Circulating plasma protein identified as a therapeutic target for intracranial aneurysm through Mendelian Randomization analysis

Background

Intracranial aneurysms are the main cause of subarachnoid hemorrhage (SAH), a severe stroke with devastating effects. However, there are no existing medications for intracranial aneurysms (IAs) and novel therapeutic targets are required. Methods: We performed a summary data-based Mendelian Randomization (MR) analysis to explore the causal association between circulating plasma proteins and the risk of IAs and SAH. Colocalization analysis was conducted to identify shared causal variants between circulating plasma proteins and IAs, as well as SAH. Finally, mediation MR analyses were conducted to clarify the role of potential plasma proteins in aneurysm formation. Results: Proteome-wide MR analysis showed that FGF5 (fibroblast growth factor 5) had a causal effect on IA and SAH risk (Pfdr < 0.05). Moreover, genetic variants affecting FGF5 expression levels showed strong evidence of colocalization with IA risk (PPH4 = 0.993) and SAH risk (PPH = 0.988), suggesting that this protein represents a potential direct target for IA intervention. Mediation analysis using two-step MR showed that systolic blood pressure and diastolic blood pressure mediate the effects of FGF5 on IA and SAH. Conclusion: Our investigation identified a causal connection between FGF5 and IAs.