title: Systems biology with high-throughput sequencing reveals genetic mechanisms underlying the metabolic syndrome in the Lyon hypertensive rat.
abstract: BACKGROUND
  The metabolic syndrome (MetS) is a collection of co-occurring complex disorders including obesity, hypertension, dyslipidemia, and insulin resistance. The Lyon hypertensive and Lyon normotensive rats are models of MetS sensitivity and resistance, respectively. To identify genetic determinants and mechanisms underlying MetS, an F2 intercross between Lyon hypertensive and Lyon normotensive was comprehensively studied.
  
  
  RESULTS
  Multidimensional data were obtained including genotypes of 1536 single-nucleotide polymorphisms, 23 physiological traits, and >150 billion nucleotides of RNA-seq reads from the livers of F2 intercross offspring and parental rats. Phenotypic and expression quantitative trait loci (eQTL) were mapped. Application of systems biology methods identified 17 candidate MetS genes. Several putative causal cis-eQTL were identified corresponding with phenotypic QTL loci. We found an eQTL hotspot on rat chromosome 17 that is causally associated with multiple MetS-related traits and found RGD1562963, a gene regulated in cis by this eQTL hotspot, as the most likely eQTL driver gene directly affected by genetic variation between Lyon hypertensive and Lyon normotensive rats.
  
  
  CONCLUSIONS
  Our study sheds light on the intricate pathogenesis of MetS and demonstrates that systems biology with high-throughput sequencing is a powerful method to study the pathogenesis of complex genetic diseases.
authors.affiliation: From the Department of Internal Medicine (J.W., A.K.M., J.M.P., Y. Xu, L.L., Y. Xing, A.E.K.), Department of Pharmacology (M.C.J.M., A.K.M., J.M.P., Y. Xu, M.G.T., J.J., A.E.K.), and Iowa Institute of Human Genetics (A.E.K.), University of Iowa, Iowa City; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (J.W., L.L., Y. Xing); and Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom (S.S.A., T.J.A.).
authors.forename: Jinkai
authors.initials: J
authors.lastname: Wang
authors.affiliation: From the Department of Internal Medicine (J.W., A.K.M., J.M.P., Y. Xu, L.L., Y. Xing, A.E.K.), Department of Pharmacology (M.C.J.M., A.K.M., J.M.P., Y. Xu, M.G.T., J.J., A.E.K.), and Iowa Institute of Human Genetics (A.E.K.), University of Iowa, Iowa City; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (J.W., L.L., Y. Xing); and Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom (S.S.A., T.J.A.).
authors.forename: Man Chun John
authors.initials: MC
authors.lastname: Ma
authors.affiliation: From the Department of Internal Medicine (J.W., A.K.M., J.M.P., Y. Xu, L.L., Y. Xing, A.E.K.), Department of Pharmacology (M.C.J.M., A.K.M., J.M.P., Y. Xu, M.G.T., J.J., A.E.K.), and Iowa Institute of Human Genetics (A.E.K.), University of Iowa, Iowa City; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (J.W., L.L., Y. Xing); and Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom (S.S.A., T.J.A.).
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Mennie
authors.affiliation: From the Department of Internal Medicine (J.W., A.K.M., J.M.P., Y. Xu, L.L., Y. Xing, A.E.K.), Department of Pharmacology (M.C.J.M., A.K.M., J.M.P., Y. Xu, M.G.T., J.J., A.E.K.), and Iowa Institute of Human Genetics (A.E.K.), University of Iowa, Iowa City; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (J.W., L.L., Y. Xing); and Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom (S.S.A., T.J.A.).
authors.forename: Janette M
authors.initials: JM
authors.lastname: Pettus
authors.affiliation: From the Department of Internal Medicine (J.W., A.K.M., J.M.P., Y. Xu, L.L., Y. Xing, A.E.K.), Department of Pharmacology (M.C.J.M., A.K.M., J.M.P., Y. Xu, M.G.T., J.J., A.E.K.), and Iowa Institute of Human Genetics (A.E.K.), University of Iowa, Iowa City; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (J.W., L.L., Y. Xing); and Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom (S.S.A., T.J.A.).
