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

Int Multiple Sclerosis Genetics,; Mitrovic, Mitja; Patsopoulos, Nikoloas; Beecham, Ashley; Dankowski, Theresa; Goris, An; Dubois, Bénédicte; D'hooghe, Marie B; Lemmens, Robin; Van Damme, Philip; Bach Sondergaard, Helle; Sellebjerg, Finn; Soelberg Sorensen, Per; Ullum, Henrik; Thorner, Lise W; Werge, Thomas; Saarela, Janna; Cournu-Rebeix, Isabelle; Damotte, Vincent; Fontaine, Bertrand; Guillot-Noel, Lena; Lathrop, Mark; Vukusik, Sandra; Gourraud, Pierre-Antoine; Andlauer, Till FM; Pongratz, Viola; Buck, Dorothea; Gasperi, Christiane; Bayas, Antonios; Heesen, Christoph; Kümpfel, Tania; Linker, Ralf; Friedemann, Paul; Stangel, Martin; Tackenberg, Björn; 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, Felix; Dardiotis, Efthimios; Agliardi, Cristina; Barizzone, Nadia; Mascia, Elisabetta; Bernardinelli, Luisa; Comi, Giancarlo; Cusi, Daniele; Esposito, Federica; Ferrè, Laura; Comi, Cristoforo; Galimberti, Daniela; Leone, Maurizio A; Sorosina, Melissa; Mescheriakova, Julia; Hintzen, Rogier; van Duijn, Cornelia; Theunissen, Charlotte E; Bos, Steffan D; Myhr, Kjell-Morten; Celius, Elisabeth G; Lie, Benedicte A; 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 J; Calavresi, Peter A; Cree, Bruce AC; Cross, Anne; Davis, Mary F; Haines, Jonathan L; de Bakker, Paul IW; Delgado, Silvia; Dembele, Marieme; Edwards, Keith; Fitzgerald, Kathryn C; Hakonarson, Hakon; Konidari, Ioanna; Lathi, Ellen; Manrique, Clara P; Pericak-Vance, Margaret A; Piccio, Laura; Schaefer, Cathy; McCabe, Cristin; Weiner, Howard; Goldstein, Jacqueline; Olsson, Tomas; Hadjigeorgiou, Georgios; Taylor, Bruce; Tajouri, Lotti; Charlesworth, Jac; Booth, David R; HArbo, Hanne F; Ivinson, Adrian J; Hauser, Stephen L; Compston, Alistair; Stewart, Graeme; Zipp, Frauke; Barcellos, Lisa F; Baranzini, Sergio E; Martinelli-Boneschi, Filippo; D'Alfonso, Sandra; Ziegler, Andreas; Oturai, Annette; McCauley, Jacob L; Sawcer, Stephen J; Oksenberg, Jorge R; De Jager, Philip L; Kockum, Ingrid; Hafler, David A; Cotsapas, Chris

doi:10.1016/j.cell.2018.09.049

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

Author:

Int Multiple Sclerosis Genetics,

Mitrovic, Mitja ; Patsopoulos, Nikoloas ; Beecham, Ashley ; Dankowski, Theresa ; Goris, An ; Dubois, Bénédicte ; D'hooghe, Marie B ; Lemmens, Robin ; Van Damme, Philip ; Bach Sondergaard, Helle ; Sellebjerg, Finn ; Soelberg Sorensen, Per ; Ullum, Henrik ; Thorner, Lise W ; Werge, Thomas ; Saarela, Janna ; Cournu-Rebeix, Isabelle ; Damotte, Vincent ; Fontaine, Bertrand ; Guillot-Noel, Lena ; Lathrop, Mark ; Vukusik, Sandra ; Gourraud, Pierre-Antoine ; Andlauer, Till FM ; Pongratz, Viola ; Buck, Dorothea ; Gasperi, Christiane ; Bayas, Antonios ; Heesen, Christoph ; Kümpfel, Tania ; Linker, Ralf ; Friedemann, Paul ; Stangel, Martin ; Tackenberg, Björn ; 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, Felix ; Dardiotis, Efthimios ; Agliardi, Cristina ; Barizzone, Nadia ; Mascia, Elisabetta ; Bernardinelli, Luisa ; Comi, Giancarlo ; Cusi, Daniele ; Esposito, Federica ; Ferrè, Laura ; Comi, Cristoforo ; Galimberti, Daniela ; Leone, Maurizio A ; Sorosina, Melissa ; Mescheriakova, Julia ; Hintzen, Rogier ; van Duijn, Cornelia ; Theunissen, Charlotte E ; Bos, Steffan D ; Myhr, Kjell-Morten ; Celius, Elisabeth G ; Lie, Benedicte A ; 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 J ; Calavresi, Peter A ; Cree, Bruce AC ; Cross, Anne ; Davis, Mary F ; Haines, Jonathan L ; de Bakker, Paul IW ; Delgado, Silvia ; Dembele, Marieme ; Edwards, Keith ; Fitzgerald, Kathryn C ; Hakonarson, Hakon ; Konidari, Ioanna ; Lathi, Ellen ; Manrique, Clara P ; Pericak-Vance, Margaret A ; Piccio, Laura ; Schaefer, Cathy ; McCabe, Cristin ; Weiner, Howard ; Goldstein, Jacqueline ; Olsson, Tomas ; Hadjigeorgiou, Georgios ; Taylor, Bruce ; Tajouri, Lotti ; Charlesworth, Jac ; Booth, David R ; HArbo, Hanne F ; Ivinson, Adrian J ; Hauser, Stephen L ; Compston, Alistair ; Stewart, Graeme ; Zipp, Frauke ; Barcellos, Lisa F ; Baranzini, Sergio E ; Martinelli-Boneschi, Filippo ; D'Alfonso, Sandra ; Ziegler, Andreas ; Oturai, Annette ; McCauley, Jacob L ; Sawcer, Stephen J ; Oksenberg, Jorge R ; De Jager, Philip L ; Kockum, Ingrid ; Hafler, David A ; Cotsapas, Chris

Keywords:

Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Cell Biology, GENOME-WIDE ASSOCIATION, GENETIC RISK, VARIANTS, METAANALYSIS, REPLICATION, POPULATION, LINKAGE, Epistasis, Genetic, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Multiple Sclerosis, Mutation, Open Reading Frames, Risk Factors, International Multiple Sclerosis Genetics Consortium. Electronic address: chris.cotsapas@yale.edu, International Multiple Sclerosis Genetics Consortium, C24/16/045#53766066, 06 Biological Sciences, 11 Medical and Health Sciences, Developmental Biology, 31 Biological sciences, 32 Biomedical and clinical sciences

Abstract:

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.