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

Nature volume 467, pages 460–464 (2010)Cite this article

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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 systems-genetics 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)—a macrophage-associated autoimmune disease—than randomly selected immune response genes (P = 8.85 × 10−6). The human locus controlling the IDIN was associated with the risk of T1D at single nucleotide polymorphism rs9585056 (P = 7.0 × 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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Figure 1: The rat Irf7 -driven inflammatory gene network.
Figure 2: Genetic mapping of regulatory hot spots for the IDIN.
Figure 3: A gene network and locus for T1D risk.

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Acknowledgements

We acknowledge funding from the German National Genome Research Network (NGFN-Plus ‘Genetics of Heart Failure’), the Helmholtz Association Alliance on Systems Biology (MSBN), EURATools (LSHG-CT-2005-019015), European Union FP6 (LSHM-CT-2006-037593), PHC ALLIANCE 2009 (19419PH), UK National Institute for Health Research Biomedical Research Unit (Royal Brompton and Harefield NHS Trusts, University Hospitals of Leicester NHS Trusts) and Biomedical Research Centre (Imperial College NHS Trust) awards, the British Heart Foundation, grant P301/10/0290 from the Grant Agency of the Czech Republic, grant 1M6837805002 from the Ministry of Education of the Czech Republic, the Fondation Leducq, the Medical Research Council UK, Research Councils UK, the Juvenile Diabetes Research Foundation International, National Institute for Health Research (UK), National Institute of Diabetes and Digestive and Kidney Diseases (USA), and the Wellcome Trust. The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. HEALTH-F4-2010-241504 (EURATRANS). O. Burren performed T1DBase analyses.

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Author notes

  1. Matthias Heinig and Enrico Petretto: These authors contributed equally to this work.

Authors and Affiliations

  1. Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Straße 10, 13125 Berlin, Germany

    Matthias Heinig, Anja Bauerfeind, Oliver Hummel, Young-Ae Lee, Svetlana Paskas, Carola Rintisch, Kathrin Saar, Herbert Schulz & Norbert Hubner

  2. Max Planck Institute for Molecular Genetics, Ihnestraße 63-73, 14195 Berlin, Germany ,

    Matthias Heinig, Helge G. Roider & Martin Vingron

  3. Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK ,

    Enrico Petretto, Leonardo Bottolo, Han Lu, Yoyo Li, Rizwan Sarwar, Sarah R. Langley, Rachel Buchan, Timothy J. Aitman & Stuart A. Cook

  4. Department of Epidemiology and Biostatistics, Faculty of Medicine, Imperial College London, Praed Street, London W2 1PG, UK,

    Enrico Petretto & Leonardo Bottolo

  5. Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 OXY, UK ,

    Chris Wallace, Jason Cooper, Deborah J. Smyth, David Clayton & John A. Todd

  6. INSERM UMRS 937, Pierre and Marie Curie University (UPMC, Paris 6) and Medical School, 91 Boulevard de l’Hôpital, Paris 75013, France ,

    Maxime Rotival, Seraya Maouche, Laurence Tiret & Francois Cambien

  7. Pediatric Pneumology and Immunology, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany ,

    Young-Ae Lee

  8. Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California San Francisco, California, 94143, USA

    Elizabeth E. Gray & Jason G. Cyster

  9. Universität zu Lübeck, Medizinische Klinik II, 23538 Lübeck, Germany ,

    Jeanette Erdmann & Heribert Schunkert

  10. Klinik und Poliklinik für Innere Medizin II, Universität Regensburg, 93053 Regensburg, Germany

    Christian Hengstenberg

  11. Department of Haematology, University of Cambridge and National Health Service Blood and Transplant, Cambridge CB2 0PT, UK,

    Willem H. Ouwehand

  12. Human Genetics, Wellcome Trust Sanger Institute, Genome Campus, Hinxton CB10 1SA, UK

    Willem H. Ouwehand & Catherine M. Rice

  13. Department of Cardiovascular Sciences, University of Leicester and Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester LE3 9QP, UK,

    Nilesh J. Samani & Alison H. Goodall

  14. Medizinische Klinik und Poliklinik, Johannes-Gutenberg Universität Mainz, Universitätsmedizin, Langenbeckstrasse 1, 55131 Mainz, Germany ,

    Stefan Blankenberg, Thomas Münzel & Tanja Zeller

  15. Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Maria-Goeppert-Straße 1, 23562 Lübeck, Germany ,

    Silke Szymczak & Andreas Ziegler

  16. Institute of Physiology, Czech Academy of Sciences and Centre for Applied Genomics, Videnska 1083, 14220 Prague 4, Czech Republic ,

    Michal Pravenec

  17. CC4, Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany ,

    Norbert Hubner

  18. National Heart and Lung Institute, Imperial College, Dovehouse Street, London SW3 6LY, UK ,

    Stuart A. Cook

  19. Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Leicester LE3 9QP, UK.,

    Peter Braund, Jay Gracey, Unni Krishnan, Jasbir S. Moore, Chris P. Nelson & Helen Pollard

