Genome-Wide Study of Early Disability Severity in Multiple Sclerosis

Two suggestive genome-wide loci for early multiple sclerosis disability severity were replicated, including rs1234317 (P = 1.08E-07) and rs929769 (P = 1.95E-07), in Swedish discovery and European replication cohorts.

• Why it matters: Genetic determinants of disability severity close to disease onset are unclear, limiting causal variant discovery and early-phase therapeutic targeting in multiple sclerosis.
• What they did: They analyzed first age-related MS severity score (ARMSS) in 7,209 individuals, then used replication, conditional analysis, fine-mapping, time-to-event phenotype association, multi-omics gene prioritization, and additional cross-trait and Mendelian randomization analyses.
• The result: Fine-mapping supported rs929769 as a single-variant 95% credible set and rs1234317/rs6657136 as a two-variant 95% credible set; prioritized effectors were TNFSF4, TNFSF18, and ADAMTS2, with drug-repurposing nominations and attenuated links to long-term disability progression.

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