Multi-omics analysis of immunologically relevant genes in multiple sclerosis to identify potential drug target

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by demyelination and immune dysregulation. Despite the established link with immune function, the genetic and pathological mechanisms connecting immune-related genes to MS remain incompletely understood.

We systematically integrated genome-wide association study (GWAS) data for various quantitative trait loci (QTLs) from public databases and literature, along with GWAS summary statistics for MS from IMSGC and FinnGen. Mendelian Randomization (MR) was used to infer potential causal relationships between immune-related factors and MS. To validate whether the same genetic variants underlie both traits, Bayesian colocalization analysis was performed. Summary-data-based Mendelian Randomization (SMR) further supported causality between the exposure and outcome. Finally, two-step MR was conducted to investigate whether immune cell subsets mediate the observed associations.

Fc receptor-like 3 (FCRL3) was identified as a protective factor for MS, supported by MR analyses at multiple levels: circulating protein (OR = 0.912, 95 % CI = 0.882-0.942), blood-derived gene expression (OR = 0.772, 95 % CI = 0.598-0.997), and cerebral cortex expression (OR = 0.573, 95 % CI = 0.455-0.721). Causality was further supported by SMR (pSMR = 5.38E-04; pHEIDI = 0.478) and Bayesian colocalization (PP.H₄ = 0.915). The protective effect of FCRL3 on MS was found to be partially mediated by CD3 expression on naïve CD4⁺ T cells.

This study systematically evaluated the causal roles of immune-related genes in MS susceptibility and identified FCRL3 as a protective factor. These findings underscore the significance of FCRL3 in MS pathogenesis and suggest its potential as a target for future immunotherapeutic strategies.