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

International Multiple Sclerosis Genetics Consortium, Giancarlo Comi, Melissa Sorosina, Federica Esposito

Research output: Contribution to journalArticle

Abstract

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. Copyright © 2018 The Author. Published by Elsevier Inc. All rights reserved.
Original languageEnglish
Pages (from-to)1679-1687.e7
JournalCell
Volume175
Issue number6
DOIs
Publication statusPublished - 2018

Fingerprint

Multiple Sclerosis
Genes
Genome-Wide Association Study
Linkage Disequilibrium
Regulatory T-Lymphocytes
Homeostasis
T-cells
Mutation

Cite this

Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk. / Consortium, International Multiple Sclerosis Genetics; Comi, Giancarlo; Sorosina, Melissa; Esposito, Federica.

In: Cell, Vol. 175, No. 6, 2018, p. 1679-1687.e7.

Research output: Contribution to journalArticle

Consortium, International Multiple Sclerosis Genetics ; Comi, Giancarlo ; Sorosina, Melissa ; Esposito, Federica. / Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk. In: Cell. 2018 ; Vol. 175, No. 6. pp. 1679-1687.e7.
@article{9a2bd2771cb347e1befabf7ab420eec2,
title = "Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk",
abstract = "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. Copyright {\circledC} 2018 The Author. Published by Elsevier Inc. All rights reserved.",
author = "Consortium, {International Multiple Sclerosis Genetics} and Giancarlo Comi and Melissa Sorosina and Federica Esposito",
year = "2018",
doi = "10.1016/j.cell.2018.09.049",
language = "English",
volume = "175",
pages = "1679--1687.e7",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "6",

}

TY - JOUR

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

AU - Consortium, International Multiple Sclerosis Genetics

AU - Comi, Giancarlo

AU - Sorosina, Melissa

AU - Esposito, Federica

PY - 2018

Y1 - 2018

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

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

U2 - 10.1016/j.cell.2018.09.049

DO - 10.1016/j.cell.2018.09.049

M3 - Article

VL - 175

SP - 1679-1687.e7

JO - Cell

JF - Cell

SN - 0092-8674

IS - 6

ER -