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Gene Variant Linked to Increased Multiple Sclerosis Severity

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Scientists have identified a genetic variant that is associated with increased disease severity in multiple sclerosis (MS) patients. The study – conducted in over 22,000 people with MS – is published in Nature.

MS therapies are limited

MS is an autoimmune and neurodegenerative disorder that is characterized by the demyelination of nerve fibers within the central nervous system (CNS). Individuals diagnosed with MS might experience a relapse remitting form of the disease, where symptoms occur in bouts of “attacks” that worsen over time, or they may suffer a gradual decline in function.

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Current MS therapies work to minimize the side effects of the inflammatory aspect of the disease. Drugs that effectively halt or prevent disability associated with neurodegeneration are lacking, in part due to our murky understanding of the molecular mechanisms underpinning this phase of the disease.

Disease variability in MS patients

Previous studies have demonstrated that MS risk is largely attributed to malfunction of the immune system, but as Dr. Sergio Baranzini, a professor of neurology at University of California, San Francisco, describes, “these risk factors don’t explain why, 10 years after diagnosis, some MS patients are in wheelchairs while others continue to run marathons.”

Baranzini is the co-author of the new study that explored whether genetic variants might be associated with different rates of MS disease progression. The researchers conducted a genome-wide association study, or GWAS, which scours the genomes of large groups of people for genetic variants.

What is a GWAS study?

An approach commonly used in genetics research, a GWAS study involves analyzing the genomes of a cohort of individuals that possess a specific phenotype, for example, having a disease such as MS, and comparing their genetic make-up. By scanning the genome for genetic variants, researchers can understand whether certain variants occur in higher frequencies in individuals with particular phenotypes – e.g., a faster rate of disease progression. If this is the case, the genetic variants are classed as being associated with that phenotype. GWAS studies help scientists to identify correlations, not causation.

“To provide insight into the potential mechanisms involved in progression, we conducted a genome-wide association study of the age-related MS severity score in 12,584 cases and replicated our findings in a further 9,805 case,” the research team explains.

The age-related MS severity score outlines how many years it takes for individuals to progress from a diagnosis of MS to a specific level of disability. After working through over 7 million genetic variants, the researchers identified one specific variant that was significantly associated with faster disease progression, called rs10191329. It sits between two genes: DYSF and ZNF638, neither of which have been connected to MS previously.  

Gene variant associated with patients becoming disabled faster

The research team found that carrying two copies of this gene variant was associated with needing a walking aid sooner, as well as increased degeneration of the brainstem and cortex.

"These genes are normally active within the brain and spinal cord, rather than the immune system,” says Dr. 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.”

“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,” says 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 study is a by-product of a large collaboration from the International MS Genetics Consortium (IMSGC), comprising over 70 research institutions from across the globe, of which Hafler is a co-founder.

The researchers are confident that identifying neuronal genetic variants associated with the neurodegenerative components of MS opens new avenues for drug development. “This gives us a new opportunity to develop new drugs that may help preserve the health of all who suffer from MS,” Harroud concludes.

Reference: Harroud A, Stridh P, McCauley JL, et al. Locus for severity implicates CNS resilience in progression of multiple sclerosis. Nature. 2023. doi: 10.1038/s41586-023-06250-x

This article is a rework of a press release issued by Yale University. Material has been edited for length and content.