MS Accelerator: Uncovering the Genetic Variant Driving Rapid Multiple Sclerosis Progression

A comprehensive study involving 22,000 multiple sclerosis patients identified a genetic variant that accelerates disease progression. This breakthrough, achieved by Yale researchers and the International MS Genetics Consortium, found that patients with two copies of the variant, near the DYSF and ZNF638 genes, experienced faster disease progression. This finding opens new avenues for developing treatments to slow MS progression.

In a first-of-its-kind breakthrough, a study involving over 22,000 multiple sclerosis patients, has identified a genetic variant that speeds up the progression of the disease.

A study of more than 22,000 people with multiple sclerosis (MS) has for the first time identified a genetic variant associated with faster progression of the disease, an accumulation of disability that can rob patients of their mobility and independence over time.

Multiple sclerosis begins as an autoimmune disease where the immune system attacks the brain and the spinal cord, resulting in symptom flares, called relapses, as well as longer-term degeneration known as progression. Despite the development of effective treatments for the inflammatory autoimmune disease, none can prevent increased disability during the neurodegenerative phase of the disease.

The new study, which includes researchers from Yale and was published in Nature on June 28, is the first to identify a genetic variant that increases disease severity, an advance that the authors say offers a key step toward understanding and eventually fighting this progressive form 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,” said Dr. David Hafler, the William S. and Lois Stiles Edgerly Professor of Neurology and Professor of Immunobiology at Yale School of Medicine, chair of the Department of Neurology, and an author of the study.

The work was the result of a large international collaboration of the International MS Genetics Consortium (IMSGC), which consists of more than 70 institutions from around the world. Hafler is a co-founder of the IMSGC.

Previous studies have shown that MS susceptibility, or risk, stems in large part from dysfunction in the immune system. Some of this dysfunction can be treated, slowing the progression of 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,” said Sergio Baranzini, a professor of neurology at the University of California, San Francisco (UCSF) and co-senior author of the study.

For the first part of the new study, researchers combined data from more than 12,000 people with MS to complete a genome-wide association study (GWAS), a research approach that 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.

They found that MS patients with two copies of the gene variant, located near the two genes that help repair damaged cells and one that helps control viral infection, experienced faster disease progression. The location of the variant suggests a possible mechanism for accelerated progression.

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

“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.”

The findings give the field its first significant leads to address the nervous system component of MS.

To confirm their findings, the scientists investigated the genetics of nearly 10,000 additional MS patients. Again, they found that those with two copies of the variant became disabled faster.

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

For more on this study, see Genetic Breakthrough: What Makes Multiple Sclerosis Worse.

Reference: “Locus for severity implicates CNS resilience in progression of multiple sclerosis” by International Multiple Sclerosis Genetics Consortium and MultipleMS Consortium, 28 June 2023, Nature.
DOI: 10.1038/s41586-023-06250-x

This work was supported in part by funding from the National Institute of Neurological Disorders and Stroke (which is part of the National Institutes of Health), the European Union’s Horizon 2020 Research and Innovation Funding Programme, and the Multiple Sclerosis Society of Canada.

Hafler is a Yale Cancer Center member in the Yale Cancer Immunology Research Program.