OBJECTIVE: To perform a 1-stage meta-analysis of genome-wide association studies (GWAS) of multiple sclerosis (MS) susceptibility and to explore functional consequences of new susceptibility loci. METHODS: We synthesized 7 MS GWAS. Each data set was imputed using HapMap phase II, and a per single nucleotide polymorphism (SNP) meta-analysis was performed across the 7 data sets. We explored RNA expression data using a quantitative trait analysis in peripheral blood mononuclear cells (PBMCs) of 228 subjects with demyelinating disease. RESULTS: We meta-analyzed 2,529,394 unique SNPs in 5,545 cases and 12,153 controls. We identified 3 novel susceptibility alleles: rs170934(T) at 3p24.1 (odds ratio [OR], 1.17; p = 1.6 × 10(-8)) near EOMES, rs2150702(G) in the second intron of MLANA on chromosome 9p24.1 (OR, 1.16; p = 3.3 × 10(-8)), and rs6718520(A) in an intergenic region on chromosome 2p21, with THADA as the nearest flanking gene (OR, 1.17; p = 3.4 × 10(-8)). The 3 new loci do not have a strong cis effect on RNA expression in PBMCs. Ten other susceptibility loci had a suggestive p < 1 × 10(-6) , some of these loci have evidence of association in other inflammatory diseases (ie, IL12B, TAGAP, PLEK, and ZMIZ1). INTERPRETATION: We have performed a meta-analysis of GWAS in MS that more than doubles the size of previous gene discovery efforts and highlights 3 novel MS susceptibility loci. These and additional loci with suggestive evidence of association are excellent candidates for further investigations to refine and validate their role in the genetic architecture of MS.
OBJECTIVE: To perform a 1-stage meta-analysis of genome-wide association studies (GWAS) of multiple sclerosis (MS) susceptibility and to explore functional consequences of new susceptibility loci. METHODS: We synthesized 7 MS GWAS. Each data set was imputed using HapMap phase II, and a per single nucleotide polymorphism (SNP) meta-analysis was performed across the 7 data sets. We explored RNA expression data using a quantitative trait analysis in peripheral blood mononuclear cells (PBMCs) of 228 subjects with demyelinating disease. RESULTS: We meta-analyzed 2,529,394 unique SNPs in 5,545 cases and 12,153 controls. We identified 3 novel susceptibility alleles: rs170934(T) at 3p24.1 (odds ratio [OR], 1.17; p = 1.6 × 10(-8)) near EOMES, rs2150702(G) in the second intron of MLANA on chromosome 9p24.1 (OR, 1.16; p = 3.3 × 10(-8)), and rs6718520(A) in an intergenic region on chromosome 2p21, with THADA as the nearest flanking gene (OR, 1.17; p = 3.4 × 10(-8)). The 3 new loci do not have a strong cis effect on RNA expression in PBMCs. Ten other susceptibility loci had a suggestive p < 1 × 10(-6) , some of these loci have evidence of association in other inflammatory diseases (ie, IL12B, TAGAP, PLEK, and ZMIZ1). INTERPRETATION: We have performed a meta-analysis of GWAS in MS that more than doubles the size of previous gene discovery efforts and highlights 3 novel MS susceptibility loci. These and additional loci with suggestive evidence of association are excellent candidates for further investigations to refine and validate their role in the genetic architecture of MS.
