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

Journal article
Authors 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
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
Published in Nature genetics
Volume 45
Issue 11
Pages 1353-60
ISSN 1546-1718
Publication year 2013
Published at Institute of Neuroscience and Physiology, Department of Clinical Neuroscience and Rehabilitation
Pages 1353-60
Language en
Links dx.doi.org/10.1038/ng.2770
www.ncbi.nlm.nih.gov/entrez/query.f...
Keywords Chromosome Mapping, European Continental Ancestry Group, genetics, Gene Frequency, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Multiple Sclerosis, genetics, immunology, Polymorphism, Single Nucleotide
Subject categories Neurosciences

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.

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