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Low frequency and rare coding variation contributes to multiple sclerosis risk

By International Multiple Sclerosis Genetics Consortium, Mitja Mitrovic, Nikolaos Patsopoulos, Ashley Beecham, Theresa Dankowski, An Goris, Benedicte Dubois, Marie-Beatrice Dhooghe, Robin Lemmens, Philip Van Damme, Kate Fitzgerald, Helle Bach Sondergaard, Finn Sellebjerg, Per Soelberg Sorensen, Henrik Ullum, Lise Wegner Thoerner, Thomas M Werge, Janna Saarela, Isabelle Cournu-Rebeix, Vincent Damotte, Bertrand Fontaine, Lena Guillot-Noel, Mark Lathrop, Sandra Vukusik, Pierre-Antoine Gourraud, Till Andlauer, Viola Pongratz, Dorothea Buck, Christiane Gasperi, Christiane Graetz, Antonios Bayas, Christoph Heesen, Tania Kumpfel, Ralf Linker, Friedemann Paul, Martin Stangel, Bjorn Tackenberg, Florian Then Bergh, Clemens Warnke, Heinz Wiendl, Brigitte Wildemann, Uwe Zettl, Ulf Ziemann, Hayrettin Tumani, Ralf Gold, Verena Grummel, Bernhard Hemmer, Benjamin Knier, Christina Lill, Efthimios Luessi, Efthimios Dardiotis, Cristina Agliardi, Nadia Barizzone, Elisabetta Mascia, Luisa Bernardinelli, Giancarlo Comi, Daniele Cusi, Federica Esposito, Laura Ferre, Cristoforo Comi, Daniela Galimberti, Maurizio Leone, Melissa Sorosina, Julia Y Mescheriakova, Rogier Hintzen, Cornelia Van Duijn, Steffan Bos, Kjell-Morten Myhr, Elisabeth Gulowsen Celius, Benedicte Lie, Anne Spurkland, Manuel Comabella, Xavier Montalban, Lars Alfredsson, Pernilla Stridh, Jan Hillert, Maja Jagodic, Fredrik Piehl, Ilijas Jelcic, Roland Martin, Mireia Sospedra, Maria Ban, Clive Hawkins, Pirro Hysi, Seema Kalra, Fredrik Karpe, Jyoti Khadake, Genevieve Lachance, Matthew Neville, Adam Santaniello, Stacy Caillier, Peter Calabresi, Bruce Cree, Anne Cross, Mary Davis, Jonathan Haines, Paul de Bakker, Silvia Delgado, Marieme Dembele, Keith Edwards, Hakon Hakonarson, Ioanna Konidari, Ellen Lathi, Clara Manrique, Margaret Pericak-Vance, Laura Piccio, Cathy Schaefer, Cristin McCabe, Howard Weiner, Thomas Olsson, Georgios Hadjigeorgiou, Bruce Taylor, Lotti Tajoori, Jac Charlesworth, David Booth, The Australia and New Zealand Genetics Consortium, The Wellcome Trust Case Control Consortium 2, Hanne Flinstad Harbo, Adrian Ivinson, Stephen Hauser, Alastair Compston, Graeme Stewart, Frauke Zipp, Lisa Barcellos, Sergio E Baranzini, Filippo Martinelli Boneschi, Sandra D'Alfonso, Andreas Ziegler, Annette Oturai, Jacob McCauley, Stephen Sawcer, Jorge Oksenberg, Philip De Jager, Ingrid Kockum, David Hafler, Chris Cotsapas

Posted 23 Mar 2018
bioRxiv DOI: 10.1101/286617 (published DOI: 10.1016/j.cell.2018.09.049)

Multiple sclerosis is a common, complex neurological disease, where almost 20% of risk heritability can be attributed to common genetic variants, including >230 identified by genome-wide association studies (Patsopoulos et al., 2017). Multiple strands of evidence suggest that the majority of the remaining heritability is also due to the additive effects of individual variants, rather than epistatic interactions between these variants, or mutations exclusive to individual families. Here, we show in 68,379 cases and controls that as much as 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, which highlight a key role for regulatory T cell homeostasis and regulation, IFNγ biology and NFκB signaling in MS pathogenesis. 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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