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A systems biology approach uncovers cell-specific gene regulatory effects of genetic associations in multiple sclerosis.

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International Multiple Sclerosis Genetics Consortium 


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.



Gene Expression Regulation, Genes, Regulator, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Multiple Sclerosis, Polymorphism, Single Nucleotide, Systems Biology

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Nat Commun

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Springer Science and Business Media LLC
Medical Research Council (G1100125)
Multiple Sclerosis Society (None)
National Institutes of Health (NIH) (via University of California) (6399sc)
National Institute of Neurological Disorders and Stroke (R01NS099240)
European Commission Horizon 2020 (H2020) Societal Challenges (733161)