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

Tobias L. Lenz, Aaron J. Deutsch, Buhm Han, Xinli Hu, Yukinori Okada, Stephen Eyre, Michael Knapp, Alexandra Zhernakova, Tom W.J. Huizinga, Gonçalo Abecasis, Jessica Becker, Guy E. Boeckxstaens, Wei Min Chen, Andre Franke, Dafna D. Gladman, Ines Gockel, Javier Gutierrez-Achury, Javier Martin, Rajan P. Nair, Markus M. NöthenSuna Onengut-Gumuscu, Proton Rahman, Solbritt Rantapää-Dahlqvist, Philip E. Stuart, Lam C. Tsoi, David A. Van Heel, Jane Worthington, Mira M. Wouters, Lars Klareskog, James T. Elder, Peter K. Gregersen, Johannes Schumacher, Stephen S. Rich, Cisca Wijmenga, Shamil R. Sunyaev, Paul I.W. De Bakker, Soumya Raychaudhuri

Research output: Contribution to journalArticlepeer-review

117 Scopus citations


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.

Original languageEnglish
Pages (from-to)1085-1090
Number of pages6
JournalNature Genetics
Issue number9
StatePublished - 27 Aug 2015
Externally publishedYes


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