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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References

  1. 1.

    et al. Integrated transcriptional profiling and linkage analysis for identification of genes underlying disease. Nature Genet. 37, 243–253 (2005)

  2. 2.

    et al. Integrated genomic approaches implicate osteoglycin (Ogn) in the regulation of left ventricular mass. Nature Genet. 40, 546–552 (2008)

  3. 3.

    et al. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434, 772–777 (2005)

  4. 4.

    , , & EBI2 mediates B cell segregation between the outer and centre follicle. Nature 460, 1122–1126 (2009)

  5. 5.

    , , , & Guidance of B cells by the orphan G protein-coupled receptor EBI2 shapes humoral immune responses. Immunity 31, 259–269 (2009)

  6. 6.

    , & Genetic mapping in human disease. Science 322, 881–888 (2008)

  7. 7.

    Molecular networks as sensors and drivers of common human diseases. Nature 461, 218–223 (2009)

  8. 8.

    et al. Variations in DNA elucidate molecular networks that cause disease. Nature 452, 429–435 (2008)

  9. 9.

    et al. Common regulatory variation impacts gene expression in a cell type-dependent manner. Science 325, 1246–1250 (2009)

  10. 10.

    , , & Genetic dissection of transcriptional regulation in budding yeast. Science 296, 752–755 (2002)

  11. 11.

    et al. Trans-acting regulatory variation in Saccharomyces cerevisiae and the role of transcription factors. Nature Genet. 35, 57–64 (2003)

  12. 12.

    , , , & PASTAA: identifying transcription factors associated with sets of co-regulated genes. Bioinformatics 25, 435–442 (2009)

  13. 13.

    et al. New insights into the genetic control of gene expression using a Bayesian multi-tissue approach. PLoS Comput. Biol. 6, e1000737 (2010)

  14. 14.

    et al. Genetical genomics: spotlight on QTL hotspots. PLoS Genet. 4, e1000232 (2008)

  15. 15.

    & Nonresolving inflammation. Cell 140, 871–882 (2010)

  16. 16.

    , & The role of inflammation in insulitis and β-cell loss in type 1 diabetes. Nature Rev. Endocrinol. 5, 219–226 (2009)

  17. 17.

    & Molecular cloning of CD68, a human macrophage marker related to lysosomal glycoproteins. Blood 81, 1607–1613 (1993)

  18. 18.

    et al. SNP and haplotype mapping for genetic analysis in the rat. Nature Genet. 40, 560–566 (2008)

  19. 19.

    et al. The genome sequence of the spontaneously hypertensive rat: analysis and functional significance. Genome Res. 20, 791–803 (2010)

  20. 20.

    et al. Genetics and beyond–the transcriptome of human monocytes and disease susceptibility. PLoS ONE 5, e10693 (2010)

  21. 21.

    , , & Statistical independence of the colocalized association signals for type 1 diabetes and RPS26 gene expression on chromosome 12q13. Biostatistics 10, 327–334 (2009)

  22. 22.

    Diabetes: a virus–gene collaboration. Nature 459, 518–519 (2009)

  23. 23.

    , , , & Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324, 387–389 (2009)

  24. 24.

    et al. A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nature Genet. 38, 617–619 (2006)

  25. 25.

    et al. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nature Genet. 41, 703–707 (2009)

  26. 26.

    et al. Interferon-α initiates type 1 diabetes in nonobese diabetic mice. Proc. Natl Acad. Sci. USA 105, 12439–12444 (2008)

  27. 27.

    et al. Follow-up of 1715 SNPs from the Wellcome Trust Case Control Consortium genome-wide association study in type I diabetes families. Genes Immun. 10 (suppl. 1). S85–S94 (2009)

  28. 28.

    et al. Interferon-α induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nature Immunol. 5, 1061–1068 (2004)

  29. 29.

    The Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007)

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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.

Author information

Author notes

    • Matthias Heinig
    •  & Enrico Petretto

    These authors contributed equally to this work.

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. Molecular Medicine, Department of Medical Sciences, 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.

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  1. Cardiogenics Consortium

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

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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.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Norbert Hubner or Stuart A. Cook.

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.

Supplementary information

PDF files

  1. 1.

    Supplementary Information

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

  2. 2.

    Supplementary Figures

    This file contains Supplementary Figures 1-9 with legends.

  3. 3.

    Supplementary Tables

    This file contains Supplementary Tables 1-10.

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DOI

https://doi.org/10.1038/nature09386

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