Abstract / Summary
Background: Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease with limited treatment options and frequent co-occurring conditions that complicate management. Genetic approaches can be applied to identify causal proteins and prioritise potential therapeutic targets across the landscape of MS and related traits. Methods We performed a proteome-wide Mendelian randomisation (MR) study using plasma protein quantitative trait loci (pQTLs) as instrumental variables to evaluate the causal effects of circulating proteins on MS risk. Colocalisation analyses were applied to assess whether genetic instruments reflected shared causal variants rather than confounding due to linkage disequilibrium. We then extended MR analyses to commonly co-occurring autoimmune, metabolic and psychiatric conditions to evaluate the broader phenotypic effects of prioritised proteins. Results We identified several proteins with consistent evidence of a causal effect on risk of MS, including STAT3, CD59, AHSG, and FCRL3. Colocalisation analyses indicated shared causal variants between MS risk and circulating protein levels. MR analyses of other outcomes revealed heterogeneity: some proteins showed MS-specific effects, whereas others also influenced a broader range of conditions. Notably, STAT3, CD59 and FCRL3 were linked exclusively to MS risk. Conclusions Our findings provide a systematic, genetically-informed prioritisation of plasma proteins as causal molecular exposures in MS. By integrating analyses across traits that often co-occur with MS, we distinguish proteins with MS-specific effects from those with effects across multiple phenotypes. These findings help refine the interpretation of circulating protein effects across MS and co-occurring conditions.