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

2019; American Association for the Advancement of Science; Volume: 365; Issue: 6460 Linguagem: Inglês

10.1126/science.aav7188

1095-9203

Nikolaos A. Patsopoulos, Sergio E. Baranzini, Adam Santaniello, Parisa Shoostari, Chris Cotsapas, Garrett Wong, Ashley Beecham, Tojo James, Joseph M. Replogle, Ioannis S. Vlachos, Cristin McCabe, Tune H. Pers, Aaron Brandes, Charles C. White, Brendan T Keenan, Maria Cimpean, Phoebe A. Winn, Ioannis-Pavlos Panteliadis, Allison Robbins, Till F. M. Andlauer, Onigiusz 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, Léna Guillot‐Noël, 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 Donata Benedetti, Luisa Bernardinelli, Paola Cavalla, Ferdinando Clarelli, Gıancarlo Comı, Daniele Cusi, Federica Esposito, Laura Ferrè, Daniela Galimberti, Clara Guaschino, Maurizio Leone, Vittorio Martinelli, Lucia Moiola, Marco Salvetti, Melissa Sorosina, Domizia Vecchio, Andrea Zauli, Silvia Santoro, Nicasio Mancini, Miriam Zuccalà, Julia Mescheriakova, Cornelia M. van Duijn, Steffan D. Bos, Elisabeth Gulowsen Celius, Anne Spurkland, Manuel Comabella, Xavier Montalbán, Lars Alfredsson, Izaura Lima Bomfim, David Gómez-Cabrero, Jan Hillert, Maja Jagodic, Magdalena Lindén, Fredrik Piehl, Ilijas Jelčić, Roland Martinꝉ, Mirela Sospedra, Amie Baker, Maria Ban, Clive Hawkins, Pirro G. Hysi, Seema Kalra, Fredrik Karpe, Jyoti Khadake, Geneviève Lachance, Paul Molyneux, Matthew Neville, John Thorpe, Elizabeth M. Bradshaw, Stacy J. Caillier, Peter A. Calabresi, Bruce Cree, Anne Cross, Mary F. Davis, Paul W. I. de Bakker, Silvia Delgado, Marieme Dembele, Keith R. Edwards, Kate Fitzgerald, Irene Y. Frohlich, Pierre‐Antoine Gourraud, Jonathan L. Haines, Hákon Hákonarson, Dorlan Kimbrough, Noriko Isobe, Ioanna Konidari, Ellen Lathi, Michelle Lee, Taibo Li, David An, Andrew Zimmer, Lohith Madireddy, Clara P. Manrique, Mitja Mitrovič, Marta Olah, Ellis Patrick, Margaret A. Pericak‐Vance, Laura Piccio, Cathy Schaefer, Howard L. Weiner, Kasper Lage, Alastair Compston, D Hafler, Hanne F. Harbo, Stephen L. Hauser, Graeme J. Stewart, Sandra D’Alfonso, Georgios Hadjigeorgiou, Bruce Taylor, Lisa F. Barcellos, David R. 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,

Atherosclerosis and Cardiovascular Diseases

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.