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

Research output: Contribution to journalArticlepeer-review

234 Scopus citations

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.

Original languageEnglish
Pages (from-to)460-464
Number of pages5
JournalNature
Volume467
Issue number7314
DOIs
StatePublished - 23 Sep 2010
Externally publishedYes

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