Genetic roots of multiple sclerosis
This paper is open access and so for the more adventuous and people with an interest in genes, I suggest that you read the paper. If not I think the abstract and summaries say sufficient. Genes focus interest on the microglia. I would say about time. There is a clear CD4 bias in the thought process as they focused on CD4 naive T cells and from a personal point of view it is sad that the message that B cells are not a single entity has yet to filter through to some of my learned colleagues. However, that is fine, it could be a student project to look at the same data without a T cell and monocyte leaning eye.
What are the genes doing? This will take many years to work out.
Is TNFRSF14 there because it is a gene designed to keep herpes virus out of cells, so is the genetic variat associated with MS poor at keeping out EBV. There are now 233 genes to work out what they are doing and if you dont look in the right place you may miss it. It will take me along time to digest all this information, but in this there is golddust that helps to understand the biology of MS. Will it give therapies, some have been tried and failed such as blockade of interleukin 12. You will see IL12a and IL12b make the top 200 list. However blockade of IL-12 does not inhibit relapsing EAE, but it is great at stopping EAE from being induced. You are not going to try and stop MS with a drug before MS has started….OK ProfG wants to do a vitamin D, anti-EBV MS prevention trial. However this highlights knowing the gene does not give you the solution. We have known about factor VII clotting gene for many years, but people still get haemophillia. However, maybe the target for the magic bullets is just round the couner. This is the beauty of sceince. Innovation is never quick enough, but from taking centuaries to find out about DNA and its diversity, we can now you can sequence a whole genome faster than you can say Genetic susctibility.
The genetics underlying who develops multiple sclerosi s (MS) have been difficult to work out. Examining more than 47,000 cases and 68,000 controls with multiple genome-wide association studies, the International Multiple Sclerosis Genetics Consortium identified more than 200 risk loci in MS (see the Perspective by Briggs). Focusing on the best candidate genes, including a model of the major histocompatibility complex region, the authors identified statistically independent effects at the genome level. Gene expression studies detected that every major immune cell type is enriched for MS susceptibility genes and that MS risk variants are enriched in brain-resident immune cells, especially microglia. Up to 48% of the genetic contribution of MS can be explained through this analysis.
INTRODUCTION Multiple sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system (CNS) that often presents in young adults. Over the past decade, certain elements of the genetic architecture of susceptibility have gradually emerged, but most of the genetic risk for MS remained unknown.
RATIONALE Earlier versions of the MS genetic map had highlighted the role of the adaptive arm of the immune system, implicating multiple different T cell subsets. We expanded our knowledge of MS susceptibility by performing a genetic association study in MS that leveraged genotype data from 47,429 MS cases and 68,374 control subjects. We enhanced this analysis with an in-depth and comprehensive evaluation of the functional impact of the susceptibility variants that we uncovered.
RESULTS We identified 233 statistically independent associations with MS susceptibility that are genome-wide significant. The major histocompatibility complex (MHC) contains 32 of these associations, and one, the first MS locus on a sex chromosome, is found in chromosome X. The remaining 200 associations are found in the autosomal (non sex chromosome) non-MHC genome (Range of genes). Our genome-wide partitioning approach and large-scale replication effort allowed the evaluation of other variants that did not meet our strict threshold of significance, such as 416 variants that had evidence of statistical replication but did not reach the level of genome-wide statistical significance. Many of these loci are likely to be true susceptibility loci. The genome-wide and suggestive effects jointly explain ~48% of the estimated heritability for MS.
Using atlases of gene expression patterns and epigenomic features, we documented that enrichment for MS susceptibility loci was apparent in many different immune cell types and tissues, whereas there was an absence of enrichment in tissue-level brain profiles. We extended the annotation analyses by analyzing new data generated from human induced pluripotent stem cell–derived neurons as well as from purified primary human astrocytes and microglia, observing that enrichment for MS genes is seen in human microglia, the resident immune cells of the brain, but not in astrocytes or neurons. Further, we have characterized the functional consequences of many MS susceptibility variants by identifying those that influence the expression of nearby genes in immune cells or brain. Last, we applied an ensemble of methods to prioritize 551 putative MS susceptibility genes that may be the target of the MS variants that meet a threshold of genome-wide significance. This extensive list of MS susceptibility genes expands our knowledge more than twofold and highlights processes relating to the development, maturation, and terminal differentiation of B, T, natural killer, and myeloid cells that may contribute to the onset of MS. These analyses focus our attention on a number of different cells in which the function of MS variants should be further investigated.
Using reference protein-protein interaction maps, these MS genes can also be assembled into 13 communities of genes encoding proteins that interact with one another; this higher-order architecture begins to assemble groups of susceptibility variants whose functional consequences may converge on certain protein complexes that can be prioritized for further evaluation as targets for MS prevention strategies.
CONCLUSION We report a detailed genetic and genomic map of MS susceptibility, one that explains almost half of this disease’s heritability. We highlight the importance of several cells of the peripheral and brain resident immune systems—implicating both the adaptive and innate arms—in the translation of MS genetic risk into an auto-immune inflammatory process that targets the CNS and triggers a neurodegenerative cascade. In particular, the myeloid component highlights a possible role for microglia that requires further investigation, and the B cell component connects to the narrative of effective B cell–directed therapies in MS. These insights set the stage for a new generation of functional studies to uncover the sequence of molecular events that lead to disease onset. This perspective on the trajectory of disease onset will lay the foundation for developing primary prevention strategies that mitigate the risk of developing MS.