Lenz, Tobias L.Deutsch, AaronHan, BuhmHu, XinliOkada, YukinoriEyre, StephenKnapp, MichaelZhernakova, AlexandraHuizinga, Tom W.J.Abecasis, GoncaloBecker, JessicaBoeckxstaens, Guy E.Chen, Wei-MinFranke, AndreGladman, Dafna D.Gockel, InesGutierrez-Achury, JavierMartin, JavierNair, Rajan P.Nöthen, Markus M.Onengut-Gumuscu, SunaRahman, ProtonRantapää-Dahlqvist, SolbrittStuart, Philip E.Tsoi, Lam C.Van Heel, David A.Worthington, JaneWouters, Mira M.Klareskog, LarsElder, James T.Gregersen, Peter K.Schumacher, JohannesRich, Stephen S.Wijmenga, CiscaSunyaev, Shamilde Bakker, Paul I.W.Raychaudhuri, Soumya2016-04-012015Lenz, T. L., A. J. Deutsch, B. Han, X. Hu, Y. Okada, S. Eyre, M. Knapp, et al. 2015. “Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases.” Nature genetics 47 (9): 1085-1090. doi:10.1038/ng.3379. http://dx.doi.org/10.1038/ng.3379.1061-4036http://nrs.harvard.edu/urn-3:HUL.InstRepos:26318601Human leukocyte antigen (HLA) genes confer strong 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 may result in additional non-additive risk effects. We tested non-additive disease contributions of classical HLA alleles in patients and matched controls for five common autoimmune diseases: rheumatoid arthritis (RA, 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 out of five diseases, we observed highly significant non-additive dominance effects (RA: P=2.5×1012; 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 dominance effects were explained by interactions between specific classical HLA alleles (RA: P=1.8×10−3; T1D: P=8.6×1027; celiac disease: P=6.0×10−100). These interactions generally increased disease risk and explained moderate but significant fractions of phenotypic variance (RA: 1.4%, T1D: 4.0%, and celiac disease: 4.1%, beyond a simple additive model).en-USAutoimmunitycomplex diseasesMHCHLAgenetic architecturenon-additive effectsinteractionsJournal Article2016-04-0110.1038/ng.3379