The 52 gene variations to be confirmed and expanded in National MS Society-funded follow-up study
In the largest MS genetics study ever undertaken, a global collaboration of scientists has identified 29 new genetic variants associated with MS, and confirmed 23 others previously associated with the disease, verifying a major role for the immune system in the development of MS. The study involved nearly 10,000 people with MS and more than 17,000 controls without MS, and was funded by the Wellcome Trust, the National Institutes of Health, the National MS Society and many other organizations. Some 250 investigators of the International MS Genetics Consortium and the Wellcome Trust Case Control Consortium 2 participated in the study, published in the August 11, 2011 issue of Nature (2011;476:214-219). The results are now to be confirmed and expanded in an independent, second large-scale set of cases with a research grant from the National MS Society.
Most of the genes implicated in the study were related to immune function, and more than one-third have previously been confirmed to be associated with autoimmune diseases. In a second study published in PLoS Genetics (2011;7), collaborators show that diseases believed to be autoimmune share many similar genetic variants. To date, the results of genetics studies in MS do not significantly improve the ability to provide genetic counseling to individuals. However the findings promise to better define the biological pathways leading to MS and enhance our ability to design better treatments for early MS.
Background: MS is believed to occur in people whose genes make them susceptible to whatever triggers the disease. In order to end MS, we need to understand the genetic roots of the disease.
The International MS Genetics Consortium (IMSGC) was formed with funding from the National MS Society to take advantage of advancing technology making it possible to conduct Genome-Wide Association Screening studies. In 2007 the Consortium published a groundbreaking initial GWAS study that clearly identified two new genes (the 2nd and 3rd susceptibility genes identified overall) that predispose people to developing MS.
That work demonstrated that the GWAS approach could successfully identify important MS genes, but also made it apparent that much larger study would be necessary to identify most of the remaining common MS susceptibility genes. The Consortium expanded to include more groups from more countries, forming the basis for its grant from The Wellcome Trust to perform such a study.
The Study: To conduct this GWAS, research groups in 15 countries studied DNA samples from 9,772 individuals with MS, and 17,376 unrelated controls without MS. The team confirmed 23 of 26 genetic associations to MS that had been suggested previously. They also identified 29 new genetic variants associated with MS risk albeit with small effects (as well as five variants with a suspected association with MS).
The team went on to perform statistical analyses to look for similarities in function among the genes near these variants. They found that a large number were related to T-cell function. T cells are believed to be the major mediators of the early immune attack that is launched on the brain and spinal cord in MS. In particular, these genes were mainly associated with T cell activation and proliferation. Two genes linked to vitamin D were also implicated; research is increasingly pointing to low vitamin D levels in patients as a risk factor for developing MS.
A second step will be to validate and replicate the findings emerging from this study. This is possible by testing any identified associations in independent, sets of cases and controls, and the first large attempt to this replication is being made possible with a research grant from the National MS Society, funded in part by a lead gift from Richard Slifka to the National MS Society’s Central New England Chapter.
This confirmation is critical because comparisons of large data sets while increasing our chance of finding even the genes of little importance, will always lead to potentially false positive associations. Moreover, in this study, new patients identified will be studied immunologically, allowing for understanding the functional relevance of the genes identified with the occurrence of MS.
Autoimmune disease genes: More than one third of the gene variants identified to date have previously been confirmed to be associated with autoimmune diseases, such as Crohn’s disease and type 1 diabetes. MS is believed to be an autoimmune disease as well.
This week researchers published further information about genes related to autoimmunity in PLoS Genetics. Investigators in the FOCIS Network of Consortia examined how 107 variants were shared by seven diseases, including MS, celiac disease, Crohn’s disease, psoriasis, rheumatoid arthritis, lupus, and type 1 diabetes. Forty-seven variants were shared by more than one disease. One variant exhibited evidence of association to all seven. The team also found evidence that different clusters of variants interact, and may constitute distinct disease-causing mechanisms in subgroups of these seven diseases.
The FOCIS Network of Consortia includes representatives from the IMSGC and similar consortia formed on behalf of other diseases, enabling the IMSGC to leverage a powerful collaboration even farther.
Read more about genetics research funded by the National MS Society, and read about opportunities to participate in this exciting research.