A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk

Matthias Heinig; Enrico Petretto; Chris Wallace; Leonardo Bottolo; Maxime Rotival; Han Lu; Yoyo Li; Rizwan Sarwar; Sarah R. Langley; Anja Bauerfeind; Oliver Hummel; Young Ae Lee; Svetlana Paskas; Carola Rintisch; Kathrin Saar; Jason Cooper; Rachel Buchan; Elizabeth E. Gray; Jason G. Cyster; Erdmann Jeanette Erdmann; Christian Hengstenberg; Seraya Maouche; Willem H. Ouwehand; Catherine M. Rice; Nilesh J. Samani; Heribert Schunkert; Alison H. Goodall; Herbert Schulz; Helge G. Roider; Martin Vingron; Stefan Blankenberg; Thomas Münzel; Tanja Zeller; Silke Szymczak; Andreas Ziegler; Laurence Tiret; Deborah J. Smyth; Michal Pravenec; Timothy J. Aitman; Francois Cambien; David Clayton; John A. Todd; Norbert Hubner; Stuart A. Cook; Peter Braund; Jay Gracey; Unni Krishnan; Jasbir S. Moore; Chris P. Nelson; Helen Pollard; Tony Attwood; Abi Crisp-Hihn; Nicola Foad; Jennifer Jolley; Heather Lloyd-Jones; David Muir; Elizabeth Murray; Karen O'Leary; Angela Rankin; Jennifer Sambrook; Tiphaine Godfroy; Jessy Brocheton; Carole Proust; Gerd Schmitz; Susanne Heimerl; Ingrid Lugauer; Stephanie Belz; Stefanie Gulde; Patrick Linsel-Nitschke; Hendrik Sager; Laura Schroeder; Per Lundmark; Ann Christine Syvannen; Jessica Neudert; Michael Scholz; Panos Deloukas; Emma Gray; Rhian Gwilliams; David Niblett

doi:10.1038/nature09386

A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk

Matthias Heinig, Enrico Petretto, Chris Wallace, Leonardo Bottolo, Maxime Rotival, Han Lu, Yoyo Li, Rizwan Sarwar, Sarah R. Langley, Anja Bauerfeind, Oliver Hummel, Young Ae Lee, Svetlana Paskas, Carola Rintisch, Kathrin Saar, Jason Cooper, Rachel Buchan, Elizabeth E. Gray, Jason G. Cyster, Erdmann Jeanette ErdmannChristian Hengstenberg, Seraya Maouche, Willem H. Ouwehand, Catherine M. Rice, Nilesh J. Samani, Heribert Schunkert, Alison H. Goodall, Herbert Schulz, Helge G. Roider, Martin Vingron, Stefan Blankenberg, Thomas Münzel, Tanja Zeller, Silke Szymczak, Andreas Ziegler, Laurence Tiret, Deborah J. Smyth, Michal Pravenec, Timothy J. Aitman, Francois Cambien, David Clayton, John A. Todd, Norbert Hubner^*, Stuart A. Cook, Peter Braund, Jay Gracey, Unni Krishnan, Jasbir S. Moore, Chris P. Nelson, Helen Pollard, Tony Attwood, Abi Crisp-Hihn, Nicola Foad, Jennifer Jolley, Heather Lloyd-Jones, David Muir, Elizabeth Murray, Karen O'Leary, Angela Rankin, Jennifer Sambrook, Tiphaine Godfroy, Jessy Brocheton, Carole Proust, Gerd Schmitz, Susanne Heimerl, Ingrid Lugauer, Stephanie Belz, Stefanie Gulde, Patrick Linsel-Nitschke, Hendrik Sager, Laura Schroeder, Per Lundmark, Ann Christine Syvannen, Jessica Neudert, Michael Scholz, Panos Deloukas, Emma Gray, Rhian Gwilliams, David Niblett

