Centers and Institutes
Published November 21, 2013 | Version v1
Journal article Open

Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects

Creators

  • 1. Harvard University
  • 2. University of California, Berkeley
  • 3. Erasmus MC
  • 4. Kaiser Permanente
  • 5. Children's Hospital Oakland Research Institute
  • 6. University of California San Francisco
  • 7. University of Chicago
  • 8. University of California at San Francisco
  • 9. Karolinska Institutet
  • 10. University of Tasmania
  • 11. University of Cambridge
  • 12. Yale University
  • 13. Frederick National Laboratory for Cancer Research

Description

The major histocompatibility complex (MHC) region is strongly associated with multiple sclerosis (MS) susceptibility. HLA-DRB1*15:01 has the strongest effect, and several other alleles have been reported at different levels of validation. Using SNP data from genome-wide studies, we imputed and tested classical alleles and amino acid polymorphisms in 8 classical human leukocyte antigen (HLA) genes in 5,091 cases and 9,595 controls. We identified 11 statistically independent effects overall: 6 HLA-DRB1 and one DPB1 alleles in class II, one HLA-A and two B alleles in class I, and one signal in a region spanning from MICB to LST1. This genomic segment does not contain any HLA class I or II genes and provides robust evidence for the involvement of a non-HLA risk allele within the MHC. Interestingly, this region contains the TNF gene, the cognate ligand of the well-validated TNFRSF1A MS susceptibility gene. The classical HLA effects can be explained to some extent by polymorphic amino acid positions in the peptide-binding grooves. This study dissects the independent effects in the MHC, a critical region for MS susceptibility that harbors multiple risk alleles.

Files

journal.pgen.1003926.pdf

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Additional details

Identifiers

DOI
10.1371/journal.pgen.1003926
Other
oai:uchicago.tind.io:10755

Funding

National Multiple Sclerosis Society
Postdoctoral Fellowship
Unknown funder
R01NS049477
Unknown funder
R01NS026799
National Institute of Neurological Disorders and Stroke
R01NS049510
National Institute of Neurological Disorders and Stroke
R01NS0495103
National Institute of Allergy and Infectious Diseases
R01AI076544
Dutch MS Research foundation
Bibbi and Niels Jensens Foundation
The Swedish Brain Foundation and Swedish research council
Stockholm County Council
562183
Swedish Council for Working life and Social Research
Knut and Alice Wallenbergs foundation
MS research Australia
John T. Reid Charitable Trusts
Trish MS Research Foundation and the Australian Research Council
Linkage Projects Scheme
National Institute for Health and Care Research
Frederick National Laboratory for Cancer Research
HHSN261200800001E
National Institutes of Health
Intramural Research Program
Frederick National Lab
National MS Society
Harry Weaver neuroscience scholar
Netherlands Organization for Scientific Research
VIDI Award

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Medicine
Center(s) or Institute(s)
Institute for Genomics and Systems Biology