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

Mitja Mitrovič,Nikolaos A. Patsopoulos,Ashley Beecham,Theresa Dankowski,An Goris,Bénédicte Dubois,Marie B. D’hooghe,Robin Lemmens,Philip Van Damme,Helle Bach Søndergaard,Finn Sellebjerg,Per Soelberg Sørensen,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 Q. Hintzen,Cornelia M. van Duijn,Charlotte E. Teunissen,Steffan Daniël 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 Jelčić,Roland Martin,Mireia Sospedra,Masashi Ban,Clive Hawkins,Pirro G. Hysi,Seema Kalra,Fredrik Karpe,Jyoti Khadake,Geneviève Lachance,Matt J. Neville,Adam Santaniello,Stacy J. Caillier,Peter A. Calabresi,Bruce A. C. 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 Bang Oturai,Jacob L. McCauley,Stephen Sawcer,Jorge R. Oksenberg,Philip L. De Jager,Ingrid Kockum,David A. Hafler,Chris Cotsapas

Biology

Linkage disequilibrium

Heritability

2018

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.

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“Low-Frequency and Rare-Coding Variation Contributes to Multiple Sclerosis Risk” is a paper by Mitja Mitrovič Nikolaos A. Patsopoulos Ashley Beecham Theresa Dankowski An Goris Bénédicte Dubois Marie B. D’hooghe Robin Lemmens Philip Van Damme Helle Bach Søndergaard Finn Sellebjerg Per Soelberg Sørensen 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 Q. Hintzen Cornelia M. van Duijn Charlotte E. Teunissen Steffan Daniël 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 Jelčić Roland Martin Mireia Sospedra Masashi Ban Clive Hawkins Pirro G. Hysi Seema Kalra Fredrik Karpe Jyoti Khadake Geneviève Lachance Matt J. Neville Adam Santaniello Stacy J. Caillier Peter A. Calabresi Bruce A. C. 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 Bang Oturai Jacob L. McCauley Stephen Sawcer Jorge R. Oksenberg Philip L. De Jager Ingrid Kockum David A. Hafler Chris Cotsapas published in 2018. It has an Open Access status of “hybrid”. You can read and download a PDF Full Text of this paper here.