Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility

Nikolaos A. Patsopoulos, Sergio E. Baranzini, Adam Santaniello, Parisa Shoostari, Chris Cotsapas, Garrett Wong, Ashley H. Beecham, Tojo James, Joseph Replogle, Ioannis S. Vlachos, Cristin McCabe, Tune H. Pers, Aaron Brandes, Charles White, Brendan Keenan, Maria Cimpean, Phoebe Winn, Ioannis Pavlos Panteliadis, Allison Robbins, Till F.M. AndlauerOnigiusz Zarzycki, Bénédicte Dubois, An Goris, Helle Bach Søndergaard, Finn Sellebjerg, Per Soelberg Sorensen, Henrik Ullum, Lise Wegner Thørner, Janna Saarela, Isabelle Cournu-Rebeix, Vincent Damotte, Bertrand Fontaine, Lena Guillot-Noel, Mark Lathrop, Sandra Vukusic, Achim Berthele, Viola Pongratz, Dorothea Buck, Christiane Gasperi, Christiane Graetz, Verena Grummel, Bernhard Hemmer, Muni Hoshi, Benjamin Knier, Thomas Korn, Christina M. Lill, Felix Luessi, Mark Mühlau, Frauke Zipp, Efthimios Dardiotis, Cristina Agliardi, Antonio Amoroso, Nadia Barizzone, Maria D. Benedetti, Luisa Bernardinelli, Paola Cavalla, Ferdinando Clarelli, Giancarlo Comi, Daniele Cusi, Federica Esposito, Laura Ferrè, Daniela Galimberti, Clara Guaschino, Maurizio A. Leone, Vittorio Martinelli, Lucia Moiola, Marco Salvetti, Melissa Sorosina, Domizia Vecchio, Andrea Zauli, Silvia Santoro, Nicasio Mancini, Miriam Zuccalà, Julia Mescheriakova, Cornelia Van Duijn, Steffan D. Bos, Elisabeth G. Celius, Anne Spurkland, Manuel Comabella, Xavier Montalban, Lars Alfredsson, Izaura L. Bomfim, David Gomez-Cabrero, Jan Hillert, Maja Jagodic, Magdalena Lindén, Fredrik Piehl, Ilijas Jelčić, Roland Martin, Mirela Sospedra, Amie Baker, Maria Ban, Clive Hawkins, Pirro Hysi, Seema Kalra, Fredrik Karpe, Jyoti Khadake, Genevieve Lachance, Paul Molyneux, Matthew Neville, John Thorpe, Elizabeth Bradshaw, Stacy J. Caillier, Peter Calabresi, Bruce A.C. Cree, Anne Cross, Mary Davis, Paul W.I. De Bakker, Silvia Delgado, Marieme Dembele, Keith Edwards, Kate Fitzgerald, Irene Y. Frohlich, Pierre Antoine Gourraud, Jonathan L. Haines, Hakon Hakonarson, Dorlan Kimbrough, Noriko Isobe, Ioanna Konidari, Ellen Lathi, Michelle H. Lee, Taibo Li, David An, Andrew Zimmer, Lohith Madireddy, Clara P. Manrique, Mitja Mitrovic, Marta Olah, Ellis Patrick, Margaret A. Pericak-Vance, Laura Piccio, Cathy Schaefer, Howard Weiner, Kasper Lage, Alastair Compston, David Hafler, Hanne F. Harbo, Stephen L. Hauser, Graeme Stewart, Sandra D’Alfonso, Georgios Hadjigeorgiou, Bruce Taylor, Lisa F. Barcellos, David Booth, Rogier Hintzen, Ingrid Kockum, Filippo Martinelli-Boneschi, Jacob L. McCauley, Jorge R. Oksenberg, Annette Oturai, Stephen Sawcer, Adrian J. Ivinson, Tomas Olsson, Philip L. De Jager

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141 Scopus citations

Abstract

We analyzed genetic data of 47,429 multiple sclerosis (MS) and 68,374 control subjects and established a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 variants within the extended MHC. We used an ensemble of methods to prioritize 551 putative susceptibility genes that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we observed enrichment for MS genes in these brain-resident immune cells, suggesting that these may have a role in targeting an autoimmune process to the central nervous system, although MS is most likely initially triggered by perturbation of peripheral immune responses.
Original languageEnglish (US)
JournalScience
Volume365
Issue number6460
DOIs
StatePublished - Sep 27 2019
Externally publishedYes

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