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

Ashley Beecham, Nikolaos Patsopoulos, Dionysia Xifara, Mary Davis, Anu Kemppinen, Chris Costapas, Tejas Shah, Chris Spencer, David Booth, An Goris, Annette Oturai, Janna Saarela, Bertrand Fontaine, Bernhard Hemmer, Claes Martin, Frauke Zipp, Sandra D'Alfonso, Filippo Martinelli-Boneschi, Bruce Taylor, Hanne HarboIngrid Kockum, Jan Hillert, Tomas Olsson, Maria Ban, Jorge Oksenberg, Rogier Hintzen, Lisa Barcellos, Cristina Agliardi, Lars Alfredsson, Mehdi Alizadeh, Carl Anderson, Robert Andrews, Helle Søndergaard, Amie Baker, Gavin Band, Sergio Baranzini, Nadia Barizzone, Jeffrey Barrett, Céline Bellenguez, Laura Bergamaschi, Luisa Bernardinelli, Achim Berthele, Viola Biberacher, Thomas Binder, Hannah Blackburn, Izaura Bomfin, Paola Brambilla, Simon Broadley, Bruno Brochet, Lou Brundin, Dorothea Buck, Helmut Butzkueven, Stacy Caillier, William Camu, Wassila Carpentier, P Cavalla, Elisabeth Celius, Irène Coman, Giancarlo Comi, 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, Andre Franke, Colin Freeman, Irene Frohlich, Daniela Galimberti, Christian Gieger, Pierre-Antoine Gourraud, Christiane Graetz, Andrew Graham, Verena Grummel, Clara Guaschino, Athena Hadjixenofontos, Hakon Hakonarson, Christopher Halfpenny, Gillian Hall, Per Hall, Anders Hamsten, James Harley, Timothy Harrower, Clive Hawkins, Garrett Hellenthal, Charles Hillier, Jeremy Hobart, Muni Hoshi, Brian Kendall, Allan Kermode, Trevor Kilpatrick, Keijo Koivisto, Ioanna Konidari, Thomas Korn, Helena Kronsbein, Cordelia Langford, Malin Larsson, Mark Lathrop, Christine Lebrun-Frenay, Jeannette Lechner-Scott, Michelle Lee, Maurizio Leone, Virpi Leppä, Giuseppe Liberatore, Benedicte Lie, Christina Lill, Magdalena Lindén, Jenny Link, Felix Luessi, Jan Lycke, Fabio Macciardi, Satu Männistö, Clara Manrique, Roland Martin, 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 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 Sorensen, Melissa Sorosina, Mireia Sospedra, Anne Spurkland, Amy Strange, Emilie Sundqvist, Vincent Thijs, John Thorpe, Anna Ticca, Pentti Tienari, Cornelia van Duijn, Elizabeth Visser, Steve Vucic, Helga Westerlind, James Wiley, Alastair Wilkins, James Wilson, Juliane Winkelmann, John Zajicek, Eva Zindler, Jonathan Haines, Margaret Pericak-Vance, Adrian Ivinson, Graeme Stewart, David Hafler, Stephen Hauser, Alastair Compston, Gil McVean, Philip De Jager, Stephen Sawcer, Jacob McCauley

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    744 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)1353-1362
    Number of pages10
    JournalNature Genetics
    Volume45
    Issue number11
    DOIs
    Publication statusPublished - Nov 2013

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