Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus

James Bentham; David L. Morris; Deborah S. Cunninghame Graham; Christopher L. Pinder; Philip Tombleson; Timothy W. Behrens; Javier Martín; Benjamin P. Fairfax; Julian C. Knight; Lingyan Chen; Joseph Replogle; Ann Christine Syvänen; Lars Rönnblom; Robert R. Graham; Joan E. Wither; John D. Rioux; Marta E. Alarcón-Riquelme; Timothy Vyse

doi:10.1038/ng.3434

Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus

James Bentham^*, David L. Morris, Deborah S. Cunninghame Graham, Christopher L. Pinder, Philip Tombleson, Timothy W. Behrens, Javier Martín, Benjamin P. Fairfax, Julian C. Knight, Lingyan Chen, Joseph Replogle, Ann Christine Syvänen, Lars Rönnblom, Robert R. Graham, Joan E. Wither, John D. Rioux, Marta E. Alarcón-Riquelme, Timothy Vyse

^*Corresponding author for this work

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Abstract

Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry, constituting a new GWAS, a meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including ten new associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n = 16) of transcription factors among SLE susceptibility genes. This finding supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE.

Original language	English
Pages (from-to)	1457-1464
Number of pages	8
Journal	Nature Genetics
Volume	47
Issue number	12
Early online date	26 Oct 2015
DOIs	https://doi.org/10.1038/ng.3434
Publication status	Published - 1 Dec 2015

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Genetic association analyses implicate aberrant_VYSE_Publishedonline26October2015_GREEN AAMAccepted author manuscript, 772 KB

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Bentham, J., Morris, D. L., Cunninghame Graham, D. S., Pinder, C. L., Tombleson, P., Behrens, T. W., Martín, J., Fairfax, B. P., Knight, J. C., Chen, L., Replogle, J., Syvänen, A. C., Rönnblom, L., Graham, R. R., Wither, J. E., Rioux, J. D., Alarcón-Riquelme, M. E., & Vyse, T. (2015). Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nature Genetics, 47(12), 1457-1464. https://doi.org/10.1038/ng.3434

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title = "Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus",

abstract = "Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry, constituting a new GWAS, a meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including ten new associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n = 16) of transcription factors among SLE susceptibility genes. This finding supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE.",

author = "James Bentham and Morris, {David L.} and {Cunninghame Graham}, {Deborah S.} and Pinder, {Christopher L.} and Philip Tombleson and Behrens, {Timothy W.} and Javier Mart{\'i}n and Fairfax, {Benjamin P.} and Knight, {Julian C.} and Lingyan Chen and Joseph Replogle and Syv{\"a}nen, {Ann Christine} and Lars R{\"o}nnblom and Graham, {Robert R.} and Wither, {Joan E.} and Rioux, {John D.} and Alarc{\'o}n-Riquelme, {Marta E.} and Timothy Vyse",

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Bentham, J , Morris, DL , Cunninghame Graham, DS, Pinder, CL, Tombleson, P, Behrens, TW, Martín, J, Fairfax, BP, Knight, JC, Chen, L, Replogle, J, Syvänen, AC, Rönnblom, L, Graham, RR, Wither, JE, Rioux, JD, Alarcón-Riquelme, ME & Vyse, T 2015, 'Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus', Nature Genetics, vol. 47, no. 12, pp. 1457-1464. https://doi.org/10.1038/ng.3434

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AU - Bentham, James

AU - Morris, David L.

AU - Cunninghame Graham, Deborah S.

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AU - Tombleson, Philip

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AU - Martín, Javier

AU - Fairfax, Benjamin P.

AU - Knight, Julian C.

AU - Chen, Lingyan

AU - Replogle, Joseph

AU - Syvänen, Ann Christine

AU - Rönnblom, Lars

AU - Graham, Robert R.

AU - Wither, Joan E.

AU - Rioux, John D.

AU - Alarcón-Riquelme, Marta E.

AU - Vyse, Timothy

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Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus

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