Locus for severity implicates CNS resilience in progression of multiple sclerosis

International Multiple Sclerosis Genetics Consortium, MultipleMS Consortium, Joost Smolders

Research output: Contribution to journalArticleAcademicpeer-review

29 Citations (Scopus)


Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that results in significant neurodegeneration in the majority of those affected and is a common cause of chronic neurological disability in young adults1,2. Here, to provide insight into the potential mechanisms involved in progression, we conducted a genome-wide association study of the age-related MS severity score in 12,584 cases and replicated our findings in a further 9,805 cases. We identified a significant association with rs10191329 in the DYSF-ZNF638 locus, the risk allele of which is associated with a shortening in the median time to requiring a walking aid of a median of 3.7 years in homozygous carriers and with increased brainstem and cortical pathology in brain tissue. We also identified suggestive association with rs149097173 in the DNM3-PIGC locus and significant heritability enrichment in CNS tissues. Mendelian randomization analyses suggested a potential protective role for higher educational attainment. In contrast to immune-driven susceptibility3, these findings suggest a key role for CNS resilience and potentially neurocognitive reserve in determining outcome in MS.

Original languageEnglish
Pages (from-to)323-331
Number of pages9
Issue number7969
Early online date28 Jun 2023
Publication statusPublished - 13 Jul 2023

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© The Author(s), under exclusive licence to Springer Nature Limited 2023.


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