAH, while MA is linked to a higher risk of uIA. These findings contribute to a better understanding of the complex relationship between headaches and IA.