title: 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 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.
authors.affiliation: Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Heinig
authors.forename: Enrico
authors.initials: E
authors.lastname: Petretto
authors.forename: Chris
authors.initials: C
authors.lastname: Wallace
authors.forename: Leonardo
authors.initials: L
authors.lastname: Bottolo
authors.forename: Maxime
authors.initials: M
authors.lastname: Rotival
authors.forename: Han
authors.initials: H
authors.lastname: Lu
authors.forename: Yoyo
authors.initials: Y
authors.lastname: Li
authors.forename: Rizwan
authors.initials: R
authors.lastname: Sarwar
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Langley
authors.forename: Anja
authors.initials: A
authors.lastname: Bauerfeind
authors.forename: Oliver
authors.initials: O
authors.lastname: Hummel
authors.forename: Young-Ae
authors.initials: YA
authors.lastname: Lee
authors.forename: Svetlana
authors.initials: S
authors.lastname: Paskas
authors.forename: Carola
authors.initials: C
authors.lastname: Rintisch
authors.forename: Kathrin
authors.initials: K
authors.lastname: Saar
authors.forename: Jason
authors.initials: J
authors.lastname: Cooper
authors.forename: Rachel
authors.initials: R
authors.lastname: Buchan
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Gray
authors.forename: Jason G
authors.initials: JG
authors.lastname: Cyster
authors.forename: Jeanette
authors.initials: J
authors.lastname: Erdmann
authors.forename: Christian
authors.initials: C
authors.lastname: Hengstenberg
authors.forename: Seraya
authors.initials: S
authors.lastname: Maouche
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Rice
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.forename: Heribert
authors.initials: H
authors.lastname: Schunkert
authors.forename: Alison H
authors.initials: AH
authors.lastname: Goodall
authors.forename: Herbert
authors.initials: H
authors.lastname: Schulz
authors.forename: Helge G
authors.initials: HG
authors.lastname: Roider
authors.forename: Martin
authors.initials: M
authors.lastname: Vingron
authors.forename: Stefan
authors.initials: S
authors.lastname: Blankenberg
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
authors.forename: Tanja
authors.initials: T
authors.lastname: Zeller
authors.forename: Silke
authors.initials: S
authors.lastname: Szymczak
authors.forename: Andreas
authors.initials: A
authors.lastname: Ziegler
authors.forename: Laurence
authors.initials: L
authors.lastname: Tiret
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Smyth
authors.forename: Michal
authors.initials: M
authors.lastname: Pravenec
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Aitman
authors.forename: Francois
authors.initials: F
authors.lastname: Cambien
authors.forename: David
authors.initials: D
authors.lastname: Clayton
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
authors.forename: Norbert
authors.initials: N
authors.lastname: Hubner
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Cook
mesh_terms: D000818:Animals; D001483:Base Sequence; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics; D033481:Chromosomes, Mammalian / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D053263:Gene Regulatory Networks / Q000235:genetics; D056426:Genetic Loci / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D050839:Interferon Regulatory Factor-7 / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D009928:Organ Specificity; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D014780:Viruses / Q000276:immunology*
chemical_list: C552997:Gpr183 protein, rat; D050839:Interferon Regulatory Factor-7; D043562:Receptors, G-Protein-Coupled
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