A genome-wide association study (GWAS) including more than 22,000 people with multiple sclerosis (MS) has uncovered the first genetic variant associated with faster progression of the autoimmune disorder, which can rob patients of their mobility and independence over time. The newly reported investigation, by an international collaboration of researchers for the International Multiple Sclerosis Genetics Consortium (IMSGC), and the MultipleMS Consortium, report a genetic variant that increases disease severity, providing the first real progress in understanding and eventually fighting this aspect of MS. The findings give the field its first leads to address the nervous system component of MS.

“Inheriting this genetic variant from both parents accelerates the time to needing a walking aid by almost four years,” said UCSF’s Sergio Baranzini PhD. “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,” added Stephen Sawcer, FRCP, PhD, at the University of Cambridge and Cambridge University Hospitals NHS Foundation Trust. Baranzini and Sawcer are co-senior authors of the team’s published paper in Nature, titled “Locus for severity implicates CNS resilience in progression of multiple sclerosis.” In their paper the team concluded, “In this GWAS, which included more than 22,000 people with MS, we have identified the first, to our knowledge, genome-wide significant modifier of long-term outcome in MS, and have thereby identified valuable potential targets for drug discovery.”

Multiple sclerosis is a central nervous system autoimmune disease that affects more than 2.8 million people worldwide, the authors wrote. The disorder results from the immune system mistakenly attacking the brain and the spinal cord, resulting in recurrent episodes of largely reversible neurological dysfunction, known as relapses, as well as longer-term neurodegeneration, known as progression. And, as the team continued, “The relative effects of these largely independent features varies between patients and during the course of illness within individuals.”

Despite the development of effective treatments for relapses, some of which were pioneered at the University of Cambridge, none can reliably prevent the accumulation of disability. The authors stated, “Over the past few decades, the introduction of a range of immunological treatments has transformed the ability to control relapse activity in the disease, leaving therapy capable of controlling progression as the greatest currently unmet clinical need.”

The newly reported work results from a large international collaboration involving more than 70 institutions from around the world, and led by researchers from UCSF and the University of Cambridge. The collaboration allowed the researchers to pool the resources needed to begin to identify the genetic factors influencing MS outcomes.

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. However the team noted, “Although these risk variants are associated with a reduced age at onset 5, it is notable that they do not appear to have any association with disease severity. “These risk factors don’t explain why, ten years after diagnosis, some MS patients are in wheelchairs while others continue to run marathons,” Baranzini stated.

For their GWAS the two consortia first combined data from over 12,000 people with MS, and used statistics to link genetic variants to particular traits related to MS severity, including the number of years it took for each individual to advance from diagnosis to a certain level of disability. After sifting through more than seven million genetic variants the scientists identified one, known as rs10191329, that was associated with faster disease progression.

The variant sits between two genes—DYSF and ZNF638—that have no prior connection to MS. DYSF is involved in repairing damaged cells, while ZNF638 helps to control viral infections. The newly identified variant’s proximity to these genes suggests that they may be involved in disease progression. “We identified a significant association with rs10191329 in the DYSF–ZNF638 locus, the risk allele of which is associated with a shortening in the median time to requiring a walking aid of a median of 3.7 years in homozygous carriers and with increased brainstem and cortical pathology in brain tissue,” the scientists noted.

“These genes are normally active within the brain and spinal cord, rather than the immune system,” said lead author Adil Harroud, PhD, a 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.”

Applying a statistical method known as Mendelian randomization to explore the importance of environmental effects, the team also found that years of education and parental age reduced the severity of MS, while smoking worsened it. “Together, these results suggest a detrimental effect of smoking in people with MS and implicate educational attainment as a potential protective factor,” they wrote. Finding correlations with these indirect measures of brain health further underlines the importance of resilience in determining the outcome of MS.

“Although it seems obvious that your brain’s resilience to injury would determine the severity of a disease like MS, this new study has pointed us towards the key processes that underlie this resilience,” Sawcer said. To confirm their findings, the scientists also investigated the genetics of nearly 10,000 additional MS patients. They found that individuals 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. “This gives us a new opportunity to develop new drugs that may help preserve the health of all who suffer from MS,” said Harroud.

Studying the genetics of multiple sclerosis has been a major theme of neurological research in Cambridge since the late 1980s. With others, members of the Department of Clinical Neurosciences have been closely involved in discovery of the vast majority of gene variants that increase susceptibility.

IMSGC founding member Alastair Compston, MBBS, PhD, FRCP, from the University of Cambridge, added: “Having been personally involved with the identification of susceptibility genes for multiple sclerosis since the 1970s, it is a tribute to those within IMSGC who led this project that fully independent risk variants for progression have now been discovered. Once more, the work illustrates the benefits of international collaboration for advancing the understanding of disease mechanisms in multiple sclerosis and other medical conditions.”

Noting limitations of their study, the authors nevertheless stated, “In conclusion, this study presents robust evidence for a role of genetic variation in MS progression … We have identified genetic loci associated with disability in MS, providing new directions for functional characterization and drug development targeted on the neurodegenerative component of the disease … Our findings identify CNS resilience and reserve as probable determinants of MS progression, and may have broader implications for neurodegeneration.”

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