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.
Details
Title
Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects
Author
Patsopoulos, Nikolaos A. : Harvard University Barcellos, Lisa F. : University of California, Berkeley Hintzen, Rogier Q. : Erasmus MC Schaefer, Catherine : Kaiser Permanente Duijn, Cornelia M. van : Erasmus MC Noble, Janelle A. : Children's Hospital Oakland Research Institute Raj, Towfique : Harvard University IMSGC ANZgene Gourraud, Pierre-Antoine : University of California San Francisco Stranger, Barbara E. : University of Chicago Oksenberg, Jorge : University of California at San Francisco Olsson, Tomas : Karolinska Institutet Taylor, Bruce V. : University of Tasmania Sawcer, Stephen : University of Cambridge Hafler, David A. : Yale University Carrington, Mary : Frederick National Laboratory for Cancer Research Jager, Philip L. De : Harvard University
Funding Information
National Multiple Sclerosis Society, Postdoctoral Fellowship R01NS049477 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, LP0776744 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, JF2138A1 Netherlands Organization for Scientific Research, VIDI Award, 016.126.354
Publication Date
2013-11-21
Language
English
Copyright Statement
This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.