Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk.
International Multiple Sclerosis Genetics Consortium. Electronic address: firstname.lastname@example.org
International Multiple Sclerosis Genetics Consortium
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International Multiple Sclerosis Genetics Consortium. Electronic address: email@example.com, & International Multiple Sclerosis Genetics Consortium. (2018). Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk.. Cell, 175 (6), 1679-1687.e7. https://doi.org/10.1016/j.cell.2018.09.049
Multiple sclerosis is a complex neurological disease, with ∼20% of risk heritability attributable to common genetic variants, including >230 identified by genome-wide association studies. Multiple strands of evidence suggest that much of the remaining heritability is also due to additive effects of common variants rather than epistasis between these variants or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that up to 5% of this heritability is explained by low-frequency variation in gene coding sequence. We identify four novel genes driving MS risk independently of common-variant signals, highlighting key pathogenic roles for regulatory T cell homeostasis and regulation, IFNγ biology, and NFκB signaling. As low-frequency variants do not show substantial linkage disequilibrium with other variants, and as coding variants are more interpretable and experimentally tractable than non-coding variation, our discoveries constitute a rich resource for dissecting the pathobiology of MS.
International Multiple Sclerosis Genetics Consortium. Electronic address: firstname.lastname@example.org, International Multiple Sclerosis Genetics Consortium, Humans, Multiple Sclerosis, Genetic Predisposition to Disease, Risk Factors, Epistasis, Genetic, Linkage Disequilibrium, Mutation, Open Reading Frames, Female, Male, Genome-Wide Association Study
Medical Research Council (G1100125)
Multiple Sclerosis Society (None)
European Commission Horizon 2020 (H2020) Societal Challenges (733161)
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External DOI: https://doi.org/10.1016/j.cell.2018.09.049
This record's URL: https://www.repository.cam.ac.uk/handle/1810/280660
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/