Zeng, Lu, Khan, Atlas, Fitzgerald, Kathryn C., Lama, Tsering, Chen, Jessy, International Multiple Sclerosis Genetics Consortium and Robertson, Neil P.  ORCID: https://orcid.org/0000-0002-5409-4909
2026.
Genome-wide association analyses highlight the neuronal contribution to multiple sclerosis susceptibility.
Nature Genetics
58
(9)
, pp. 2177-2191.
10.1038/s41588-026-02731-7
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Abstract
Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease. Previous genetic studies have identified susceptibility loci that primarily impact immune cells and microglia. Here we performed a multi-ancestry genome-wide association study of 20,831 MS cases and 729,220 controls and identified 236 susceptibility variants outside of the major histocompatibility complex, including four novel genomic loci. We also derived a polygenic score for MS; while optimized for European ancestry, it is informative for African American and Latino individuals. Integrating single-cell data from blood and brain tissue, we identified 76 candidate causal genes. Inhibitory neurons emerged as a key target cell type for MS-associated 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 individuals with no MS and greater sNfL levels in individuals with MS, suggesting that MS susceptibility may reflect reduced central nervous system resilience to inflammatory challenges.
| Item Type: | Article |
|---|---|
| Date Type: | Publication |
| Status: | Published |
| Schools: | Schools > Medicine |
| Additional Information: | For full list of authors see https://doi.org/10.1038/s41588-026-02731-7 Rights Retention Policy applied |
| Publisher: | Nature Research |
| ISSN: | 1061-4036 |
| Date of First Compliant Deposit: | 18 September 2026 |
| Date of Acceptance: | 24 July 2026 |
| Last Modified: | 18 Sep 2026 15:45 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/189678 |
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