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

Human 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, N(cases)=5,337), type 1 diabetes (T1D, N(cases)=5,567), psoriasis vulgaris (N(cases)=3,089), idiopathic achalasia (N(cases)=727), and celiac disease (N(cases)=11,115). In four out of five diseases, we observed highly significant non-additive dominance effects (RA: 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 dominance effects were explained by interactions between specific classical HLA alleles (RA: 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 (RA: 1.4%, T1D: 4.0%, and celiac disease: 4.1%, beyond a simple additive model).