Genetic Discovery Sheds Light on Multiple Sclerosis Progression and Future Treatments

Scientists Uncover Genetic Variant Linked to Faster Multiple Sclerosis Progression, Paving the Way for Improved Therapies

In a groundbreaking breakthrough, researchers have identified the first genetic variant associated with accelerated progression of multiple sclerosis (MS), a debilitating neurological condition that often leads to mobility loss. This significant finding marks a pivotal shift in MS research, focusing on the nervous system and providing promising avenues for the development of future treatments.

The study, encompassing a vast cohort of over 22,000 individuals diagnosed with MS, has revealed the initial genetic marker associated with more rapid disease advancement, which can ultimately strip patients of their ability to move independently over time.

Multiple sclerosis arises when the immune system erroneously attacks the brain and spinal cord, causing relapses of symptoms and long-term degeneration. Although effective treatments for symptom flares exist, pioneered by the University of California, San Francisco (UCSF), none have reliably prevented the accumulation of disability.

The findings, published in the journal Nature on June 28, represent a significant milestone in comprehending and combating this facet of MS. According to Sergio Baranzini, PhD, a professor of neurology at UCSF and co-senior author of the study, inheriting this particular genetic variant from both parents shortens the time until the need for mobility aids by nearly four years.

This research was the culmination of a large-scale international collaboration involving over 70 institutions worldwide, led by researchers from UCSF and the University of Cambridge. Stephen Sawcer, a professor at Cambridge and co-senior author of the study, expressed hope that understanding how this genetic variant influences MS severity will pave the way for a new generation of treatments capable of halting disease progression.

A Shift in Focus towards the Nervous System

To unravel the mystery surrounding MS severity, two prominent MS research consortia, the International Multiple Sclerosis Genetics Consortium (IMSGC) and the MultipleMS Consortium, joined forces. This alliance allowed MS researchers worldwide to pool their resources and begin deciphering the genetic factors that influence MS outcomes.

Previous studies have shown that MS susceptibility primarily stems from immune system dysfunction, some of which can be addressed to slow down the disease. However, as Baranzini points out, these risk factors fail to explain why some individuals with MS become wheelchair-bound a decade after diagnosis while others continue to engage in physically demanding activities.

By combining data from over 12,000 individuals with MS, the two consortia conducted a genome-wide association study (GWAS), meticulously linking genetic variants to specific traits related to MS severity. These traits included the time it took for each person to progress from diagnosis to a particular disability level.

After scrutinizing more than seven million genetic variants, the scientists discovered one variant associated with hastened disease progression. Positioned between two genes, DYSF and ZNF638, which were not previously connected to MS, this variant offers insights into potential involvement in disease progression. DYSF plays a role in cellular repair, while ZNF638 assists in controlling viral infections. The proximity of the variant to these genes suggests their potential role in MS severity.

Adil Harroud, MD, the lead author of the study and former postdoctoral researcher in Baranzini’s lab, highlights that these genes normally exhibit activity in the brain and spinal cord rather than the immune system. He emphasizes that the findings imply that the resilience and repair mechanisms within the nervous system determine the course of MS progression, underscoring the need for focused therapeutic interventions in these areas of human biology.

This study’s outcomes provide a vital starting point for addressing the nervous system component of MS, offering researchers their first actionable leads.

Sawcer notes that while it may seem self-evident that the brain’s

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• Nature: Locus for severity implicates CNS resilience in progression of multiple sclerosis
• University of California, San Francisco (UCSF)
• University of Cambridge
• International Multiple Sclerosis Genetics Consortium
• MultipleMS Consortium