4.8 Article

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

Journal

NATURE COMMUNICATIONS
Volume 7, Issue -, Pages -

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms10464

Keywords

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Funding

  1. NIH [R01AG043930, U01 AA016662, U01 AA013499, R01-LM010685, UL1 RR024975, UL1 TR000445, R01 GM072285]
  2. UTHSC Center for Integrative and Translational Genomics
  3. UT-Oak Ridge National Laboratory Governor Chair
  4. Gladstone Institutes
  5. EPFL
  6. Swiss Initiative for Systems Biology [51RTP0-151019, 2013/153]
  7. SNSF [31003A-140780, CSRII3-136201]
  8. Nestle Chair in Energy Metabolism
  9. American Lebanese Syrian Associated Charities

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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 similar to 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 similar to 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.

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