TY - JOUR
T1 - Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases
AU - Lenz, Tobias L
AU - Deutsch, Aaron J
AU - Han, Buhm
AU - Hu, Xinli
AU - Okada, Yukinori
AU - Eyre, Stephen
AU - Knapp, Michael
AU - Zhernakova, Alexandra
AU - Huizinga, Tom W J
AU - Abecasis, Gonçalo
AU - Becker, Jessica
AU - Boeckxstaens, Guy E
AU - Chen, Wei-Min
AU - Franke, Andre
AU - Gladman, Dafna D
AU - Gockel, Ines
AU - Gutierrez-Achury, Javier
AU - Martin, Javier
AU - Nair, Rajan P
AU - Nöthen, Markus M
AU - Onengut-Gumuscu, Suna
AU - Rahman, Proton
AU - Rantapää-Dahlqvist, Solbritt
AU - Stuart, Philip E
AU - Tsoi, Lam C
AU - van Heel, David A
AU - Worthington, Jane
AU - Wouters, Mira M
AU - Klareskog, Lars
AU - Elder, James T
AU - Gregersen, Peter K
AU - Schumacher, Johannes
AU - Rich, Stephen S
AU - Wijmenga, Cisca
AU - Sunyaev, Shamil R
AU - de Bakker, Paul I W
AU - Raychaudhuri, Soumya
PY - 2015/9
Y1 - 2015/9
N2 - 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.
AB - 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.
U2 - 10.1038/ng.3379
DO - 10.1038/ng.3379
M3 - Letter
C2 - 26258845
SN - 1061-4036
VL - 47
SP - 1085
EP - 1090
JO - Nature Genetics
JF - Nature Genetics
IS - 9
ER -