Genetic subtypes associated with multiple sclerosis severity and response to treatment

Kreft, Karim L., Mekkes, Nienke J., Uzochukwu, Emeka, Loveless, Sam ORCID: https://orcid.org/0000-0002-5124-4115, Wynford-Thomas, Ray, Harding, Katharine Elizabeth, Wardle, Mark, Holmans, Peter, Brown, J. William L., Lawton, Michael, Tallantyre, Emma Clare ORCID: https://orcid.org/0000-0002-3760-6634, Holtman, Inge R. and Robertson, Neil P. ORCID: https://orcid.org/0000-0002-5409-4909 2026. Genetic subtypes associated with multiple sclerosis severity and response to treatment. Journal of Neurology, Neurosurgery and Psychiatry 10.1136/jnnp-2025-337337

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Abstract

Background Predicting response to treatment and long-term disability in multiple sclerosis (MS) remains challenging. In other complex diseases, combining genetic risk variants has enabled the detection of relevant clinical endophenotypes associated with important outcomes, but this strategy has never been applied to MS. Methods We applied unsupervised hierarchical clustering to genomic risk scores in a prospective Welsh MS cohort (n=1455) and replicated the findings in the postmortem Netherlands Brain Bank (NBB) MS (NBB-MS) cohort (n=272). Disease progression was assessed using survival analysis to determine the time to Expanded Disability Status Scale (EDSS) milestones. Results Three genomic clusters were identified, each with similar genetic profiles. Baseline demographics did not differ between clusters. Welsh patients in cluster 1 attained EDSS 6 and EDSS 8 significantly later than clusters 2 and 3 (by 6 years, p=3×10 −3 and 13 years, p=0.02, respectively). These findings were replicated in the NBB-MS cohort (6-year delay to EDSS 6 for cluster 1 vs 2, p=0.04). Genomic clustering independently predicted disease progression (HRs 1.3–2.0, all p<0.05), beyond established risk factors. Clusters 2 and 3 showed a greater annual increase in T2 lesion load on serial MR imaging (p=0.04). In cluster 2, patients receiving disease-modifying treatments had delayed progression to EDSS 6 (p=3×10 − ³), while no such benefit was observed in clusters 1 or 3. Cluster 2 patients also had earlier onset of symptoms, including dysphagia (p=0.02) and spasticity (p=8×10 − ⁴) in the NBB-MS cohort. Conclusions Genetic clustering reveals clinically meaningful MS subtypes with distinct prognoses and treatment responses, highlighting its potential role in precision medicine for MS management.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Medicine
Publisher:	BMJ Publishing Group
ISSN:	0022-3050
Date of Acceptance:	17 December 2025
Last Modified:	28 Jan 2026 11:00
URI:	https://orca.cardiff.ac.uk/id/eprint/184261

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