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Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis

2013; Nature Portfolio; Volume: 45; Issue: 11 Linguagem: Inglês

10.1038/ng.2770

1546-1718

Ashley Beecham, Nikolaos A. Patsopoulos, Dionysia K. Xifara, Mary F. Davis, Anu Kemppinen, Chris Cotsapas, Tejas Shah, Chris C. A. Spencer, David J. Booth, An Goris, Annette Oturai, Janna Saarela, Bertrand Fontaine, Bernhard Hemmer, Claes Martin, Frauke Zipp, Sandra D’Alfonso, Filippo Martinelli Boneschi, Bruce Taylor, Hanne F. Harbo, Ingrid Kockum, Jan Hillert, Tomas Olsson, Maria Ban, Jorge R. Oksenberg, Rogier Hintzen, Lisa F. Barcellos, Cristina Agliardi, Lars Alfredsson, Mehdi Alizadeh, Carl A. Anderson, Robert Andrews, Helle Bach Søndergaard, Amie Baker, Gavin Band, Sergio E. Baranzini, Nadia Barizzone, Jeffrey C. Barrett, Céline Bellenguez, Laura Bergamaschi, Luisa Bernardinelli, Achim Berthele, Viola Biberacher, Thomas M.C. Binder, Hannah Blackburn, Izaura Lima Bomfim, Paola Brambilla, Simon Broadley, Bruno Brochet, Lou Brundin, Dorothea Buck, Helmut Butzkueven, Stacy J. Caillier, William Camu, Wassila Carpentier, Paola Cavalla, Elisabeth Gulowsen Celius, Irène Coman, Gıancarlo Comı, Lucia Corrado, Leentje Cosemans, Isabelle Cournu‐Rebeix, Bruce Cree, Daniele Cusi, Vincent Damotte, Gilles Defer, Silvia Delgado, Panos Deloukas, Alessia Di Sapio, Alexander Dilthey, Peter Donnelly, Bénédicte Dubois, Martin Duddy, Sarah Edkins, Irina Elovaara, Federica Esposito, Nikos Evangelou, Barnaby Fiddes, Judith Field, André Franke, Colin Freeman, Irene Y. Frohlich, Daniela Galimberti, Christian Gieger, Pierre‐Antoine Gourraud, Christiane Graetz, Andrew Graham, Verena Grummel, Clara Guaschino, Athena Hadjixenofontos, Hákon Hákonarson, Christopher Halfpenny, Gillian Hall, Per Hall, Anders Hamsten, James Harley, Timothy Harrower, Clive Hawkins, Garrett Hellenthal, Charles Hillier, Jeremy Hobart, Muni Hoshi, Sarah Hunt, Maja Jagodic, Ilijas Jelčić, Angela Jochim, B. Kendall, Allan G. Kermode, Trevor J. Kilpatrick, Keijo Koivisto, Ioanna Konidari, Thomas Korn, Helena Kronsbein, Cordelia Langford, Malin Larsson, Mark Lathrop, Christine Lebrun‐Frénay, Jeannette Lechner‐Scott, Michelle Lee, Maurizio Leone, Virpi Leppä, Giuseppe Liberatore, Benedicte A. Lie, Christina M. Lill, Magdalena Lindén, Jenny Link, Felix Luessi, Jan Lycke, Fabìo Macciardi, Satu Männistö, Clara P. Manrique, Roland Martinꝉ, Vittorio Martinelli, Deborah Mason, Gordon Mazibrada, Cristin McCabe, Inger‐Lise Mero, Julia Mescheriakova, Loukas Moutsianas, Kjell‐Morten Myhr, Guy Nagels, Richard Nicholas, Petra Nilsson, Fredrik Piehl, Matti Pirinen, Siân Price, Hong Quach, Mauri Reunanen, Wim Robberecht, Neil P. Robertson, Mariaemma Rodegher, David Rog, Marco Salvetti, Nathalie Schnetz‐Boutaud, Finn Sellebjerg, Rebecca Selter, Catherine Schaefer, Sandip Shaunak, Ling Shen, Simon Shields, Volker Siffrin, Mark Slee, Per Soelberg Sørensen, Melissa Sorosina, Mireia Sospedra, Anne Spurkland, Amy Strange, Emilie Sundqvist, Vincent Thijs, John Thorpe, Anna Ticca, Pentti J. Tienari, Cornelia M. van Duijn, Elizabeth Visser, Steve Vucic, Helga Westerlind, James S. Wiley, Alastair Wilkins, James F. Wilson, Juliane Winkelmann, John Zajicek, Eva Zindler, Jonathan L. Haines, Margaret A Pericak‐Vance, Adrian J. Ivinson, Graeme J. Stewart, D Hafler, Stephen L. Hauser, Alastair Compston, Gil McVean, Philip L. De Jager, Stephen Sawcer, Jacob L. McCauley,

Genetic Associations and Epidemiology

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.