The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk
Open accessAbstract
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 approaches. 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 (IRF7)-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 migration, 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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“Such integration of genetic information with network modeling has been used to highlight pathways that contribute to disease and to identify “key drivers” in biologic processes [72–74, 78].”
From Multi-omics approaches to disease (2017) · cites this paper as [78]
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Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls
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Self-citationIRF-7 is the master regulator of type-I interferon-dependent immune responses
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Self-citationGenetic Mapping in Human Disease
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The role of inflammation in insulitis and β-cell loss in type 1 diabetes
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Rare Variants of IFIH1 , a Gene Implicated in Antiviral Responses, Protect Against Type 1 Diabetes
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Self-citationVariations in DNA elucidate molecular networks that cause disease
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Multi-omics approaches to disease
Hasin, Y., Seldin, M., & Lusis, A. (2017) · Genome Biology · doi:10.1186/s13059-017-1215-1 · Cited by 2,953
Systematic identification of trans eQTLs as putative drivers of known disease associations
Westra, H.-J., Peters, M. J., Esko, T., Yaghootkar, H., Schurmann, C., Kettunen, J., Christiansen, M. W., Fairfax, B. P., Schramm, K., Powell, J. E., et al. (2013) · Nature Genetics · doi:10.1038/ng.2756 · Cited by 1,658
Self-citationThe role of regulatory variation in complex traits and disease
Albert, F. W., & Kruglyak, L. (2015) · Nature Reviews Genetics · doi:10.1038/nrg3891 · Cited by 1,047
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DNA methylation and body-mass index: a genome-wide analysis
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Metadata
- Authors
- Cardiogenics Consortium, Heinig, M., Petretto, E., Wallace, C., Bottolo, L., Rotival, M., Lu, H., Li, Y., Sarwar, R., Langley, S. R., Bauerfeind, A., Hummel, O., Lee, Y.-A., Paskas, S., Rintisch, C., Saar, K., Cooper, J., Buchan, R., Gray, E. E., Cyster, J. G., Erdmann, J., Hengstenberg, C., Maouche, S., Ouwehand, W. H., Rice, C. M., Samani, N. J., Schunkert, H., Goodall, A. H., Schulz, H., Roider, H. G., Vingron, M., Blankenberg, S., Münzel, T., Zeller, T., Szymczak, S., Ziegler, A., Tiret, L., Smyth, D. J., Pravenec, M., Aitman, T. J., Cambien, F., Clayton, D., Todd, J. A., Hubner, N., & Cook, S. A.
- Affiliations
- Max Delbrück Center (DE)
- Hammersmith Hospital (GB)
- University of Cambridge (GB)
- Inserm (FR)
- Howard Hughes Medical Institute (US)
- University of Lübeck (DE)
- University of Regensburg (DE)
- National Health Service (GB)
- Wellcome Sanger Institute (GB)
- University of Leicester (GB)
- Max Planck Institute for Molecular Genetics (DE)
- Johannes Gutenberg University Mainz (DE)
- University Hospital Schleswig-Holstein (DE)
- Czech Academy of Sciences (CZ)
- Corresponding author
- Cook, Stuart A.
- ORCID
- Heinig, Matthias
- Petretto, Enrico
- Wallace, Chris
- Bottolo, Leonardo
- Rotival, Maxime
- Sarwar, Rizwan
- Langley, Sarah R.
- Hummel, Oliver
- Lee, Young-Ae
- Saar, Kathrin
- Cooper, Jason
- Buchan, Rachel
- Gray, Elizabeth E.
- Cyster, Jason G.
- Erdmann, Jeanette
- Maouche, Seraya
- Ouwehand, Willem H.
- Samani, Nilesh J.
- Schunkert, Heribert
- Goodall, Alison H.
- Schulz, Herbert
- Roider, Helge G.
- Vingron, Martin
- Blankenberg, Stefan
- Münzel, Thomas
- Zeller, Tanja
- Szymczak, Silke
- Ziegler, Andreas
- Smyth, Deborah J.
- Pravenec, Michal
- Aitman, Timothy J.
- Clayton, David
- Todd, John A.
- Cook, Stuart A.
- Venue
- Nature
- Published
- 2010-09
- Volume
- 467
- Issue
- 7314
- Pages
- 460-464
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3657719
- OpenAlex
- W2166903146
- Cited by
- 283
- References
- 30
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 9 · 2023: 8 · 2022: 9 · 2021: 23 · 2020: 8 · 2019: 16 · 2018: 13 · 2017: 20 · 2016: 20 · 2015: 22 · 2014: 27 · 2013: 26 · 2012: 38
- FWCI
- 18.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- University of Regensburg Publication Server (University of Regensburg) (acceptedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- National University of Singapore (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- ASEP (submittedVersion, public-domain)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Leicester Research Archive (University of Leicester) (submittedVersion)
- Site cant be reached (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Juvenile Diabetes Research Foundation International
- Wellcome Trust (FP7/2007–2013, 061858, 089989, 076113)
- University Hospitals of Leicester NHS Trust
- National Institute for Health and Care Research (FP7/2007–2013, NF-SI-0508-10275)
- British Heart Foundation (P301/10/0290)
- Research Councils UK
- Imperial College London
- European Commission (2007–2013, LSHG-CT-2005-019015, FP7 2007-2013, LSHM-CT 2006–037593, FP7/2007, 241504)
- Fondation Leducq
- Grantová Agentura České Republiky (1M6837805002)
- Medical Research Council
- National Institute of Diabetes and Digestive and Kidney Diseases
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- type 1 diabetes, IRF7, EBI2, GPR183, macrophages, Epstein-Barr virus, monocytes, gene co-expression network, autoimmune disease susceptibility, systems genetics
- MeSH terms
- Animals, Base Sequence, Chromosomes, Human, Pair 13, Diabetes Mellitus, Type 1, Humans, Immunity, Innate, Inflammation, Macrophages, Organ Specificity, Viruses, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Chromosomes, Mammalian, Quantitative Trait Loci, Receptors, G-Protein-Coupled, Interferon Regulatory Factor-7, Rats, Gene Regulatory Networks, Genome-Wide Association Study, Genetic Loci
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