Causal Relationship Between Circulating Leukocyte Characteristics and Immune Cell Traits With Multiple Sclerosis Risk: A Two-Sample Bidirectional Mendelian Randomisation Study.

The present study aimed to investigate MR-based evidence for potential causal relationships between circulating leukocytes, immune cell traits, and multiple sclerosis (MS) using a two-sample, bidirectional Mendelian randomisation (MR) approach. We analysed summary-level data from large-scale genome-wide association studies conducted by the International Multiple Sclerosis Genetics Consortium, the Blood Cell Consortium, and Immune Cell traits. Using inverse variance weighted (IVW), weighted mode, weighted median, simple mode, and MR-Egger methods, we estimated genetically predicted associations. The MR-Egger intercept assessed horizontal pleiotropy, Cochran's Q test examined genetic heterogeneity, and leave-one-out procedures evaluated the sensitivity of the results. We adjusted for multiple comparisons using the false discovery rate (FDR). Forward MR analysis using IVW as the primary method revealed associations between increased white blood cell count (OR = 1.16, 95% CI = 1.05-1.29, P = 0.004, PFDR = 0.031) and lymphocyte count (OR = 1.18, 95% CI = 1.06-1.31, P = 0.003, PFDR = 0.035) with a higher risk of developing MS. Conversely, the CD25hi CD45RA-CD4 not Treg %CD4+ (OR = 0.87, 95% CI = 0.808-0.942, P = 0.0005, PFDR = 0.075) and the CD16-CD56 on HLA DR+ NK (OR = 0.85, 95% CI = 0.780-0.935, P = 0.0007, PFDR = 0.093) were associated with a reduced risk of MS. In reverse MR analyses, MS showed no robust evidence of a causal effect on white blood cell or lymphocyte counts. Although an FDR-significant reverse association was observed for the IgD+ CD38 + B-cell absolute count subtype, leave-one-out sensitivity analysis indicated instability. Therefore, this finding was not considered reliable evidence of reverse causality. Genetic predisposition to increased white blood cell and lymphocyte counts elevates the risk of MS, while certain immune cell traits may reduce this risk.