Scientists Identify Risk Genes that Regulate Peripheral Immune Cells and Microglia in Multiple Sclerosis
By Jamie Talan
November 7, 2019
Article In Brief
An analysis of genetic data from 47,429 MS patients and 68,374 controls established a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 variants within the extended MHC.
An international consortium of scientists has identified hundreds of variants of multiple sclerosis (MS), including new ones that regulate peripheral immune cells and microglia.
The findings, made possible through a chip designed to assess the genes involved in the development of MS, suggests that MS is triggered by a more general dysfunction of the immune system, which involves not just T cells but B cells, monocytes, natural killer cells, and other immune cells.
The findings were reported in the September 29 issue of Science.
“The question we want to solve is what makes people susceptible to developing MS,” said Philip L. De Jager, MD, PhD, professor of neurology and director of the Columbia Multiple Sclerosis Center and the Center for Translational and Computational Neuroimmunology at Columbia University Irving Medical Center.
“Once we understand which genes are involved, we may be able to identify people at high-risk of developing MS and identify strategies to prevent this disease.”
Study Design, Findings
The International Multiple Genetics Consortium, comprised of MS neurologists and geneticists, was established in 2003 to encourage the sharing of genetic data and increase the number of patients for genetic studies as well as the statistical power of gene discovery studies. After several successful studies, the consortium conducted a meta-analysis and identified information on approximately 100 single nucleotide polymorphisms (SNPs) that they believed were important for the onset of MS.
For this new study, they recruited more than 10,000 additional MS patients through a grant from the National MS Society.
After assembling all available genome-wide data, the consortium designed a customized gene chip consisting of over 90,000 SNPs. They used the chip to replicate their initial studies. They tried to replicate every SNP that was significant, with a p value of .05 or greater. Then, they did a systematic analysis of each loci and realized that 20 percent of the loci had more than one variant; one even had five variants and each held an independent disease risk. In total, they analyzed genotype data from 47,429 MS cases and 68,374 control subjects, identifying 233 risk variants.
They found that 32 of these variants were part of the major histocompatibility complex. One of the variants was found on the X chromosome, which is the first time a sex chromosome has been linked to MS. (The variant lies within an enhancer peak specific for T cells.)
“These genome-wide and suggestive effects jointly explain about 48% of the estimated heritability for MS,” the researchers wrote.
The researchers wanted to know more about the functional consequences of these variants in the development of MS, so they tried to identify the cell types involved in this process. They looked at gene-expression activity in human induced pluripotent stem cell–derived neurons as well as from purified primary human astrocytes and microglia. They did not see enrichment in the neurons or astrocytes but were surprised to find enrichment in human microglia, which are the brain's resident immune cells.
They also found that the adaptive T cells are not the only player in MS. In addition to microglia, they identified MS loci susceptibility enrichment in B cells, monocytes, myeloid cells, and NK cells.
The consortium wanted to understand how the variants affect the gene product, the proteins encoded by genes. They found that the 233 variants had functional connections to 551 genes. They performed a protein-protein analysis and observed that about one-third of the genes were connected in some way. Patterns began emerging and could be organized into 13 groups of genes that encode proteins that work together to trigger the initial MS event.
Among other next steps, the scientists would like to study each cell type, perturbing the implicated pathways, to establish the common molecular events that lead to MS. Then, they may be able to better understand what makes some people vulnerable in the first place.
“There are still so many unanswered questions,” said Dr. De Jager. Molecular pathways can interact with different cell subtypes, he said.
One of the puzzles the scientists addressed in the paper is this: “Is risk of disease driven by altered function of only one of the implicated cell types, or are all of them contributing to susceptibility equally? This question highlights the important issue of the context in which these variants are exerting their effects.
“Even where a function is reported, further work is needed to demonstrate that the effect is the causal functional change,” the study authors wrote. “This is particularly true of the role of the CNS in MS susceptibility; we mostly have data at the level of the human cortex, a complex tissue with many different cell types, including resident microglia and a small number of infiltrating macrophage and lymphocytes. MS variants clearly influence gene expression in this tissue, and we must now resolve the implicated cell types and whether pathways shared with immune cells are having their MS susceptibility effect in the periphery or in the brain, and more deeply identify additional functional consequences.”
“The power here is looking at a large number of people with and without MS and then identifying risk gene variants that are concentrated in the MS population,” said Amit Bar-Or, MD, FRCPC, the Melissa and Paul Anderson president's distinguished professor of neurology at the Perelman School of Medicine at the University of Pennsylvania. “Each of these variants contributes a relatively small amount to the risk of developing MS and no single variant is abnormal, per se, but people with MS have on average more of them than people without MS.”
“The focus is on gene variants that put people at risk for MS, not variants that modulate the course of the disease. Their effort is particularly important in providing clues to prevent this disease. It's a very nice body of work and represents a huge effort to collect biological data from very large populations. It sets the stage with the new benchmark in understanding the genetics of MS.”
“Although this large study explains about half the MS heritability, there are likely epigenetic factors also contributing to the risk of developing MS,” Dr. Bar-Or continued. “There is also so much more to be understood in terms of the functional consequences of these variants.”
“These results are important because they provide credence for many prior neuroimmunological studies that show a role of both the adaptive and innate immune systems, and specific immune cell types in MS pathogenesis,” said Jiwon Oh, MD, PhD, staff neurologist at St. Michael's Hospital, scientist at the Keenan Research Centre of the Li Ka Shing Knowledge Institute, and assistant professor of neurology at the University of Toronto. “Understanding the relevant cell types involved with the development of MS helps guide our future research.”
Dr. De Jager disclosed no competing interests.