TY - JOUR

T1 - Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk

AU - International Multiple Sclerosis Genetics Consortium. Electronic address: chris.cotsapas@yale.edu

AU - Sellebjerg, Finn Thorup

AU - Ullum, Henrik

AU - Werge, Thomas

N1 - Copyright © 2018 The Author. Published by Elsevier Inc. All rights reserved.

PY - 2018/11/29

Y1 - 2018/11/29

N2 - 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.

AB - 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.

U2 - 10.1016/j.cell.2018.09.049

DO - 10.1016/j.cell.2018.09.049

M3 - Journal article

C2 - 30343897

VL - 175

SP - 1679-1687.e7

JO - Cell

JF - Cell

SN - 0092-8674

IS - 6

ER -