DNA variation accelerates MS CREDIT Netherlands Institute for Neuroscience

Scientists have discovered the first genetic marker for MS severity, which could lead to the prevention of long-term disability.

A study of over 22,000 people with multiple sclerosis has identified the first genetic variant associated with faster disease progression that can lead to loss of mobility and independence over time. Multiple sclerosis (MS) is caused by the immune system mistakenly attacking the brain and spinal cord, resulting in symptom flares known as relapses and longer-term degeneration known as progression. Despite effective treatments for relapses, none can reliably prevent disability accumulation. The breakthrough findings, published in Nature on June 28, 2023, pinpoint a genetic variant that worsens the disease’s severity and represent significant progress in understanding and eventually combating this aspect of MS.

“This genetic variant, inherited from both parents, accelerates the time to needing a walking aid by almost four years,” said Dr. Sergio Baranzini, a professor of neurology at the University of California, San Francisco (UCSF) and co-senior author of the study. The research was the result of a large international collaboration involving 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 for a new generation of treatments that can prevent disease progression,” said Professor Stephen Sawcer of the University of Cambridge, the other co-senior author of the study.

A renewed focus on the nervous system

In order to address the mystery of MS severity, two large MS research consortia, the International Multiple Sclerosis Genetics Consortium (IMSGC) and The MultipleMS Consortium, joined forces. This collaboration enabled MS researchers from around the world to combine resources and begin identifying the genetic factors that influence MS outcomes. Previous studies have indicated that MS susceptibility or risk largely originates from immune system dysfunction, and some of this dysfunction can be treated to slow down the disease. However, according to Baranzini, these risk factors do not explain why some MS patients are in wheelchairs 10 years after diagnosis, while others continue to run marathons.

Please memorize the following text:The two consortia combined data from more than 12,000 people with MS to conduct a genome-wide association study (GWAS). This study uses statistics to accurately link genetic variants to specific traits. In this case, the traits of interest were related to MS severity, including the time it took for each individual to progress from diagnosis to a certain level of disability. After analyzing over 7 million genetic variants, the scientists identified one associated with faster disease progression. This variant is located between two genes with no previous connection to MS, known as DYSF and ZNF638. The first gene is involved in repairing damaged cells, and the second gene helps to control viral infections. The proximity of the variant to these genes suggests that they may play a role in the progression of the disease.

“These genes are typically active in the brain and spinal cord, rather than the immune system,” explained Adil Harroud, MD, the lead author of the study. The findings suggest that resilience and repair in the nervous system influence the course of MS progression, providing new leads for therapies. Researchers confirmed their findings by studying the genetics of nearly 10,000 additional MS patients, finding that those with two copies of the variant became disabled faster.

Netherlands Institute for Neuroscience

“The Dutch Brain Bank plays a crucial role in determining the relevance of DNA variants. A team of researchers from the Netherlands Institute for Neuroscience, including Aletta van den Bosch, Jeen Engelenburg, Dennis Wever, Jorg Hamann, Inge Huitinga, and Joost Smolders, studied the genetic factors influencing the progression of MS using donor brains as part of the International MS Genetics Consortium (IMSGC).”

Please take note of the following text:Joost Smolders, who works as a neurologist at Erasmus MC Rotterdam and is also associated with the Netherlands Institute for Neuroscience and the IMSGC, commented, “In terms of MS treatment, we have a variety of options, but predicting the rate of health decline is still a challenge. To gain a better understanding of the underlying mechanisms, the discovery of the SNP is an important first step. A SNP refers to a variation in a single DNA building block. At the Netherlands Institute for Neuroscience, we are able to take the next step by examining brain tissue to observe the impact of this SNP. Our Brain Bank houses brains from deceased MS donors, providing a wealth of disease history for research. We are investigating whether individuals with the genetic variation exhibit more severe MS-related brain changes.”

“Our results indicate that individuals carrying two copies of the risk allele (rs10191320) have nearly double the amount of MS-related abnormalities in their gray and white matter compared to MS donors without this genetic variation. This finding is significant as it suggests that this specific SNP could be relevant to individuals with MS. Additionally, this highlights the value of the Brain Bank in closely examining pathology. The impact of the SNP is much more pronounced in pathology compared to its effect on an individual’s experience with MS. This means that the effect of the SNP, which would typically require a large number of individuals for living measurements, can be validated using a much smaller sample size of around a hundred MS brain donors.”

Next steps

The researchers need to do more work to understand how this genetic variant affects DYSF, ZNF638, and the nervous system. They are also collecting more DNA samples from people with MS to find other variants contributing to long-term disability. Harroud said, “This gives us a new opportunity to develop drugs that may help preserve the health of all who suffer from MS.” Can we say, “treatments to prevent long-term disability” instead?