A genetic variant for multiple sclerosis severity has been identified, the first known variant of this kind, researchers reported last night.
An international collaboration of more than 70 institutions studied more than 22,000 people with MS to identify a variant associated with increased disease progression.
The findings are published in the latest edition of Nature.
The work was the result of a large international collaboration of more than 70 institutions from around the world, led by researchers from UCSF (USA) and the University of Cambridge (UK).
Co-senior study author Professor Sergio Baranzini, of US-based UCSF, which led the study with the University of Cambridge, UK, said: “Inheriting this genetic variant from both parents accelerates the time to needing a walking aid by almost four years.”
For this study, two large MS research consortia – The International Multiple Sclerosis Genetics Consortium (IMSGC) and The MultipleMS Consortium – joined forces and combined data from more than 12,000 people with MS to complete a genome-wide association study (GWAS).
The traits of interest in this research were related to MS severity, including the years it took for each individual to advance from diagnosis to a certain level of disability.
They sifted through more than seven million genetic variants to find one that was associated with faster disease progression.
It sits between DYSF and ZNF638 – two genes with no prior connection to MS. The former is involved in repairing damaged cells, while the latter helps to control viral infections.
Dr Adil Harroud, lead study author, said: “These genes are normally active within the brain and spinal cord, rather than the immune system. 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 team used Mendelian randomisation to explore the importance of environmental effects and found that years of education and parental age reduced the severity of MS, while smoking worsened it. Finding correlation with these indirect measures of brain health further underlines the importance of resilience in determining the outcome of MS.
Co-senior author Professor Stephen Sawcer from the University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, said: “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.”
To confirm their findings, the scientists investigated the genetics of nearly 10,000 additional MS patients and found those with two copies of the variant became disabled faster.
They researchers say further work is needed to determine how this genetic variant affects DYSF, ZNF638, and the nervous system more generally.
International Multiple Sclerosis Genetics Consortium and MultipleMS Consortium. Locus for severity implicates CNS resilience in progression of multiple sclerosis. Nature 28 June 2023; doi: 10.1038/s41586-023-06250-x
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