title: Topological analysis of metabolic networks integrating co-segregating transcriptomes and metabolomes in type 2 diabetic rat congenic series.
abstract: The genetic regulation of metabolic phenotypes (i.e., metabotypes) in type 2 diabetes mellitus occurs through complex organ-specific cellular mechanisms and networks contributing to impaired insulin secretion and insulin resistance. Genome-wide gene expression profiling systems can dissect the genetic contributions to metabolome and transcriptome regulations. The integrative analysis of multiple gene expression traits and metabolic phenotypes (i.e., metabotypes) together with their underlying genetic regulation remains a challenge. Here, we introduce a systems genetics approach based on the topological analysis of a combined molecular network made of genes and metabolites identified through expression and metabotype quantitative trait locus mapping (i.e., eQTL and mQTL) to prioritise biological characterisation of candidate genes and traits.
  
  
  
  We used systematic metabotyping by1H NMR spectroscopy and genome-wide gene expression in white adipose tissue to map molecular phenotypes to genomic blocks associated with obesity and insulin secretion in a series of rat congenic strains derived from spontaneously diabetic Goto-Kakizaki (GK) and normoglycemic Brown-Norway (BN) rats. We implemented a network biology strategy approach to visualize the shortest paths between metabolites and genes significantly associated with each genomic block.
  
  
  
  Despite strong genomic similarities (95-99 %) among congenics, each strain exhibited specific patterns of gene expression and metabotypes, reflecting the metabolic consequences of series of linked genetic polymorphisms in the congenic intervals. We subsequently used the congenic panel to map quantitative trait loci underlying specific mQTLs and genome-wide eQTLs. Variation in key metabolites like glucose, succinate, lactate, or 3-hydroxybutyrate and second messenger precursors like inositol was associated with several independent genomic intervals, indicating functional redundancy in these regions. To navigate through the complexity of these association networks we mapped candidate genes and metabolites onto metabolic pathways and implemented a shortest path strategy to highlight potential mechanistic links between metabolites and transcripts at colocalized mQTLs and eQTLs. Minimizing the shortest path length drove prioritization of biological validations by gene silencing.
  
  
  
  These results underline the importance of network-based integration of multilevel systems genetics datasets to improve understanding of the genetic architecture of metabotype and transcriptomic regulation and to characterize novel functional roles for genes determining tissue-specific metabolism.
authors.affiliation: Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Sir Alexander Fleming Building, Imperial College, London, SW7 2AZ, UK. m.dumas@imperial.ac.uk.|Centre de Résonance Magnétique Nucléaire à Très Hauts Champs, 5 rue de la Doua, Villeurbanne, 69100, France. m.dumas@imperial.ac.uk.|Metabometrix Ltd, Prince Consort Road, London, SW7 2BP, UK. m.dumas@imperial.ac.uk.
authors.forename: Marc-Emmanuel
authors.initials: ME
authors.lastname: Dumas
authors.affiliation: Centre de Résonance Magnétique Nucléaire à Très Hauts Champs, 5 rue de la Doua, Villeurbanne, 69100, France.|UMR Modélisation Systémique Appliquée aux Ruminants, INRA, AgroParisTech, Université Paris-Saclay, Paris, 75005, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Domange
authors.affiliation: Sorbonne Universities, University Pierre & Marie Curie, University Paris Descartes, Sorbonne Paris Cité, INSERM, UMR_S 1138, Cordeliers Research Centre, Paris, 75006, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Calderari
authors.affiliation: Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Sir Alexander Fleming Building, Imperial College, London, SW7 2AZ, UK.
authors.forename: Andrea Rodríguez
authors.initials: AR
authors.lastname: Martínez
authors.affiliation: Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Sir Alexander Fleming Building, Imperial College, London, SW7 2AZ, UK.
authors.forename: Rafael
authors.initials: R
authors.lastname: Ayala
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7BN, UK.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Wilder
authors.affiliation: Sorbonne Universities, University Pierre & Marie Curie, University Paris Descartes, Sorbonne Paris Cité, INSERM, UMR_S 1138, Cordeliers Research Centre, Paris, 75006, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Suárez-Zamorano
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7BN, UK.
authors.forename: Stephan C
authors.initials: SC
authors.lastname: Collins
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7BN, UK.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Wallis
authors.affiliation: Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Sir Alexander Fleming Building, Imperial College, London, SW7 2AZ, UK.|MRC-University of Glasgow Centre for Virus Research, Glasgow, G61 1QH, UK.
authors.forename: Quan
authors.initials: Q
authors.lastname: Gu
authors.affiliation: Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Sir Alexander Fleming Building, Imperial College, London, SW7 2AZ, UK.|Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Centre for Magnetic Resonance, Wuhan Institute of Physics and Mathematics, University of Chinese Academy of Sciences, Wuhan, 430071, China.
authors.forename: Yulan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: UMR Modélisation Systémique Appliquée aux Ruminants, INRA, AgroParisTech, Université Paris-Saclay, Paris, 75005, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Hue
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7BN, UK.
authors.forename: Georg W
authors.initials: GW
authors.lastname: Otto
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7BN, UK.
authors.forename: Karène
authors.initials: K
authors.lastname: Argoud
authors.affiliation: Centre de Résonance Magnétique Nucléaire à Très Hauts Champs, 5 rue de la Doua, Villeurbanne, 69100, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Navratil
authors.affiliation: Metabometrix Ltd, Prince Consort Road, London, SW7 2BP, UK.
authors.forename: Steve C
authors.initials: SC
authors.lastname: Mitchell
authors.affiliation: Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Sir Alexander Fleming Building, Imperial College, London, SW7 2AZ, UK.
authors.forename: John C
authors.initials: JC
authors.lastname: Lindon
authors.affiliation: Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Sir Alexander Fleming Building, Imperial College, London, SW7 2AZ, UK.
authors.forename: Elaine
authors.initials: E
authors.lastname: Holmes
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7BN, UK.|Centre for Computational Biology, University of Birmingham, Haworth Building, Birmingham, B15 2TT, UK.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Cazier
authors.affiliation: Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Sir Alexander Fleming Building, Imperial College, London, SW7 2AZ, UK.
authors.forename: Jeremy K
authors.initials: JK
authors.lastname: Nicholson
authors.affiliation: Division of Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Sir Alexander Fleming Building, Imperial College, London, SW7 2AZ, UK. dominique.gauguier@crc.jussieu.fr.|Sorbonne Universities, University Pierre & Marie Curie, University Paris Descartes, Sorbonne Paris Cité, INSERM, UMR_S 1138, Cordeliers Research Centre, Paris, 75006, France. dominique.gauguier@crc.jussieu.fr.|The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7BN, UK. dominique.gauguier@crc.jussieu.fr.
authors.forename: Dominique
authors.initials: D
authors.lastname: Gauguier
mesh_terms: D000818:Animals; D020296:Animals, Congenic; D002874:Chromosome Mapping; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D063990:Gene Ontology; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways; D055442:Metabolome; D058977:Molecular Sequence Annotation; D040641:Quantitative Trait Loci; D019655:Quantitative Trait, Heritable; D011914:Rats, Inbred BN; D049490:Systems Biology; D059467:Transcriptome
keywords: 1H NMR; Genome Mapping; Metabolic networks; Metabolomics; Transcriptomics; eQTL; mQTL