A new large-scale genetic map implicates broad immune system dysfunction in patients with multiple sclerosis (MS), suggests a key role of brain immune cells called microglia, and indicates an MS-related gene variant located in the X chromosome.

Altogether, the findings — the result of the largest reported study of MS to date — provide the basis for up to 48% of the heritability for this disease.

The study, “Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility,” was published in the journal Science.

Earlier genetic studies have implicated several immune T-cell subsets in a person’s susceptibility for developing MS. But other elements of the immune system have since been linked with this disease. Aiming to better understand the risk for MS, a team within the International Multiple Sclerosis Genetic Consortium (IMSGC) assessed the genetic profile of 47,429 MS patients and 68,374 healthy individuals.

The analysis revealed 233 sites or loci in the human genome significantly linked with MS onset. Among them, 32 are related to the major histocompatibility complex — a set of cell surface proteins that boost immune responses — and one (rs2807267) is found in the X chromosome.

The researchers, from the U.S. and Europe, analyzed patterns of gene expression — the production of proteins from DNA — and epigenetics, or altered gene expression, though not in the gene itself. They found a greater concentration of MS susceptibility loci in several immune cell types and tissues, but not in the central nervous system (CNS), or the brain and spinal cord.

This finding “has important implications as we begin to consider prevention strategies to block the onset of the disease by early targeting of peripheral immune cells,” the scientists said.

A subsequent analysis in stem cell-derived neurons, and in cultures of other types of brain cells, revealed that MS-related genes were also concentrated — or enriched — in microglia, the resident immune cells of the CNS. This was not found in nerve cells and in astrocytes, the first responders to brain injury.

Among immune cells with MS loci were not only T- and B-cells, but also those implicated in innate immunity, such as natural killer cells. One of the identified variants was in the SLC12A5 gene, which is known to be associated with risk for rheumatoid arthritis, also an autoimmune disease. Another was in the CLECL1 gene, and was found increased in microglia in the cortex, the brain’s outer layer.

Using a protein-protein interaction analysis, the team then found that 190 genes could be organized into 13 clusters that code for proteins that interact with one another.

“The study has created a detailed genetic map of MS, identifying … regions of the human genome that influence a large number of different immune cells, highlighting the fact that this disease is not caused by a single immune cell type but rather by a broad dysfunction of the immune system,” Philip De Jager, MD, PhD, the study’s principal investigator, and director of the Multiple Sclerosis Center at Columbia University Irving Medical Center, said in a press release. Taken together with 416 other gene variants — that, although not being statistically significant are likely true susceptibility loci — the findings explain approximately 48% of the estimated heritability for MS, the researchers said. Nikolaos Patsopoulos, PhD, MD, from the Ann Romney Center for Neurologic Diseases of Brigham & Women’s Hospital and Harvard Medical School, said the research “more than doubled” the knowledge of MS genetics and “highlights the complexity of the genetic contribution to MS susceptibility by identifying several regions of the genome with multiple genetic variants that play a small role.” “Further,” Patsopoulos added, “we report the first ever association of genetic variant in chromosome X with MS, a disease that affects mainly young women.” Tomas Olson, a study co-author from the Karolinska Institutet, in Sweden, cautioned that the reported genetic variants do not cause MS per se, but rather interact with environmental factors to increase the likelihood “that a viral infection or other exposure triggers an autoimmune reaction against the brain and spinal cord.” “These insights set the stage for a new generation of functional studies to uncover the sequence of molecular events that lead to disease onset,” the investigators concluded. “This perspective … will lay the foundation for developing primary prevention strategies that mitigate the risk of developing MS.”