Authors: Philip L De Jager; Lori B Chibnik; Jing Cui; Joachim Reischl; Stephan Lehr; K Claire Simon; Cristin Aubin; David Bauer; Jürgen F Heubach; Rupert Sandbrink; Michaela Tyblova; Petra Lelkova; Eva Havrdova; Christoph Pohl; Dana Horakova; Alberto Ascherio; David A Hafler; Elizabeth W Karlson Journal: Lancet Neurol Date: 2009-10-29 Impact factor: 44.182
Authors: Corinna F Brereton; Caroline E Sutton; Stephen J Lalor; Ed C Lavelle; Kingston H G Mills Journal: J Immunol Date: 2009-07-01 Impact factor: 5.422
Authors: Philip L De Jager; Xiaoming Jia; Joanne Wang; Paul I W de Bakker; Linda Ottoboni; Neelum T Aggarwal; Laura Piccio; Soumya Raychaudhuri; Dong Tran; Cristin Aubin; Rebeccah Briskin; Susan Romano; Sergio E Baranzini; Jacob L McCauley; Margaret A Pericak-Vance; Jonathan L Haines; Rachel A Gibson; Yvonne Naeglin; Bernard Uitdehaag; Paul M Matthews; Ludwig Kappos; Chris Polman; Wendy L McArdle; David P Strachan; Denis Evans; Anne H Cross; Mark J Daly; Alastair Compston; Stephen J Sawcer; Howard L Weiner; Stephen L Hauser; David A Hafler; Jorge R Oksenberg Journal: Nat Genet Date: 2009-06-14 Impact factor: 38.330
Authors: Jeanette Erdmann; Anika Grosshennig; Peter S Braund; Inke R König; Christian Hengstenberg; Alistair S Hall; Patrick Linsel-Nitschke; Sekar Kathiresan; Ben Wright; David-Alexandre Trégouët; Francois Cambien; Petra Bruse; Zouhair Aherrahrou; Arnika K Wagner; Klaus Stark; Stephen M Schwartz; Veikko Salomaa; Roberto Elosua; Olle Melander; Benjamin F Voight; Christopher J O'Donnell; Leena Peltonen; David S Siscovick; David Altshuler; Piera Angelica Merlini; Flora Peyvandi; Luisa Bernardinelli; Diego Ardissino; Arne Schillert; Stefan Blankenberg; Tanja Zeller; Philipp Wild; Daniel F Schwarz; Laurence Tiret; Claire Perret; Stefan Schreiber; Nour Eddine El Mokhtari; Arne Schäfer; Winfried März; Wilfried Renner; Peter Bugert; Harald Klüter; Jürgen Schrezenmeir; Diana Rubin; Stephen G Ball; Anthony J Balmforth; H-Erich Wichmann; Thomas Meitinger; Marcus Fischer; Christa Meisinger; Jens Baumert; Annette Peters; Willem H Ouwehand; Panos Deloukas; John R Thompson; Andreas Ziegler; Nilesh J Samani; Heribert Schunkert Journal: Nat Genet Date: 2009-02-08 Impact factor: 38.330
Authors: Sekar Kathiresan; Benjamin F Voight; Shaun Purcell; Kiran Musunuru; Diego Ardissino; Pier M Mannucci; Sonia Anand; James C Engert; Nilesh J Samani; Heribert Schunkert; Jeanette Erdmann; Muredach P Reilly; Daniel J Rader; Thomas Morgan; John A Spertus; Monika Stoll; Domenico Girelli; Pascal P McKeown; Chris C Patterson; David S Siscovick; Christopher J O'Donnell; Roberto Elosua; Leena Peltonen; Veikko Salomaa; Stephen M Schwartz; Olle Melander; David Altshuler; Diego Ardissino; Pier Angelica Merlini; Carlo Berzuini; Luisa Bernardinelli; Flora Peyvandi; Marco Tubaro; Patrizia Celli; Maurizio Ferrario; Raffaela Fetiveau; Nicola Marziliano; Giorgio Casari; Michele Galli; Flavio Ribichini; Marco Rossi; Francesco Bernardi; Pietro Zonzin; Alberto Piazza; Pier M Mannucci; Stephen M Schwartz; David S Siscovick; Jean Yee; Yechiel Friedlander; Roberto Elosua; Jaume Marrugat; Gavin Lucas; Isaac Subirana; Joan Sala; Rafael Ramos; Sekar Kathiresan; James B Meigs; Gordon Williams; David M Nathan; Calum A MacRae; Christopher J O'Donnell; Veikko Salomaa; Aki S Havulinna; Leena Peltonen; Olle Melander; Goran Berglund; Benjamin F Voight; Sekar Kathiresan; Joel N Hirschhorn; Rosanna Asselta; Stefano Duga; Marta Spreafico; Kiran Musunuru; Mark J Daly; Shaun Purcell; Benjamin F