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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk
Cell, Volume 175, No. 6, Year 2018
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Description
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. © 2018 The Author; In a large multi-cohort study, unexplained heritability for multiple sclerosis is detected in low-frequency coding variants that are missed by GWAS analyses, further underscoring the role of immune genes in MS pathology. © 2018 The Author
Authors & Co-Authors
Beecham, Ashley Harris
Unknown Affiliation
Dankowski, Theresa
Unknown Affiliation
Goris, An
Unknown Affiliation
Dubois, Bénédicte D.
Unknown Affiliation
D'Hooghe, Marie Béatrice
Unknown Affiliation
Lemmens, Robin
Unknown Affiliation
van Damme, Philip
Unknown Affiliation
Sellebjerg, Finn Thorup
Unknown Affiliation
Sørensen, Per Soelberg
Unknown Affiliation
Ullum, Henrik
Unknown Affiliation
Thørner, Lise Wegner
Unknown Affiliation
Werge, Thomas M.
Unknown Affiliation
Saarela, Janna
Unknown Affiliation
Fontaine, Bertrand
Unknown Affiliation
Guillot-Noël, Léna
Unknown Affiliation
Lathrop, Mark G.
Unknown Affiliation
Gourraud, Pierre Antoine F.
Unknown Affiliation
Andlauer, Till F.M.
Unknown Affiliation
Buck, Dorothea
Unknown Affiliation
Gasperi, Christiane
Unknown Affiliation
Bayas, Antonios
Unknown Affiliation
Kum̈pfel, Tania
Unknown Affiliation
Linker, Ralf Andreas
Unknown Affiliation
Paul, Friedemann
Unknown Affiliation
Stangel, Martin
Unknown Affiliation
Tackenberg, Björn
Unknown Affiliation
Then-Bergh, Florian
Unknown Affiliation
Warnke, Clemens
Unknown Affiliation
Wiendl, Heinz S.
Unknown Affiliation
Wildemann, Brigitte T.
Unknown Affiliation
Zettl, Uwe Klaus
Unknown Affiliation
Ziemann, Ulf
Unknown Affiliation
Tumani, Hayrettin T.
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Gold, Ralf
Unknown Affiliation
Hemmer, Bernhard
Unknown Affiliation
Knier, Benjamin
Unknown Affiliation
Lill, Christina M.
Unknown Affiliation
Luessi, Felix
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Dardiotis, Efthymios
Unknown Affiliation
Agliardi, Cristina
Unknown Affiliation
Bernardinelli, Luisa
Unknown Affiliation
Comi, Giancarlo C.
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Cusi, Daniele
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Comi, Cristoforo
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Hintzen, Rogier Q.
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van Duijn, Cornelia M.
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Myhr, Kjell Morten
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Celius, Elisabeth Gulowsen
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Lie, Benedicte Alexandra
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Spurkland, Anne
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Montalban, Xavier
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Alfredsson, Lars S.
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Hillert, Jan A.
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Jagodić, Maja
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Piehl, Fredrik
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Jelčić, Ilijas
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Hysi, Dr Pirro
Unknown Affiliation
Karpe, Fredrik
Unknown Affiliation
Lachance, Geneviève
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Neville, Matt J.
Unknown Affiliation
Calabresi, Peter Arthur
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Haines, Jonathan L.
Unknown Affiliation
de Bakker, Paul I.W.
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Fitzgerald, Kathryn C.
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Håkonarson, Håkon H.
Unknown Affiliation
Kunkle, Brian W.
Unknown Affiliation
Schaefer, Catherine A.
Unknown Affiliation
Olsson, Tomas P.
Unknown Affiliation
Hadjigeorgiou, Georgios M.
Unknown Affiliation
Taylor, Bruce V.M.
Unknown Affiliation
Tajouri, Lotti
Unknown Affiliation
Charlesworth, Jac C.
Unknown Affiliation
Booth, David Richmond
Unknown Affiliation
Hauser, Stephen L.
Unknown Affiliation
Zipp, Frauke
Unknown Affiliation
Barcellos, Lisa F.
Unknown Affiliation
Martinelli-Boneschi, Filippo
Unknown Affiliation
D’Alfonso, Sandra
Unknown Affiliation
Ziegler, Andreas E.
Unknown Affiliation
McCauley, Jacob L.
Unknown Affiliation
Sawcer, Stephen J.
Unknown Affiliation
Oksenberg, Jorge R.
Unknown Affiliation
de Jager, Philip Lawrence
Unknown Affiliation
Kockum, Ingrid Skelton
Unknown Affiliation
Hafler, David A.
Unknown Affiliation
Statistics
Citations: 92
Authors: 85
Identifiers
Doi:
10.1016/j.cell.2018.09.049
ISSN:
00928674
Research Areas
Genetics And Genomics
Study Design
Cohort Study
Study Approach
Quantitative