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    Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases 
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    • Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases
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    Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases

    Volume
    47
    Pagination
    1085 - 1090
    DOI
    10.1038/ng.3379
    Journal
    Nature Genetics
    Issue
    9
    ISSN
    1061-4036
    Metadata
    Show full item record
    Abstract
    © 2015 Nature America, Inc. All rights reserved. Human leukocyte antigen (HLA) genes confer substantial risk for autoimmune diseases on a log-additive scale. Here we speculated that differences in autoantigen-binding repertoires between a heterozygote's two expressed HLA variants might result in additional non-additive risk effects. We tested the non-additive disease contributions of classical HLA alleles in patients and matched controls for five common autoimmune diseases: rheumatoid arthritis (ncases = 5,337), type 1 diabetes (T1D; ncases = 5,567), psoriasis vulgaris (ncases = 3,089), idiopathic achalasia (ncases = 727) and celiac disease (ncases = 11,115). In four of the five diseases, we observed highly significant, non-additive dominance effects (rheumatoid arthritis, P = 2.5 × 10-12; T1D, P = 2.4 × 10-10; psoriasis, P = 5.9 × 10-6; celiac disease, P = 1.2 × 10-87). In three of these diseases, the non-additive dominance effects were explained by interactions between specific classical HLA alleles (rheumatoid arthritis, P = 1.8 × 10-3; T1D, P = 8.6 × 10-27; celiac disease, P = 6.0 × 10-100). These interactions generally increased disease risk and explained moderate but significant fractions of phenotypic variance (rheumatoid arthritis, 1.4%; T1D, 4.0%; celiac disease, 4.1%) beyond a simple additive model.
    Authors
    Lenz, TL; Deutsch, AJ; Han, B; Hu, X; Okada, Y; Eyre, S; Knapp, M; Zhernakova, A; Huizinga, TWJ; Abecasis, G
    URI
    http://qmro.qmul.ac.uk/xmlui/handle/123456789/11945
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    • Centre for Genomics and Child Health [667]
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