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

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). Here, 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:
 [1] ;  [2] ;  [2] ;  [3] ;  [2] ;  [2] ;  [3] ;  [2] ;  [2] ;  [2] ;  [4] ;  [5] ;  [2] ;  [4] ;  [4] ;  [6] ;  [7] ;  [8] ;  [8] ; ORCiD logo [8] more »;  [9] ;  [5] ;  [4] ;  [3] ;  [2] ;  [2] « less
  1. Univ. of Tennessee Health Science Center, Memphis, TN (United States); St. Jude Children's Research Hospital, Memphis, TN (United States)
  2. Univ. of Tennessee Health Science Center, Memphis, TN (United States)
  3. Ecole Polytechnique Federale de Lausanne, Lausanne (Switzlerland)
  4. Vanderbilt Univ. School of Medicine, Nashville, TN (United States)
  5. Univ. of California, Los Angeles, CA (United States)
  6. Gladstone Institutes, San Francisco, CA (United States); Univ. of California, San Francisco, CA (United States)
  7. Univ. of Tennessee Health Science Center, Memphis, TN (United States); Univ. of Nebraska, Lincoln, NE (United States)
  8. Univ. of Tennessee, Knoxville, TN (United States); Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
  9. St. Jude Children's Research Hospital, Memphis, TN (United States)
Publication Date:
Grant/Contract Number:
AC05-00OR22725
Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 7; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Research Org:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES
OSTI Identifier:
1327651