Summary: Researchers have identified four new genes that act independently as risk factors for multiple sclerosis.
An international collaboration led by scientists at Yale has cracked a tough nut in multiple sclerosis: Where are all the genes?
Previous work by the International Multiple Sclerosis Genetics Consortium (IMSGC) has identified 233 genetic risk variants. However, these only account for about 20% of overall disease risk, with the remaining genetic culprits proving elusive. To find them, the IMSGC pooled more than 68,000 MS patients and control subjects from Australia, ten European countries, and the United States. This time, researchers looked for rare variants that directly damage gene sequence. They found four new genes that act independently as risk factors for the disabling autoimmune disorder, they report Oct. 18 in the journal Cell.
“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,” said Yale’s Chris Cotsapas, associate professor of neurology and genetics and corresponding author of the study. “These variants explain an extra 5% of risk.”
Previous theories have held that combinations of common variants act in concert to explain more risk than each one alone, or that some families carry private mutations that cause disease only in those individuals.
“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.”
The novel variants identified code for proteins, making them easier to study, and offer researchers promising new ways to study MS, researchers said.
Source: Ziba Kashef – Yale
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Original Research: Open access research for “Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk” by International Multiple Sclerosis Genetics Consortium in Cell. Published October 18 2018.
Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk
Multiple sclerosis is a complex neurological disease, with ∼20% of risk heritability attributable to common genetic variants, including >230 identified by genome-wide association studies. Multiple strands of evidence suggest that much of the remaining heritability is also due to additive effects of common variants rather than epistasis between these variants or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that up to 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common-variant signals, highlighting key pathogenic roles for regulatory T cell homeostasis and regulation, IFNγ biology, and NFκB signaling. As low-frequency variants do not show substantial linkage disequilibrium with other variants, and as coding variants are more interpretable and experimentally tractable than non-coding variation, our discoveries constitute a rich resource for dissecting the pathobiology of MS.