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

International Multiple Sclerosis Genetics Consortium (IMSGC), Ashley H Beecham, Nikolaos A Patsopoulos, Dionysia K Xifara, Mary F Davis, Anu Kemppinen, Chris Cotsapas, Tejas S 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 F Harbo, Ingrid Kockum, Jan Hillert, Tomas Olsson, Maria Ban, Jorge R Oksenberg, Rogier Hintzen, Lisa F Barcellos, Wellcome Trust Case Control Consortium 2 (WTCCC2), International IBD Genetics Consortium (IIBDGC), Cristina Agliardi, Lars Alfredsson, Mehdi Alizadeh, Carl Anderson, Robert Andrews, Helle Bach Søndergaard, Amie Baker, Gavin Band, Sergio E Baranzini, Nadia Barizzone, Jeffrey Barrett, Céline 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, Irène 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, Bénédicte Dubois, 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 Jelčić, Angela Jochim, 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 H Lee, Maurizio A Leone, Virpi Leppä, Giuseppe Liberatore, Benedicte A Lie, Christina M Lill, Magdalena Lindén, Jenny Link, Felix Luessi, Jan Lycke, Fabio Macciardi, Satu Männistö, 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, Siân E Price, Hong Quach, Mauri 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, 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 M 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 Stewart, David Hafler, Stephen L Hauser, Alastair Compston, Gil McVean, Philip De Jager, Stephen J Sawcer, Jacob L McCauley, International Multiple Sclerosis Genetics Consortium (IMSGC), Ashley H Beecham, Nikolaos A Patsopoulos, Dionysia K Xifara, Mary F Davis, Anu Kemppinen, Chris Cotsapas, Tejas S 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 F Harbo, Ingrid Kockum, Jan Hillert, Tomas Olsson, Maria Ban, Jorge R Oksenberg, Rogier Hintzen, Lisa F Barcellos, Wellcome Trust Case Control Consortium 2 (WTCCC2), International IBD Genetics Consortium (IIBDGC), Cristina Agliardi, Lars Alfredsson, Mehdi Alizadeh, Carl Anderson, Robert Andrews, Helle Bach Søndergaard, Amie Baker, Gavin Band, Sergio E Baranzini, Nadia Barizzone, Jeffrey Barrett, Céline 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, Irène 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, Bénédicte Dubois, 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 Jelčić, Angela Jochim, 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 H Lee, Maurizio A Leone, Virpi Leppä, Giuseppe Liberatore, Benedicte A Lie, Christina M Lill, Magdalena Lindén, Jenny Link, Felix Luessi, Jan Lycke, Fabio Macciardi, Satu Männistö, 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, Siân E Price, Hong Quach, Mauri 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, 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 M 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 Stewart, David Hafler, Stephen L Hauser, Alastair Compston, Gil McVean, Philip De Jager, Stephen J Sawcer, Jacob L McCauley

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.

Conflict of interest statement

The authors have no competing financial interests

Figures

Figure 1. Discovery phase results
Figure 1. Discovery phase results
Primary association analysis of 161,311 autosomal variants in the discovery phase (based on 14,498 cases and 24,091 healthy controls). The outer most track shows the numbered autosomal chromosomes. The second track indicates the gene closest to the most associated SNP meeting all replication criteria. Previously identified associations are indicated in grey. The third track indicates the physical position of the 184 fine-mapping intervals (green). The inner most track indicates −log(p) (two-sided) for each SNP (scaled from 0-12 which truncates the signal in several regions, see Supplementary Table 1). Additionally, contour lines are given at the a priori discovery(−log(p) = 4) and genome-wide significance (-log(p) = 7.3) thresholds. Orange indicates -log(p) ≥ 4 and < 7.3, while red indicates −log(p) ≥ 7.3. Details of the full discovery phase results can be found in ImmunoBase.
Figure 2. Bayesian fine-mapping within primary regions…
Figure 2. Bayesian fine-mapping within primary regions of association
a) Summary of the extent of fine-mapping across 66 regions in 9,617 healthy controls from the UK, showing the the physical extent of, the number of variants, and the number of genes spanned by the posterior 90% and 50% credible sets. b) Detail of fine-mapping in region of TNFSF14. Above the x-axis indicates the Bayes Factor summarizing evidence for association for the SNPs prior to conditioning (blue markers) while below the x-axis indicates the Bayes Factor after conditioning on the lead SNP (rs1077667). Mb=Megabases.

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