Causal Effect of Blood Cell Perturbation Phenotypes on Multiple Sclerosis via Immune Mediation: A Mendelian Randomization Study

Multiple sclerosis (MS) is an inflammatory disease that affects the central nervous system, characterized by myelin damage caused by immune dysfunction and genetic factors. Nevertheless, the role of peripheral blood and immune cells in the development of MS remains poorly defined. We employed a two-sample Mendelian randomization (MR) approach, analyzing data from 91 blood cell perturbation phenotypes and 731 immune cell traits. Causal inference was conducted using multiple robust MR techniques, including inverse variance weighting, with mediation analysis and sensitivity tests (Cochran's Q, MR-Egger intercept, and leave-one-out analysis) performed to validate the results.The present study identified significant associations between 9 blood cell perturbation phenotypes and 34 immune cell traits with MS risk. The effect of neutrophil disturbances on MS was partially mediated by HLA-DR expression on B cells, with a mediation proportion of approximately 16.38%. Moreover, sensitivity analyses confirmed the robustness of these findings.This study suggests that specific blood cell perturbations may increase MS risk and reveals the mediating role of immune cells between blood and nervous system disturbances. In addition, we provide genetic evidence for understanding MS immune mechanisms, which could help guide the development of targeted immunotherapies.