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
authors.affiliation: From the Department of Internal Medicine (J.W., A.K.M., J.M.P., Y. Xu, L.L., Y. Xing, A.E.K.), Department of Pharmacology (M.C.J.M., A.K.M., J.M.P., Y. Xu, M.G.T., J.J., A.E.K.), and Iowa Institute of Human Genetics (A.E.K.), University of Iowa, Iowa City; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (J.W., L.L., Y. Xing); and Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom (S.S.A., T.J.A.).
authors.forename: Lan
authors.initials: L
authors.lastname: Lin
authors.affiliation: From the Department of Internal Medicine (J.W., A.K.M., J.M.P., Y. Xu, L.L., Y. Xing, A.E.K.), Department of Pharmacology (M.C.J.M., A.K.M., J.M.P., Y. Xu, M.G.T., J.J., A.E.K.), and Iowa Institute of Human Genetics (A.E.K.), University of Iowa, Iowa City; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (J.W., L.L., Y. Xing); and Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom (S.S.A., T.J.A.).
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Traxler
authors.affiliation: From the Department of Internal Medicine (J.W., A.K.M., J.M.P., Y. Xu, L.L., Y. Xing, A.E.K.), Department of Pharmacology (M.C.J.M., A.K.M., J.M.P., Y. Xu, M.G.T., J.J., A.E.K.), and Iowa Institute of Human Genetics (A.E.K.), University of Iowa, Iowa City; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (J.W., L.L., Y. Xing); and Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom (S.S.A., T.J.A.).
authors.forename: Jessica
authors.initials: J
authors.lastname: Jakoubek
authors.affiliation: From the Department of Internal Medicine (J.W., A.K.M., J.M.P., Y. Xu, L.L., Y. Xing, A.E.K.), Department of Pharmacology (M.C.J.M., A.K.M., J.M.P., Y. Xu, M.G.T., J.J., A.E.K.), and Iowa Institute of Human Genetics (A.E.K.), University of Iowa, Iowa City; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (J.W., L.L., Y. Xing); and Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom (S.S.A., T.J.A.).
authors.forename: Santosh S
authors.initials: SS
authors.lastname: Atanur
authors.affiliation: From the Department of Internal Medicine (J.W., A.K.M., J.M.P., Y. Xu, L.L., Y. Xing, A.E.K.), Department of Pharmacology (M.C.J.M., A.K.M., J.M.P., Y. Xu, M.G.T., J.J., A.E.K.), and Iowa Institute of Human Genetics (A.E.K.), University of Iowa, Iowa City; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (J.W., L.L., Y. Xing); and Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom (S.S.A., T.J.A.).
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Aitman
authors.affiliation: From the Department of Internal Medicine (J.W., A.K.M., J.M.P., Y. Xu, L.L., Y. Xing, A.E.K.), Department of Pharmacology (M.C.J.M., A.K.M., J.M.P., Y. Xu, M.G.T., J.J., A.E.K.), and Iowa Institute of Human Genetics (A.E.K.), University of Iowa, Iowa City; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (J.W., L.L., Y. Xing); and Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom (S.S.A., T.J.A.). anne-kwitek@uiowa.edu yxing@ucla.edu.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xing
authors.affiliation: From the Department of Internal Medicine (J.W., A.K.M., J.M.P., Y. Xu, L.L., Y. Xing, A.E.K.), Department of Pharmacology (M.C.J.M., A.K.M., J.M.P., Y. Xu, M.G.T., J.J., A.E.K.), and Iowa Institute of Human Genetics (A.E.K.), University of Iowa, Iowa City; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (J.W., L.L., Y. Xing); and Physiological Genomics and Medicine Group, Medical Research Council Clinical Sciences Centre, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom (S.S.A., T.J.A.). anne-kwitek@uiowa.edu yxing@ucla.edu.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Kwitek
mesh_terms: D000818:Animals; D033481:Chromosomes, Mammalian / Q000235:genetics*; D006973:Hypertension / Q000235:genetics*; D024821:Metabolic Syndrome / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D051381:Rats; D049490:Systems Biology
keywords: genetics; systems biology; transcriptome