Mapping of multiple susceptibility variants within the MHC region for 7 immune-mediated diseases

The human MHC represents the strongest susceptibility locus for autoimmune diseases. However, the identification of the true predisposing gene(s) has been handicapped by the strong linkage disequilibrium across the region. Furthermore, most studies to date have been limited to the examination of a s...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2009-11, Vol.106 (44), p.18680-18685
Main Authors: Rioux, John D, Goyette, Philippe, Vyse, Timothy J, Hammarström, Lennart, Fernando, Michelle M.A, Green, Todd, De Jager, Philip L, Foisy, Sylvain, Wang, Joanne, de Bakker, Paul I.W, Leslie, Stephen, McVean, Gilean, Padyukov, Leonid, Alfredsson, Lars, Annese, Vito, Hafler, David A, Pan-Hammarström, Qiang, Matell, Ritva, Sawcer, Stephen J, Compston, Alastair D, Cree, Bruce A.C, Mirel, Daniel B, Daly, Mark J, Behrens, Tim W, Klareskog, Lars, Gregersen, Peter K, Oksenberg, Jorge R, Hauser, Stephen L
Format: Article
Language:English
Subjects:
Alleles
Autoimmune diseases
Biological Sciences
Chromosome Mapping
Databases, Genetic
Deoxyribonucleic acid
Disease susceptibility
DNA
Genes
Genetic loci
Genetic Predisposition to Disease
Genetic Testing
Genomics
Genotype & phenotype
Haplotypes
HLA antigens
HLA Antigens - genetics
Human genetics
Humans
Immune System Diseases - genetics
Major Histocompatibility Complex - genetics
Major Histocompatibility Complex - immunology
Medical genetics
Medicin och hälsovetenskap
Polymorphism, Single Nucleotide - genetics
Polymorphism, Single Nucleotide - immunology
Regression analysis
Systemic lupus erythematosus
Ulcerative colitis
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Summary:The human MHC represents the strongest susceptibility locus for autoimmune diseases. However, the identification of the true predisposing gene(s) has been handicapped by the strong linkage disequilibrium across the region. Furthermore, most studies to date have been limited to the examination of a subset of the HLA and non-HLA genes with a marker density and sample size insufficient for mapping all independent association signals. We genotyped a panel of 1,472 SNPs to capture the common genomic variation across the 3.44 megabase (Mb) classic MHC region in 10,576 DNA samples derived from patients with systemic lupus erythematosus, Crohn's disease, ulcerative colitis, rheumatoid arthritis, myasthenia gravis, selective IgA deficiency, multiple sclerosis, and appropriate control samples. We identified the primary association signals for each disease and performed conditional regression to identify independent secondary signals. The data demonstrate that MHC associations with autoimmune diseases result from complex, multilocus effects that span the entire region.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.0909307106