A study of more than 22,000 people with multiple sclerosis has discovered the first genetic variant associated with faster disease progression that can rob patients of their mobility and independence over time.
The work, published in the journal Nature, is the result of a large international collaboration of more than 70 institutions from around the world, led by researchers from UCSF (USA) and the University of Cambridge (UK). Yolanda Blanco, Sara Llufriu and Albert Saiz, from the Neuroimmunology-Multiple Sclerosis Unit at the Hospital Clínic Barcelona and the IDIBAPS Pathogenesis of autoimmune neuronal disorders and Advanced imaging in neuroimmunological diseases (ImaginEM) groups, and Xavier Montalban, Manuel Comabella, Sunny Malhotra and Luciana Midaglia from the Multiple Sclerosis Centre of Catalonia (Cemcat), participated in this study.
In multiple sclerosis (MS) the immune system mistakenly attacks the brain and the spinal cord, resulting in symptom flares known as relapses, as well as longer-term degeneration known as progression. Despite the development of effective treatments for relapses, none can significantly prevent the accumulation of disability.
The study’s findings point to a genetic variant that increases the disease’s severity and provide the first real progress in understanding, and eventually fighting, this aspect of MS. "Inheriting this genetic variant from both parents accelerates the time to needing a walking aid by almost four years", said Sergio Baranzini, neurology professor at UCSF and co-senior author of the study.
“Understanding how the variant exerts its effects on MS severity will hopefully pave the way to a new generation of treatments that are able to prevent disease progression”, said Stephen Sawcer, a professor at the University of Cambridge and the other co-senior author of the study.
Change the focus to understand Multiple Sclerosis
In order to carry out the study, two large MS research consortia joined forces: the International Multiple Sclerosis Genetics Consortium (IMSGC) and the MultipleMS Consortium (MultipleMS). This enabled MS researchers from around the world to pool the resources needed to begin to identify the genetic factors influencing MS outcomes.
Previous studies have shown that MS susceptibility, or risk, stems in large part from dysfunction in the immune system, and some of this dysfunction can be treated, slowing down the disease. But “these risk factors don’t explain why, 10 years after diagnosis, some MS patients are in wheelchairs, while others continue to run marathons”, explained the researchers.
The two consortia combined data from more than 12,000 people with MS to complete a genome-wide association study (GWAS), which uses statistics to carefully link genetic variants to particular traits. In this case, the traits of interest were related to MS severity, including the years it took for each individual to advance from diagnosis to a certain level of disability.
After sifting through more than seven million genetic variants, the scientists found one that was associated with faster disease progression. The variant sits between two genes with no prior connection to MS, called DYSF and ZNF638. The first is involved in repairing damaged cells and the second helps to control viral infections. The variant’s proximity to these genes suggests that they may be involved in the disease’s progression.
These genes are normally active within the brain and spinal cord, rather than the immune system. The study’s findings suggest that resilience and repair in the nervous system determine the course of MS progression.
“Although it seems obvious that your brain’s resilience to injury would determine the severity of a disease like MS, this new study has pointed us towards the key processes that underlie his resilience", said the researchers.
The findings give the first leads to address the nervous system component of MS.
An ever-expanding coalition to address MS severity
To confirm their findings, the scientists investigated the genetics of nearly 10,000 additional MS patients. Those with two copies of the variant became disabled faster.
Further work will be necessary to determine exactly how this genetic variant affects DYSF, ZNF638, and the nervous system more generally. The researchers are also collecting an even larger set of DNA samples from people with MS, expecting to find other variants that contribute to long-term disability.
Funding: This work was supported in part by funding from the NIH/NINDS (R01NS099240), the European Union’s Horizon 2020 Research and Innovation Funding Programme, the National Multiple Sclerosis Society, and MS Canada.
Adil Harroud et. al. Locus for severity implicates CNS resilience in progression of multiple sclerosis. Nature (2023). DOI: 10.1038/s41586-023-06250-x