New clues in understanding faster disease progression in multiple sclerosis

Florey scientists help identify the first genetic marker for multiple sclerosis (MS) severity, opening the door to preventing long-term disability.

Melbourne scientists have joined MS researchers from around the world by contributing to a study that has identified genetic factors influencing outcomes in people with MS.

The study of more than 22,000 people with MS has discovered the first genetic variant associated with faster disease progression, which 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 flare-ups 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 findings, published today in Nature, point to a genetic variant that increases disease severity, providing the first real progress in understanding and eventually fighting this aspect of MS.

The Florey’s Neurogenetics Group Head, Associate Professor Justin Rubio, said the team in Melbourne provided the study with clinical data and DNA samples from people in Victoria living with MS.

“We don’t understand why the rate of disability accumulation in people with MS is so variable, leaving some using a wheelchair after 10 years and others running marathons,” said Associate Professor Rubio, Chair of the ANZgene MS Genetics Consortium.

“By identifying these genetic variants, we’re demonstrating that genes expressed in the nervous system are important modifiers of MS outcome, which opens the door for new treatments for MS progression,” he said.

The Nature study, which analysed samples from North America, Europe and Australia, involved more than 70 institutions and was led by researchers from the University of California San Francisco (UCSF) and the University of Cambridge.

“Inheriting this genetic variant from both parents accelerates the time to needing a walking aid by almost four years,” said Sergio Baranzini, UCSF Professor of Neurology and co-senior author of the study.

“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 Professor Stephen Sawcer, of the University of Cambridge and the study’s other co-senior author.

Two consortia, the International Multiple Sclerosis Genetics Consortium and the MultipleMS Consortium, combined data from more than 12,000 people with MS to complete a genome-wide association study, which links genetic variants to particular traits.

After sifting through more than 7 million genetic variants, the scientists found one associated with faster disease progression. The variant sits between two genes with no prior connection to MS, called DYSF and ZNF638. The first is involved in repairing damaged cells, and the second helps to control viral infections. The variant’s proximity to these genes suggests they may be involved in disease progression.

“These genes are normally active within the brain and spinal cord, rather than the immune system,” said Dr Adil Harroud, lead author of the study and former postdoctoral researcher in the Baranzini 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 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. Those with two copies of the variant became disabled faster.

Further work will be necessary to determine exactly how this genetic variant affects DYSF, ZNF638, and the nervous system more generally. The researchers are also collecting an even larger set of DNA samples from people with MS, expecting to find other variants that contribute to long-term disability in MS.

“MS is the most common neurodegenerative disease in young adults. This discovery provides an important new piece in the puzzle that could lead to the development of new treatment options for people with MS,” Associate Professor Rubio said.

The Florey leads important MS research in Australia, with projects underway to understand the role of nervous system repair in MS progression; to find novel therapies; and to discover early detection methods and treatment options.

Notes to editor:
This work was supported in part by funding from the NIH/NINDS (R01NS099240), the European Union’s Horizon 2020 Research and Innovation Funding Programme, and the Multiple Sclerosis Society of Canada.