Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases
1085 - 1090
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© 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 (n<inf>cases</inf> = 5,337), type 1 diabetes (T1D; n<inf>cases</inf> = 5,567), psoriasis vulgaris (n<inf>cases</inf> = 3,089), idiopathic achalasia (n<inf>cases</inf> = 727) and celiac disease (n<inf>cases</inf> = 11,115). In four of the five diseases, we observed highly significant, non-additive dominance effects (rheumatoid arthritis, P = 2.5 × 10<sup>-12</sup>; T1D, P = 2.4 × 10<sup>-10</sup>; psoriasis, P = 5.9 × 10<sup>-6</sup>; celiac disease, P = 1.2 × 10<sup>-87</sup>). 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<sup>-3</sup>; T1D, P = 8.6 × 10<sup>-27</sup>; celiac disease, P = 6.0 × 10<sup>-100</sup>). 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.
AuthorsLenz, TL; Deutsch, AJ; Han, B; Hu, X; Okada, Y; Eyre, S; Knapp, M; Zhernakova, A; Huizinga, TWJ; Abecasis, G; Becker, J; Boeckxstaens, GE; Chen, WM; Franke, A; Gladman, DD; Gockel, I; Gutierrez-Achury, J; Martin, J; Nair, RP; Nöthen, MM; Onengut-Gumuscu, S; Rahman, P; Rantapää-Dahlqvist, S; Stuart, PE; Tsoi, LC; Van Heel, DA; Worthington, J; Wouters, MM; Klareskog, L; Elder, JT; Gregersen, PK; Schumacher, J; Rich, SS; Wijmenga, C; Sunyaev, SR; De Bakker, PIW; Raychaudhuri, S
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