Low-frequency variation in gene coding sequence explains up to 5% of multiple sclerosis risk heritability, identifying four novel genes driving MS risk independently of common-variant signals.
Case-Control (n=68,379)
Does low-frequency variation in gene coding sequence contribute to Multiple Sclerosis risk?
Low-frequency coding variants explain up to 5% of multiple sclerosis heritability and identify four novel risk genes, providing new targets for understanding MS pathobiology.
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.
Mitrovič et al. (Thu,) conducted a case-control in Multiple sclerosis (n=68,379). Low-frequency variation in gene coding sequence was evaluated on Proportion of MS risk heritability explained. Low-frequency variation in gene coding sequence explains up to 5% of multiple sclerosis risk heritability, identifying four novel genes driving MS risk independently of common-variant signals.