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. Nöthen; Suna 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

doi:10.1038/ng.3379

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

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Abstract

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_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 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 language	English
Pages (from-to)	1085-1090
Number of pages	6
Journal	Nature Genetics
Volume	47
Issue number	9
DOIs	https://doi.org/10.1038/ng.3379
State	Published - 27 Aug 2015
Externally published	Yes

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Lenz, T. L., Deutsch, A. J., Han, B., Hu, X., Okada, Y., Eyre, S., Knapp, M., Zhernakova, A., Huizinga, T. W. J., Abecasis, G., Becker, J., Boeckxstaens, G. E., Chen, W. M., Franke, A., Gladman, D. D., Gockel, I., Gutierrez-Achury, J., Martin, J., Nair, R. P., ... Raychaudhuri, S. (2015). Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases. Nature Genetics, 47(9), 1085-1090. https://doi.org/10.1038/ng.3379

@article{da238c13afa84f5085a14b456a0466e3,

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

abstract = "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.",

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

note = "Funding Information: This project was supported by grants from the German Research Foundation (DFG; LE 2593/1-1 and LE 2593/2-1 (T.L.L.), GO 1795/1-1 (I.G.), KN 378/2-1 (M.K.) and SCHU 1596/5-1 (J.S.)), by grants from the US National Institutes of Health (1R01AR062886 (P.I.W.d.B.), R01AR065183 (J.T.E.), 1R01AR063759-01A1 (S.R.), 5U01GM092691 (S.R.) and 1UH2AR067677-01 (S.R.)), by the IMI (European Union)–funded program BTCure (L.K.) and by the Netherlands Organization for Scientific Research (Vernieuwingsimpuls VIDI Award NWO project 016.126.354 (P.I.W.d.B.)). Sample collection for J.M. was supported by a grant from the Instituto de Salud Carlos III (RD12/0009). M.M.N. received support for this work from the Alfried Krupp von Bohlen und Halbach-Stiftung and is a member of the DFG-funded Excellence Cluster ImmunoSensation. Publisher Copyright: {\textcopyright} 2015 Nature America, Inc. All rights reserved.",

year = "2015",

month = aug,

day = "27",

doi = "10.1038/ng.3379",

language = "English",

volume = "47",

pages = "1085--1090",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

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Lenz, 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 2015, 'Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases', Nature Genetics, vol. 47, no. 9, pp. 1085-1090. https://doi.org/10.1038/ng.3379

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

N1 - Funding Information: This project was supported by grants from the German Research Foundation (DFG; LE 2593/1-1 and LE 2593/2-1 (T.L.L.), GO 1795/1-1 (I.G.), KN 378/2-1 (M.K.) and SCHU 1596/5-1 (J.S.)), by grants from the US National Institutes of Health (1R01AR062886 (P.I.W.d.B.), R01AR065183 (J.T.E.), 1R01AR063759-01A1 (S.R.), 5U01GM092691 (S.R.) and 1UH2AR067677-01 (S.R.)), by the IMI (European Union)–funded program BTCure (L.K.) and by the Netherlands Organization for Scientific Research (Vernieuwingsimpuls VIDI Award NWO project 016.126.354 (P.I.W.d.B.)). Sample collection for J.M. was supported by a grant from the Instituto de Salud Carlos III (RD12/0009). M.M.N. received support for this work from the Alfried Krupp von Bohlen und Halbach-Stiftung and is a member of the DFG-funded Excellence Cluster ImmunoSensation. Publisher Copyright: © 2015 Nature America, Inc. All rights reserved.

PY - 2015/8/27

Y1 - 2015/8/27

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.

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VL - 47

SP - 1085

EP - 1090

JO - Nature Genetics

JF - Nature Genetics

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ER -

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

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