title: Joint mouse-human phenome-wide association to test gene function and disease risk.
abstract: 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.
authors.affiliation: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.|St Jude Proteomics Facility, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Xusheng
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
authors.forename: Ashutosh K
authors.initials: AK
authors.lastname: Pandey
authors.affiliation: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
authors.forename: Megan K
authors.initials: MK
authors.lastname: Mulligan
authors.affiliation: Laboratory of Integrative and Systems Physiology, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne 1015, Switzerland.
authors.forename: Evan G
authors.initials: EG
authors.lastname: Williams
authors.affiliation: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
authors.forename: Khyobeni
authors.initials: K
authors.lastname: Mozhui
authors.affiliation: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
authors.forename: Zhengsheng
authors.initials: Z
authors.lastname: Li
authors.affiliation: Laboratory of Integrative and Systems Physiology, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne 1015, Switzerland.
authors.forename: Virginija
authors.initials: V
authors.lastname: Jovaisaite
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
authors.forename: L Darryl
authors.initials: LD
authors.lastname: Quarles
authors.affiliation: Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
authors.forename: Zhousheng
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.|Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Capra
authors.affiliation: Department of Human Genetics, University of California, Los Angeles, California 90095, USA.
authors.forename: Zugen
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Molecular Resource Center, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Taylor
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Bastarache
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: Xinnan
authors.initials: X
authors.lastname: Niu
authors.affiliation: Gladstone Institutes, San Francisco, California 94158, USA.|Division of Biostatistics and Institute for Human Genetics, University of California, San Francisco, California 94158, USA.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Pollard
authors.affiliation: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.|Animal Science Department, University of Nebraska, Lincoln, Nebraska 68583, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Ciobanu
authors.affiliation: Joint Institute for Computational Sciences, University of Tennessee-Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, USA.
authors.forename: Alexander O
authors.initials: AO
authors.lastname: Reznik
authors.affiliation: Joint Institute for Computational Sciences, University of Tennessee-Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, USA.
authors.forename: Artem V
authors.initials: AV
authors.lastname: Tishkov
authors.affiliation: Joint Institute for Computational Sciences, University of Tennessee-Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, USA.
authors.forename: Igor B
authors.identifier: http://orcid.org/0000-0002-6708-5323
authors.initials: IB
authors.lastname: Zhulin
authors.affiliation: St Jude Proteomics Facility, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Junmin
authors.initials: J
authors.lastname: Peng
authors.affiliation: Department of Human Genetics, University of California, Los Angeles, California 90095, USA.
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.|Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Denny
authors.affiliation: Laboratory of Integrative and Systems Physiology, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne 1015, Switzerland.
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.affiliation: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Williams
mesh_terms: D000818:Animals; D015519:Bone Density / Q000235:genetics; D017173:Caenorhabditis elegans; D005649:Fumarate Hydratase / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D015723:Gene Library; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D023281:Genomics; D006801:Humans; D051379:Mice; D008811:Mice, Inbred DBA; D040641:Quantitative Trait Loci
chemical_list: D005649:Fumarate Hydratase
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