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

2018; Cell Press; Volume: 175; Issue: 6 Linguagem: Inglês

10.1016/j.cell.2018.09.049

1097-4172

Mitja Mitrovič, Nikolaos A. Patsopoulos, Ashley Beecham, Theresa Dankowski, An Goris, Bénédicte Dubois, Marie D’hooghe, Robin Lemmens, Philip Van Damme, Helle Bach Søndergaard, Finn Sellebjerg, Per Soelberg Sorensen, Henrik Ullum, Lise Wegner Thørner, Thomas Werge, Janna Saarela, Isabelle Cournu‐Rebeix, Vincent Damotte, Bertrand Fontaine, Léna Guillot‐Noël, Mark Lathrop, Sandra Vukusik, Pierre‐Antoine Gourraud, Till F. M. Andlauer, Viola Pongratz, Dorothea Buck, Christiane Gasperi, Antonios Bayas, Christoph Heesen, Tania Kümpfel, Ralf A. Linker, Friedemann Paul, Martin Stangel, Björn Tackenberg, Florian Then Bergh, Clemens Warnke, Heinz Wiendl, Brigitte Wildemann, Uwe K. Zettl, Ulf Ziemann, Hayrettin Tumani, Ralf Gold, Verena Grummel, Bernhard Hemmer, Benjamin Knier, Christina M. Lill, Felix Luessi, Efthimios Dardiotis, Cristina Agliardi, Nadia Barizzone, Elisabetta Mascia, Luisa Bernardinelli, Giancarlo Comi, Daniele Cusi, Federica Esposito, Laura Ferrè, Cristoforo Comi, Daniela Galimberti, Maurizio Leone, Melissa Sorosina, Julia Mescheriakova, Rogier Hintzen, Cornelia M. van Duijn, Charlotte E. Teunissen, Steffan D. Bos, Kjell‐Morten Myhr, Elisabeth Gulowsen Celius, Benedicte A. Lie, Anne Spurkland, Manuel Comabella, Xavier Montalbán, Lars Alfredsson, Pernilla Stridh, Jan Hillert, Maja Jagodic, Fredrik Piehl, Ilijas Jelc̆ić, Roland Martinꝉ, Mireia Sospedra, Maria Ban, Clive Hawkins, Pirro G. Hysi, Seema Kalra, Fredrik Karpe, Jyoti Khadake, Geneviève Lachance, Matthew Neville, Adam Santaniello, Stacy J. Caillier, Peter A. Calabresi, Bruce Cree, Anne H. Cross, Mary F. Davis, Jonathan L. Haines, Paul I. W. de Bakker, Silvia Delgado, Marieme Dembele, Keith R. Edwards, Kathryn C. Fitzgerald, Hákon Hákonarson, Ioanna Konidari, Ellen Lathi, Clara P. Manrique, Margaret A. Pericak‐Vance, Laura Piccio, Cathy Schaefer, Cristin McCabe, Howard L. Weiner, Jacqueline I. Goldstein, Tomas Olsson, Georgios M. Hadjigeorgiou, Bruce Taylor, Lotti Tajouri, Jac Charlesworth, David R. Booth, Hanne F. Harbo, Adrian J. Ivinson, Stephen L. Hauser, Alastair Compston, Graeme J. Stewart, Frauke Zipp, Lisa F. Barcellos, Sergio E. Baranzini, Filippo Martinelli Boneschi, Sandra D’Alfonso, Andreas Ziegler, Annette Oturai, Jacob L. McCauley, Stephen Sawcer, Jorge R. Oksenberg, Philip L. De Jager, Ingrid Kockum, D Hafler, Chris Cotsapas,

vaccines and immunoinformatics approaches

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.