Genome-wide association analyses highlight the neuronal contribution to multiple sclerosis susceptibility

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease. Genetic studies have identified susceptibility loci that primarily impact immune cells and microglia. Here we show that a multi-ancestry genome-wide association study of 20,831 individuals with MS and 729,220 controls identified 236 susceptibility variants outside the major histocompatibility complex, including four novel genomic loci. We derived a polygenic score for MS; optimized for European ancestry, it is informative for African-American and Latino participants. Integrating single-cell data from blood and brain tissue, we identified 76 candidate causal genes. Notably, inhibitory neurons emerged as a key target cell type for MS variants, with seven loci, including STAT3, displaying altered expression only in these cells. The STAT3 variant is also associated with cognition and white matter integrity in non-MS individuals and greater sNfL levels in MS participants, suggesting that MS susceptibility may reflect reduced central nervous system resilience to inflammatory challenges.