Low frequency and rare coding variation contributes to multiple sclerosis risk
International Multiple Sclerosis Genetics Consortium,
Philip Van Damme,
Helle Bach Sondergaard,
Per Soelberg Sorensen,
Lise Wegner Thoerner,
Florian Then Bergh,
Julia Y Mescheriakova,
Cornelia Van Duijn,
Elisabeth Gulowsen Celius,
Paul de Bakker,
The Australia and New Zealand Genetics Consortium,
The Wellcome Trust Case Control Consortium 2,
Hanne Flinstad Harbo,
Filippo Martinelli Boneschi,
Stephen J. Sawcer,
Philip De Jager,
Posted 23 Mar 2018
bioRxiv DOI: 10.1101/286617 (published DOI: 10.1016/j.cell.2018.09.049)
Posted 23 Mar 2018
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.
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