Voight; Shaun Purcell; James Nemesh; Joshua M Korn; Steven A McCarroll; Stephen M Schwartz; Jean Yee; Sekar Kathiresan; Gavin Lucas; Isaac Subirana; Roberto Elosua; Aarti Surti; Candace Guiducci; Lauren Gianniny; Daniel Mirel; Melissa Parkin; Noel Burtt; Stacey B Gabriel; Nilesh J Samani; John R Thompson; Peter S Braund; Benjamin J Wright; Anthony J Balmforth; Stephen G Ball; Alistair S Hall; Heribert Schunkert; Jeanette Erdmann; Patrick Linsel-Nitschke; Wolfgang Lieb; Andreas Ziegler; Inke König; Christian Hengstenberg; Marcus Fischer; Klaus Stark; Anika Grosshennig; Michael Preuss; H-Erich Wichmann; Stefan Schreiber; Heribert Schunkert; Nilesh J Samani; Jeanette Erdmann; Willem Ouwehand; Christian Hengstenberg; Panos Deloukas; Michael Scholz; Francois Cambien; Muredach P Reilly; Mingyao Li; Zhen Chen; Robert Wilensky; William Matthai; Atif Qasim; Hakon H Hakonarson; Joe Devaney; Mary-Susan Burnett; Augusto D Pichard; Kenneth M Kent; Lowell Satler; Joseph M Lindsay; Ron Waksman; Christopher W Knouff; Dawn M Waterworth; Max C Walker; Vincent Mooser; Stephen E Epstein; Daniel J Rader; Thomas Scheffold; Klaus Berger; Monika Stoll; Andreas Huge; Domenico Girelli; Nicola Martinelli; Oliviero Olivieri; Roberto Corrocher; Thomas Morgan; John A Spertus; Pascal McKeown; Chris C Patterson; Heribert Schunkert; Erdmann Erdmann; Patrick Linsel-Nitschke; Wolfgang Lieb; Andreas Ziegler; Inke R König; Christian Hengstenberg; Marcus Fischer; Klaus Stark; Anika Grosshennig; Michael Preuss; H-Erich Wichmann; Stefan Schreiber; Hilma Hólm; Gudmar Thorleifsson; Unnur Thorsteinsdottir; Kari Stefansson; James C Engert; Ron Do; Changchun Xie; Sonia Anand; Sekar Kathiresan; Diego Ardissino; Pier M Mannucci; David Siscovick; Christopher J O'Donnell; Nilesh J Samani; Olle Melander; Roberto Elosua; Leena Peltonen; Veikko Salomaa; Stephen M Schwartz; David Altshuler Journal: Nat Genet Date: 2009-02-08 Impact factor: 38.330
Authors: Alessandro Didonna; Noriko Isobe; Stacy J Caillier; Kathy H Li; Alma L Burlingame; Stephen L Hauser; Sergio E Baranzini; Nikolaos A Patsopoulos; Jorge R Oksenberg Journal: Hum Mol Genet Date: 2015-10-03 Impact factor: 6.150
Authors: Jean Shin; Celine Bourdon; Manon Bernard; Michael D Wilson; Eva Reischl; Melanie Waldenberger; Barbara Ruggeri; Gunter Schumann; Sylvane Desrivieres; Alexander Leemans; Michal Abrahamowicz; Gabriel Leonard; Louis Richer; Luigi Bouchard; Daniel Gaudet; Tomas Paus; Zdenka Pausova Journal: Hum Mol Genet Date: 2015-07-28 Impact factor: 6.150
Authors: A Gyllenberg; F Piehl; L Alfredsson; J Hillert; I L Bomfim; L Padyukov; M Orho-Melander; E Lindholm; M Landin-Olsson; Å Lernmark; T Olsson; I Kockum Journal: Genes Immun Date: 2014-01-16 Impact factor: 2.676
Authors: Hanne F Harbo; Noriko Isobe; Pål Berg-Hansen; Steffan D Bos; Stacy J Caillier; Marte W Gustavsen; Inger-Lise Mero; Elisabeth Gulowsen Celius; Stephen L Hauser; Jorge R Oksenberg; Pierre-Antoine Gourraud Journal: Mult Scler Date: 2013-10-07 Impact factor: 6.312
Authors: Daniel C Factor; Anna M Barbeau; Kevin C Allan; Lucille R Hu; Mayur Madhavan; An T Hoang; Kathryn E A Hazel; Parker A Hall; Sagar Nisraiyya; Fadi J Najm; Tyler E Miller; Zachary S Nevin; Robert T Karl; Bruna R Lima; Yanwei Song; Alexandra G Sibert; Gursimran K Dhillon; Christina Volsko; Cynthia F Bartels; Drew J Adams; Ranjan Dutta; Michael D Gallagher; William Phu; Alexey Kozlenkov; Stella Dracheva; Peter C Scacheri; Paul J Tesar; Olivia Corradin Journal: Cell Date: 2020-04-03 Impact factor: 41.582