Identifying the Genetic Variant That Increases Disease Severity in MS

Research of over 22,000 patients with multiple sclerosis (MS) has for the first time discovered a genetic variant linked with speedier progression of the disease, a buildup of disability that can deprive patients of their mobility and independence over time.

Multiple sclerosis commences as an autoimmune disease in which the immune system attacks the brain and spinal cord, causing symptom flare-ups known as relapses as well as long-term damage known as progression. Despite the development of effective treatments for the inflammatory autoimmune disease, none of them can avoid increased disability throughout the disease’s neurodegenerative phase.

The latest study, which includes Yale investigators and was published in Nature on June 28^th, 2023, is the first to find a genetic variant that worsens disease severity, a breakthrough that the authors say is a critical step toward comprehending and eventually combating this progressive type of MS.

While we have identified genetic variants that are predominantly immune related associated with risk of developing MS, this is the first study to identify neuronal genetic variants associated with the neurodegenerative aspects of the disease.”

Dr David Hafler, William S. and Lois Stiles Edgerly Professor, Neurology, Yale School of Medicine

Dr David Hafler is also a Professor of Immunobiology and Chair of the Department of Neurology, and an author of the study.

The research was the outcome of a huge international effort led by the International MS Genetics Consortium (IMSGC), which includes more than 70 institutions from around the world. Hafler is one of the IMSGC’s co-founders.

Previous research has indicated that MS susceptibility, or risk, is caused in significant part by immune system dysfunction. Some of this dysfunction can be treated, reducing the disease’s progression.

However, “these risk factors don’t explain why, 10 years after diagnosis, some MS patients are in wheelchairs while others continue to run marathons,” said Sergio Baranzini, a Professor of Neurology at the University of California, San Francisco and Co-Senior Author of the study.

For the first part of the new research, investigators gathered data from more than 12,000 individuals with MS to conduct a genome-wide association study (GWAS), a research method that systematically links genetic variants to specific behaviors using statistics. In this example, the qualities of interest were linked to MS severity, particularly the number of years it took each person to progress from diagnosis to a certain level of disability.

After sorting through more than seven million genetic variants, the researchers discovered one linked to rapid disease progression. The variation is located between two genes known to be unrelated to MS, DYSF, and ZNF638.

Researchers discovered that MS patients who had two copies of the gene variant, which was found near two genes that assist repair damaged cells and one that helps regulate viral infection, progressed faster. The variant’s position implies a potential mechanism for faster development.

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

Sergio Baranzini, Professor, Neurology, University of California, San Francisco

“These genes are normally active within the brain and spinal cord, rather than the immune system,” said Adil Harroud, Assistant Professor of Neurology at the Montreal Neurological Institute and lead author of the study. “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,” adds Adil Harroud.

The results provide the field with its first substantial leads in addressing the nervous system component of MS.

To back up their results, the researchers looked at the genetics of nearly 10,000 more MS patients. They discovered that those who had two copies of the variant were disabled sooner.

“This gives us a new opportunity to develop new drugs that may help preserve the health of all who suffer from MS,” Harroud concludes.