To identify plasma proteins causally implicated in multiple sclerosis (MS) using an integrated genetic-proteomic approach.
Approach:
Methodology: Utilized Mendelian randomization and colocalization to analyze 2,545 protein measurements from 3 cohorts, totaling 80,824 individuals, and assessed their association with MS in an independent set of 14,802 cases and 26,703 controls.
Key Findings:
Nominated 39 causal proteins associated with MS risk.
Validated predictive value of these proteins in individuals diagnosed with MS up to 15 years prior.
Identified DKKL1 as a candidate with protective effects on MS risk and severity.
Improved fine-mapping resolution by over 10-fold and identified novel MS risk loci.
Interpretation:
The findings refine genetic factors and pathways involved in MS onset and highlight protein biomarkers that may enhance early risk stratification and inform targeted therapies.
Limitations:
Discordance across proteomic platforms remains unresolved.
Prediagnostic validation has not been performed.
Relevance of identified proteins to disease severity is unclear.
Conclusion:
The integrated approach provides insights into causal proteins and genetic factors related to MS, potentially aiding in early detection and therapeutic strategies.
