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Multiple Sclerosis GWAS Points to Role for Central Nervous System in Disease Severity, Progression

NEW YORK – An international team led by investigators at the University of California San Francisco and the University of Cambridge has uncovered genetic risk variants with ties to multiple sclerosis (MS) severity. Unlike variants associated with MS susceptibility, which have been linked to the immune system, the new variants seem to play a role in the central nervous system.

For a study published in Nature on Wednesday, members of the International Multiple Sclerosis Genetics Consortium and the MultipleMS Consortium performed a genome-wide association study involving 12,584 individuals with MS, searching for variants linked to increased disease severity in relatively young individuals. After assessing suspicious variants in another 9,805 MS cases, they were left with one variant that showed significant ties to shorter time to progression.

"This is the first discovery of a genetic association with MS severity," co-senior and co-corresponding author Sergio Baranzini, a professor of neurology at UCSF, said in an email.

The variant, known as rs10191329, turned up at the DYSF-ZNF638 locus and was linked to a shorter time to using a walking aid, the team explained. In MS patients carrying two copies of rs10191329, for example, use of a walking aid occurred a median 3.7 years earlier than it did in individuals without the risk variant.

Homozygous rs10191329 carriers also tended to have higher-than-usual pathology in the brain's cortical region and brainstem, the researchers explained. They noted that the low-frequency risk variant rs149097173 had ties to MS progression, as well. That variant fell at a DNM3-PIGC locus in or around other genes showing enhanced CNS tissue expression.

"Both severity variants had a clinically meaningful association with time to needing a walking aid, with the median interval from onset shortened by 3.7 years for homozygous risk allele carriers of the DYSF-ZNF638 variant (rs10191329) and 3.3 years for risk allele carriers of the DNM3-PIGC variant (rs149097173)," the authors reported. "Although not comparable in terms of probable mechanism, the magnitude of this effect matches that of treatment with a disease-modifying agent such as beta-interferon."

More than 200 variants have been linked to MS susceptibility in past GWAS, the team explained, including MS-associated variants occurring in the major histocompatibility complex and other immune-related genes and regions. Even so, the risk variants tallied so far do not appear to correspond with disease severity, despite some ties to earlier-than-usual disease onset.

While genetic studies of MS risk have highlighted the importance of immune contributors, Baranzini explained, the latest research suggests MS severity is also influenced by genetics, involving CNS-related pathways and phenotypes that are distinct from those implicated in susceptibility.

"[T]his work represents the first evidence that MS severity (as is susceptibility) is also influenced by genetics, but the genetic determinants for both phenotypes are different," he said. 

"Successful unraveling of the genetic basis for disease susceptibility has implicated dysregulation across immune cells as a driver of MS onset," the authors reported. "Our findings identify CNS resilience and reserve as probable determinants of MS progression and may have broader implications for neurodegeneration."

Together, the new variants not only offer insights into the biological underpinnings of MS progression, they wrote, but also point to potential avenues for staving off reversible "relapse" symptoms as well as progressive neurological features of the disease.

"MS has undergone a therapeutic revolution in the past few decades, with the emergence of ever more effective immune therapies that reduce and even halt relapses," the authors wrote. "Despite this, treatment of progression remains an unmet need. 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."

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