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 common, complex neurological disease, where almost 20% of risk heritability can be attributed to common genetic variants, including >230 identified by genome-wide association studies (Patsopoulos et al., 2017). Multiple strands of evidence suggest that the majority of the remaining heritability is also due to the additive effects of individual variants, rather than epistatic interactions between these variants, or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that as much as 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, which highlight a key role for regulatory T cell homeostasis and regulation, IFNg biology and NFκB signaling in MS pathogenesis. 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
Multiple Sclerosis Society (861)
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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/