Researchers Uncover First Genetic Factor Associated with Disease Severity in Multiple Sclerosis

Summary: Researchers identify the first genetic risk factor associated with longer-term outcomes and progression in multiple sclerosis (MS). They found that this genetic factor increases risk of disability progression by almost 4 years as measured by shorter time to EDSS 6.0. Identifying new pathways involved in MS disability progression has the potential to guide the development of future therapies.

Background: Prior studies have identified over 200 genetic factors associated with MS susceptibility, the increased risk of developing MS. However, we have not yet identified genes that affect longer-term health outcomes.

Details: A large international research consortium examined whether there were any factors that influence risk of disability progression in MS. The study analyzed data from over 22,000 individuals with MS from across North America, Europe, and Australia, who were followed over their disease course. Disability was measured using the expanded disability status scale (EDSS).

Results: From this study, the researchers identified a genetic factor, or genetic variant, associated with longer-term outcomes and increased risk of MS disease severity. The genetic variant is rs10191329 and was found within the DYSF-ZNF638 genes. The gene variant was found to be associated with:

  • A shorter median time to needing a mobility aid (an EDSS of 6.0) by 3.7 years
  • Increased risk of lesions at key brain locations associated with neurodegeneration and progression

The researchers also looked at other lifestyle modifiable factors influencing progression. They found that those who had higher levels of education were associated with lower risk of disability progression. While heavy smokers showed faster rates of progression. Note that the risks associated with smoking can reverse upon quitting smoking. They found no association between MS severity and vitamin D or body mass index (BMI).

Impact: This study is the first to provide evidence for the role of genetic factors in MS disease severity. Effective treatments targeting progression remain a major unmet need. This work has provided potential new targets for drug development. Future research is needed to understand other risk factors associated with disease severity, such as social determinants of health (e.g., neighbourhood environments, work exposures, pollution, and patterns of healthcare utilization). More research and validation is needed on this newly identified genetic factor prior to use in clinic or for genetic testing.


Article published in Nature on June 28, 2023 – Locus for severity implicates CNS resilience in progression of multiple sclerosis. Link to article – here.

Additional Information:

Learn more about risk factors of MS – here.