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

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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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.

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Correspondence to Norbert Hubner or Stuart A. Cook.

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