An international collaboration led by Yale researchers has identified four novel genes that affect an individual’s risk for multiple sclerosis.
In a new study led by professor of genetics and neurology Chris Cotsapas, the researchers analyzed over 68,000 control subjects and patients with multiple sclerosis from Australia, 10 European countries and multiple U.S. states. Multiple sclerosis is an autoimmune disease of the central nervous system and a common cause of neurologic disability in young adults. They found that nearly 5 percent of heritability for the disease is explained by rare genetic variants. The study was published on Oct. 18 in Cell by the International Multiple Sclerosis Genetics Consortium.
“From previous work, we knew that common variants explain a big fraction of multiple sclerosis risk but not all,” Cotsapas said. “This kept puzzling us, because we couldn’t figure out where the rest of heritable risk was. We decided to challenge the common disease, common variant dogma and look at whether rarer variants affect risk too. Surprisingly, we found that it was true — they explain a small, but significant, part of risk.”
The human genome encompasses about three billion “letters” of DNA. Although the DNA sequences of two individuals are almost identical, letters can vary among individuals, contributing to the differences in inherited traits we see between people, explained Mitja Mitrovic, research scientist at the School of Medicine and first author of the paper.
These differences are termed genetic variants, and they can exist at different frequencies in the population, ranging from 50 percent to one in a million.
Previous work by the Consortium has identified 233 genetic risk variants for multiple sclerosis. However, these common variants only account for about 20 percent of overall disease risk, while the remaining genetic causes remaining elusive. So, the researchers turned to rarer variants — those with a frequency below 1 percent in the general population — that directly damage gene sequence.
“It’s very hard to elucidate the direct mechanism of why a variant that changes expression of the gene results in multiple sclerosis, for example. It’s hard to put a link between that, whereas where you have a broken gene, which we measured, then you have a direct association [between the variant and the disease].”
About 90 percent of autoimmune diseases, which include multiple sclerosis, are caused by genes that do not actually code for proteins, according to professor of neurology and immunobiology and co-author David Hafler. But this study is novel in that it examines protein-coding genes.
While the research has not led directly to new treatments for the disease, the team’s findings will help scientists elucidate the underlying cause of the disease, according to Hafler.
“It’s early days — we have discovered a set of new genes that drive multiple sclerosis risk, but we don’t really understand how these influence individual patients’ experience[s] yet. That’s what we are working on now,” Cotsapas said.
Common symptoms of multiple sclerosis include blurry vision, numbness, lack of coordination and bladder or bowel problems.
Eui Young Kim | euiyoung.kim@yale.edu .