MS, it’s in the Genes

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A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis. International Multiple Sclerosis Genetics Consortium. Nat Commun. 2019:10(1):2236.

Madireddy LPatsopoulos NACotsapas CBos SDBeecham AMcCauley JKim KJia XSantaniello ACaillier SJAndlauer TFMBarcellos LFBerge TBernardinelli LMartinelli-Boneschi FBooth DRBriggs FCelius EGComabella MComi GCree BACD’Alfonso SDedham KDuquette PEfthimios DEsposito FFontaine BGasperi CGoris ADubois BGourraud PAHadjigeorgiou GHaines JHawkins CHemmer BHintzen RHorakova DIsobe NKalra SKira JIKhalil MKockum ILill CMLincoln MRLuessi FMartin ROturai APalotie APericak-Vance MAHenry RSaarela JIvinson AOlsson TTaylor BVStewart GJHarbo HFCompston AHauser SLHafler DAZipp FDe Jager PSawcer SOksenberg JRBaranzini SE.

Genome-wide association studies (GWAS) have identified more than 50,000 unique associations with common human traits. While this represents a substantial step forward, establishing the biology underlying these associations has proven extremely difficult. Even determining which cell types and which particular gene(s) are relevant continues to be a challenge. Here, we conduct a cell-specific pathway analysis of the latest GWAS in multiple sclerosis (MS), which had analyzed a total of 47,351 cases and 68,284 healthy controls and found more than 200 non-MHC genome-wide associations. Our analysis identifies pan immune cell as well as cell-specific susceptibility genes in T cells, B cells and monocytes. Finally, genotype-level data from 2,370 patients and 412 controls is used to compute intra-individual and cell-specific susceptibility pathways that offer a biological interpretation of the individual genetic risk to MS. This approach could be adopted in any other complex trait for which genome-wide data is available.

We have spent 20-30 years or more studying the genetics of MS and have got nowhere fast in terms of finding new treatments. The genetic studies have confirmed what was known long before millions were pumped into Genome projects that a major contributer to MS risk are the transplantation antigens that determine how we recognise ourselves and invaders/Infections. However, it is amazing that we know the human genome structure and what tooks millions and years of research can now be do for a few quid and a couple of weeks. The genome centres are a machine and they are sequencing most of the World’s organisms, so we now know the genome sequence of the slug and lettuce (OK I made this up and don’t really know what they have done, but you get the point)

MS has been mapped and to date they know the locations of about 233 genes that are associated with MS and a further 416 variants potentially associated with MS . These are in the most part perfectly normal gene variants that have come together maybe to help fight infection, but in doing so increase your risk of MS or other conditions.

.Genetics of MS. BioRxiv jul 13 2017 http://dx.doi.org/10.1101/143933

In this study they aim to look at cell risk pathways

The looked at each gene and looked at what regulates them

They determined the genes were relevant to T cells, B cells and monocytes. There was more of an absence of CNS genes suggesting that immunity was the central issue

In summary, this analysis underscores the notion that total MS risk is not only carried by accumulation of risk alleles, but also by how the genes and proteins affected by those polymorphisms interact within each cell type. 

The study did a gene sequence of CD4, CD8 and CD14+ monocytes..so I wonder that they missed?

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