Australian researchers have contributed to the discovery of four new genes driving multiple sclerosis risk.
Professor David Booth and Professor Graeme Stewart from the Westmead Institute and the University of Sydney are key researchers involved in the International Multiple Sclerosis Genetics Consortium (IMSGC) that identified the new genes.
Each of the four genes is an independent risk factor for MS, adding to the 233 genetic risk variants previously identified by the consortium.
Professor Booth said it was promising that in just over a decade the consortium had found nearly 250 separate genetic risk factors for multiple sclerosis.
“As recently as 2006, we had only one. However, we simply could not have found these new MS risk genes by continuing to look at common genetic variants.
“We had to look for rarer variants, which meant looking at many, many more people. The different approach we took means that we’ve found four new genes that actually represent a significant proportion of MS risk,” he said.
The consortium’s work also showed that nearly 5% of MS heritability is explained by coding low-frequency variants
To find the genes, the IMSGC pooled data from more than 68,000 MS patients and control subjects across Australia, Europe and the United States to look for rare variants that directly damage the gene sequence.
More than 3000 Australians with MS and controls contributed DNA samples to the study, including samples held in the Westmead MS DNA biobank.
Professor Stewart is optimistic that the findings will help researchers find new ways to treat MS, but says much work remains to be done.
“The mechanisms whereby our newly discovered variants alter MS risk will require detailed experimental dissection: even when we can directly implicate specific genes and variants, these can have diverse consequences across multiple cell types,” the researchers write in Cell.
“For example, perforin 1 has key – and potentially distinct – roles in cytotoxic T cells, regulatory helper T cells, NK cells, and other cell types. Both the effects of the variant on each of these functions and their relevance to MS pathogenesis will thus require demonstration, as is the case for the genes central to IFNγ biology, Treg function, and the NFκB signaling pathway.”
The other Australian contributors to the study include Professor Bruce Taylor and Dr Jac Charlesworth from the University of Tasmania, and Dr Lotti Tajouri from Bond University.
Associate Professor Cotsapas at Yale University led the international collaboration.
The IMSGC was founded in 2003 to study the genetic basis of MS. It comprises more than 200 laboratories across the world and has identified almost 250 separate MS genetic risk factors.