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Joint mouse-human phenome-wide association to test gene function and disease risk.

  • Wang X Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
  • Pandey AK Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
  • Mulligan MK Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
  • Williams EG Laboratory of Integrative and Systems Physiology, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne 1015, Switzerland.
  • Mozhui K Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
  • Li Z Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
  • Jovaisaite V Laboratory of Integrative and Systems Physiology, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne 1015, Switzerland.
  • Quarles LD Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
  • Xiao Z Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
  • Huang J Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
  • Capra JA Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
  • Chen Z Department of Human Genetics, University of California, Los Angeles, California 90095, USA.
  • Taylor WL Molecular Resource Center, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
  • Bastarache L Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
  • Niu X Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
  • Pollard KS Gladstone Institutes, San Francisco, California 94158, USA.
  • Ciobanu DC Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
  • Reznik AO Joint Institute for Computational Sciences, University of Tennessee-Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, USA.
  • Tishkov AV Joint Institute for Computational Sciences, University of Tennessee-Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, USA.
  • Zhulin IB Joint Institute for Computational Sciences, University of Tennessee-Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, USA.
  • Peng J St Jude Proteomics Facility, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
  • Nelson SF Department of Human Genetics, University of California, Los Angeles, California 90095, USA.
  • Denny JC Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
  • Auwerx J Laboratory of Integrative and Systems Physiology, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne 1015, Switzerland.
  • Lu L Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
  • Williams RW Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
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  • 2016-02-03
Published in:
  • Nature communications. - 2016
Animals
Bone Density
Caenorhabditis elegans
Fumarate Hydratase
Gene Expression Regulation
Gene Library
Genetic Predisposition to Disease
Genetic Variation
Genome-Wide Association Study
Genomics
Humans
Mice
Mice, Inbred DBA
Quantitative Trait Loci
English Phenome-wide association is a novel reverse genetic strategy to analyze genome-to-phenome relations in human clinical cohorts. Here we test this approach using a large murine population segregating for ∼5 million sequence variants, and we compare our results to those extracted from a matched analysis of gene variants in a large human cohort. For the mouse cohort, we amassed a deep and broad open-access phenome consisting of ∼4,500 metabolic, physiological, pharmacological and behavioural traits, and more than 90 independent expression quantitative trait locus (QTL), transcriptome, proteome, metagenome and metabolome data sets--by far the largest coherent phenome for any experimental cohort (www.genenetwork.org). We tested downstream effects of subsets of variants and discovered several novel associations, including a missense mutation in fumarate hydratase that controls variation in the mitochondrial unfolded protein response in both mouse and Caenorhabditis elegans, and missense mutations in Col6a5 that underlies variation in bone mineral density in both mouse and human.
Language
  • English
Open access status
gold
Identifiers
Persistent URL
https://sonar.ch/global/documents/69552
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