What makes multiple sclerosis worse, and how to make it better

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. Multiple sclerosis (MS) is the result of the immune system mistakenly attacking 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 reliably prevent the accumulation of disability. The breakthrough findings, published in Nature on June 28, 2023, 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, PhD, professor of neurology at the University of California, San Francisco (UCSF) and co-senior author of the study. The work was the result of a large international collaboration of more than 70 institutions from around the world, led by researchers from UCSF and the University of Cambridge. "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 Cambridge and the other co-senior author of the study.

A renewed focus on the nervous system

To address the mystery of MS severity, two large MS research consortia joined forces: The International Multiple Sclerosis Genetics Consortium (IMSGC) and The MultipleMS Consortium. 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 Baranzini.

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 7 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," said Adil Harroud, MD, lead author of the study and former postdoctoral researcher in Baranzini's lab. "Our findings suggest that resilience and repair in the nervous system determine the course of MS progression and that we should focus on these parts of human biology for better therapies." The findings give the field its first leads to address the nervous system component of MS."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 this resilience," Sawcer said. 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.

Netherlands Institute for Neuroscience

But how do we know how relevant this DNA variant actually is? That's where the Dutch Brain Bank steps in. A team of researchers from the Netherlands Institute for Neuroscience (Aletta van den Bosch, Jeen Engelenburg, Dennis Wever, Jorg Hamann, Inge Huitinga and Joost Smolders), within the International MS Genetics Consortium (IMSGC), looked at the genetic architecture underlying the course of MS, using donor brains.

Joost Smolders (aside from his employment at the Netherlands Institute for Neuroscience, also working as a neurologist at Erasmus MC Rotterdam and member of the IMSGC): 'In terms of treatment, there's already a lot that we can do for people with MS, but we can't yet predict the speed at which their health deteriorates. For this we need more insight into underlying mechanisms, with the discovery of the SNP being an important first step. A SNP is a variation in the DNA of a single DNA building block. At the Netherlands Institute for Neuroscience, we can perform the second step, which involves looking into the brain tissue to see the effect of this SNP. At the Brain Bank, we have brains from deceased donors with MS who already have an entire disease history behind them, all available for research. We asked ourselves whether carriers of the genetic abnormality had more severe MS-related changes in their brains.'

'Our results show that homozygous carriers of the risk allele (rs10191320), or double carriers of the gene, have almost twice as many MS abnormalities in their gray and white matter than MS donors without this genetic variation. This is very important, because it allows us to validate that this SNP may really be relevant to people with MS. This also illustrates the strength of the Brain Bank: you can look at the pathology very closely. The effect of such a SNP is magnified far more in the pathology than in the effect it has on someone's experience with MS. Something that would typically require tens of thousands of people with MS for living measurements can be confirmed with a hundred or so of these particular MS brain donors.'

Next steps

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. "This gives us a new opportunity to develop new drugs that may help preserve the health of all who suffer from MS," said Harroud. Could we say instead, "treatments to prevent long-term disability"?