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, 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 () and Stuart A. Cook ()
Additional contact information
Matthias Heinig: Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Straße 10
Enrico Petretto: Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK
Chris Wallace: Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 OXY, UK
Leonardo Bottolo: Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK
Maxime Rotival: INSERM UMRS 937, Pierre and Marie Curie University (UPMC, Paris 6) and Medical School, 91 Boulevard de l’Hôpital, Paris 75013, France
Han Lu: Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK
Yoyo Li: Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK
Rizwan Sarwar: Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK
Sarah R. Langley: Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK
Anja Bauerfeind: Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Straße 10
Oliver Hummel: Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Straße 10
Young-Ae Lee: Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Straße 10
Svetlana Paskas: Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Straße 10
Carola Rintisch: Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Straße 10
Kathrin Saar: Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Straße 10
Jason Cooper: Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 OXY, UK
Rachel Buchan: Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK
Elizabeth E. Gray: University of California San Francisco
Jason G. Cyster: University of California San Francisco
Jeanette Erdmann: Universität zu Lübeck, Medizinische Klinik II, 23538 Lübeck, Germany
Christian Hengstenberg: Klinik und Poliklinik für Innere Medizin II, Universität Regensburg
Seraya Maouche: INSERM UMRS 937, Pierre and Marie Curie University (UPMC, Paris 6) and Medical School, 91 Boulevard de l’Hôpital, Paris 75013, France
Willem H. Ouwehand: University of Cambridge and National Health Service Blood and Transplant, Cambridge CB2 0PT, UK
Catherine M. Rice: Human Genetics, Wellcome Trust Sanger Institute, Genome Campus
Nilesh J. Samani: University of Leicester and Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester LE3 9QP, UK
Heribert Schunkert: Universität zu Lübeck, Medizinische Klinik II, 23538 Lübeck, Germany
Alison H. Goodall: University of Leicester and Leicester NIHR Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester LE3 9QP, UK
Herbert Schulz: Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Straße 10
Helge G. Roider: Max Planck Institute for Molecular Genetics, Ihnestraße 63-73, 14195 Berlin, Germany
Martin Vingron: Max Planck Institute for Molecular Genetics, Ihnestraße 63-73, 14195 Berlin, Germany
Stefan Blankenberg: Medizinische Klinik und Poliklinik, Johannes-Gutenberg Universität Mainz, Universitätsmedizin, Langenbeckstrasse 1, 55131 Mainz, Germany
Thomas Münzel: Medizinische Klinik und Poliklinik, Johannes-Gutenberg Universität Mainz, Universitätsmedizin, Langenbeckstrasse 1, 55131 Mainz, Germany
Tanja Zeller: Medizinische Klinik und Poliklinik, Johannes-Gutenberg Universität Mainz, Universitätsmedizin, Langenbeckstrasse 1, 55131 Mainz, Germany
Silke Szymczak: Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Maria-Goeppert-Straße 1, 23562 Lübeck, Germany
Andreas Ziegler: Institut für Medizinische Biometrie und Statistik, Universität zu Lübeck, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Maria-Goeppert-Straße 1, 23562 Lübeck, Germany
Laurence Tiret: INSERM UMRS 937, Pierre and Marie Curie University (UPMC, Paris 6) and Medical School, 91 Boulevard de l’Hôpital, Paris 75013, France
Deborah J. Smyth: Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 OXY, UK
Michal Pravenec: Institute of Physiology, Czech Academy of Sciences and Centre for Applied Genomics, Videnska 1083, 14220 Prague 4, Czech Republic
Timothy J. Aitman: Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK
Francois Cambien: INSERM UMRS 937, Pierre and Marie Curie University (UPMC, Paris 6) and Medical School, 91 Boulevard de l’Hôpital, Paris 75013, France
David Clayton: Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 OXY, UK
John A. Todd: Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 OXY, UK
Norbert Hubner: Max-Delbrück-Center for Molecular Medicine (MDC), Robert-Rössle-Straße 10
Stuart A. Cook: Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK

Nature, 2010, vol. 467, issue 7314, 460-464

Abstract: Gene networks linked to type 1 diabetes Genome-wide association studies (GWAS) have highlighted a number of genes with connections to type 1 diabetes and other common diseases, but in most instances the mechanism by which DNA variation affects disease risk is far from clear. Recent advances in rat genomics now make a systems-genetics approach possible, which should help to reveal links between diseases and gene functions. Using gene expression studies across seven types of rat tissue, together with GWAS and human genetics, Heinig et al. have now identified the inflammatory network driven by interferon regulatory factor 7 (IRF7) as a contributor to type 1 diabetes risk. They also implicate the innate viral response pathway and macrophages in the aetiology of the disease. The study shows how co-expression networks across species provide functional annotation of genes, and how this can be used to reveal a signal of common genetic variation of small effect that is not detected by GWAS.

Date: 2010
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DOI: 10.1038/nature09386

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