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Multiple Sclerosis Genetic Study Links Immune Processes, Microglia to Disease Risk

NEW YORK – A large-scale study into the genetics of multiple sclerosis has found that many different types of immune cells and tissues, including microglia in the brain, appear to be involved in risk for the disease.

The results, which explain almost half the estimated heritability of MS, could be used to gain further insights into the molecular events that lead to the onset of the disease and to develop effective prevention strategies.

MS is an autoimmune inflammatory degenerative disease of the central nervous system that often starts in young adulthood and affects 2.3 million individuals worldwide. While prior genetic studies have implicated the adaptive immune system in the disease, in particular T cells, much of the genetic architecture of MS has remained unknown.

For their study, published in Science yesterday, members of the International Multiple Sclerosis Genetics Consortium analyzed genotyping data from a total of more than 47,000 MS patients and more than 68,000 unaffected controls. These included both existing datasets and two large-scale new datasets for replication studies.

Overall, the researchers identified 233 associations with MS susceptibility that had genome-wide significance, including 32 loci on the major histocompatibility complex and one on the X chromosome. The latter might help explain why MS affects almost three times more women than men. In addition, they uncovered hundreds of variants that did not reach statistical significance but are likely to also be susceptibility loci. Together, these associations explain about 48 percent of MS heritability.

Using gene expression and epigenomic data for T cells, monocytes, peripheral blood mononuclear cells, and prefrontal cortex tissue, the researchers found that MS risk loci are enriched in many types of immune cells and tissues, as well as in microglia, which are the immune cells of the brain, but not in other types of brain cells.

Together with other functional studies into the effects of MS risk variants, they identified a list of 551 putative MS susceptibility genes with involvement in both innate and adaptive immune responses, many of which have roles in the development, maturation, and differentiation of B cells, T cells, natural killer cells, and myeloid cells.

"Beyond the characterization of the molecular events that trigger MS, this map will also inform the development of primary prevention strategies because we can leverage this information to identify the subset of individuals who are at greatest risk of developing MS," the authors wrote. "Although insufficient by itself, an MS genetic risk score has a role to play in guiding the management of the population of individuals 'at risk' of MS (such as family members) when deployed in combination with other measures of risk and biomarkers that capture intermediate phenotypes along the trajectory from health to disease."

"Several effective therapeutics for managing MS target various immune cells; thus, there is promise for the development of therapeutics that target these [more than] 235 MS susceptibility variants," wrote Farren Briggs, a researcher in the Department of Population and Quantitative Health Sciences at Case Western Reserve University School of Medicine, in an accompanying commentary.