Discovery of the first genetic marker of the severity of MS

Scientists identify first genetic marker for MS severity, opening door to prevention of long-term disability.

A study of more than 22,000 people with multiple sclerosis has found 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 spinal cord, leading to flare-ups of symptoms called relapses as well as longer-term degeneration called progression. Despite the development of effective treatments for relapses, none can reliably prevent the accumulation of disabilities. The groundbreaking findings, published in Nature on June 28, 2023, point to a genetic variant that increases the severity of the disease and bring the first real advances in understanding and possibly fighting this aspect of MS.

Inheriting this genetic variant from both parents accelerates the time it takes to need a walking aid by almost four years.”

Sergio Baranzini, PhD, professor of neurology at the University of California, San Francisco (UCSF) and study co-lead author

The work is the result of an extensive international collaboration of more than 70 institutions 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 for a new generation of treatments that can prevent disease progression,” said Stephen Sawcer, Cambridge professor and co-author. principal of the study.

A renewed look at the nervous system

To solve the mystery of how serious MS is, two major MS research consortia have joined forces: the International Multiple Sclerosis Genetics Consortium (IMSGC) and the MultipleMS Consortium. This has allowed MS researchers around the world to pool the resources needed to begin identifying genetic factors influencing MS outcomes. Previous studies have shown that MS susceptibility, or risk, stems largely from immune system dysfunction, and that some of these dysfunctions can be treated, slowing 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,” Baranzini explained.

The two consortia combined data from more than 12,000 people with MS to perform 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 the severity of MS, including the years it took for each individual to go from diagnosis to a certain level of disability. After sifting through more than 7 million genetic variants, scientists found one that was associated with faster disease progression. The variant lies between two genes with no prior link to MS, called DYSF and ZNF638. The former is involved in repairing damaged cells, and the latter helps control viral infections. The proximity of the variant to these genes suggests that they may be involved in disease progression.

“These genes are normally active in the brain and spinal cord, rather than the immune system,” said Adil Harroud, MD, lead study author and former postdoctoral researcher in Baranzini’s lab. “Our findings suggest that nervous system resilience and repair determine the course of MS progression and that we should focus on these parts of human biology for better therapies.” The results give the field its first clues to address the nervous system component of MS.” Although it seems obvious that your brain’s resistance to injury would determine the severity of a disease like MS, this new study has given us geared toward the key processes that underlie this resilience,” Sawcer said. To confirm their findings, the scientists studied the genetics of nearly 10,000 other MS patients. Those who had two copies of the variant were more quickly.

Netherlands Institute for Neuroscience

But how do we know how relevant this DNA variant really is? This is where the Dutch Brain Bank comes 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), examined the genetic architecture underlying the evolution of MS, using donor brains.

Joost Smolders (besides his job at the Netherlands Institute for Neuroscience, also working as a neurologist at Erasmus MC Rotterdam and a member of the IMSGC): “In terms of treatment, we can already do a lot for people with MS, but we cannot yet predict the rate at which their health is deteriorating. For this, we need to better understand the underlying mechanisms, the discovery of the SNP being an important first step. A SNP is a variation in DNA of a single DNA building block. At the Netherlands Institute for Neuroscience, we can do the second step, which is to look at brain tissue to see the effect of that SNP. At the Brain Bank, we have brains from deceased donors with MS who already have a history of the disease behind them, all available for research. We wondered if carriers of the genetic defect had more severe brain changes linked to MS.

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

Next steps

Further work will be needed to determine exactly how this genetic variant affects DYSF, ZNF638, and the nervous system more generally. 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 can help safeguard the health of everyone who suffers from MS,” Harroud said. Could we instead say “treatments to prevent long-term disability”?