^*Corresponding author for this work

171 Citations (Scopus)

Abstract

Combined analyses of gene networks and DNA sequence variation can provide new insights into the aetiology of common diseases that may not be apparent from genome-wide association studies alone. Recent advances in rat genomics are facilitating systemsgenetics approaches^1,2. Here we report the use of integrated genome-wide approaches across seven rat tissues to identify gene networks and the loci underlying their regulation. We defined an interferon regulatory factor 7 (IRF7³)-driven inflammatory network (IDIN) enriched for viral response genes, which represents a molecular biomarker for macrophages and which was regulated in multiple tissues by a locus on rat chromosome 15q25. We show that Epstein-Barr virus induced gene 2 (Ebi2, also known as Gpr183), which lies at this locus and controls B lymphocyte migration^4,5, is expressed in macrophages and regulates the IDIN. The human orthologous locus on chromosome 13q32 controlled the human equivalent of the IDIN, which was conserved in monocytes. IDIN genes were more likely to associate with susceptibility to type 1 diabetes (T1D)-amacrophage-associated autoimmune disease-than randomly selected immune response genes (P=58.853×10^-6). The human locus controlling the IDIN was associated with the risk of T1D at single nucleotide polymorphism rs9585056 (P=57.03×10^-10; odds ratio, 1.15), which was one of five single nucleotide polymorphisms in this region associated with EBI2 (GPR183) expression. These data implicate IRF7 network genes and their regulatory locus in the pathogenesis of T1D.

Original language	English
Journal	Nature
Volume	467
Issue number	7314
Pages (from-to)	460-464
Number of pages	5
ISSN	0028-0836
DOIs	https://doi.org/10.1038/nature09386
Publication status	Published - 23.09.2010

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10.1038/nature09386

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Heinig, M., Petretto, E., Wallace, C., Bottolo, L., Rotival, M., Lu, H., Li, Y., Sarwar, R., Langley, S. R., Bauerfeind, A., Hummel, O., Lee, Y. A., Paskas, S., Rintisch, C., Saar, K., Cooper, J., Buchan, R., Gray, E. E., Cyster, J. G., ... Niblett, D. (2010). A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk. Nature, 467(7314), 460-464. https://doi.org/10.1038/nature09386

@article{c18c52adf3d74be8b63365c040fad89e,

title = "A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk",

abstract = "Combined analyses of gene networks and DNA sequence variation can provide new insights into the aetiology of common diseases that may not be apparent from genome-wide association studies alone. Recent advances in rat genomics are facilitating systemsgenetics approaches1,2. Here we report the use of integrated genome-wide approaches across seven rat tissues to identify gene networks and the loci underlying their regulation. We defined an interferon regulatory factor 7 (IRF73)-driven inflammatory network (IDIN) enriched for viral response genes, which represents a molecular biomarker for macrophages and which was regulated in multiple tissues by a locus on rat chromosome 15q25. We show that Epstein-Barr virus induced gene 2 (Ebi2, also known as Gpr183), which lies at this locus and controls B lymphocyte migration4,5, is expressed in macrophages and regulates the IDIN. The human orthologous locus on chromosome 13q32 controlled the human equivalent of the IDIN, which was conserved in monocytes. IDIN genes were more likely to associate with susceptibility to type 1 diabetes (T1D)-amacrophage-associated autoimmune disease-than randomly selected immune response genes (P=58.853×10-6). The human locus controlling the IDIN was associated with the risk of T1D at single nucleotide polymorphism rs9585056 (P=57.03×10-10; odds ratio, 1.15), which was one of five single nucleotide polymorphisms in this region associated with EBI2 (GPR183) expression. These data implicate IRF7 network genes and their regulatory locus in the pathogenesis of T1D.",

author = "Matthias Heinig and Enrico Petretto and Chris Wallace and Leonardo Bottolo and Maxime Rotival and Han Lu and Yoyo Li and Rizwan Sarwar and Langley, {Sarah R.} and Anja Bauerfeind and Oliver Hummel and Lee, {Young Ae} and Svetlana Paskas and Carola Rintisch and Kathrin Saar and Jason Cooper and Rachel Buchan and Gray, {Elizabeth E.} and Cyster, {Jason G.} and {Jeanette Erdmann}, Erdmann and Christian Hengstenberg and Seraya Maouche and Ouwehand, {Willem H.} and Rice, {Catherine M.} and Samani, {Nilesh J.} and Heribert Schunkert and Goodall, {Alison H.} and Herbert Schulz and Roider, {Helge G.} and Martin Vingron and Stefan Blankenberg and Thomas M{\"u}nzel and Tanja Zeller and Silke Szymczak and Andreas Ziegler and Laurence Tiret and Smyth, {Deborah J.} and Michal Pravenec and Aitman, {Timothy J.} and Francois Cambien and David Clayton and Todd, {John A.} and Norbert Hubner and Cook, {Stuart A.} and Peter Braund and Jay Gracey and Unni Krishnan and Moore, {Jasbir S.} and Nelson, {Chris P.} and Helen Pollard and Tony Attwood and Abi Crisp-Hihn and Nicola Foad and Jennifer Jolley and Heather Lloyd-Jones and David Muir and Elizabeth Murray and Karen O'Leary and Angela Rankin and Jennifer Sambrook and Tiphaine Godfroy and Jessy Brocheton and Carole Proust and Gerd Schmitz and Susanne Heimerl and Ingrid Lugauer and Stephanie Belz and Stefanie Gulde and Patrick Linsel-Nitschke and Hendrik Sager and Laura Schroeder and Per Lundmark and Syvannen, {Ann Christine} and Jessica Neudert and Michael Scholz and Panos Deloukas and Emma Gray and Rhian Gwilliams and David Niblett",

