Immune Processes Linked to Multiple Sclerosis Genetics

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.

The role of the adaptive arm of the immune system, particularly its CD4+ T cell component, has become clearer, with multiple different T cell subsets being implicated. Although the T cell component plays an important role, functional and epigenomic annotation studies have begun to suggest that other elements of the immune system may be involved as well.

Scientists involved with the International Multiple Sclerosis Genetics Consortium (Boston, MA, USA) 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. For the autosomal non- major histocompatibility complex (MHC) genome, they applied a partitioning approach to create regions of ±1 Mbp around the most statistically significant single nucleotide polymorphisms (SNP). The team designed the MS Chip using the Illumina iSelect platform, adding ~90K custom selected SNPs to the Illumina Exome Core content (~200K SNPs).

The team 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. Using gene expression and epigenomic data for T cells, monocytes, peripheral blood mononuclear cells, and prefrontal cortex tissue, the scientists 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.

The authors concluded that beyond the characterization of the molecular events that trigger MS, this map will also inform the development of primary prevention strategies because they can leverage this information to identify the subset of individuals who are at greatest risk of developing MS. 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. The study was published on September 27, 2019, in the journal Science.

Related Links:
International Multiple Sclerosis Genetics Consortium