Low frequency and rare coding variation contributes to multiple sclerosis risk
Authors:   International Multiple Sclerosis Genetics Consortium, Mitrovic Mitja , Patsopoulos Nikolaos , Beecham Ashley , Dankowski Theresa , Goris An , Dubois Benedicte , Dhooghe Marie-Beatrice , Lemmens Robin , Van Damme Philip , Fitzgerald Kate , Bach Sondergaard Helle , Sellebjerg Finn , Sorensen Per Soelberg , Ullum Henrik , Wegner Thoerner Lise , Werge Thomas , Saarela Janna , Cournu-Rebeix Isabelle , Damotte Vincent , Fontaine Bertrand , Guillot-Noel Lena , Lathrop Mark , Vukusik Sandra , Gourraud Pierre-Antoine , Andlauer Till , Pongratz Viola , Buck Dorothea , Gasperi Christiane , Graetz Christiane , Bayas Antonios , Heesen Christoph , Kumpfel Tania , Linker Ralf , Paul Friedemann , Stangel Martin , Tackenberg Bjorn , Then Bergh Florian , Warnke Clemens , Wiendl Heinz , Wildemann Brigitte , Zettl Uwe , Ziemann Ulf , Tumani Hayrettin , Gold Ralf , Grummel Verena , Hemmer Bernhard , Knier Benjamin , Lill Christina , Luessi Efthimios , Dardiotis Efthimios , Agliardi Cristina , Barizzone Nadia , Mascia Elisabetta , Bernardinelli Luisa , Comi Giancarlo , Cusi Daniele , Esposito Federica , Ferre Laura , Comi Cristoforo , Galimberti Daniela , Leone Maurizio , Sorosina Melissa , Mescheriakova Julia Y , Hintzen Rogier , Van Duijn Cornelia , Bos Steffan , Myhr Kjell-Morten , Celius Elisabeth Gulowsen , Lie Benedicte , Spurkland Anne , Comabella Manuel , Montalban Xavier , Alfredsson Lars , Stridh Pernilla , Hillert Jan , Jagodic Maja , Piehl Fredrik , Jelcic Ilijas , Martin Roland , Sospedra Mireia , Ban Maria , Hawkins Clive , Hysi Pirro , Kalra Seema , Karpe Fredrik , Khadake Jyoti , Lachance Genevieve , Neville Matthew , Santaniello Adam , Caillier Stacy , Calabresi Peter , Cree Bruce , Cross Anne , Davis Mary , Haines Jonathan , de Bakker Paul , Delgado Silvia , Dembele Marieme , Edwards Keith , Hakonarson Hakon , Konidari Ioanna , Lathi Ellen , Manrique Clara , Pericak-Vance Margaret , Piccio Laura , Schaefer Cathy , McCabe Cristin , Weiner Howard , Olsson Thomas , Hadjigeorgiou Georgios , Taylor Bruce , Tajoori Lotti , Charlesworth Jac , Booth David ,   The Australia and New Zealand Genetics Consortium,   The Wellcome Trust Case Control Consortium 2, Harbo Hanne Flinstad , Ivinson Adrian , Hauser Stephen , Compston Alastair , Stewart Graeme , Zipp Frauke , Barcellos Lisa , Baranzini Sergio , Martinelli Boneschi Filippo , D'Alfonso Sandra , Ziegler Andreas , Oturai Annette , McCauley Jacob , Sawcer Stephen , Oksenberg Jorge , De Jager Philip , Kockum Ingrid , Hafler David , Cotsapas Chris 
Published: March 2018

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.