year = "2010",

month = sep,

day = "23",

doi = "10.1038/nature09386",

language = "English",

volume = "467",

pages = "460--464",

journal = "Nature",

issn = "0028-0836",

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Heinig, M, Petretto, E, Wallace, C, Bottolo, L, Rotival, M, Lu, H, Li, Y, Sarwar, R, Langley, SR, Bauerfeind, A, Hummel, O, Lee, YA, Paskas, S, Rintisch, C, Saar, K, Cooper, J, Buchan, R, Gray, EE, Cyster, JG, Jeanette Erdmann, E, Hengstenberg, C, Maouche, S, Ouwehand, WH, Rice, CM, Samani, NJ, Schunkert, H, Goodall, AH, Schulz, H, Roider, HG, Vingron, M, Blankenberg, S, Münzel, T, Zeller, T, Szymczak, S, Ziegler, A, Tiret, L, Smyth, DJ, Pravenec, M, Aitman, TJ, Cambien, F, Clayton, D, Todd, JA, Hubner, N, Cook, SA, Braund, P, Gracey, J, Krishnan, U, Moore, JS, Nelson, CP, Pollard, H, Attwood, T, Crisp-Hihn, A, Foad, N, Jolley, J, Lloyd-Jones, H, Muir, D, Murray, E, O'Leary, K, Rankin, A, Sambrook, J, Godfroy, T, Brocheton, J, Proust, C, Schmitz, G, Heimerl, S, Lugauer, I, Belz, S, Gulde, S, Linsel-Nitschke, P, Sager, H, Schroeder, L, Lundmark, P, Syvannen, AC, Neudert, J, Scholz, M, Deloukas, P, Gray, E, Gwilliams, R & Niblett, D 2010, 'A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk', Nature, vol. 467, no. 7314, pp. 460-464. https://doi.org/10.1038/nature09386

TY - JOUR

T1 - A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk

AU - Heinig, Matthias

AU - Petretto, Enrico

AU - Wallace, Chris

AU - Bottolo, Leonardo

AU - Rotival, Maxime

AU - Lu, Han

AU - Li, Yoyo

AU - Sarwar, Rizwan

AU - Langley, Sarah R.

AU - Bauerfeind, Anja

AU - Hummel, Oliver

AU - Lee, Young Ae

AU - Paskas, Svetlana

AU - Rintisch, Carola

AU - Saar, Kathrin

AU - Cooper, Jason

AU - Buchan, Rachel

AU - Gray, Elizabeth E.

AU - Cyster, Jason G.

AU - Jeanette Erdmann, Erdmann

AU - Hengstenberg, Christian

AU - Maouche, Seraya

AU - Ouwehand, Willem H.

AU - Rice, Catherine M.

AU - Samani, Nilesh J.

AU - Schunkert, Heribert

AU - Goodall, Alison H.

AU - Schulz, Herbert

AU - Roider, Helge G.

AU - Vingron, Martin

AU - Blankenberg, Stefan

AU - Münzel, Thomas

AU - Zeller, Tanja

AU - Szymczak, Silke

AU - Ziegler, Andreas

AU - Tiret, Laurence

AU - Smyth, Deborah J.

AU - Pravenec, Michal

AU - Aitman, Timothy J.

AU - Cambien, Francois

AU - Clayton, David

AU - Todd, John A.

AU - Hubner, Norbert

AU - Cook, Stuart A.

