Rare Mutations Affecting Immune System and MS Risk Identified in Large Study

An international consortium studying more than 68,000 people, about half of them multiple sclerosis (MS) patients, found rare genetic variations that account for up to 5 percent of the heritable MS risk, a study reports.

The newly discovered mutations were associated with either an increased or a reduced susceptibility to MS, and all appear to impact the immune system.

This research also highlights the relevance of studying large patient populations to identify rare genetic risk factors that would not be evident in common genome-wide association studies (GWAS).

The study, “Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk,” was published in the journal Cell.

Although common genetic variants (present in more than 5 percent of the population) account for part of the heritable MS risk, they cannot account for its whole.

Over the last 15 years, the International Multiple Sclerosis Genetics Consortium (IMSGC), an international collaboration with the aim of identifying all inherited risk factors for MS, found 233 common mutations mediating MS risk.

However, these common variations only explain about 20 percent of MS genetic risk, with others still unknown.

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Led by scientists at Yale University, the IMSGC team decided to take a different approach than that commonly used, and looked at mutations which appear infrequently in the population.

The team analyzed genetic data from a large sample of patients and healthy controls: 32,367 MS cases and 36,012 controls from 14 different countries, including Australia, Europe, and the United States. By gathering such a large dataset, researchers had enough statistical power to look for rare gene variants with sufficient depth.

They identified new and rare mutations in four genes, which drove either a higher or a lower susceptibility to MS, independently of other common variants already known.

Importantly, these low-frequency variants were able to explain nearly 5 percent of heritability seen in MS.

“We simply would not have found them by continuing to look at common genetic variants; we had to look for rarer events, which means looking at many, many more people,” Chris Cotsapas, an associate professor of neurology and genetics at Yale and senior author of the study, said in a news release. “These variants explain an extra 5% of risk.”

Previous studies have suggested that the combination of common variants work together to increase the risk to a greater extent than each variant alone, or that some families carry mutations that cause disease. However, researchers now believe that these theories are wrong.

“We’ve looked in thousands of people to test those theories, and they just aren’t true,” Cotsapas said. “The data don’t bear them out.”

Overall, the discovery of these low-frequency genetic variants “constitute a rich resource for dissecting the pathobiology [the biological mechanism] of MS,” the researchers wrote.

The newly discovered variants are present in genes which “have clear immunological functions, confirming that MS pathogenesis is primarily driven by immune dysfunction,” they added.