Original Article

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

  1. Nikolaos A. Patsopoulos MD, PhD1,2,3,
  2. the Bayer Pharma MS Genetics Working Group, the Steering Committees of Studies Evaluating IFNβ-1b and a CCR1-Antagonist, ANZgene Consortium, GeneMSA, International Multiple Sclerosis Genetics Consortium2,
  3. Paul I. W. de Bakker PhD2,3,4,5,*

Article first published online: 21 DEC 2011

DOI: 10.1002/ana.22609

Issue

Annals of Neurology

Annals of Neurology

Volume 70, Issue 6, pages 897–912, December 2011

Additional Information

How to Cite

Patsopoulos, N. A., the Bayer Pharma MS Genetics Working Group, the Steering Committees of Studies Evaluating IFNβ-1b and a CCR1-Antagonist, ANZgene Consortium, GeneMSA, International Multiple Sclerosis Genetics Consortium and de Bakker, P. I. W. (2011), Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci. Ann Neurol., 70: 897–912. doi: 10.1002/ana.22609

Author Information

  1. 1

    Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston, MA

  2. 2

    Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA

  3. 3

    Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA

  4. 4

    Department of Medical Genetics, Division of Biomedical Genetics, University Medical Center, Utrecht, the Netherlands

  5. 5

    Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, the Netherlands

*Program in NeuroPsychiatric Genomics, Department of Neurology, Brigham & Women's Hospital, 77 Avenue Louis Pasteur, NRB168, Boston, MA 02115

  1. †

    Full list of authors is given in the Appendix on page 910-911.

Publication History

  1. Issue published online: 21 DEC 2011
  2. Article first published online: 21 DEC 2011
  3. Accepted manuscript online: 17 AUG 2011 01:54PM EST
  4. Manuscript Accepted: 8 APR 2011
  5. Manuscript Revised: 30 MAR 2011
  6. Manuscript Received: 2 NOV 2010

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Abstract

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: rs170934T 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. ANN NEUROL 2011;70:897–912

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