• Open Access

A second major histocompatibility complex susceptibility locus for multiple sclerosis

Authors

  • Tai Wai Yeo MSc,

    1. Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom
    Search for more papers by this author
    • T.W.Y. and P.L.D. contributed equally to this work.

  • Philip L. De Jager PhD,

    1. Department of Neurology, Center for Neurologic Diseases, Brigham and Women's Hospital, Boston
    2. Harvard Medical School, Boston
    3. Program in Medical and Population Genetics, The Broad Institute at the Massachusetts Institute of Technology and Harvard University, Cambridge, MA
    Search for more papers by this author
    • T.W.Y. and P.L.D. contributed equally to this work.

  • Simon G. Gregory PhD,

    1. Duke University Medical Center, Center for Human Genetics, Durham, NC
    Search for more papers by this author
  • Lisa F. Barcellos PhD,

    1. Department of Neurology, School of Medicine, University of California San Francisco, San Francisco
    2. Division of Epidemiology, School of Public Health, University of California at Berkeley, Berkeley, CA
    Search for more papers by this author
  • Amie Walton BSc,

    1. Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom
    Search for more papers by this author
  • An Goris PhD,

    1. Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom
    Search for more papers by this author
  • Chiara Fenoglio PhD,

    1. Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom
    2. Department of Neurological Sciences, Dino Ferrari Center, University of Milan, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
    Search for more papers by this author
  • Maria Ban PhD,

    1. Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom
    Search for more papers by this author
  • Craig J. Taylor PhD,

    1. Tissue Typing Laboratory, Addenbrooke's Hospital, United Kingdom
    Search for more papers by this author
  • Reyna S. Goodman BSc,

    1. Tissue Typing Laboratory, Addenbrooke's Hospital, United Kingdom
    Search for more papers by this author
  • Emily Walsh PhD,

    1. Program in Medical and Population Genetics, The Broad Institute at the Massachusetts Institute of Technology and Harvard University, Cambridge, MA
    Search for more papers by this author
  • Cara S. Wolfish BSc,

    1. Department of Neurology, Center for Neurologic Diseases, Brigham and Women's Hospital, Boston
    2. Program in Medical and Population Genetics, The Broad Institute at the Massachusetts Institute of Technology and Harvard University, Cambridge, MA
    Search for more papers by this author
  • Roger Horton MSc,

    1. Wellcome Trust Sanger Institute, Genome Campus, Hinxton, United Kingdom
    Search for more papers by this author
  • James Traherne PhD,

    1. Department of Pathology, Immunology Division, University of Cambridge, Cambridge, United Kingdom
    Search for more papers by this author
  • Stephan Beck PhD,

    1. Wellcome Trust Sanger Institute, Genome Campus, Hinxton, United Kingdom
    Search for more papers by this author
  • John Trowsdale PhD,

    1. Department of Pathology, Immunology Division, University of Cambridge, Cambridge, United Kingdom
    Search for more papers by this author
  • Stacy J. Caillier BSc,

    1. Department of Neurology, School of Medicine, University of California San Francisco, San Francisco
    Search for more papers by this author
  • Adrian J. Ivinson PhD,

    1. Harvard Medical School, Boston
    2. Harvard Center for Neurodegeneration and Repair, Boston, MA
    Search for more papers by this author
  • Todd Green BSc,

    1. Program in Medical and Population Genetics, The Broad Institute at the Massachusetts Institute of Technology and Harvard University, Cambridge, MA
    2. The Center for Genome Research, Massachusetts General Hospital, Boston, MA
    Search for more papers by this author
  • Susan Pobywajlo MPH,

    1. Department of Neurology, Center for Neurologic Diseases, Brigham and Women's Hospital, Boston
    2. Program in Medical and Population Genetics, The Broad Institute at the Massachusetts Institute of Technology and Harvard University, Cambridge, MA
    Search for more papers by this author
  • Eric S. Lander PhD,

    1. Program in Medical and Population Genetics, The Broad Institute at the Massachusetts Institute of Technology and Harvard University, Cambridge, MA
    Search for more papers by this author
  • Margaret A. Pericak-Vance PhD,

    1. Duke University Medical Center, Center for Human Genetics, Durham, NC
    Search for more papers by this author
  • Jonathan L. Haines PhD,

    1. Center for Human Genetics Research, Vanderbilt University Medical Center, Nashville, TN
    Search for more papers by this author
  • Mark J. Daly PhD,

    1. Program in Medical and Population Genetics, The Broad Institute at the Massachusetts Institute of Technology and Harvard University, Cambridge, MA
    2. The Center for Genome Research, Massachusetts General Hospital, Boston, MA
    Search for more papers by this author
  • Jorge R. Oksenberg PhD,

    1. Department of Neurology, School of Medicine, University of California San Francisco, San Francisco
    2. Institute for Human Genetics, School of Medicine, University of California San Francisco, San Francisco, CA
    Search for more papers by this author
  • Stephen L. Hauser MD,

    1. Department of Neurology, School of Medicine, University of California San Francisco, San Francisco
    2. Institute for Human Genetics, School of Medicine, University of California San Francisco, San Francisco, CA
    Search for more papers by this author
  • Alastair Compston PhD,

    1. Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom
    Search for more papers by this author
  • David A. Hafler MD,

    1. Department of Neurology, Center for Neurologic Diseases, Brigham and Women's Hospital, Boston
    2. Harvard Medical School, Boston
    3. Program in Medical and Population Genetics, The Broad Institute at the Massachusetts Institute of Technology and Harvard University, Cambridge, MA
    Search for more papers by this author
  • John D. Rioux PhD,

    1. Department of Neurology, Center for Neurologic Diseases, Brigham and Women's Hospital, Boston
    2. Harvard Medical School, Boston
    3. Program in Medical and Population Genetics, The Broad Institute at the Massachusetts Institute of Technology and Harvard University, Cambridge, MA
    4. Montréal Heart Institute and Université de Montréal, Montréal, Québec, Canada
    Search for more papers by this author
  • Stephen Sawcer PhD

    Corresponding author
    1. Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom
    • University of Cambridge, Department of Clinical Neuroscience, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, United Kingdom
    Search for more papers by this author

Abstract

Objective

Variation in the major histocompatibility complex (MHC) on chromosome 6p21 is known to influence susceptibility to multiple sclerosis with the strongest effect originating from the HLA-DRB1 gene in the class II region. The possibility that other genes in the MHC independently influence susceptibility to multiple sclerosis has been suggested but remains unconfirmed.

Methods

Using a combination of microsatellite, single nucleotide polymorphism, and human leukocyte antigen (HLA) typing, we screened the MHC in trio families looking for evidence of residual association above and beyond that attributable to the established DRB1*1501 risk haplotype. We then refined this analysis by extending the genotyping of classical HLA loci into independent cases and control subjects.

Results

Screening confirmed the presence of residual association and suggested that this was maximal in the region of the HLA-C gene. Extending analysis of the classical loci confirmed that this residual association is partly due to allelic heterogeneity at the HLA-DRB1 locus, but also reflects an independent effect from the HLA-C gene. Specifically, the HLA-C*05 allele, or a variant in tight linkage disequilibrium with it, appears to exert a protective effect (p = 3.3 × 10−5).

Interpretation

Variation in the HLA-C gene influences susceptibility to multiple sclerosis independently of any effect attributable to the nearby HLA-DRB1 gene. Ann Neurol 2007

Ancillary