Potential drug targets for intracranial aneurysms identified through Mendelian randomization analysis

The proteome is a key source of therapeutic targets. We conducted a comprehensive Mendelian randomization analysis across the proteome to identify potential causal relationships between proteins and the development of intracranial aneurysms (IAs). We conducted a Mendelian randomization study to explore potential therapeutic targets for IAs, using genetic data from the International Stroke Genetics Consortium. Genetic instruments for 734 plasma proteins and 154 cerebrospinal fluid (CSF) proteins were derived from recent genome-wide association studies. Independent validation was performed using datasets from FinnGen, deCODE, and the UK Biobank. We identified six proteins genetically associated with IAs risk. Among them, plasma RELT and CSF PDGF Rb passed false discovery rate (FDR) correction and were consistently validated in external cohorts. RELT was associated with a reduced risk of unruptured intracranial aneurysms, while PDGF Rb was linked to an increased risk of subarachnoid hemorrhage. Additionally, CSF levels of sFRP-3, IL-1 sRII, IL-1 R4, and LY86 showed initial associations with SAH risk; however, these associations were not confirmed in external validation. All findings were supported by sensitivity analyses. Our integrative analysis identifies RELT and PDGF Rb as robust, genetically supported protein candidates potentially involved in the pathogenesis of intracranial aneurysms and subarachnoid hemorrhage. These findings provide a foundation for future functional validation and clinical studies aimed at biomarker discovery or therapeutic targeting.