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 mean there are 3 million changes in one individual. The challenge then becomes whether any of these changes 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 on how many people have them. If at least 1 in 20 people have that exact change it is considered “common” and if less than 1 in 20 people have that change it is considered rare.
Most of the research into the genetic causes of MS has concentrated on these common genetic changes or changes that don’t just occur in one or two individuals. This approach has been very successful, and over the last 15 years has resulted in the discovery of over 230 genetic changes which can influence the risk of developing MS. However, these 230 changes are known only to account for 20% of the genetic risk of MS.
Research has now turned to where the remaining genetic risk is coming from. Historically, it had been thought that this remaining risk had to be due to either:
a) interactions of the known genes (that is, they were acting in unison to contribute even more to the MS) or,
b) from rare genetic changes which up to now were too difficult to detect due to technical limitations and the need for vast numbers of DNA samples to discover them.
A landmark paper published today from the International MS Genetics Consortium, including a number of Australian genetics researchers; Professor David Booth, Professor Graeme Stewart, Professor Bruce Taylor, Dr Jac Charlesworth and Dr Lotti Tajouri, has shown that it is, in fact, rare changes that 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, including 2,321 people from Australia. Data on the genetic changes was gathered using a specially designed “gene chip” that captured information across many gene changes simultaneously. The Australian scientists in this study are also members of a vital research collaboration called the Australian New Zealand MS Genetics Consortium – a research platform of MS Research Australia. This platform brings together neurologists, genetic researchers, molecular biologists, data scientists and other researchers, from all around Australia and New Zealand to understand the role of genes in MS.
Seven rare changes were shown to be linked to MS risk, with four of these changes mapping 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 NSW 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”.
The new genes indicate that control of immune cells known as T 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.