Study suggests genetic link to MS disease progression

June 30, 2023
A study of more than 22,000 people with multiple sclerosis has discovered the first genetic variant linked to faster disease progression. The findings provide the first real progress in understanding and eventually fighting this aspect of MS. The researchers said this provides an opportunity to develop new drugs that may help preserve the health of all who suffer from MS.

To address the mystery of MS severity, the International Multiple Sclerosis Genetics Consortium and The MultipleMS Consortium joined forces. This enabled a large international collaboration of more than 70 institutions from around the world – led by researchers from University of California, San Francisco, and the University of Cambridge – to pool the resources needed to begin to identify the genetic factors influencing MS outcomes. 

The two groups 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 initial diagnosis to a certain level of disability. After sifting through more than 7 million genetic variants, the scientists found one that was linked to faster disease progression. The variant sits between two genes with no prior connection to MS: 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 it may be involved in the disease’s progression.

The researchers said the findings suggest that resilience and repair in the nervous system determine the course of MS progression and focusing on these parts of human biology may lead to 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. They found that those with two copies of the variant became disabled faster.

According to the authors, in terms of treatment, there’s already a lot that can be done for people with MS, but the speed at which health deteriorates can’t yet be predicted. For this, more insight into underlying mechanisms is needed, with the discovery of the SNP being an important first step. A SNP is a variation in the DNA of a single DNA building block. 

A team of researchers from the Netherlands Institute for Neuroscience within the International MS Genetics Consortium, looked at the genetic architecture underlying the course of MS using donor brains from the Dutch Brain Bank. The Brain Bank has brains from deceased donors with MS who already have an entire disease history behind them, all available for research. Looking into the brain tissue to see the effect of this SNP, researchers asked whether carriers of the genetic abnormality had more severe MS-related changes in their brains.

The results suggest that homozygous carriers of the risk allele (rs10191320), or double carriers of the gene, have almost twice as many MS abnormalities in their gray and white matter than MS donors without this genetic variation. This is very important, because it allows researchers to validate that this SNP may really be relevant to people with MS. The effect of such a SNP is magnified far more in the pathology than in the effect it has on someone’s experience with MS.

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. 

The findings were published in the journal Nature.

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