Proteome-Wide Mendelian Randomization Identifies Causal Proteins for Multiple Sclerosis Susceptibility and Severity

Background: Despite significant advances in identifying genetic risk factors for multiple sclerosis (MS), the causal involvement of circulating proteins in disease development and severity remains largely unexplored. Understanding these protein-mediated pathways could reveal novel therapeutic opportunities for this complex neurological disorder. Methods: We performed a proteome-wide Mendelian randomization study integrating data from four large-scale protein quantitative trait loci studies to investigate causal relationships between plasma proteins and both MS susceptibility and severity. Results: Our analysis revealed four plasma proteins with significant causal effects on MS susceptibility: ALPI and MXRA8 were associated with increased risk, while IDUA and NID2 showed protective effects. For disease severity, MANSC1 and LYVE1 were associated with worse disability, whereas CBR1 demonstrated protective effects. Conclusions: Our study provides genetic evidence supporting associations between specific plasma proteins and MS susceptibility and severity, implicating biological pathways related to gut–brain axis signaling, extracellular matrix remodeling, and oxidative stress. These findings improve our understanding of MS biology and identify candidate proteins for future functional validation, therapeutic investigation, and biomarker research.