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dc.contributor.authorInternational Multiple Sclerosis Genetics Consortium. Electronic address: chris.cotsapas@yale.edu
dc.contributor.authorInternational Multiple Sclerosis Genetics Consortium
dc.date.accessioned2018-09-21T15:22:50Z
dc.date.available2018-09-21T15:22:50Z
dc.date.issued2018-11-29
dc.identifier.issn0092-8674
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/280660
dc.description.abstractMultiple 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.
dc.format.mediumPrint-Electronic
dc.languageeng
dc.publisherElsevier BV
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectInternational Multiple Sclerosis Genetics Consortium. Electronic address: chris.cotsapas@yale.edu
dc.subjectInternational Multiple Sclerosis Genetics Consortium
dc.subjectHumans
dc.subjectMultiple Sclerosis
dc.subjectGenetic Predisposition to Disease
dc.subjectRisk Factors
dc.subjectEpistasis, Genetic
dc.subjectLinkage Disequilibrium
dc.subjectMutation
dc.subjectOpen Reading Frames
dc.subjectFemale
dc.subjectMale
dc.subjectGenome-Wide Association Study
dc.titleLow-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk.
dc.typeArticle
prism.endingPage1687.e7
prism.issueIdentifier6
prism.publicationDate2018
prism.publicationNameCell
prism.startingPage1679
prism.volume175
dc.identifier.doi10.17863/CAM.28026
dcterms.dateAccepted2018-09-24
rioxxterms.versionofrecord10.1016/j.cell.2018.09.049
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-11
dc.identifier.eissn1097-4172
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (G1100125)
pubs.funder-project-idMultiple Sclerosis Society (None)
pubs.funder-project-idEuropean Commission Horizon 2020 (H2020) Societal Challenges (733161)
cam.issuedOnline2018-10-18
cam.orpheus.successThu Jan 30 10:54:21 GMT 2020 - The item has an open VoR version.
rioxxterms.freetoread.startdate2100-01-01


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International