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

International Multiple Sclerosis Genetics Consortium

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.

Original languageEnglish (US)
Pages (from-to)1679-1687.e7
JournalCell
Volume175
Issue number6
DOIs
StatePublished - Nov 29 2018

Fingerprint

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

International Multiple Sclerosis Genetics Consortium (2018). Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk. Cell, 175(6), 1679-1687.e7. https://doi.org/10.1016/j.cell.2018.09.049

Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk. / International Multiple Sclerosis Genetics Consortium.

In: Cell, Vol. 175, No. 6, 29.11.2018, p. 1679-1687.e7.

Research output: Contribution to journalArticle

International Multiple Sclerosis Genetics Consortium 2018, 'Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk', Cell, vol. 175, no. 6, pp. 1679-1687.e7. https://doi.org/10.1016/j.cell.2018.09.049
International Multiple Sclerosis Genetics Consortium. Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk. Cell. 2018 Nov 29;175(6):1679-1687.e7. https://doi.org/10.1016/j.cell.2018.09.049
International Multiple Sclerosis Genetics Consortium. / Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk. In: Cell. 2018 ; Vol. 175, No. 6. pp. 1679-1687.e7.
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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.",
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