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The Genomic map of multiple sclerosis: over 45 novel susceptibility variants and translation of genetics to biology

Prior Multiple Sclerosis susceptibility maps are incomplete and have limited annotation.

With over 45 additional susceptibility variants, we now present a comprehensive view of MS genetic susceptibility and provide a detailed map of proximal biological effects that identify new molecular pathways involved in the transition from health to MS.

Objectives: To identify MS susceptibility associations outside of the validated MS susceptibility loci and uncover new biological processes that drive the onset of MS.

Methods: A genome-wide discovery study of ~8 million SNPs in each of 14,802 multiple sclerosis (MS) cases and 26,703 controls was followed by a deep replication study of >80,000 SNPs in over 19,217 MS cases and 17,842 controls. The 4,716 SNPs with p< 0.05 in the discovery study are included. Functional evaluations of the results are conducted using DEPICT for pathway analysis, as well as analyses of immune cell RNA expression data from ImmVar and reference epigenomic maps from the Epigenome Roadmap and ENCODE projects.

Results: At the end of the replication study, over 45 new susceptibility variants are identified with 10 MHC and >150 non-MHC SNPs meet a threshold of genome-wide significance (p-value < 5 x 10^-8). Importantly, the depth of the replication effort identifies multiple, independent effects in many regions that were previously unresolvable: for example, theEVI5 region has up to four independent susceptibility variants.

Uncovering this multiplicity of associations in certain regions is critical to our efforts to model the biological consequences of MS susceptibility variants and to develop predictive algorithms. With >150 independent susceptibility effects and a high resolution analysis of each locus in hand, we have created a reference map of MS susceptibility and now turn to the task of understanding the biology of MS susceptibility.

With the new MS map and multiple approaches to epigenomic annotation and functional evaluations, it is clear that non-TH1/Th17/Treg processes are important in the onset of MS. Myeloid, NK and CD8 cells are now implicated, and B and dendritic cell functions are suggested to be altered by MS variants. Leveraging RNA data from 405 subjects with purified CD4 T and monocytes, 29% of MS variants with RNA effects are unique to monocytes, which is now the same as for T cells (29%). Pathway analyses highlight an enrichment of NK and B cell activation molecular networks in addition to T cell effects.


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