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

Ashley H Beecham, Nikolaos A Patsopoulos, Dionysia K Xifara, Mary F Davis, Anu Kemppinen, Chris Cotsapas, Tejas S Shah, Chris Spencer, David R Booth, An Goris, Annette Oturai, Janna Saarela, Bertrand Fontaine, Bernhard Hemmer, Claes Martin, Frauke Zipp, Sandra D'Alfonso, Filippo Martinelli-Boneschi, Bruce V Taylor, Hanne F HarboIngrid Kockum, Jan Hillert, Tomas Olsson, Maria Ban, Jorge R Oksenberg, Rogier Hintzen, Lisa F Barcellos, Ines Barroso, Jenefer M Blackwell, Elvira Bramon, Matthew A Brown, Juan Pablo Casas, Aiden Corvin, Audrey Duncanson, Janusz Jankowski, Hugh S Markus, Christopher G Mathew, Colin NA Palmer, Robert Plomin, Anna Rautanen, Richard C Trembath, Ananth C Viswanathan, Nicholas W Wood, Eleni Giannoulatou, Richard D Pearson, Zhan Su, Damjan Vukcevic, Rhian Gwilliam, Suzannah J Bumpstead, Serge Dronov, Matthew Gillman, Emma Gray, Naomi Hammond, Alagurevathi Jayakumar, Owen T McCann, Jennifer Liddle, Simon C Potter, Radhi Ravindrarajah, Michelle Ricketts, Matthew Waller, Paul Weston, Sara Widaa, Pamela Whittaker, Murray Barclay, Laurent Peyrin-Biroulet, Mathias Chamaillard, Jean-Frederic Colombel, Mario Cottone, Anthony Croft, Renata D'Inca, Jonas Halfvarson, Katherine Hanigan, Paul Henderson, Jean-Pierre Hugot, Amir Karban, Nicholas Alexander Kennedy, Mohammed Azam Khan, Marc Lemann, Arie Levine, Dunecan C O Massey, Monica Milla, Grant W Montgomery, Sok Meng Evelyn Ng, Ioannis Oikonomou, Harald Peeters, Deborah Denise Proctor, Jean-Francois Rahier, Rebecca Roberts, Paul Rutgeerts, Frank Seibold, Laura Stronati, Kirstin M Taylor, Leif Torkvist, Gerd Achim Kullak-Ublick, Johan Van Limbergen, Andre Van Gossum, Morten H Vatn, Hu Zhang, Wei Zhang, Jane M Andrews, Peter A Bampton, Timothy Florin, Richard Blair Gearry, Krupa Krishnaprasad, Ian Lawrance, Gillian Mahy, Graham Radford-Smith, Lisa A Simms, Leila Amininijad, Isabelle Cleynen, Olivier Dewit, Denis Franchimont, Michel Georges, Debby Laukens, Emilie Theatre, Severine Vermeire, Guy Aumais, Leonard Baidoo, Arthur M Barrie III, Karen Beck, Edmond-Jean Bernard, David G Binion, Alain Bitton, Steve R Brant, Judy H Cho, Albert Cohen, Kenneth Croitoru, Mark J Daly, Lisa W Datta, Colette Deslandres, Richard H Duerr, Debra Dutridge, John Ferguson, Joann Fultz, Philippe Goyette, Gordon R Greenberg, Talin Haritunians, Gilles Jobin, Seymour Katz, Raymond G Lahaie, Dermot P McGovern, Linda Nelson, Kaida Ning, Pierre Pare, Miguel D Regueiro, John D Rioux, Elizabeth Ruggiero, L Philip Schumm, Marc Schwartz, Regan Scott, Yashoda Sharma, Mark S Silverberg, Denise Spears, A Hillary Steinhart, Joanne M Stempak, Jason M Swoger, Constantina Tsagarelis, Clarence Zhang, Hongyu Zhao, Cristina Agliardi, Lars Alfredsson, Mehdi Alizadeh, Carl Anderson, Robert Andrews, Helle Bach Sondergaard, Amie Baker, Gavin Band, Sergio E Baranzini, Nadia Barizzone, Jeffrey Barrett, Celine Bellenguez, Laura Bergamaschi, Luisa Bernardinelli, Achim Berthele, Viola Biberacher, Thomas M C Binder, Hannah Blackburn, Izaura L Bomfim, Paola Brambilla, Simon Broadley, Bruno Brochet, Lou Brundin, Dorothea Buck, Helmut Butzkueven, Stacy J Caillier, William Camu, Wassila Carpentier, Paola Cavalla, Elisabeth G Celius, Irene Coman, Giancarlo Comi, Lucia Corrado, Leentje Cosemans, Isabelle Cournu-Rebeix, Bruce A C Cree, Daniele Cusi, Vincent Damotte, Gilles Defer, Silvia R Delgado, Panos Deloukas, Alessia Di Sapio, Alexander T Dilthey, Peter Donnelly, Benedicte Dubios, Martin Duddy, Sarah Edkins, Irina Elovaara, Federica Esposito, Nikos Evangelou, Barnaby Fiddes, Judith Field, Andre Franke, Colin Freeman, Irene Y 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, Sarah E Hunt, Maja Jagodic, Ilijas Jelcic, Angela Jochim, Brian Ross Kendall, Allan Kermode, Trevor J Kilpatrick, Keijo Koivisto, Ioanna Konidari, Thomas Korn, Helena C Kronsbein, Cordelia Langford, Malin Larsson, Mark G Lathrop, Christine Lebrun-Frenay, Jeannette Lechner-Scott, Michelle H Lee, Maurizio A Leone, Virpi Leppa, Giuseppe Liberatore, Benedicte A Lie, Christina M Lill, Magdalena Linden, Jenny Link, Felix Luessi, Jan Lycke, Fabio Macciardi, Satu Mannisto, Clara P 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, Sian E Price, Hong Quach, Mauri I Reunanen, Wim Robberecht, Neil P Robertson, Mariaemma Rodegher, David Rog, Marco Salvetti, Nathalie C Schnetz-Boutaud, Finn Sellebjerg, Rebecca C Selter, Catherine Schaefer, Sandip Shaunak, Ling Shen, Simon Shields, Volken Siffrin, Mark Slee, Per Soelberg Sorensen, Melissa Sorosina, Mireia Sospedra, Anne Spurkland, Amy Strange, Emilie Sundqvist, Vincent N Thijs, John Thorpe, Anna Ticca, Pentti Tienari, Cornelia M van Duijn, Elizabeth M Visser, Steve Vucic, Helga Westerlind, James Wiley, Alastair Wilkins, James F Wilson, Juliane Winkelmann, John Zajicek, Eva Zindler, Jonathan L Haines, Margaret A Pericak-Vance, Adrian J Ivinson, Graeme Stewart, David Hafler, Stephen L Hauser, Alastair Compston, Gil McVean, Philip L De Jager, Stephen J Sawcer, Jacob L McCauley

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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 - 1360
Number of pages8
JournalNature Genetics
Volume45
Issue number11
DOIs
Publication statusPublished - 2013

Cite this

Beecham, A. H., Patsopoulos, N. A., Xifara, D. K., Davis, M. F., Kemppinen, A., Cotsapas, C., Shah, T. S., Spencer, C., Booth, D. R., Goris, A., Oturai, A., Saarela, J., Fontaine, B., Hemmer, B., Martin, C., Zipp, F., D'Alfonso, S., Martinelli-Boneschi, F., Taylor, B. V., ... McCauley, J. L. (2013). Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nature Genetics, 45(11), 1353 - 1360. https://doi.org/10.1038/ng.2770