Scientists have identified the first genetic marker for multiple sclerosis (MS) severity, opening the door to preventing long-term disability.

A study of more than 22,000 people with multiple sclerosis has discovered the first genetic variant associated with faster disease progression that can rob patients of their mobility and independence over time.

MS is the result of the immune system mistakenly attacking the brain and the spinal cord, resulting in symptom flares known as relapses as well as longer-term degeneration known as progression. Despite the development of effective treatments for relapses, none can reliably prevent the accumulation of disability.

The breakthrough findings, published in Nature, point to a genetic variant that increases the disease’s severity and provide the first real progress in understanding and eventually fighting this aspect of MS.

“Inheriting this genetic variant from both parents accelerates the time to needing a walking aid by almost four years,” said Sergio Baranzini, PhD, professor of neurology at University of California San Francisco (UCSF) and co-senior author of the study.

The work was the result of a large international collaboration of more than 70 institutions from around the world — including the Menzies Institute for Medical Research at the University of Tasmania — 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 to a new generation of treatments that are able to prevent disease progression,” said Stephen Sawcer, a professor at the University of Cambridge and the other co-senior author of the study.

An international collaboration

To address the mystery of MS severity, two large MS research consortia joined forces: The International Multiple Sclerosis Genetics Consortium (IMSGC) and MultipleMS. This enabled MS researchers from around the world to pool the resources needed to begin to identify the genetic factors influencing MS outcomes.

Significant data contributions have been made to this project by clinicians and scientists from Australia and New Zealand via the Australian and New Zealand MS Genetics Consortium (ANZgene), which is funded and coordinated by MS Australia.

Professor Bruce Taylor, study co-author and neurologist at the Menzies Institute for Medical Research has been an active member of ANZgene since its inception in 2007.

“Through ANZgene, Menzies has contributed significant amounts of data to the world’s largest MS genetic projects,” said Professor Taylor.

“The current paper contains data from some 250 Tasmanians with MS, which has been collected over the last 13 years and collated at Menzies,” he added.

Professor Taylor went on to explain “For this project there was a specific need for not only data from people living with MS, but also for carefully conducted measures of disability. This allowed us to determine which genes were associated with the risk of progression.”

Previous studies have shown that MS susceptibility, or risk, stems in large part from dysfunction in the immune system, and some of this dysfunction can be treated, slowing down 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,” explained Baranzini.

The two consortia combined data from more than 12,000 people with MS to complete a genome-wide association study which 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.

Renewed focus on the nervous system

After sifting through more than seven million genetic variants, the scientists found one that was associated with faster disease progression. The variant sits between two genes — one that’s involved in repairing damaged cells, the other that helps to control viral infections — with no prior connection to MS. The variant’s proximity to these genes suggests that they may be involved in the disease’s progression.

“These genes are normally active within the brain and spinal cord, rather than the immune system,” said Adil Harroud, MD, lead author of the study and former postdoctoral researcher in Baranzini’s lab. “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 lead to address the nervous system component of MS.

To confirm their findings, the scientists investigated the genetics of nearly 10,000 additional MS patients. 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,” said Harroud.

Notes:

• Menzies would like to thank the people with MS who donated their samples and MS Australia for its ongoing support of MS research in Australia.
• This work was supported in part by funding from the NIH/NINDS (R01NS099240), the European Union’s Horizon 2020 Research and Innovation Funding Programme, the National Multiple Sclerosis Society, and the Multiple Sclerosis Society of Canada.
• Menzies Institute for Medical Research exists to perform internationally significant medical research leading to healthier, longer and better lives for Tasmanians. Learn more at https://www.menzies.utas.edu.au.