AU - Braund, Peter

AU - Gracey, Jay

AU - Krishnan, Unni

AU - Moore, Jasbir S.

AU - Nelson, Chris P.

AU - Pollard, Helen

AU - Attwood, Tony

AU - Crisp-Hihn, Abi

AU - Foad, Nicola

AU - Jolley, Jennifer

AU - Lloyd-Jones, Heather

AU - Muir, David

AU - Murray, Elizabeth

AU - O'Leary, Karen

AU - Rankin, Angela

AU - Sambrook, Jennifer

AU - Godfroy, Tiphaine

AU - Brocheton, Jessy

AU - Proust, Carole

AU - Schmitz, Gerd

AU - Heimerl, Susanne

AU - Lugauer, Ingrid

AU - Belz, Stephanie

AU - Gulde, Stefanie

AU - Linsel-Nitschke, Patrick

AU - Sager, Hendrik

AU - Schroeder, Laura

AU - Lundmark, Per

AU - Syvannen, Ann Christine

AU - Neudert, Jessica

AU - Scholz, Michael

AU - Deloukas, Panos

AU - Gray, Emma

AU - Gwilliams, Rhian

AU - Niblett, David

PY - 2010/9/23

Y1 - 2010/9/23

N2 - Combined analyses of gene networks and DNA sequence variation can provide new insights into the aetiology of common diseases that may not be apparent from genome-wide association studies alone. Recent advances in rat genomics are facilitating systemsgenetics approaches1,2. Here we report the use of integrated genome-wide approaches across seven rat tissues to identify gene networks and the loci underlying their regulation. We defined an interferon regulatory factor 7 (IRF73)-driven inflammatory network (IDIN) enriched for viral response genes, which represents a molecular biomarker for macrophages and which was regulated in multiple tissues by a locus on rat chromosome 15q25. We show that Epstein-Barr virus induced gene 2 (Ebi2, also known as Gpr183), which lies at this locus and controls B lymphocyte migration4,5, is expressed in macrophages and regulates the IDIN. The human orthologous locus on chromosome 13q32 controlled the human equivalent of the IDIN, which was conserved in monocytes. IDIN genes were more likely to associate with susceptibility to type 1 diabetes (T1D)-amacrophage-associated autoimmune disease-than randomly selected immune response genes (P=58.853×10-6). The human locus controlling the IDIN was associated with the risk of T1D at single nucleotide polymorphism rs9585056 (P=57.03×10-10; odds ratio, 1.15), which was one of five single nucleotide polymorphisms in this region associated with EBI2 (GPR183) expression. These data implicate IRF7 network genes and their regulatory locus in the pathogenesis of T1D.

AB - Combined analyses of gene networks and DNA sequence variation can provide new insights into the aetiology of common diseases that may not be apparent from genome-wide association studies alone. Recent advances in rat genomics are facilitating systemsgenetics approaches1,2. Here we report the use of integrated genome-wide approaches across seven rat tissues to identify gene networks and the loci underlying their regulation. We defined an interferon regulatory factor 7 (IRF73)-driven inflammatory network (IDIN) enriched for viral response genes, which represents a molecular biomarker for macrophages and which was regulated in multiple tissues by a locus on rat chromosome 15q25. We show that Epstein-Barr virus induced gene 2 (Ebi2, also known as Gpr183), which lies at this locus and controls B lymphocyte migration4,5, is expressed in macrophages and regulates the IDIN. The human orthologous locus on chromosome 13q32 controlled the human equivalent of the IDIN, which was conserved in monocytes. IDIN genes were more likely to associate with susceptibility to type 1 diabetes (T1D)-amacrophage-associated autoimmune disease-than randomly selected immune response genes (P=58.853×10-6). The human locus controlling the IDIN was associated with the risk of T1D at single nucleotide polymorphism rs9585056 (P=57.03×10-10; odds ratio, 1.15), which was one of five single nucleotide polymorphisms in this region associated with EBI2 (GPR183) expression. These data implicate IRF7 network genes and their regulatory locus in the pathogenesis of T1D.

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U2 - 10.1038/nature09386

DO - 10.1038/nature09386

M3 - Journal articles

C2 - 20827270

AN - SCOPUS:77957126059

SN - 0028-0836

VL - 467

SP - 460

EP - 464

JO - Nature

JF - Nature

IS - 7314

ER -

A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk

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