Identification of Plasma Protein Biomarkers for Early-Onset Stroke through Mendelian Randomization

Background: Stroke incidence is declining in older adults but rising in younger populations. Circulating plasma proteins are promising biomarkers of vascular disease, yet their causal role in early-onset stroke (EOS) remains unclear. We used proteome-wide Mendelian randomization (MR) to identify proteins causally associated with EOS and its subtypes. Methods: We conducted two-sample MR using protein quantitative trait loci from 54,219 UK Biobank participants and summary-level association results from up to 11,114 EOS cases (onset <60 years) and 435,540 controls in the Early-Onset Stroke Consortium. Variants within {+/-}200 kb of protein-coding genes associated with protein levels (p [&le;]1x10-5) were clumped for linkage disequilibrium and used as instrumental variables. Causal effects were estimated using inverse-variance weighted MR, with sensitivity analyses to assess robustness. Stroke subtypes were defined using TOAST criteria. Results: Among 1,041 proteins tested, 11 were significantly associated with EOS after multiple testing correction. Genetically predicted higher levels of proteins encoded by ABO, F11, F7, MLN, BTD, MEP1B, and VAMP8 increased EOS risk (ORs ~1.05-1.32 per SD), whereas higher levels of proteins encoded by FN1, GRK5, EHBP1, and FCN2 were protective. Eight additional proteins showed subtype-specific associations. Key signals converged on coagulation and thromboinflammatory pathways, particularly ABO, F11, and F7, with consistent evidence across analyses. Cross-trait analyses demonstrated overlap with late-onset stroke, venous thromboembolism, and cardiometabolic risk factors, supporting shared biological mechanisms. Drug-target mapping highlighted Factor XI as a leading therapeutic target, supported by existing inhibitors (e.g., abelacimab, milvexian). Conclusions: This large-scale proteome-wide MR study identified multiple plasma proteins with likely causal roles in EOS, implicating coagulation, platelet activation, extracellular matrix remodeling, and immune pathways in disease etiology. These findings highlight biologically plausible biomarkers and prioritize druggable targets, particularly Factor XI, for prevention of EOS and demonstrate the value of proteogenomic approaches for uncovering disease mechanisms and informing precision prevention strategies.