Multi-omics integration provides biological insight and prioritizes potential drug targets in multiple sclerosis progression.

INTRODUCTION: Current therapies for multiple sclerosis (MS) primarily reduce relapse rates and delay disability by targeting inflammation, while have limited efficacy against disease progression driven by neurodegenerative processes. We sought to identify and validate proteins for MS progression by integrating a large genome-wide association study (GWAS) of MS progression with large-scale protein quantitative trait loci data from blood and brain.

METHODS: We conducted proteome-wide association studies (PWAS) to nominate proteins; applied summary-data Mendelian randomization and colocalization to evaluate association; and performed functional annotation (pathway enrichment, drug-target mapping, and protein-protein interaction networks) to prioritize therapeutic potential. Additionally, we performed external validation through bulk and cell-type-specific expression analyses and prioritized protein evaluation. The final key proteins were determined by triangulating evidence across all these streams.

RESULTS: We identified 48 genetically prioritized proteins. Functional annotation prioritized 14 with therapeutic potential and highlighted 13 non-MS drugs for repurposing. Triangulation of evidence with multi-omics external validation highlighted six key proteins: RRM2B (a Cladribine target), CBR1, and ETFA, which are linked to existing drugs; DNM3 (a GWAS-implicated locus), CAB39L, and NMRAL1, which emerged as validated novel proteins providing biological insight into MS progression.

CONCLUSION: Our multi-omics integration prioritizes proteins implicated in MS progression, providing mechanistic insights into neurodegeneration and a foundation for future therapeutic exploration in progressive MS.