Rare genetic changes discovered to increase MS risk

• Genes can change a person’s risk of developing MS, and “common” variations to genes have been shown to account for 20% of the genetic risk of developing MS.
• In a landmark paper from the International MS Genetics Consortium rare changes to genes have been shown to contribute a further 5% of the overall genetic risk of MS.
• Four completely new genes related to MS were identified that highlight the role of the immune system in MS.

Genetic studies are challenging, as while we humans are 99.9% genetically similar, we are 0.1% different, and given our genome is made up of 3 billion DNA letters that means there are 3 million genes which are different from one individual to another.

The challenge then becomes whether any of these differences are just harmless and add to our uniqueness or whether they can actually lead to disease. To overcome this challenge geneticists describe DNA changes as common or rare depending how many people have them.

If at least 1 in 20 people have that exact type of change it is considered “common” and if less than 1 in 20 people have that change it is considered rare.

Research so far in MS has concentrated on what is known as the “common” changes to genes. This approach has been very successful, and research over the last 15 years has identified over 230 changes related to MS, accounting for 20% of the genetic risk of developing the disease.

What else contributes to the genetic risk of MS?

Research has now turned to where the remaining genetic risk is coming from. Historically, it has been thought that this remaining risk had to be due to interactions of the known genes, that is, they were acting in unison to contribute even more to the MS, or the remaining risk was coming from rare genetic changes which were too difficult to detect due to technical limitations and the need for vast numbers of DNA samples.

A landmark paper from the International MS Genetics Consortium has shown that rare changes contribute a further 5% of the overall genetic risk of MS.

The study, led by Associate Professor Chris Cotsapas from Yale University in the US, examined a huge 118,350 rare genetic changes in 32,367 people with MS and compared them to 36,012 people without MS. Published in the prestigious scientific journal Cell, the study included participants worldwide. Data on the genetic changes were gathered using a specially designed “gene chip” that captured information across many gene changes simultaneously.

What do these rare genes do?

Seven rare changes were shown to be linked to MS risk, with four of these changes relating to genes that previously have not been connected to MS. The newly discovered genes have clear functions within the immune system, providing further evidence that MS is driven by immune cells mistakenly attacking the brain and spinal cord. The analysis also indicated that, despite the huge number of samples included in this study, there are still more genetic associations with MS that remain to be discovered.

Professor David Booth from the Westmead Institute for Medical Research in Australia and an author on the study commented “Previous studies have sought common variants affecting MS. This study used a special genotyping chip and a very large number of samples of DNA to see, for the first time, if rare variants contributed to risk. We have found four new genetic associations which indicate particular types of immune processes are important in MS. Scientists will now drill down into the details of these processes to find new ways to treat the condition”.

“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,” added Associate Professor Chris Cotsapas, the lead author from Yale University, “These variants explain an extra 5% of risk.”

The discovery of the new genes indicates that control of immune cells and specific signalling pathways within the immune system are likely to play a key role in MS. Follow up experiments will now determine the effect of these new genetic changes on the function of cells within the body and their potential role in MS. Once this is established, it may provide new targets for therapy development.