Potential drug targets for multiple sclerosis identified through Mendelian randomization analysis.

Multiple sclerosis (MS) is a complex autoimmune disease, and several therapies for MS have been developed and widely used. However, existing medications for MS were far from satisfactory due to their failure to suppress relapses and alleviate disease progression. Novel drug targets for MS prevention are still needed. We performed Mendelian randomization (MR) to explore potential drug targets for MS using summary statistics from the International Multiple Sclerosis Genetics Consortium (NCase = 47,429, NControl = 68,374) and further replicated in UK Biobank (NCase = 1,356, NControl = 395,209) and FinnGen cohorts (NCase = 1,326, NControl = 359,815). Genetic instruments for 734 plasma and 154 cerebrospinal fluid (CSF) proteins were obtained from recently published genome-wide association studies (GWAS). The reverse causality detection using bidirectional MR analysis and Steiger filtering, Bayesian colocalization, and phenotype scanning that searched previously-reported genetic variant-trait associations were implemented to consolidate the MR findings further. In addition, the protein-protein interaction (PPI) network was performed to reveal potential associations among proteins and/ or present MS medications. At Bonferroni significance (P < 5.63×10-5), MR analysis revealed six protein-MS pairs. In plasma, per SD increase in FCRL3, TYMP and AHSG had a protective effect. Odds ratio (OR) for the proteins above were 0.83 (95% confidence interval [CI], 0.79-0.89), 0.59 (95% CI, 0.48-0.71), and 0.88 (95% CI, 0.83-0.94), respectively. In CSF, per 10-fold increase in MMEL1 (OR, 5.03; 95% CI, 3.42-7.41) increased the risk of MS, while SLAMF7 (OR, 0.42; 95% CI, 0.29-0.60) and CD5L (OR, 0.30; 95%CI, 0.18-0.52) decreased the risk. None of the six above proteins had reverse causality. Bayesian colocalization suggested that FCRL3 (coloc.abf-posterior probability of hypothesis 4 [PPH4] = 0.889), TYMP (coloc.susie-PPH4 = 0.896), AHSG (coloc.abf-PPH4 = 0.957, coloc.susie-PPH4 = 0.973), MMEL1 (coloc.abf-PPH4 = 0.930), and SLAMF7 (coloc.abf-PPH4 = 0.947) shared the same variant with MS. FCRL3, TYMP, and SLAMF7 interacted with target proteins of current MS medications. MMEL1 was replicated in both UK Biobank and FinnGen cohorts. Our integrative analysis suggested that genetically-determined levels of circulating FCRL3, TYMP, AHSG, CSF MMEL1, and SLAMF7 had causal effects on MS risk. These findings suggested those five proteins might be promising drug targets for MS and warrant further clinical investigation, especially FCRL3 and SLAMF7.