Genetic Variation in WNT9B Increases Relapse Hazard in Multiple Sclerosis.

Area of Science:

• Genetics
• Neurology
• Immunology

Background:

• Multiple sclerosis (MS) is characterized by genetic susceptibility variants, yet disease heterogeneity, particularly relapse occurrence, remains poorly understood.
• Relapses are a critical feature of MS, impacting patient outcomes and serving as a primary endpoint in clinical trials.

Purpose of the Study:

• To identify genetic variations associated with the hazard of relapse in multiple sclerosis (MS) using the largest study population to date.
• To explore the role of genetic risk scores and specific pathways in MS relapse prediction.

Main Methods:

• A genomewide association study (GWAS) was conducted in a discovery cohort and validated in a replication cohort.
• Survival analysis using Cox proportional hazards models assessed time to relapse in 991 patients experiencing 2,231 relapses before treatment.
• Gene ontology pathway analysis was performed to investigate associated biological pathways.

Main Results:

• The low-frequency variant rs11871306 within WNT9B achieved genomewide significance for predicting relapse hazard (meta-analysis HR = 2.15, p = 2.07 × 10^-10).
• Pathway analysis revealed an association between the "response to vitamin D" pathway and relapse hazard (p = 4.33 × 10^-6).
• MS genetic risk scores did not demonstrate association with relapse hazard.

Conclusions:

• Genetic factors influencing MS heterogeneity and relapse occurrence differ from those associated with general MS susceptibility.
• Genetic variations within the Wnt signaling and vitamin D pathways appear to contribute to variations in MS relapse frequency.
• These pathways represent potential targets for modulating MS disease activity.