  20. Department of Haematology, University of Cambridge and National Health Service Blood and Transplant, Cambridge, CB2 2PT, UK

    Tony Attwood, Abi Crisp-Hihn, Nicola Foad, Jennifer Jolley, Heather Lloyd-Jones, David Muir, Elizabeth Murray, Karen O’Leary, Angela Rankin & Jennifer Sambrook

  21. INSERM UMRS 937, Pierre and Marie Curie University (UPMC, Paris 6) and Medical School, 91 Boulevard de l’Hôpital, Paris 75013, France.,

    Tiphaine Godfroy, Jessy Brocheton & Carole Proust

  22. Institut für Klinische Chemie und Laboratoriumsmedizin, Universität Regensburg, 93053 Regensburg, Germany.,

    Gerd Schmitz

  23. Klinik und Poliklinik für Innere Medizin II, Universität Regensburg, 93053 Regensburg, Germany.,

    Susanne Heimerl & Ingrid Lugauer

  24. Universität zu Lübeck, Medizinische Klinik II, 23538 Lübeck, Germany.,

    Stephanie Belz, Stefanie Gulde, Patrick Linsel-Nitschke, Hendrik Sager & Laura Schroeder

  25. Department of Medical Sciences, Molecular Medicine, Uppsala University, SE-751 85 Uppsala, Sweden

    Per Lundmark & Ann-Christine Syvannen

  26. Trium, Analysis Online GmbH, Hohenlindenerstraße 1, 81677 München, Germany.,

    Jessica Neudert & Michael Scholz

  27. Wellcome Trust Sanger Institute, Genome Campus, Hinxton CB10 1SA, Cambridge.,

    Panos Deloukas, Emma Gray, Rhian Gwilliams & David Niblett.

Authors
  1. Matthias Heinig
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  2. Enrico Petretto
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  3. Chris Wallace
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  4. Leonardo Bottolo
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  5. Maxime Rotival
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  6. Han Lu
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  7. Yoyo Li
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  12. Young-Ae Lee
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  13. Svetlana Paskas
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  14. Carola Rintisch
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  15. Kathrin Saar
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  16. Jason Cooper
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  17. Rachel Buchan
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  18. Elizabeth E. Gray
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  19. Jason G. Cyster
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  20. Jeanette Erdmann
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  21. Christian Hengstenberg
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  22. Seraya Maouche
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  23. Willem H. Ouwehand
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  24. Catherine M. Rice
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  28. Herbert Schulz
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  30. Martin Vingron
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  35. Andreas Ziegler
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  36. Laurence Tiret
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  39. Timothy J. Aitman
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  40. Francois Cambien
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  41. David Clayton
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  42. John A. Todd
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  43. Norbert Hubner
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  44. Stuart A. Cook
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Consortia

Cardiogenics Consortium

  • 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.

Contributions

S.A.C., N.H. and E.P. initiated the study. M.H., E.P., N.H. and S.A.C. participated in the conception, design and coordination of the study. H.L., Y.L., R.S., Y.A.L., S.P., C.R., K.S. and R.B. performed genetic, biochemical and functional analyses in rats. E.E.G. and J.G.C. provided Ebi2GFP/+ mouse data. M.P. and T.J.A. contributed materials and discussion of the manuscript. M.H., E.P., C.W., D.J.S., D.C., A.B., S.R.L., L.B., M.R. and L.T. designed and applied the modelling methodology and statistical analyses. M.H., E.P. and H. Schulz performed eQTL analysis in the rat. L.B. designed and performed the Bayesian analysis. C.W., D.J.S. and D.C. performed association analyses in humans. M.H., O.H., H.R. and M.V. designed and performed bioinformatics analyses in rats. J.E., C.H., S.M., W.H.O., C.M.R., N.J.S., H. Schunkert, A.H.G., S.B., T.M., T.Z., S.S., A.Z., M.R., L.T. and F.C. provided the human monocyte expression data and contributed to the transcriptomic analyses in the Cardiogenics Study and Gutenberg Heart Study cohorts. M.H., E.P., N.H. and S.A.C. wrote the paper with significant contributions from C.W. and J.A.T. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Norbert Hubner or Stuart A. Cook.

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Competing interests

The authors declare no competing financial interests.

Additional information

Microarray expression data in the rat have been deposited at ArrayExpress with the following identity codes: skeletal muscle, E-TABM-458; aorta, E-MTAB-322; liver, E-MTAB-323.

A list of participants and their affiliations appears at the end of the paper.

Supplementary information

Supplementary Information

This file contains Supplementary Information and Data, additional references and a list of contributors to the Cardiogenics Transcriptomic Study. (PDF 403 kb)

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Heinig, M., Petretto, E., Wallace, C. et al. A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk. Nature 467, 460–464 (2010). https://doi.org/10.1038/nature09386

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