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

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References

1. Hubner, N. et al. Integrated transcriptional profiling and linkage analysis for identification of genes underlying disease. Nature Genet. 37, 243–253 (2005)
   Article CAS Google Scholar
2. Petretto, E. et al. Integrated genomic approaches implicate osteoglycin (Ogn) in the regulation of left ventricular mass. Nature Genet. 40, 546–552 (2008)
   Article CAS Google Scholar
3. Honda, K. et al. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434, 772–777 (2005)
   Article ADS CAS Google Scholar
4. Pereira, J. P., Kelly, L. M., Xu, Y. & Cyster, J. G. EBI2 mediates B cell segregation between the outer and centre follicle. Nature 460, 1122–1126 (2009)
   Article ADS CAS Google Scholar
5. Gatto, D., Paus, D., Basten, A., Mackay, C. R. & Brink, R. Guidance of B cells by the orphan G protein-coupled receptor EBI2 shapes humoral immune responses. Immunity 31, 259–269 (2009)
   Article CAS Google Scholar
6. Altshuler, D., Daly, M. J. & Lander, E. S. Genetic mapping in human disease. Science 322, 881–888 (2008)
   Article ADS CAS Google Scholar
7. Schadt, E. E. Molecular networks as sensors and drivers of common human diseases. Nature 461, 218–223 (2009)
   Article ADS CAS Google Scholar
8. Chen, Y. et al. Variations in DNA elucidate molecular networks that cause disease. Nature 452, 429–435 (2008)
   Article ADS CAS Google Scholar
9. Dimas, A. S. et al. Common regulatory variation impacts gene expression in a cell type-dependent manner. Science 325, 1246–1250 (2009)
   Article ADS CAS Google Scholar
10. Brem, R. B., Yvert, G., Clinton, R. & Kruglyak, L. Genetic dissection of transcriptional regulation in budding yeast. Science 296, 752–755 (2002)
    Article ADS CAS Google Scholar
11. Yvert, G. et al. _Trans_-acting regulatory variation in Saccharomyces cerevisiae and the role of transcription factors. Nature Genet. 35, 57–64 (2003)
    Article CAS Google Scholar
12. Roider, H. G., Manke, T., O’Keeffe, S., Vingron, M. & Haas, S. A. PASTAA: identifying transcription factors associated with sets of co-regulated genes. Bioinformatics 25, 435–442 (2009)
    Article CAS Google Scholar
13. Petretto, E. et al. New insights into the genetic control of gene expression using a Bayesian multi-tissue approach. PLoS Comput. Biol. 6, e1000737 (2010)
    Article Google Scholar
14. Breitling, R. et al. Genetical genomics: spotlight on QTL hotspots. PLoS Genet. 4, e1000232 (2008)
    Article Google Scholar
15. Nathan, C. & Ding, A. Nonresolving inflammation. Cell 140, 871–882 (2010)
    Article CAS Google Scholar
16. Eizirik, D. L., Colli, M. L. & Ortis, F. The role of inflammation in insulitis and β-cell loss in type 1 diabetes. Nature Rev. Endocrinol. 5, 219–226 (2009)
    Article CAS Google Scholar
17. Holness, C. L. & Simmons, D. L. Molecular cloning of CD68, a human macrophage marker related to lysosomal glycoproteins. Blood 81, 1607–1613 (1993)
    CAS PubMed Google Scholar
18. Saar, K. et al. SNP and haplotype mapping for genetic analysis in the rat. Nature Genet. 40, 560–566 (2008)
    Article CAS Google Scholar
19. Atanur, S. S. et al. The genome sequence of the spontaneously hypertensive rat: analysis and functional significance. Genome Res. 20, 791–803 (2010)
    Article CAS Google Scholar
20. Zeller, T. et al. Genetics and beyond–the transcriptome of human monocytes and disease susceptibility. PLoS ONE 5, e10693 (2010)
    Article ADS Google Scholar
21. Plagnol, V., Smyth, D. J., Todd, J. A. & Clayton, D. G. Statistical independence of the colocalized association signals for type 1 diabetes and RPS26 gene expression on chromosome 12q13. Biostatistics 10, 327–334 (2009)
    Article Google Scholar
22. von Herrath, M. Diabetes: a virus–gene collaboration. Nature 459, 518–519 (2009)
    Article ADS CAS Google Scholar
23. Nejentsev, S., Walker, N., Riches, D., Egholm, M. & Todd, J. A. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324, 387–389 (2009)
    Article ADS CAS Google Scholar
24. Smyth, D. J. 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)
    Article CAS Google Scholar
25. Barrett, J. C. 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)
    Article CAS Google Scholar
26. Li, Q. et al. Interferon-α initiates type 1 diabetes in nonobese diabetic mice. Proc. Natl Acad. Sci. USA 105, 12439–12444 (2008)
    Article ADS CAS Google Scholar
27. Cooper, J. D. 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)
    Article Google Scholar
28. Kawai, T. 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)
    Article CAS Google Scholar
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.

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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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8. Rizwan Sarwar
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9. Sarah R. Langley
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10. Anja Bauerfeind
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11. Oliver Hummel
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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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25. Nilesh J. Samani
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26. Heribert Schunkert
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27. Alison H. Goodall
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28. Herbert Schulz
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29. Helge G. Roider
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30. Martin Vingron
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31. Stefan Blankenberg
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32. Thomas Münzel
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33. Tanja Zeller
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34. Silke Szymczak
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35. Andreas Ziegler
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36. Laurence Tiret
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37. Deborah J. Smyth
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38. Michal Pravenec
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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 Ebi2 GFP/+ 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 toNorbert 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)

Supplementary Figures

This file contains Supplementary Figures 1-9 with legends. (PDF 2461 kb)

Supplementary Tables

This file contains Supplementary Tables 1-10. (PDF 1077 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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• Received: 18 December 2009
• Accepted: 28 July 2010
• Published: 08 September 2010
• Issue Date: 23 September 2010
• DOI: https://doi.org/10.1038/nature09386