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Low frequency and rare coding variation contributes to multiple sclerosis risk

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Item Type:Preprint
Title:Low frequency and rare coding variation contributes to multiple sclerosis risk
Abstract: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, IFNγ 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.
Publisher:Cold Spring Harbor Laboratory Press
Article Number:286617
Date:23 March 2018
Additional Information:Friedemann Paul is a member of the International Multiple Sclerosis Genetics Consortium.
Official Publication:https://doi.org/10.1101/286617

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