Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci

Nikolaos A. Patsopoulos, Bayer Pharma MS Genetics Working Group, Steering Committees of Studies Evaluating IFNβ‐1b and a CCR1‐Antagonist, ANZgene, GeneMSA, International Multiple Sclerosis Genetics Consortium, Federica Esposito, Joachim Reischl, Stephan Lehr, David Bauer, Jürgen Heubach, Rupert Sandbrink, Christoph Pohl, Gilles Edan, Ludwig Kappos, David Miller, Javier Montalbán, Chris H. Polman, Mark S. Freedman, Hans Peter HartungBarry G.W. Arnason, Giancarlo Comi, Stuart Cook, Massimo Filippi, Douglas S. Goodin, Douglas Jeffery, Paul O'Connor, George C. Ebers, Dawn Langdon, Anthony T. Reder, Anthony Traboulsee, Frauke Zipp, Sebastian Schimrigk, Jan Hillert, Melanie Bahlo, David R. Booth, Simon Broadley, Matthew A. Brown, Brian L. Browning, Sharon R. Browning, Helmut Butzkueven, William M. Carroll, Caron Chapman, Simon J. Foote, Lyn Griffiths, Allan G. Kermode, Trevor J. Kilpatrick, Jeanette Lechner-Scott, Mark Marriott, Deborah Mason, Pablo Moscato, Robert N. Heard, Michael P. Pender, Victoria M. Perreau, Devindri Perera, Justin P. Rubio, Rodney J. Scott, Mark Slee, Jim Stankovich, Graeme J. Stewart, Bruce V. Taylor, Niall Tubridy, Ernest Willoughby, James Wiley, Paul Matthews, Filippo M. Boneschi, Alastair Compston, Jonathan Haines, Stephen L. Hauser, Jacob McCauley, Adrian Ivinson, Jorge R. Oksenberg, Margaret Pericak-Vance, Stephen J. Sawcer, Philip L. De Jager, David A. Hafler, Paul I.W. de Bakker

Research output: Contribution to journalReview articlepeer-review

285 Citations (Scopus)


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, rs2150702G in the second intron of MLANA on chromosome 9p24.1 (OR, 1.16; p = 3.3 × 10-8), and rs6718520A 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.

Original languageEnglish
Pages (from-to)897-912
Number of pages16
JournalAnnals of Neurology
Issue number6
Publication statusPublished - 21 Dec 2011
Externally publishedYes


  • Multiple sclerosis
  • genetics
  • genome
  • pathway analysis


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